Use of Aspirin for Prevention of Recurrent Atherosclerotic Cardiovascular Disease Among Adults — 20 States and the District of Columbia, 2013.
Fang Jing,George Mary G,Hong Yuling,Loustalot Fleetwood
MMWR. Morbidity and mortality weekly report
The effectiveness of regular aspirin therapy in reducing risk (secondary prevention) for myocardial infarction, ischemic stroke, and fatal coronary events among persons with preexisting atherosclerotic cardiovascular disease (ASCVD) is well established and recommended in current guidelines. Reported use of aspirin or other antiplatelet agents for secondary ASCVD prevention has varied widely across settings and data collection methods, from 54% of outpatient visits for those with ischemic vascular disease to 98% at the time of discharge for acute coronary syndrome. To estimate the prevalence of aspirin use for secondary ASCVD prevention among community-dwelling adults, CDC analyzed 2013 Behavioral Risk Factor Surveillance System (BRFSS) data from 20 states and the District of Columbia. Overall, 70.8% of adult respondents with existing ASCVD reported using aspirin regularly (every day or every other day). Within this group, 93.6% reported using aspirin for heart attack prevention, 79.6% for stroke prevention and 76.2% for both heart attack and stroke prevention. Differences in use were found by age, sex, race/ethnicity, and ASCVD risk status, and state. Most of the state differences were not statistically significant; however, these estimates can be used to promote the use of aspirin as a low-cost and highly effective intervention.
Short- versus long-term duration of dual antiplatelet therapy in patients treated for in-stent restenosis: a PRODIGY trial substudy (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia).
Campo Gianluca,Tebaldi Matteo,Vranckx Pascal,Biscaglia Simone,Tumscitz Carlo,Ferrari Roberto,Valgimigli Marco
Journal of the American College of Cardiology
OBJECTIVES:This study sought to investigate the clinical outcome of patients treated with percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) randomized to short (6 months) versus long (24 months) dual antiplatelet therapy (DAPT) regimen. BACKGROUND:It is still unclear if patients treated for ISR may benefit from a long DAPT regimen. METHODS:For the present purpose, we selected 224 patients undergoing the PCI procedure for ISR enrolled in the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial and randomized to short (6 months) versus long (24 months) DAPT regimen. The primary objective was the cumulative incidence of death, nonfatal myocardial infarction (MI), or cerebrovascular accident at 24 months. Safety endpoints were moderate and major bleeding complications. RESULTS:Overall, 114 patients were allocated to short DAPT regimen, whereas 110 patients were allocated to long DAPT regimen. Twenty-seven patients reached the primary endpoint (19 in short DAPT regimen vs. 8 in long DAPT regimen; p = 0.02). The cumulative incidence of the primary endpoint at 24 months was 16.7% in the short DAPT regimen group compared with 7.3% in the long DAPT regimen group (p = 0.034). This is principally due to a lower occurrence of death and MI in the long DAPT regimen group as compared to the short DAPT regimen group (6.5% vs. 15.5%; p = 0.03). There was no difference in the occurrence of bleeding complications between long and short DAPT regimen. CONCLUSIONS:Our study offers preliminary evidence that patients receiving a new PCI procedure for ISR may benefit from long-term administration of aspirin plus clopidogrel. (Synergy Between Stent and Drugs to Avoid Ischemic Recurrences After Percutaneous Coronary Intervention [PRODIGY]; NCT00611286).
10.1016/j.jacc.2013.09.043
Smoking is associated with adverse clinical outcomes in patients undergoing revascularization with PCI or CABG: the SYNTAX trial at 5-year follow-up.
Zhang Yao-Jun,Iqbal Javaid,van Klaveren David,Campos Carlos M,Holmes David R,Kappetein Arie Pieter,Morice Marie-Claude,Banning Adrian P,Grech Ever D,Bourantas Christos V,Onuma Yoshinobu,Garcia-Garcia Hector M,Mack Michael J,Colombo Antonio,Mohr Friedrich W,Steyerberg Ewout W,Serruys Patrick W
Journal of the American College of Cardiology
BACKGROUND:Cigarette smoking is a well-known risk factor for development of coronary artery disease (CAD). However, some studies have suggested a "smoker's paradox," meaning neutral or favorable outcomes in smokers who have developed CAD, especially myocardial infarction (MI). OBJECTIVES:The study aimed to examine the association of smoking status with clinical outcomes in the randomized controlled SYNTAX (SYNergy Between PCI With TAXUS and Cardiac Surgery) trial at 5-year follow-up. METHODS:Detailed smoking history was collected at baseline, 6-month, 1-year, 3-year, and 5-year follow-up. The composite endpoints included death/MI/stroke (primary endpoint) plus major adverse cardiac and cerebrovascular events (MACCE) (combination of death/MI/stroke and target lesion revascularization) according to patient smoking status. The comparison of 5-year clinical outcomes between the groups according to smoking status was performed with Cox regression using smoking status at baseline or smoking as a time-dependent covariate. RESULTS:A sizeable proportion (n = 322, 17.9%) of patients had changing smoking status during 5-year follow-up. One in 5 patients with complex CAD was smoking at baseline. However, 60% stopped after revascularization while others continued to smoke. Smokers had worse clinical outcomes due to a higher incidence of recurrent MI in both revascularization arms. Smoking was an independent predictor of the composite endpoint of death/MI/stroke (hazard ratio [HR]: 1.8; 95% confidence interval [CI]: 1.3 to 2.5; p = 0.001) and MACCE (HR: 1.4; 95% CI: 1.1 to 1.7; p = 0.02). CONCLUSIONS:Smoking is associated with poor clinical outcomes after revascularization in patients with complex CAD. This places further emphasis on efforts at smoking cessation to improve revascularization benefits. (SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries; NCT00114972).
10.1016/j.jacc.2015.01.014
Predictive value of programmed ventricular stimulation after catheter ablation of post-infarction ventricular tachycardia.
Yokokawa Miki,Kim Hyungjin Myra,Baser Kazim,Stevenson William,Nagashima Koichi,Della Bella Paolo,Vergara Pasquale,Hindricks Gerhard,Arya Arash,Zeppenfeld Katja,de Riva Silva Marta,Daoud Emile G,Kumar Sunil,Kuck Karl-Heinz,Tilz Ronald,Mathew Shibu,Ghanbari Hamid,Latchamsetty Rakesh,Morady Fred,Bogun Frank M
Journal of the American College of Cardiology
BACKGROUND:A recent meta-analysis demonstrated a survival benefit in post-infarction patients whose ventricular tachycardia (VT) was rendered noninducible by catheter ablation. Furthermore, patients with noninducible VT had a lower VT recurrence rate than did patients whose VT remained inducible after ablation. OBJECTIVES:The purpose of this multicenter cohort study was to assess whether noninducibility after VT ablation is independently associated with improved survival. METHODS:Data from 1,064 patients who underwent VT ablation for post-infarction VT at seven international centers were analyzed. The ablation procedure was considered successful if no VT was inducible at the end of the procedure and unsuccessful if VT remained inducible or if programmed stimulation was not performed at the end of the ablation. RESULTS:Median follow-up time was 633 days. Noninducibility was independently associated with lower mortality (adjusted hazard ratio: 0.65; 95% confidence interval: 0.53 to 0.79; p<0.001). Atrial fibrillation, diabetes, and age were other independent predictors of higher mortality. Ablation of only the clinical VT in patients who also had inducible, nonclinical VTs was not associated with improved survival. CONCLUSIONS:Noninducibility after VT ablation in patients with post-infarction VT is independently associated with lower mortality during long-term follow-up.
10.1016/j.jacc.2015.02.058
Use of Outpatient Cardiac Rehabilitation Among Heart Attack Survivors - 20 States and the District of Columbia, 2013 and Four States, 2015.
Fang Jing,Ayala Carma,Luncheon Cecily,Ritchey Matthew,Loustalot Fleetwood
MMWR. Morbidity and mortality weekly report
Heart disease is the leading cause of death in the United States (1). Each year, approximately 790,000 adults have a myocardial infarction (heart attack), including 210,000 that are recurrent heart attacks (2). Cardiac rehabilitation (rehab) includes exercise counseling and training, education for heart-healthy living, and counseling to reduce stress. Cardiac rehab provides patients with education regarding the causes of heart attacks and tools to initiate positive behavior change, and extends patients' medical management after a heart attack to prevent future negative sequelae (3). A systematic review has shown that after a heart attack, patients using cardiac rehab were 53% (95% confidence interval [CI] = 41%-62%) less likely to die from any cause and 57% (95% CI = 21%-77%) less likely to experience cardiac-related mortality than were those who did not use cardiac rehab (3). However, even with long-standing national recommendations encouraging use of cardiac rehab (4), the intervention has been underutilized. An analysis of 2005 Behavioral Risk Factor Surveillance System (BRFSS) data found that only 34.7% of adults who reported a history of a heart attack also reported subsequent use of cardiac rehab (5). To update these estimates, CDC used the most recent BRFSS data from 2013 and 2015 to assess the use of cardiac rehab among adults following a heart attack. Overall use of cardiac rehab was 33.7% in 20 states and the District of Columbia (DC) in 2013 and 35.5% in four states in 2015. Cardiac rehab use was underutilized overall and differences were evident by sex, age, race/ethnicity, level of education, cardiovascular risk status, and by state. Increasing use of cardiac rehab after a heart attack should be encouraged by health systems and supported by the public health community.
10.15585/mmwr.mm6633a1
A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents: paclitaxel-eluting balloon vs. everolimus-eluting stent).
Alfonso Fernando,Pérez-Vizcayno Maria Jose,Cárdenas Alberto,García Del Blanco Bruno,Seidelberger Bernhard,Iñiguez Andrés,Gómez-Recio Manuel,Masotti Mónica,Velázquez M Teresa,Sanchís Juan,García-Touchard Arturo,Zueco Javier,Bethencourt Armando,Melgares Rafael,Cequier Angel,Dominguez Antonio,Mainar Vicente,López-Mínguez José R,Moreu José,Martí Vicens,Moreno Raúl,Jiménez-Quevedo Pilar,Gonzalo Nieves,Fernández Cristina,Macaya Carlos,
Journal of the American College of Cardiology
OBJECTIVES:This study sought to compare the efficacy of drug-eluting balloons (DEB) with that of everolimus-eluting stents (EES) in patients with bare-metal stents (BMS) in-stent restenosis (ISR). BACKGROUND:Treatment of patients with ISR remains a challenge. METHODS:This was a prospective, multicenter, randomized trial comparing DEB with EES in patients with bare-metal stents (BMS) in-stent restenosis (ISR). The primary endpoint was the minimal lumen diameter at 9 months' follow-up. RESULTS:A total of 189 patients with BMS-ISR from 25 Spanish sites were included (95 were allocated to DEB and 94 to EES). Procedural success was achieved in all patients. At late angiography (median 249 days; 92% of eligible patients), patients in the EES arm had a significantly larger minimal lumen diameter (2.36 ± 0.6 mm vs. 2.01 ± 0.6 mm, p < 0.001; absolute mean difference: 0.35 mm; 95% confidence interval [CI]: 0.16 to 0.53) and a lower percent of diameter stenosis (13 ± 17% vs. 25 ± 20%, p < 0.001). However, late loss (0.04 ± 0.5 mm vs. 0.14 ± 0.5 mm, p = 0.14) and binary restenosis rate (4.7% vs. 9.5%, p = 0.22) were very low and similar in both groups. Clinical follow-up (median 365 days) was obtained in all (100%) patients. Occurrences of the combined clinical outcome measure (cardiac death, myocardial infarction, and target vessel revascularization; 6% vs. 8%; hazard ratio [HR]: 0.76; 95% CI: 0.26 to 2.18, p = 0.6) and the need for target vessel revascularization (2% vs. 6%; HR: 0.32: 95% CI: 0.07 to 1.59, p = 0.17) were similar in the 2 groups. CONCLUSIONS:In patients with BMS-ISR, both DEB and EES provided excellent clinical results with a very low rate of clinical and angiographic recurrences. However, compared with DEB, EES provide superior late angiographic findings. (Restenosis Intra-stent of Bare Metal Stents: Paclitaxel-eluting Balloon vs. Everolimus-eluting Stent [RIBS V]; NCT01239953).
10.1016/j.jacc.2013.12.006
Scar Homogenization Versus Limited-Substrate Ablation in Patients With Nonischemic Cardiomyopathy and Ventricular Tachycardia.
Gökoğlan Yalçın,Mohanty Sanghamitra,Gianni Carola,Santangeli Pasquale,Trivedi Chintan,Güneş Mahmut F,Bai Rong,Al-Ahmad Amin,Gallinghouse G Joseph,Horton Rodney,Hranitzky Patrick M,Sanchez Javier E,Beheiry Salwa,Hongo Richard,Lakkireddy Dhanunjaya,Reddy Madhu,Schweikert Robert A,Dello Russo Antonio,Casella Michela,Tondo Claudio,Burkhardt J David,Themistoclakis Sakis,Di Biase Luigi,Natale Andrea
Journal of the American College of Cardiology
BACKGROUND:Scar homogenization improves long-term ventricular arrhythmia-free survival compared with standard limited-substrate ablation in patients with post-infarction ventricular tachycardia (VT). Whether such benefit extends to patients with nonischemic cardiomyopathy and scar-related VT is unclear. OBJECTIVES:The aim of this study was to assess the long-term efficacy of an endoepicardial scar homogenization approach compared with standard ablation in this population. METHODS:Consecutive patients with dilated nonischemic cardiomyopathy (n = 93), scar-related VTs, and evidence of low-voltage regions on the basis of pre-defined criteria on electroanatomic mapping (i.e., bipolar voltage <1.5 mV) underwent either standard VT ablation (group 1 [n = 57]) or endoepicardial ablation of all abnormal potentials within the electroanatomic scar (group 2 [n = 36]). Acute procedural success was defined as noninducibility of any VT at the end of the procedure; long-term success was defined as freedom from any ventricular arrhythmia at follow-up. RESULTS:Acute procedural success rates were 69.4% and 42.1% after scar homogenization and standard ablation, respectively (p = 0.01). During a mean follow-up period of 14 ± 2 months, single-procedure success rates were 63.9% after scar homogenization and 38.6% after standard ablation (p = 0.031). After multivariate analysis, scar homogenization and left ventricular ejection fraction were predictors of long-term success. During follow-up, the rehospitalization rate was significantly lower in the scar homogenization group (p = 0.035). CONCLUSIONS:In patients with dilated nonischemic cardiomyopathy, scar-related VT, and evidence of low-voltage regions on electroanatomic mapping, endoepicardial homogenization of the scar significantly increased freedom from any recurrent ventricular arrhythmia compared with a standard limited-substrate ablation. However, the success rate with this approach appeared to be lower than previously reported with ischemic cardiomyopathy, presumably because of the septal and midmyocardial distribution of the scar in some patients.
10.1016/j.jacc.2016.08.033
Pioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial (Insulin Resistance Intervention After Stroke).
Yaghi Shadi,Furie Karen L,Viscoli Catherine M,Kamel Hooman,Gorman Mark,Dearborn Jennifer,Young Lawrence H,Inzucchi Silvio E,Lovejoy Anne M,Kasner Scott E,Conwit Robin,Kernan Walter N,
Circulation
BACKGROUND:The IRIS trial (Insulin Resistance Intervention after Stroke) demonstrated that pioglitazone reduced the risk for a composite outcome of stroke or myocardial infarction among nondiabetic patients with insulin resistance and a recent stroke or transient ischemic attack. The current planned secondary analysis uses updated 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. METHODS:Participants were randomly assigned to receive pioglitazone (45 mg/d target dose) or placebo within 180 days of a qualifying ischemic stroke or transient ischemic attack and were followed for a maximum of 5 years. An independent committee, blinded to treatment assignments, adjudicated all potential stroke outcomes. Time to first stroke event was compared by treatment group, overall and by type of event (ischemic or hemorrhagic), using survival analyses and Cox proportional hazards models. RESULTS:Among 3876 IRIS participants (mean age, 63 years; 65% male), 377 stroke events were observed in 319 participants over a median follow-up of 4.8 years. Pioglitazone was associated with a reduced risk for any stroke at 5 years (8.0% in comparison with 10.7% for the placebo group; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.94; log-rank =0.01). Pioglitazone reduced risk for ischemic strokes (HR, 0.72; 95% CI, 0.57-0.91; =0.005) but had no effect on risk for hemorrhagic events (HR, 1.00; 95% CI, 0.50-2.00; =1.00). CONCLUSIONS:Pioglitazone was effective for secondary prevention of ischemic stroke in nondiabetic patients with insulin resistance. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00091949.
10.1161/CIRCULATIONAHA.117.030458
10-Year Mortality Outcome of a Routine Invasive Strategy Versus a Selective Invasive Strategy in Non-ST-Segment Elevation Acute Coronary Syndrome: The British Heart Foundation RITA-3 Randomized Trial.
Henderson Robert A,Jarvis Christopher,Clayton Tim,Pocock Stuart J,Fox Keith A A
Journal of the American College of Cardiology
BACKGROUND:The RITA-3 (Third Randomised Intervention Treatment of Angina) trial compared outcomes of a routine early invasive strategy (coronary arteriography and myocardial revascularization, as clinically indicated) to those of a selective invasive strategy (coronary arteriography for recurrent ischemia only) in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). At a median of 5 years' follow-up, the routine invasive strategy was associated with a 24% reduction in the odds of all-cause mortality. OBJECTIVES:This study reports 10-year follow-up outcomes of the randomized cohort to determine the impact of a routine invasive strategy on longer-term mortality. METHODS:We randomized 1,810 patients with NSTEACS to receive routine invasive or selective invasive strategies. All randomized patients had annual follow-up visits up to 5 years, and mortality was documented thereafter using data from the Office of National Statistics. RESULTS:Over 10 years, there were no differences in mortality between the 2 groups (all-cause deaths in 225 [25.1%] vs. 232 patients [25.4%]: p = 0.94; and cardiovascular deaths in 135 [15.1%] vs. 147 patients [16.1%]: p = 0.65 in the routine invasive and selective invasive groups, respectively). Multivariate analysis identified several independent predictors of 10-year mortality: age, previous myocardial infarction, heart failure, smoking status, diabetes, heart rate, and ST-segment depression. A modified post-discharge Global Registry of Acute Coronary Events (GRACE) score was used to calculate an individual risk score for each patient and to form low-risk, medium-risk, and high-risk groups. Risk of death within 10 years varied markedly from 14.4 % in the low-risk group to 56.2% in the high-risk group. This mortality trend did not depend on the assigned treatment strategy. CONCLUSIONS:The advantage of reduced mortality of routine early invasive strategy seen at 5 years was attenuated during later follow-up, with no evidence of a difference in outcome at 10 years. Further trials of contemporary intervention strategies in patients with NSTEACS are warranted. (Third Randomised Intervention Treatment of Angina trial [RITA-3]; ISRCTN07752711).
10.1016/j.jacc.2015.05.051
Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population.
Kaasenbrood Lotte,Boekholdt S Matthijs,van der Graaf Yolanda,Ray Kausik K,Peters Ron J G,Kastelein John J P,Amarenco Pierre,LaRosa John C,Cramer Maarten J M,Westerink Jan,Kappelle L Jaap,de Borst Gert J,Visseren Frank L J
Circulation
BACKGROUND:Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. METHODS:The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. RESULTS:The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%-28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%-17%). CONCLUSIONS:Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.
10.1161/CIRCULATIONAHA.116.021314
Ablation of Stable VTs Versus Substrate Ablation in Ischemic Cardiomyopathy: The VISTA Randomized Multicenter Trial.
Di Biase Luigi,Burkhardt J David,Lakkireddy Dhanujaya,Carbucicchio Corrado,Mohanty Sanghamitra,Mohanty Prasant,Trivedi Chintan,Santangeli Pasquale,Bai Rong,Forleo Giovanni,Horton Rodney,Bailey Shane,Sanchez Javier,Al-Ahmad Amin,Hranitzky Patrick,Gallinghouse G Joseph,Pelargonio Gemma,Hongo Richard H,Beheiry Salwa,Hao Steven C,Reddy Madhu,Rossillo Antonio,Themistoclakis Sakis,Dello Russo Antonio,Casella Michela,Tondo Claudio,Natale Andrea
Journal of the American College of Cardiology
BACKGROUND:Catheter ablation reduces ventricular tachycardia (VT) recurrence and implantable cardioverter defibrillator shocks in patients with VT and ischemic cardiomyopathy. The most effective catheter ablation technique is unknown. OBJECTIVES:This study determined rates of VT recurrence in patients undergoing ablation limited to clinical VT along with mappable VTs ("clinical ablation") versus substrate-based ablation. METHODS:Subjects with ischemic cardiomyopathy and hemodynamically tolerated VT were randomized to clinical ablation (n = 60) versus substrate-based ablation that targeted all "abnormal" electrograms in the scar (n = 58). Primary endpoint was recurrence of VT. Secondary endpoints included periprocedural complications, 12-month mortality, and rehospitalizations. RESULTS:At 12-month follow-up, 9 (15.5%) and 29 (48.3%) patients had VT recurrence in substrate-based and clinical VT ablation groups, respectively (log-rank p < 0.001). More patients undergoing clinical VT ablation (58%) were on antiarrhythmic drugs after ablation versus substrate-based ablation (12%; p < 0.001). Seven (12%) patients with substrate ablation and 19 (32%) with clinical ablation required rehospitalization (p = 0.014). Overall 12-month mortality was 11.9%; 8.6% in substrate ablation and 15.0% in clinical ablation groups, respectively (log-rank p = 0.21). Combined incidence of rehospitalization and mortality was significantly lower with substrate ablation (p = 0.003). Periprocedural complications were similar in both groups (p = 0.61). CONCLUSIONS:An extensive substrate-based ablation approach is superior to ablation targeting only clinical and stable VTs in patients with ischemic cardiomyopathy presenting with tolerated VT. (Ablation of Clinical Ventricular Tachycardia Versus Addition of Substrate Ablation on the Long Term Success Rate of VT Ablation (VISTA); NCT01045668).
10.1016/j.jacc.2015.10.026
Carotid Stent Fractures Are Not Associated With Adverse Events: Results From the ACT-1 Multicenter Randomized Trial (Carotid Angioplasty and Stenting Versus Endarterectomy in Asymptomatic Subjects Who Are at Standard Risk for Carotid Endarterectomy With Significant Extracranial Carotid Stenotic Disease).
Weinberg Ido,Beckman Joshua A,Matsumura Jon S,Rosenfield Kenneth,Ansel Gary M,Chaturvedi Seemant,Gray William,Metzger D Chris,Riles Tom,Shu Yu,Wechsler Lawrence,Jaff Michael R
Circulation
BACKGROUND:The impact of carotid artery stent fractures on the incidence of adverse clinical events remains unclear. The objective of this study is to report the stent fracture rate and its association with in-stent restenosis and adverse outcomes in the ACT-1 trial (Carotid Angioplasty and Stenting Versus Endarterectomy in Asymptomatic Subjects Who Are at Standard Risk for Carotid Endarterectomy With Significant Extracranial Carotid Stenotic Disease). METHODS:ACT-1 is a prospective multicenter trial of patients who have standard surgical risk with severe asymptomatic carotid artery stenosis randomly assigned to carotid artery stenting or carotid endarterectomy (Abbott Vascular). The primary end point was a composite of death, stroke, or myocardial infarction during the 30 days after the procedure or ipsilateral stroke during the 365 days after the procedure. After 771 patients were enrolled, successively randomly assigned patients were required to undergo annual radiographic (x-ray) analysis for stent fracture. Images were independently adjudicated by a core laboratory. RESULTS:Of 1021 patients treated with carotid artery stenting during a mean follow-up of 3.1±1.6 years, 939 had at least 1 x-ray during the follow-up period. Stent fracture was reported in 51 (5.4%) patients. With a maximum follow-up period of 5 years, adverse clinical outcomes occurred in 39 patients with at least 1 x-ray during the follow-up. Of 826 (80.9%) subjects who underwent both duplex ultrasound and x-ray, 822 (99.5%) were interpretable. There was no association between stent fracture and the primary end point (=0.86) or with restenosis (=0.53). CONCLUSIONS:In this large, independently adjudicated, multicenter study, the stent fracture rate was low and not associated with major adverse clinical events or in-stent restenosis. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00106938.
10.1161/CIRCULATIONAHA.117.030030
Indoleamine 2,3-Dioxygenase Fine-Tunes Immune Homeostasis in Atherosclerosis and Colitis through Repression of Interleukin-10 Production.
Metghalchi Sarvenaz,Ponnuswamy Padmapriya,Simon Tabassome,Haddad Yacine,Laurans Ludivine,Clément Marc,Dalloz Marion,Romain Mélissa,Esposito Bruno,Koropoulis Vincent,Lamas Bruno,Paul Jean-Louis,Cottin Yves,Kotti Salma,Bruneval Patrick,Callebert Jacques,den Ruijter Hester,Launay Jean-Marie,Danchin Nicolas,Sokol Harry,Tedgui Alain,Taleb Soraya,Mallat Ziad
Cell metabolism
Indoleamine 2,3-dioxygenase 1 (Ido1) is a rate-limiting enzyme that catalizes the degradation of tryptophan along the kynurenine pathway. Here, we show that Ido1 activity sustains an immunostimulatory potential through inhibition of interleukin (Il)10. In atherosclerosis, Ido1-dependent inhibition of Il10 translates into disease exacerbation. The resistance of Ido1-deficient mice to enhanced immune activation is broken in Ido1/Il10 double-deficient mice, which show exaggerated immune responses and develop severe spontaneous colitis. We demonstrate that Ido1 activity is required for the regulation of Il10 and that kynurenic acid (Kna), an Ido1-derived metabolite, is responsible for reduced Il10 production through activation of a cAMP-dependent pathway and inhibition of Erk1/2 phosphorylation. Resupplementation of Ido1-deficient mice with Kna limits Il10 expression and promotes atherosclerosis. In human atherosclerotic lesions, increased levels of Kna are associated with an unstable plaque phenotype, and its blood levels predict death and recurrent myocardial infarction in patients with coronary artery disease.
10.1016/j.cmet.2015.07.004
Validating Utility of Dual Antiplatelet Therapy Score in a Large Pooled Cohort From 3 Japanese Percutaneous Coronary Intervention Studies.
Yoshikawa Yusuke,Shiomi Hiroki,Watanabe Hirotoshi,Natsuaki Masahiro,Kondo Hirokazu,Tamura Toshihiro,Nakagawa Yoshihisa,Morimoto Takeshi,Kimura Takeshi
Circulation
BACKGROUND:The dual antiplatelet therapy (DAPT) score was developed to estimate ischemic and bleeding risks from the DAPT study. However, few studies validated its utility externally. We sought to validate the utility of the DAPT score in the Japanese population. METHODS:In a pooled cohort of 3 studies conducted in Japan (the CREDO-Kyoto [Coronary Revascularization Demonstrating Outcome Study in Kyoto] Registry Cohort-2, RESET [Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial], and NEXT [NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial]), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention among patients with a DAPT score ≥2 (high DS) and a DAPT score <2 (low DS). RESULTS:Among 12 223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3944 patients had high DS and 8279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%, =0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%, =0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%, =0.03; 1.5% versus 0.8%, =0.002; 0.7% versus 0.3%, <0.001, respectively), whereas the cumulative incidences of noncardiac death and GUSTO severe bleeding were significantly lower in high DS than in low DS (2.4% versus 3.9%, <0.001; 1.0% versus 1.6%, =0.03, respectively). CONCLUSIONS:In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.
10.1161/CIRCULATIONAHA.117.028924
Associations Between Adding a Radial Artery Graft to Single and Bilateral Internal Thoracic Artery Grafts and Outcomes: Insights From the Arterial Revascularization Trial.
Circulation
BACKGROUND:Whether the use of the radial artery (RA) can improve clinical outcomes in coronary artery bypass graft surgery remains unclear. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral internal thoracic artery (BITA) over single left internal thoracic artery (SITA). In the ART, a large proportion of patients (≈20%) also received an RA graft instead of a saphenous vein graft (SVG). We aimed to investigate the associations between using the RA instead of an SVG to supplement SITA or BITA grafts and outcomes by performing a post hoc analysis of the ART. METHODS:Patients enrolled in the ART (n=3102) were classified on the basis of conduits actually received (as treated). The analysis included 2737 patients who received an RA graft (RA group; n=632) or SVG only (SVG group; n=2105) in addition to SITA or BITA grafts. The primary end point was the composite of myocardial infarction, cardiovascular death, and repeat revascularization at 5 years. Propensity score matching and stratified Cox regression were used to compare the 2 strategies. RESULTS:Myocardial infarction, cardiovascular death, and repeat revascularization cumulative incidence was 2.3% (95% confidence interval [CI], 1.1-3.4), 3.5% (95% CI, 2.1-5.0), and 4.4% (95% CI, 2.8-6.0) in the RA group and 3.4% (95% CI, 2.0-4.8), 4.0% (95% CI, 2.5-5.6), and 7.6% (95% CI, 5.5-9.7) in the SVG group, respectively. The composite end point was significantly lower in the RA group (8.8%; 95% CI, 6.5-11.0) compared with the SVG group (13.6%; 95% CI, 10.8-16.3; =0.005). This association was present when an RA graft was used to supplement both SITA and BITA grafts (interaction =0.62). CONCLUSIONS:This post hoc ART analysis showed that an additional RA was associated with lower risk for midterm major adverse cardiac events when used to supplement SITA or BITA grafts. CLINICAL TRIAL REGISTRATION:URL: https://www.situ.ox.ac.uk/surgical-trials/art. Unique identifier: ISRCTN46552265.
10.1161/CIRCULATIONAHA.117.027659
High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: A landmark analysis of the ARCTIC study.
Montalescot Gilles,Rangé Grégoire,Silvain Johanne,Bonnet Jean-Louis,Boueri Ziad,Barthélémy Olivier,Cayla Guillaume,Belle Loic,Van Belle Eric,Cuisset Thomas,Elhadad Simon,Pouillot Christophe,Henry Patrick,Motreff Pascal,Carrié Didier,Rousseau Hélène,Aubry Pierre,Monségu Jacques,Sabouret Pierre,O'Connor Stephen A,Abtan Jérémie,Kerneis Mathieu,Saint-Etienne Christophe,Beygui Farzin,Vicaut Eric,Collet Jean-Philippe,
Circulation
BACKGROUND:Individualizing antiplatelet therapy after platelet function testing did not improve outcome after coronary stenting in the Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting (ARCTIC) study. Whether results are different during the phase of secondary prevention starting after hospital discharge, when periprocedural events have been excluded, is unknown. METHODS AND RESULTS:In ARCTIC, 2440 patients were randomized before coronary stenting to a strategy of platelet function monitoring (VerifyNow P2Y12/aspirin point-of-care assay) with drug adjustment in suboptimal responders to antiplatelet therapy or to a conventional strategy without monitoring and without drug or dose changes. We performed a landmark analysis starting at the time of hospital discharge evaluating the primary end point of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization through 1 year. After discharge, the primary end point occurred in 8.6% of patients in the monitoring arm and 7.9% in the conventional arm (hazard ratio, 1.105; 95% confidence interval, 0.835-1.461; P=0.48). Stent thrombosis or urgent revascularization occurred in 4.4% and 4.5% in the monitoring and conventional arms, respectively (P=0.99). There was no difference for any of the other ischemic end points. Major bleeding event rates were 1.8% in the monitoring arm and 2.8% in the conventional arm (P=0.11), whereas major or minor bleeding event rates were 2.3% and 3.4%, respectively (P=0.10). CONCLUSIONS:Detection of platelet hyper-reactivity by platelet function testing in patients undergoing coronary stenting with further therapeutic adjustment does not reduce ischemic recurrences after intervention. On-treatment platelet hyperreactivity cannot be considered as a risk factor requiring intervention for secondary prevention after percutaneous coronary revascularization. CLINICAL TRIAL REGISTRATION URL:http://www.clinicaltrials.gov. Unique identifier: NCT00827411.
10.1161/CIRCULATIONAHA.113.007524
Predictors of long-term recurrent vascular events after ischemic stroke at young age: the Italian Project on Stroke in Young Adults.
Pezzini Alessandro,Grassi Mario,Lodigiani Corrado,Patella Rosalba,Gandolfo Carlo,Zini Andrea,Delodovici Maria Luisa,Paciaroni Maurizio,Del Sette Massimo,Toriello Antonella,Musolino Rossella,Calabrò Rocco Salvatore,Bovi Paolo,Adami Alessandro,Silvestrelli Giorgio,Sessa Maria,Cavallini Anna,Marcheselli Simona,Bonifati Domenico Marco,Checcarelli Nicoletta,Tancredi Lucia,Chiti Alberto,Del Zotto Elisabetta,Spalloni Alessandra,Giossi Alessia,Volonghi Irene,Costa Paolo,Giacalone Giacomo,Ferrazzi Paola,Poli Loris,Morotti Andrea,Rasura Maurizia,Simone Anna Maria,Gamba Massimo,Cerrato Paolo,Micieli Giuseppe,Melis Maurizio,Massucco Davide,De Giuli Valeria,Iacoviello Licia,Padovani Alessandro,
Circulation
BACKGROUND:Data on long-term risk and predictors of recurrent thrombotic events after ischemic stroke at a young age are limited. METHODS AND RESULTS:We followed 1867 patients with first-ever ischemic stroke who were 18 to 45 years of age (mean age, 36.8±7.1 years; women, 49.0%), as part of the Italian Project on Stroke in Young Adults (IPSYS). Median follow-up was 40 months (25th to 75th percentile, 53). The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. One hundred sixty-three patients had recurrent thrombotic events (average rate, 2.26 per 100 person-years at risk). At 10 years, cumulative risk was 14.7% (95% confidence interval, 12.2%-17.9%) for primary end point, 14.0% (95% confidence interval, 11.4%-17.1%) for brain ischemia, and 0.7% (95% confidence interval, 0.4%-1.3%) for myocardial infarction or other arterial events. Familial history of stroke, migraine with aura, circulating antiphospholipid antibodies, discontinuation of antiplatelet and antihypertensive medications, and any increase of 1 traditional vascular risk factor were independent predictors of the composite end point in multivariable Cox proportional hazards analysis. A point-scoring system for each variable was generated by their β-coefficients, and a predictive score (IPSYS score) was calculated as the sum of the weighted scores. The area under the receiver operating characteristic curve of the 0- to 5-year score was 0.66 (95% confidence interval, 0.61-0.71; mean, 10-fold internally cross-validated area under the receiver operating characteristic curve, 0.65). CONCLUSIONS:Among patients with ischemic stroke aged 18 to 45 years, the long-term risk of recurrent thrombotic events is associated with modifiable, age-specific risk factors. The IPSYS score may serve as a simple tool for risk estimation.
10.1161/CIRCULATIONAHA.113.005663
Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33). PATIENTS AND METHODS:These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities. RESULTS:Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses. CONCLUSION:Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.
10.1200/JCO.2013.51.5304
Thirty-Day Readmissions After Endovascular or Surgical Therapy for Critical Limb Ischemia: Analysis of the 2013 to 2014 Nationwide Readmissions Databases.
Kolte Dhaval,Kennedy Kevin F,Shishehbor Mehdi H,Abbott J Dawn,Khera Sahil,Soukas Peter,Mamdani Shafiq T,Hyder Omar N,Drachman Douglas E,Aronow Herbert D
Circulation
BACKGROUND:Thirty-day readmission rates have gained increasing importance as a key quality metric. A significant number of patients are hospitalized for the management of critical limb ischemia (CLI), but limited data are available on the incidence, predictors, and causes of 30-day readmission after hospitalization for CLI. METHODS:Hospitalizations for a primary diagnosis of CLI during which patients underwent endovascular or surgical therapy (revascularization and/or amputation) and were discharged alive were identified in the 2013 to 2014 Nationwide Readmissions Databases. Incidence, reasons, and costs of 30-day unplanned readmissions were determined. Hierarchical logistic regression models were used to identify independent predictors of 30-day readmissions. RESULTS:We included 60 998 (national estimate, 135 110) index CLI hospitalizations (mean age, 68.9±11.9 years; 40.8% women; 24.6% for rest pain, 37.2% for ulcer, and 38.2% for gangrene). The 30-day readmission rate was 20.4%. Presentation with ulcer or gangrene, age ≥65 years, female sex, large hospital size, teaching hospital status, known coronary artery disease, heart failure, diabetes mellitus, chronic kidney disease, anemia, coagulopathy, obesity, major bleeding, acute myocardial infarction, vascular complications, and sepsis were identified as independent predictors of 30-day readmission. Mode of revascularization was not independently associated with readmissions. Infections (23.5%), persistent or recurrent manifestations of peripheral artery disease (22.2%), cardiac conditions (11.4%), procedural complications (11.0%), and endocrine issues (5.7%) were the most common reasons for readmission. The inflation-adjusted aggregate costs of 30-day readmissions for CLI during the study period were $624 million. CONCLUSIONS:Approximately 1 in 5 patients hospitalized for CLI and undergoing revascularization is readmitted within 30 days. Risk of readmission is influenced by CLI presentation, patient demographics, comorbidities, and in-hospital complications, but not by the mode of revascularization.
10.1161/CIRCULATIONAHA.117.027625
Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes.
Roe Matthew T,Li Qian H,Bhatt Deepak L,Bittner Vera A,Diaz Rafael,Goodman Shaun G,Harrington Robert A,Jukema J Wouter,Lopez-Jaramillo Patricio,Lopes Renato D,Louie Michael J,Moriarty Patrick M,Szarek Michael,Vogel Robert,White Harvey D,Zeiher Andreas M,Baccara-Dinet Marie T,Steg Ph Gabriel,Schwartz Gregory G
Circulation
BACKGROUND:The 2018 US cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with low-density lipoprotein cholesterol ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL despite maximum tolerated statin therapy. Such patients are considered at very high risk (VHR) based on a history of >1 major atherosclerotic cardiovascular disease (ASCVD) event or a single ASCVD event and multiple high-risk conditions. We investigated the association of US guideline-defined risk categories with the occurrence of ischemic events after acute coronary syndrome and reduction of those events by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor. METHODS:In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), patients with recent acute coronary syndrome and residual dyslipidemia despite optimal statin therapy were randomly assigned to alirocumab or placebo. The primary trial outcome (major adverse cardiovascular events, ie, coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) was examined according to American College of Cardiology/American Heart Association risk category. RESULTS:Of 18 924 participants followed for a median of 2.8 years, 11 935 (63.1%) were classified as VHR: 4450 (37.3%) had multiple prior ASCVD events and 7485 (62.7%) had 1 major ASCVD event and multiple high-risk conditions. Major adverse cardiovascular events occurred in 14.4% of placebo-treated patients at VHR versus 5.6% of those not at VHR. In the VHR category, major adverse cardiovascular events occurred in 20.4% with multiple prior ASCVD events versus 10.7% with 1 ASCVD event and multiple high-risk conditions. Alirocumab was associated with consistent relative risk reductions in both risk categories (hazard ratio=0.84 for VHR; hazard ratio=0.86 for not VHR; =0.820) and by stratification within the VHR group (hazard ratio=0.86 for multiple prior ASCVD events; hazard ratio=0.82 for 1 major ASCVD event and multiple high-risk conditions; =0.672). The absolute risk reduction for major adverse cardiovascular events with alirocumab was numerically greater (but not statistically different) in the VHR group versus those not at VHR (2.1% versus 0.8%; =0.095) and among patients at VHR with multiple prior ASCVD events versus a single prior ASCVD event (2.4% versus 1.8%; =0.661). CONCLUSIONS:The US guideline criteria identify patients with recent acute coronary syndrome and dyslipidemia who are at VHR for recurrent ischemic events and who may derive a larger absolute benefit from treatment with alirocumab. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.
10.1161/CIRCULATIONAHA.119.042551
Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk.
Moeckel Douglas,Jeong Soon Soeg,Sun Xiaofeng,Broekman M Johan,Nguyen Annie,Drosopoulos Joan H F,Marcus Aaron J,Robson Simon C,Chen Ridong,Abendschein Dana
Science translational medicine
In patients with acute myocardial infarction undergoing reperfusion therapy to restore blood flow through blocked arteries, simultaneous inhibition of platelet P2Y12 receptors with the current standard of care neither completely prevents recurrent thrombosis nor provides satisfactory protection against reperfusion injury. Additionally, these antiplatelet drugs increase the risk of bleeding. To devise a different strategy, we engineered and optimized the apyrase activity of human nucleoside triphosphate diphosphohydrolase-3 (CD39L3) to enhance scavenging of extracellular adenosine diphosphate, a predominant ligand of P2Y12 receptors. The resulting recombinant protein, APT102, exhibited greater than four times higher adenosine diphosphatase activity and a 50 times longer plasma half-life than did native apyrase. Treatment with APT102 before coronary fibrinolysis with intravenous recombinant human tissue-type plasminogen activator in conscious dogs completely prevented thrombotic reocclusion and significantly decreased infarction size by 81% without increasing bleeding time. In contrast, clopidogrel did not prevent coronary reocclusion and increased bleeding time. In a murine model of myocardial reperfusion injury caused by transient coronary artery occlusion, APT102 also decreased infarct size by 51%, whereas clopidogrel was not effective. These preclinical data suggest that APT102 should be tested for its ability to safely and effectively maximize the benefits of myocardial reperfusion therapy in patients with arterial thrombosis.
10.1126/scitranslmed.3009246
Cost-Effectiveness of Long-Term Ticagrelor in Patients With Prior Myocardial Infarction: Results From the PEGASUS-TIMI 54 Trial.
Magnuson Elizabeth A,Li Haiyan,Wang Kaijun,Vilain Katherine,Shafiq Ali,Bonaca Marc P,Bhatt Deepak L,Cohen Marc,Steg Philippe Gabriel,Storey Robert F,Braunwald Eugene,Sabatine Marc S,Cohen David J,
Journal of the American College of Cardiology
BACKGROUND:In patients with a myocardial infarction (MI) 1 to 3 years earlier, treatment with ticagrelor + low-dose aspirin (ASA) reduces the risk of cardiovascular (CV) death, MI, or stroke compared with low-dose aspirin alone, but at an increased risk of major bleeding. OBJECTIVES:The authors evaluated cost-effectiveness of ticagrelor + low-dose ASA in patients with prior MI within the prior 3 years. METHODS:The authors performed a prospective economic substudy alongside the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial, which randomized 21,162 patients to ASA alone, ticagrelor 60 mg twice daily + low-dose ASA, or ticagrelor 90 mg twice daily + low-dose ASA. Medical resource use data were collected over a median 33-month follow-up. Costs were assessed from the U.S. health care system perspective. In-trial data relating to survival, utility, and costs were combined with lifetime projections to evaluate lifetime cost-effectiveness of the Food and Drug Administration-approved lower-dose ticagrelor regimen (60 mg twice daily). RESULTS:Hospitalization costs were similar for ticagrelor 60 mg and placebo ($2,262 vs. $2,333; 95% confidence interval for difference -$303 to $163; p = 0.54); after inclusion of a daily ticagrelor 60 mg cost of $10.52, total costs were higher for ticagrelor ($10,016 vs. $2,333; 95% CI: $7,441 to $7,930; p < 0.001). In-trial quality-adjusted life-years (QALYs) were similar (2.28 vs. 2.27; p = 0.34). Over a lifetime horizon, ticagrelor was associated with QALY gains of 0.078 and incremental costs of $7,435, yielding an incremental cost-effectiveness ratio (ICER) of $94,917/QALY gained. Several high-risk groups had more favorable ICERs, including patients with >1 prior MI, multivessel disease, diabetes, renal dysfunction (all with ICERs $50,000 to $70,000/QALY gained), patients age <75 years (ICER = $44,779/QALY gained), and patients with peripheral artery disease (ICER = $13,427/QALY gained). CONCLUSIONS:For patients with a history of MI >1 year previously, long-term treatment with ticagrelor 60 mg + low-dose ASA yields a cost-effectiveness ratio suggesting intermediate value based on current guidelines. Ticagrelor appears to provide higher value for patients in several recognized high-risk subgroups. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562).
10.1016/j.jacc.2017.05.063
Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.
Kofoed Klaus F,Kelbæk Henning,Hansen Peter Riis,Torp-Pedersen Christian,Høfsten Dan,Kløvgaard Lene,Holmvang Lene,Helqvist Steffen,Jørgensen Erik,Galatius Søren,Pedersen Frants,Bang Lia,Saunamaki Kari,Clemmensen Peter,Linde Jesper J,Heitmann Merete,Wendelboe Nielsen Olav,Raymond Ilan E,Kristiansen Ole Peter,Svendsen Ida Hastrup,Bech Jan,Dominguez Vall-Lamora Maria Helena,Kragelund Charlotte,Hansen Thomas Fritz,Dahlgaard Hove Jens,Jørgensen Tem,Fornitz Gitte G,Steffensen Rolf,Jurlander Birgit,Abdulla Jawdat,Lyngbæk Stig,Elming Hanne,Therkelsen Susette Krohn,Abildgaard Ulrik,Jensen Jan Skov,Gislason Gunnar,Køber Lars V,Engstrøm Thomas
Circulation
BACKGROUND:The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome is not well defined. We tested the hypothesis that a strategy of very early ICA and possible revascularization within 12 hours of diagnosis is superior to an invasive strategy performed within 48 to 72 hours in terms of clinical outcomes. METHODS:Patients admitted with clinical suspicion of non-ST-segment elevation acute coronary syndrome in the Capital Region of Copenhagen, Denmark, were screened for inclusion in the VERDICT trial (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) ( ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48 to 72 hours. The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure. RESULTS:A total of 2147 patients were randomized; 1075 patients allocated to very early invasive evaluation had ICA performed at a median of 4.7 hours after randomization, whereas 1072 patients assigned to standard invasive care had ICA performed 61.6 hours after randomization. Among patients with significant coronary artery disease identified by ICA, coronary revascularization was performed in 88.4% (very early ICA) and 83.1% (standard invasive care). Within a median follow-up time of 4.3 (interquartile range, 4.1-4.4) years, the primary end point occurred in 296 (27.5%) of participants in the very early ICA group and 316 (29.5%) in the standard care group (hazard ratio, 0.92; 95% CI, 0.78-1.08). Among patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140, a very early invasive treatment strategy improved the primary outcome compared with the standard invasive treatment (hazard ratio, 0.81; 95% CI, 0.67-1.01; P value for interaction=0.023). CONCLUSIONS:A strategy of very early invasive coronary evaluation does not improve overall long-term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, very early invasive therapy improves long-term outcomes. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT02061891.
10.1161/CIRCULATIONAHA.118.037152
Coronary stent thrombosis with vorapaxar versus placebo: results from the TRA 2° P-TIMI 50 trial.
Bonaca Marc P,Scirica Benjamin M,Braunwald Eugene,Wiviott Stephen D,O'Donoghue Michelle L,Murphy Sabina A,Morrow David A
Journal of the American College of Cardiology
BACKGROUND:Vorapaxar, a novel thrombin receptor antagonist, reduces cardiovascular death and recurrent thrombotic events when added to standard antiplatelet therapy in patients with stable atherosclerotic vascular disease. OBJECTIVES:The goal of this study was to test the hypothesis that treatment with vorapaxar reduces the rate of coronary stent thrombosis (ST) in stable patients with a history of coronary stenting. METHODS:TRA 2° P-TIMI 50 (Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50) was a multinational, randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients with prior myocardial infarction, peripheral arterial disease, or stroke. We evaluated the rates of definite ST as adjudicated by a central events committee using Academic Research Consortium (ARC) criteria. RESULTS:A total of 26,449 patients were randomized, with 14,042 (53%) having a history of a coronary stent implantation before randomization, and an additional 449 patients receiving a coronary stent during the trial (total 14,491). During follow-up (median 2.5 years), there were 152 definite ST events, with the majority (92%) occurring late or very late. Vorapaxar reduced ARC definite ST (1.1% vs. 1.4%, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.51 to 0.98; p = 0.037). The reduction was consistent, regardless of time from percutaneous coronary intervention, history of diabetes, use of drug-eluting stents, and use of dual antiplatelet therapy (DAPT) at randomization. Vorapaxar increased GUSTO moderate/severe bleeding (HR: 1.57, 95% CI: 1.26 to 1.94; p < 0.001). CONCLUSIONS:The rate of ARC definite ST in stable patients, the majority of whom were receiving DAPT, was approximately 1.4% at 3 years. In stable patients with coronary stenting receiving standard antiplatelet therapy, vorapaxar administered for long-term secondary prevention significantly reduced ARC definite ST, including very late ST. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2° P-TIMI 50] [P04737]; NCT00526474).
10.1016/j.jacc.2014.09.037
Coronary Atherosclerotic Phenotype and Plaque Healing in Patients With Recurrent Acute Coronary Syndromes Compared With Patients With Long-term Clinical Stability: An In Vivo Optical Coherence Tomography Study.
Vergallo Rocco,Porto Italo,D'Amario Domenico,Annibali Gianmarco,Galli Mattia,Benenati Stefano,Bendandi Francesco,Migliaro Stefano,Fracassi Francesco,Aurigemma Cristina,Leone Antonio Maria,Buffon Antonino,Burzotta Francesco,Trani Carlo,Niccoli Giampaolo,Liuzzo Giovanna,Prati Francesco,Fuster Valentin,Jang Ik-Kyung,Crea Filippo
JAMA cardiology
Importance:At one end of the coronary artery disease (CAD) spectrum, there are patients with multiple recurrent acute coronary syndromes (rACS), and at the other end there are those with long-standing clinical stability. Predicting the natural history of these patients is challenging because unstable plaques often heal without resulting in ACS. Objective:To assess in vivo the coronary atherosclerotic phenotype as well as the prevalence and characteristics of healed coronary plaques by optical coherence tomography (OCT) imaging in patients at the extremes of the CAD spectrum. Design, Setting, and Participants:This is an observational, single-center cohort study with prospective clinical follow-up. From a total of 823 consecutive patients enrolled in OCT Registry of the Fondazione Policlinico A. Gemelli-IRCCS, Rome, Italy, from March 2009 to February 2016, 105 patients were included in the following groups: (1) patients with rACS, defined as history of at least 3 acute myocardial infarctions (AMIs) or at least 4 ACS with at least 1 AMI; (2) patients with long-standing stable angina pectoris (ls-SAP), defined as a minimum 3-year history of stable angina; and (3) patients with a single unheralded AMI followed by a minimum 3-year period of clinical stability (sAMI). Data were analyzed from January to August 2018. Exposures:Intracoronary OCT imaging of nonculprit coronary segments. Main Outcomes and Measures:Coronary plaque features and the prevalence of healed coronary plaques in nonculprit segments as assessed by intracoronary OCT imaging. Results:Of 105 patients, 85 were men (81.0%); the median (interquartile range) age was 68 (63-75) years. Median (interquartile range) time of clinical stability was 9 (5.0-15.0) years in the ls-SAP group and 8 (4.5-14.5) years in the sAMI group. Patients in the rACS and sAMI groups showed similar prevalence of lipid-rich plaque and thin-cap fibroatheroma, which was significantly higher than in those with ls-SAP (lipid-rich plaque 80.0% [n = 24 of 30] vs 76.3% [n = 29 of 38] vs 37.8% [n = 14 of 37], respectively; P < .001; thin-cap fibroatheroma 40.0% [n = 12 of 30] vs 34.2% [n = 13 of 38] vs 8.1% [n = 3 of 37], respectively; P = .006). Spotty calcifications were more frequently observed in patients with rACS than in those with ls-SAP and sAMI (70.0% [n = 21 of 30] vs 40.5% [n = 15 of 37] vs 44.7% [n = 17 of 38], respectively; P = .04). Healed coronary plaques were rarely observed in patients with rACS, whereas their prevalence was significantly higher in patients with ls-SAP and sAMI (3.3% [n = 1 of 30] vs 29.7% [n = 11 of 37] vs 28.9% [n = 11 of 38], respectively; P = .01). Conclusions and Relevance:Patients with rACS have a distinct atherosclerotic phenotype compared with those with ls-SAP, including higher prevalence of thin-cap fibroatheroma and lower prevalence of healed coronary plaques, suggesting that atherosclerotic profile and plaque healing may play a role in leading the natural history of patients with CAD.
10.1001/jamacardio.2019.0275
Association of Lipoprotein(a) With Risk of Recurrent Ischemic Events Following Acute Coronary Syndrome: Analysis of the dal-Outcomes Randomized Clinical Trial.
Schwartz Gregory G,Ballantyne Christie M,Barter Philip J,Kallend David,Leiter Lawrence A,Leitersdorf Eran,McMurray John J V,Nicholls Stephen J,Olsson Anders G,Shah Prediman K,Tardif Jean-Claude,Kittelson John
JAMA cardiology
Importance:It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). Objective:To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. Design, Setting, and Participants:This nested case-cohort analysis was performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina or myocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. Interventions:Patients were randomly assigned to receive treatment with dalcetrapib, 600 mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. Main Outcomes and Measures:Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. Results:The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9) mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95% CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. Conclusions and Relevance:For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS. Trial Registration:clinicaltrials.gov Identifier: NCT00658515.
10.1001/jamacardio.2017.3833
Direct Oral Anticoagulants in Addition to Antiplatelet Therapy for Secondary Prevention After Acute Coronary Syndromes: A Systematic Review and Meta-analysis.
JAMA cardiology
Importance:Patients with acute coronary syndrome (ACS) remain at high risk for experiencing recurrent ischemic events. Direct oral anticoagulants (DOAC) have been proposed for secondary prevention after ACS. Objective:To evaluate the safety and efficacy of DOAC in addition to antiplatelet therapy (APT) after ACS, focusing on treatment effects stratified by baseline clinical presentation (non-ST-segment elevation ACS [NSTE-ACS] vs ST-segment elevation myocardial infarction [STEMI]). Data Sources:PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched from inception to March 1, 2017. Study Selection:Randomized clinical trials on DOAC after ACS were evaluated for inclusion. Overall, 473 studies were screened, 19 clinical trials were assessed as potentially eligible, and 6 were included in the meta-analysis. Data Extraction and Synthesis:Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to abstract data and assess quality and validity. The risk of bias tool, version 2.0 (Cochrane) was used for risk of bias assessment. Data were pooled using random-effects models. Main Outcomes and Measures:The prespecified primary efficacy end point was the composite of cardiovascular death, myocardial infarction, and stroke. The prespecified primary safety end point was major bleeding. Results:Six trials that included 29 667 patients were identified (14 580 patients [49.1%] with STEMI and 15 036 [50.7%] with NSTE-ACS). The primary efficacy end point risk was significantly lower in patients who were treated with DOAC as compared with APT alone (odds ratio [OR], 0.85; 95% CI, 0.77-0.93; P < .001). This benefit was pronounced in patients with STEMI (OR, 0.76; 95% CI, 0.66-0.88; P < .001), while no significant treatment effect was observed in patients with NSTE-ACS (OR, 0.92; 95% CI, 0.78-1.09; P = .36; P for interaction = .09). With respect to safety, DOACs were associated with a higher risk of major bleeding as compared with APT alone (OR, 3.17; 95% CI, 2.27-4.42; P < .001), with consistent results in patients with STEMI (OR, 3.45; 95% CI, 1.95-6.09; P < .001) and NSTE-ACS (OR, 2.19; 95% CI, 1.38-3.48; P < .001; P for interaction = .23). Conclusions and Relevance:To our knowledge, these findings are the first evidence to support differential treatment effects of DOAC in addition to APT according to ACS baseline clinical presentation. In patients with NSTE-ACS, the risk-benefit profile of DOAC appears unfavorable. Conversely, DOAC in addition to APT might represent an attractive option for patients with STEMI.
10.1001/jamacardio.2017.5306
Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.
Newby L Kristin,Marber Michael S,Melloni Chiara,Sarov-Blat Lea,Aberle Laura H,Aylward Philip E,Cai Gengqian,de Winter Robbert J,Hamm Christian W,Heitner John F,Kim Raymond,Lerman Amir,Patel Manesh R,Tanguay Jean-Francois,Lepore John J,Al-Khalidi Hussein R,Sprecher Dennis L,Granger Christopher B,
Lancet (London, England)
BACKGROUND:p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial. METHODS:From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962. FINDINGS:Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ. INTERPRETATION:p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes. FUNDING:GlaxoSmithKline.
10.1016/S0140-6736(14)60417-7
Papillary Muscle Approximation Versus Restrictive Annuloplasty Alone for Severe Ischemic Mitral Regurgitation.
Nappi Francesco,Lusini Mario,Spadaccio Cristiano,Nenna Antonio,Covino Elvio,Acar Christophe,Chello Massimo
Journal of the American College of Cardiology
BACKGROUND:Guidelines recommend surgery for patients with severe ischemic mitral regurgitation (MR). Nonrandomized studies suggest that subvalvular repair is associated with longer survival, but randomized studies are lacking. OBJECTIVES:This study sought to investigate the benefit of papillary muscle surgery on long-term clinical outcomes of patients with ischemic MR. METHODS:Ninety-six patients with severe ischemic MR were randomized to either undersizing restrictive mitral annuloplasty (RA) or papillary muscle approximation with undersizing restrictive mitral annuloplasty (PMA) associated with complete surgical myocardial revascularization. The primary endpoint was change in left ventricular end-diastolic diameter (LVEDD) after 5 years, measured as the absolute difference from baseline, which was evaluated by paired Student t tests. Secondary endpoints included changes in echocardiographic parameters, overall mortality, the composite cardiac endpoint (major adverse cardiac and cerebrovascular events [MACCE]), and quality of life (QOL) during the 5-year follow-up. RESULTS:At 5 years, mean LVEDD was 56.5 ± 5.7 mm with PMA versus 60.6 ± 4.6 mm with RA (mean change from baseline -5.8 ± 4.1 mm and -0.2 ± 2.3 mm, respectively; p < 0.001). Ejection fraction was 44.1 ± 6% in the PMA group versus 39.9 ± 3.9% in the RA group (mean change from baseline 8.8 ± 5.9% and 2.5 ± 4.3%, respectively; p < 0.001). There was no statistically significant difference in mortality at 5 years, but freedom from MACCE favored PMA in the last year of follow-up. PMA significantly reduced tenting height, tenting area, and interpapillary distance soon after surgery and for the long-term, and significantly lowered moderate-to-severe MR recurrence. No differences were found in QOL measures. CONCLUSIONS:Compared with RA only, PMA exerted a long-term beneficial effect on left ventricular remodeling and more effectively restored the mitral valve geometric configuration in ischemic MR, which improved long-term cardiac outcomes, but did not produce differences in overall mortality and QOL.
10.1016/j.jacc.2016.03.478
Frequency, Predictors, and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients With Symptomatic Atherosclerosis.
Cavallari Ilaria,Morrow David A,Creager Mark A,Olin Jeffrey,Bhatt Deepak L,Steg P Gabriel,Storey Robert F,Cohen Marc,Scirica Benjamin S,Piazza Gregory,Goodrich Erica L,Braunwald Eugene,Sabatine Marc S,Bonaca Marc P
Circulation
BACKGROUND:Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. METHODS:TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials. RESULTS:Of 47 611 patients with stable vascular disease followed for 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier rate at 3 years, 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease, and malignancy. The burden of atherosclerosis manifested as an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (hazard ratio, 0.71; 95% confidence interval, 0.56-0.89; =0.003). CONCLUSIONS:The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01225562.
10.1161/CIRCULATIONAHA.117.031062
Increased risk of subsequent myocardial infarction in patients with type 2 diabetes: a retrospective cohort study using the U.K. General Practice Research Database.
Liang Huifang,Vallarino Carlos,Joseph Guiandre,Manne Sudhakar,Perez Alfonso,Zhang Shumin
Diabetes care
OBJECTIVE:To compare the risk of subsequent myocardial infarction (MI) between patients with and without type 2 diabetes mellitus (T2DM) in a retrospective cohort study. RESEARCH DESIGN AND METHODS:Patients with their first MI recorded in the U.K. General Practice Research Database in 1997-2008 were classified as T2DM, diagnosed before or within 28 days after the date of the first recorded MI (i.e., the index date), or non-T2DM. Patients diagnosed within 28 days after the index date were assumed to have developed T2DM at baseline (i.e., before the index date). The primary outcome was the first subsequent MI. The secondary outcomes were all-cause death and a composite of all-cause death or subsequent MI. Cox proportional hazards models were fit to obtain hazard ratios (HRs) for all outcomes. RESULTS:A total of 7,411 T2DM (median age 72 years; men 63.4%) and 48,726 non-T2DM patients (median age 69 years; men 65.3%) were included. The crude incidences (per 1,000 patient-years) in T2DM vs. non-T2DM were 32.8 vs. 22.8 for subsequent MI, 83.7 vs. 52.1 for all-cause death, and 106.5 vs. 69.9 for the composite end point. The adjusted HRs for subsequent MI, all-cause death, and their combination were 1.41 (95% CI 1.27-1.56), 1.50 (1.41-1.60), and 1.42 (1.34-1.50), respectively, in women and 1.23 (1.14-1.34), 1.40 (1.33-1.47), and 1.33 (1.27-1.39) in men. CONCLUSIONS:Compared with non-T2DM, T2DM was associated with an increased risk for subsequent MI, all-cause death, and their composite end point. The risk tends to be higher in women than in men.
10.2337/dc13-1953
Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).
Bohula Erin A,Wiviott Stephen D,Giugliano Robert P,Blazing Michael A,Park Jeong-Gun,Murphy Sabina A,White Jennifer A,Mach Francois,Van de Werf Frans,Dalby Anthony J,White Harvey D,Tershakovec Andrew M,Cannon Christopher P,Braunwald Eugene
Circulation
BACKGROUND:Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. METHODS:Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. RESULTS:Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; =0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; =0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; =0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; =0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; =0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; =0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; =0.011) with ezetimibe added to simvastatin therapy. CONCLUSIONS:The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.
10.1161/CIRCULATIONAHA.117.029095
Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): an open-label, randomised controlled trial.
Kelbæk Henning,Høfsten Dan Eik,Køber Lars,Helqvist Steffen,Kløvgaard Lene,Holmvang Lene,Jørgensen Erik,Pedersen Frants,Saunamäki Kari,De Backer Ole,Bang Lia E,Kofoed Klaus F,Lønborg Jacob,Ahtarovski Kiril,Vejlstrup Niels,Bøtker Hans E,Terkelsen Christian J,Christiansen Evald H,Ravkilde Jan,Tilsted Hans-Henrik,Villadsen Anton B,Aarøe Jens,Jensen Svend E,Raungaard Bent,Jensen Lisette O,Clemmensen Peter,Grande Peer,Madsen Jan K,Torp-Pedersen Christian,Engstrøm Thomas
Lancet (London, England)
BACKGROUND:Despite successful treatment of the culprit artery lesion by primary percutaneous coronary intervention (PCI) with stent implantation, thrombotic embolisation occurs in some cases, which impairs the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). We aimed to assess the clinical outcomes of deferred stent implantation versus standard PCI in patients with STEMI. METHODS:We did this open-label, randomised controlled trial at four primary PCI centres in Denmark. Eligible patients (aged >18 years) had acute onset symptoms lasting 12 h or less, and ST-segment elevation of 0·1 mV or more in at least two or more contiguous electrocardiographic leads or newly developed left bundle branch block. Patients were randomly assigned (1:1), via an electronic web-based system with permuted block sizes of two to six, to receive either standard primary PCI with immediate stent implantation or deferred stent implantation 48 h after the index procedure if a stabilised flow could be obtained in the infarct-related artery. The primary endpoint was a composite of all-cause mortality, hospital admission for heart failure, recurrent infarction, and any unplanned revascularisation of the target vessel within 2 years' follow-up. Patients, investigators, and treating clinicians were not masked to treatment allocation. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01435408. FINDINGS:Between March 1, 2011, and Feb 28, 2014, we randomly assigned 1215 patients to receive either standard PCI (n=612) or deferred stent implantation (n=603). Median follow-up time was 42 months (IQR 33-49). Events comprising the primary endpoint occurred in 109 (18%) patients who had standard PCI and in 105 (17%) patients who had deferred stent implantation (hazard ratio 0·99, 95% CI 0·76-1·29; p=0·92). Procedure-related myocardial infarction, bleeding requiring transfusion or surgery, contrast-induced nephopathy, or stroke occurred in 28 (5%) patients in the conventional PCI group versus 27 (4%) patients in the deferred stent implantation group, with no significant differences between groups. INTERPRETATION:In patients with STEMI, routine deferred stent implantation did not reduce the occurrence of death, heart failure, myocardial infarction, or repeat revascularisation compared with conventional PCI. Results from ongoing randomised trials might shed further light on the concept of deferred stenting in this patient population. FUNDING:Danish Agency for Science, Technology and Innovation, and Danish Council for Strategic Research.
10.1016/S0140-6736(16)30072-1
Serial Measurement of High-Sensitivity Troponin I and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus in the EXAMINE Trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care).
Cavender Matthew A,White William B,Jarolim Petr,Bakris George L,Cushman William C,Kupfer Stuart,Gao Qi,Mehta Cyrus R,Zannad Faiez,Cannon Christopher P,Morrow David A
Circulation
BACKGROUND:We aimed to describe the relationship between changes in high-sensitivity cardiac troponin I (hsTnI) and cardiovascular outcomes. METHODS:The EXAMINE trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) was a phase IIIb clinical outcomes trial designed to evaluate the cardiovascular safety of alogliptin, a nonselective dipeptidyl peptidase 4 inhibitor. Patients with type 2 diabetes mellitus, glycohemoglobin between 6.5% and 11% (or between 7% and 11% if they were on insulin), and a recent acute coronary syndrome (between 15 and 90 days before randomization) were eligible for the trial. hsTnI was measured using the Abbott ARCHITECT assay at baseline and 6 months in patients randomized in the EXAMINE trial. This analysis was restricted to patients randomized ≥30 days after qualifying acute coronary syndrome to mitigate the potential for persistent hsTnI elevation after acute coronary syndrome (n=3808). The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. Cardiovascular death or heart failure was a prespecified, adjudicated secondary end point. RESULTS:At baseline, hsTnI was detectable (≥1.9 ng/L) in 93% of patients and >99 percentile upper reference limit in 16%. There was a strong relationship between increasing hsTnI, both at baseline and 6 months, and the incidence of cardiovascular events through 24 months (<0.001 for each). Patients with undetectable hsTnI at baseline and 6 months were at the lowest risk of future cardiovascular events. Stable patients with hsTnI ≥99th percentile upper reference limit at 6 months were at increased risk of cardiovascular death, myocardial infarction, or stroke compared with patients with hsTnI <99 percentile upper reference limit irrespective of whether hsTnI was newly elevated (28.1% versus 8.8%; adjusted hazard ratio, 2.65; 95% confidence interval, 1.64-4.28; <0.001) or persistently so (22.5% versus 8.8%; adjusted hazard ratio, 1.90; 95% confidence interval, 1.33-2.70; <0.001). Alogliptin neither increased nor decreased the risk of cardiovascular events compared with placebo in patients with high baseline hsTnI (22.3% versus 23.0%; hazard ratio, 0.87; 95% confidence interval, 0.60-1.25; =0.44). CONCLUSIONS:Serial assessment of hsTnI revealed a substantial proportion of patients with type 2 diabetes mellitus without clinically recognized events had dynamic or persistently elevated values and were at high risk of recurrent events. hsTnI may have a role in personalizing preventive strategies in patients with diabetes mellitus based on risk. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00968708.
10.1161/CIRCULATIONAHA.116.024632
Thrombus Aspiration in Patients With High Thrombus Burden in the TOTAL Trial.
Jolly Sanjit S,Cairns John A,Lavi Shahar,Cantor Warren J,Bernat Ivo,Cheema Asim N,Moreno Raul,Kedev Sasko,Stankovic Goran,Rao Sunil V,Meeks Brandi,Chowdhary Saqib,Gao Peggy,Sibbald Matthew,Velianou James L,Mehta Shamir R,Tsang Michael,Sheth Tej,Džavík Vladimír,
Journal of the American College of Cardiology
BACKGROUND:Routine thrombus aspiration in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) does not improve clinical outcomes. However, there is remaining uncertainty about the potential benefit in those patients with high thrombus burden, where there is a biological rationale for greater benefit. OBJECTIVES:The purpose of this study was to evaluate the benefit of thrombus aspiration among STEMI patients with high thrombus burden. METHODS:TOTAL (ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI) was a randomized trial of routine manual thrombectomy versus PCI alone in patients with STEMI (n = 10,732). High thrombus burden (Thrombolysis In Myocardial Infarction thrombus grade ≥3) was a pre-specified subgroup. RESULTS:The primary outcome of cardiovascular (CV) death, MI, cardiogenic shock, or heart failure was not different at 1 year with thrombus aspiration in patients with high thrombus burden (8.1% vs. 8.3% thrombus aspiration; hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.84 to 1.13) or low thrombus burden (6.0% vs. 5.0% thrombus aspiration; HR: 1.22; 95% CI: 0.73 to 2.05; interaction p = 0.41). However, among patients with high thrombus burden, stroke at 30 days was more frequent with thrombus aspiration (31 [0.7%] thrombus aspiration vs. 16 [0.4%] PCI alone, HR: 1.90; 95% CI: 1.04 to 3.48). In the high thrombus burden group, thrombus aspiration did not significantly improve CV mortality at 30 days (HR: 0.78; 95% CI: 0.61 to 1.01; p = 0.06) and at 1 year (HR: 0.88; 95% CI: 0.72 to 1.09; p = 0.25). Irrespective of treatment assignment, high thrombus burden was an independent predictor of death (HR: 1.78; 95% CI: 1.05 to 3.01). CONCLUSIONS:In patients with high thrombus burden, routine thrombus aspiration did not improve outcomes at 1 year and was associated with an increased rate of stroke. High thrombus burden is still an important predictor of outcome in STEMI. (A Trial of routine aspiration ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI [TOTAL]; NCT01149044).
10.1016/j.jacc.2018.07.047
Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial.
Damask Amy,Steg P Gabriel,Schwartz Gregory G,Szarek Michael,Hagström Emil,Badimon Lina,Chapman M John,Boileau Catherine,Tsimikas Sotirios,Ginsberg Henry N,Banerjee Poulabi,Manvelian Garen,Pordy Robert,Hess Sibylle,Overton John D,Lotta Luca A,Yancopoulos George D,Abecasis Goncalo R,Baras Aris,Paulding Charles,
Circulation
BACKGROUND:Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment. METHODS:ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients. RESULTS:The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile; <0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared with placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and a relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio, 0.63 [95% CI, 0.46-0.86]; =0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78-0.98]; =0.022; interaction =0.04). CONCLUSIONS:A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
10.1161/CIRCULATIONAHA.119.044434
Noninvasive Cardiac Testing vs Clinical Evaluation Alone in Acute Chest Pain: A Secondary Analysis of the ROMICAT-II Randomized Clinical Trial.
Reinhardt Samuel W,Lin Chien-Jung,Novak Eric,Brown David L
JAMA internal medicine
Importance:The incremental benefit of noninvasive testing in addition to clinical evaluation (history, physical examination, an electrocardiogram [ECG], and biomarker assessment) vs clinical evaluation alone for patients who present to the emergency department (ED) with acute chest pain is unknown. Objective:To examine differences in outcomes with clinical evaluation and noninvasive testing (coronary computed tomographic angiography [CCTA] or stress testing) vs clinical evaluation alone. Design, Setting, and Participants:This study was a retrospective analysis of data from the randomized multicenter Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT-II) trial. Data for 1000 patients who presented with chest pain to the EDs at 9 hospitals in the United States were evaluated. Interventions:Clinical evaluation plus noninvasive testing (CCTA or stress test) vs clinical evaluation alone. Main Outcomes and Measures:Primary outcome was length of stay (LOS). Secondary outcomes included hospital admission, direct ED discharge, downstream testing, rates of invasive coronary angiography, revascularization, major adverse cardiac events (MACE), repeated ED visit or hospitalization for recurrent chest pain at 28 days, and cost. Safety end points were missed acute coronary syndrome (ACS) and cumulative radiation exposure during the index visit and follow-up period. Results:Of the 1000 patients randomized, 118 patients (12%) (mean [SD] age, 53.2 [7.8]; 49 [42%] were female) did not undergo noninvasive testing, whereas 882 (88%) (mean [SD] age, 54.4 [8.14] years; 419 [48%] were female) received CCTA or stress testing. There was no difference in baseline characteristics or clinical presentation between groups. Patients who underwent clinical evaluation alone experienced a shorter LOS (20.3 vs 27.9 hours; P < .001), lower rates of diagnostic testing (P < .001) and angiography (2% vs 11%; P < .001), lower median costs ($2261.50 vs $2584.30; P = .009), and less cumulative radiation exposure (0 vs 9.9 mSv; P < .001) during the 28-day study period. Lack of testing was associated with a lower rate of diagnosis of ACS (0% vs 9%; P < .001) and less coronary angiography and percutaneous coronary intervention (PCI) during the index visit (0% vs 10%; P < .001, and 0% vs 4%; P = .02, respectively). There was no difference in rates of PCI (2% vs 5%; P = .15), coronary artery bypass surgery (0% vs 1%; P = .61), return ED visits (5.8% vs 2.8%; P = .08), or MACE (2% vs 1%; P = .24) in the 28-day follow-up period. Conclusions and Relevance:In patients presenting to the ED with acute chest pain, negative biomarkers, and a nonischemic ECG result, noninvasive testing with CCTA or stress testing leads to longer LOS, more downstream testing, more radiation exposure, and greater cost without an improvement in clinical outcomes. Trial Registration:clinicaltrials.gov Identifier: NCT01084239.
10.1001/jamainternmed.2017.7360
Prognostic Value of Plasma Soluble Corin in Patients With Acute Myocardial Infarction.
Zhou Xiang,Chen Jianchang,Zhang Qing,Shao Jing,Du Kang,Xu Xiaohua,Kong Yuan
Journal of the American College of Cardiology
BACKGROUND:Recent studies in animal models and humans have shown that corin is critically involved in the regulation of salt-water balance, blood pressure, and cardiac function. OBJECTIVES:The goal of this study was to investigate the prognostic value of plasma soluble corin in patients with acute myocardial infarction (AMI). METHODS:We enrolled 1,382 consecutive AMI patients in a prospective cohort study and explored the association of plasma corin with AMI outcomes using multivariable Cox proportional hazards analysis. RESULTS:Patients with low corin levels were more likely to be female and to have histories of hypertension and heart failure (HF). Kaplan-Meier survival curves indicated that patients with corin levels above the median had a lower incidence of major adverse cardiac events (MACE) and all-cause mortality compared with those whose corin levels were below the median. Multivariate Cox regression analysis suggested that log corin was an independent predictor of MACE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.42 to 0.96; p = 0.029), together with age, previous histories of AMI, HF, and diabetes, Killip class, percutaneous coronary intervention, coronary artery bypass graft, beta-blocker use, and log N-terminal pro-B-type natriuretic peptide. The C-statistic and integrated discrimination improvement for MACE were improved significantly by the addition of corin to the reference model. Moreover, log corin was also found to be a significant predictor of death (HR: 0.65; 95% CI: 0.41 to 0.97; p = 0.036) and HF hospitalization (HR: 0.48; 95% CI: 0.23 to 0.90; p = 0.009) after adjustment for clinical variables and established biomarkers of adverse prognosis. CONCLUSIONS:Our study demonstrates that corin is a valuable prognostic marker of MACE in patients with AMI, independent of established conventional risk factors.
10.1016/j.jacc.2016.02.035
Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study.
Li Linxin,Geraghty Olivia C,Mehta Ziyah,Rothwell Peter M,
Lancet (London, England)
BACKGROUND:Lifelong antiplatelet treatment is recommended after ischaemic vascular events, on the basis of trials done mainly in patients younger than 75 years. Upper gastrointestinal bleeding is a serious complication, but had low case fatality in trials of aspirin and is not generally thought to cause long-term disability. Consequently, although co-prescription of proton-pump inhibitors (PPIs) reduces upper gastrointestinal bleeds by 70-90%, uptake is low and guidelines are conflicting. We aimed to assess the risk, time course, and outcomes of bleeding on antiplatelet treatment for secondary prevention in patients of all ages. METHODS:We did a prospective population-based cohort study in patients with a first transient ischaemic attack, ischaemic stroke, or myocardial infarction treated with antiplatelet drugs (mainly aspirin based, without routine PPI use) after the event in the Oxford Vascular Study from 2002 to 2012, with follow-up until 2013. We determined type, severity, outcome (disability or death), and time course of bleeding requiring medical attention by face-to-face follow-up for 10 years. We estimated age-specific numbers needed to treat (NNT) to prevent upper gastrointestinal bleeding with routine PPI co-prescription on the basis of Kaplan-Meier risk estimates and relative risk reduction estimates from previous trials. FINDINGS:3166 patients (1582 [50%] aged ≥75 years) had 405 first bleeding events (n=218 gastrointestinal, n=45 intracranial, and n=142 other) during 13 509 patient-years of follow-up. Of the 314 patients (78%) with bleeds admitted to hospital, 117 (37%) were missed by administrative coding. Risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age (≥75 years hazard ratio [HR] 3·10, 95% CI 2·27-4·24; p<0·0001), particularly for fatal bleeds (5·53, 2·65-11·54; p<0·0001), and was sustained during long-term follow-up. The same was true of major upper gastrointestinal bleeds (≥75 years HR 4·13, 2·60-6·57; p<0·0001), particularly if disabling or fatal (10·26, 4·37-24·13; p<0·0001). At age 75 years or older, major upper gastrointestinal bleeds were mostly disabling or fatal (45 [62%] of 73 patients vs 101 [47%] of 213 patients with recurrent ischaemic stroke), and outnumbered disabling or fatal intracerebral haemorrhage (n=45 vs n=18), with an absolute risk of 9·15 (95% CI 6·67-12·24) per 1000 patient-years. The estimated NNT for routine PPI use to prevent one disabling or fatal upper gastrointestinal bleed over 5 years fell from 338 for individuals younger than 65 years, to 25 for individuals aged 85 years or older. INTERPRETATION:In patients receiving aspirin-based antiplatelet treatment without routine PPI use, the long-term risk of major bleeding is higher and more sustained in older patients in practice than in the younger patients in previous trials, with a substantial risk of disabling or fatal upper gastrointestinal bleeding. Given that half of the major bleeds in patients aged 75 years or older were upper gastrointestinal, the estimated NNT for routine PPI use to prevent such bleeds is low, and co-prescription should be encouraged. FUNDING:Wellcome Trust, Wolfson Foundation, British Heart Foundation, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Oxford Biomedical Research Centre.
10.1016/S0140-6736(17)30770-5
Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome).
Whellan David J,Tricoci Pierluigi,Chen Edmond,Huang Zhen,Leibowitz David,Vranckx Pascal,Marhefka Gregary D,Held Claes,Nicolau Jose C,Storey Robert F,Ruzyllo Witold,Huber Kurt,Sinnaeve Peter,Weiss A Teddy,Dery Jean-Pierre,Moliterno David J,Van de Werf Frans,Aylward Philip E,White Harvey D,Armstrong Paul W,Wallentin Lars,Strony John,Harrington Robert A,Mahaffey Kenneth W
Journal of the American College of Cardiology
OBJECTIVES:This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). BACKGROUND:Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. METHODS:Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. RESULTS:Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). CONCLUSIONS:In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).
10.1016/j.jacc.2013.10.048
Reduction in Ischemic Events With Ticagrelor in Diabetic Patients With Prior Myocardial Infarction in PEGASUS-TIMI 54.
Bhatt Deepak L,Bonaca Marc P,Bansilal Sameer,Angiolillo Dominick J,Cohen Marc,Storey Robert F,Im Kyungah,Murphy Sabina A,Held Peter,Braunwald Eugene,Sabatine Marc S,Steg Ph Gabriel
Journal of the American College of Cardiology
BACKGROUND:Patients with diabetes appear to be at elevated risk of atherothrombotic events. OBJECTIVES:The purpose of this study was to determine the effect of antiplatelet therapy with ticagrelor on recurrent ischemic events in patients with diabetes and prior myocardial infarction (MI). METHODS:We examined the subgroups of patients with diabetes (n = 6,806) and without diabetes (n = 14,355) from PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54), in which 21,162 patients with a history of MI 1 to 3 years prior and with additional risk factors were randomized to ticagrelor (90 or 60 mg twice daily) or placebo. Patients were followed for a median of 33 months. The primary efficacy endpoint was major adverse cardiovascular events (MACE) (cardiovascular death, MI, stroke) and the primary safety endpoint was TIMI (Thrombolysis In Myocardial Infarction) major bleeding. RESULTS:The relative risk reduction in MACE with ticagrelor was consistent for the pooled doses versus placebo in patients with diabetes (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.72 to 0.99; p = 0.035) and without diabetes (HR: 0.84; 95% CI: 0.74 to 0.96; p = 0.013; p interaction = 0.99). As patients with diabetes were at higher risk of MACE, the absolute risk reduction tended to be greater in patients with versus without diabetes (1.5% vs. 1.1%, with corresponding 3-year number needed to treat of 67 vs. 91). In patients with diabetes requiring pharmacological therapy (n = 5,960), the absolute risk reduction was 1.9% with a 3-year number needed to treat of 53. Additionally, in patients with diabetes, ticagrelor reduced cardiovascular death by 22% and coronary heart disease death by 34%. Similar to patients without diabetes, there was increased TIMI major bleeding in patients with diabetes (HR: 2.56; 95% CI: 1.52 to 4.33; p = 0.0004). CONCLUSIONS:In patients with diabetes with prior MI, adding ticagrelor to aspirin significantly reduces the risk of recurrent ischemic events, including cardiovascular and coronary heart disease death. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562).
10.1016/j.jacc.2016.03.529
Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins.
Schwartz Gregory G,Abt Markus,Bao Weihang,DeMicco David,Kallend David,Miller Michael,Mundl Hardi,Olsson Anders G
Journal of the American College of Cardiology
BACKGROUND:Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. OBJECTIVES:This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. METHODS:Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. RESULTS:Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dal-OUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p<0.001). The hazard ratio in the highest/lowest quintile (>175/≤80 mg/dl) was 1.61 (95% confidence interval: 1.34 to 1.94). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p=0.03), with a hazard ratio of 1.50 [corrected] (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/≤135 mg/dl). The relationship of triglycerides to risk was independent of low-density lipoprotein cholesterol in both studies. CONCLUSIONS:Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515).
10.1016/j.jacc.2015.03.544
Association of Fibroblast Growth Factor 23 With Recurrent Cardiovascular Events in Patients After an Acute Coronary Syndrome: A Secondary Analysis of a Randomized Clinical Trial.
Bergmark Brian A,Udell Jacob A,Morrow David A,Cannon Christopher P,Steen Dylan L,Jarolim Petr,Budaj Andrzej,Hamm Christian,Guo Jianping,Im KyungAh,Kuder Julia F,Braunwald Eugene,Sabatine Marc S,O'Donoghue Michelle L
JAMA cardiology
Importance:Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with myocardial fibrosis and renin-angiotensin system upregulation, potentially providing prognostic information distinct from standard cardiovascular (CV) biomarkers. Objective:To evaluate the association of FGF-23 with recurrent CV events in patients after an acute coronary syndrome (ACS). Design, Setting, and Participants:C-terminal FGF-23 was measured in plasma samples using an established enzyme-linked immunosorbent assay system for 4947 patients within 30 days of ACS (median, 14 days) and with 1 additional CV risk factor in the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial of the lipoprotein-associated phospholipase A2 inhibitor darapladib vs placebo performed from December 1, 2009, to April 24, 2014 (median follow-up, 2.5 years). Analyses were adjusted for clinical risk factors, renal function, and established cardiorenal biomarkers. This secondary analysis was performed from September 25, 2014, to October 1, 2017. Exposure:The FGF-23 concentration at baseline. Main Outcomes and Measures:The primary end point for this post hoc analysis was the composite of CV death or hospitalization for heart failure. Results:In this study, baseline FGF-23 concentrations were available for 4947 patients (median age, 64.0 years; interquartile range, 59.0-71.0 years; 1276 [25.8%] female). Patients with higher FGF-23 concentrations were older and more likely female, with a greater proportion of hypertension, diabetes, and previous myocardial infarction. After multivariable adjustment for baseline clinical characteristics and established biomarkers (high-sensitivity troponin I, brain-type natriuretic peptide, and high-sensitivity C-reactive protein), FGF-23 concentration in the top quartile was independently associated with an increased risk of CV death or heart failure hospitalization (adjusted hazard ratio [HR], 2.35; 95% CI, 1.82-3.02; P < .001) and its individual components. Elevated FGF-23 concentration was also associated with an increased risk of all-cause mortality (adjusted HR, 2.27; 95% CI, 1.73-2.97; P < .001) and CV death, myocardial infarction, or stroke (adjusted HR, 1.42; 95% CI, 1.17-1.71; P < .001). When analyses were stratified by patient sex, the association between FGF-23 and CV risk, including CV death or heart failure, appeared to be attenuated in women (adjusted HR, 1.11; 95% CI, 0.70-1.76; P = .67) compared with men (HR, 3.11; 95% CI, 2.29-4.22; P < .001; P < .001 for interaction). Conclusions and Relevance:In patients stabilized after ACS, elevated FGF-23 concentrations may be associated with recurrent major CV events and all-cause mortality, providing information independent of established clinical risk factors and cardiorenal biomarkers. A potential sex difference in these findings deserves further study.
10.1001/jamacardio.2018.0653
Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study.
Lamberts Morten,Gislason Gunnar H,Lip Gregory Y H,Lassen Jens Flensted,Olesen Jonas Bjerring,Mikkelsen Anders P,Sørensen Rikke,Køber Lars,Torp-Pedersen Christian,Hansen Morten Lock
Circulation
BACKGROUND:The optimal long-term antithrombotic treatment of patients with coexisting atrial fibrillation and stable coronary artery disease is unresolved, and commonly, a single antiplatelet agent is added to oral anticoagulation. We investigated the effectiveness and safety of adding antiplatelet therapy to vitamin K antagonist (VKA) in atrial fibrillation patents with stable coronary artery disease. METHODS AND RESULTS:Atrial fibrillation patients with stable coronary artery disease (defined as 12 months from an acute coronary event) between 2002 and 2011 were identified. The subsequent risk of cardiovascular events and serious bleeding events (those that required hospitalization) was examined with adjusted Cox regression models according to ongoing antithrombotic therapy. A total of 8700 patients were included (mean age, 74.2 years; 38% women). During a mean follow-up of 3.3 years, crude incidence rates were 7.2, 3.8, and 4.0 events per 100 person-years for myocardial infarction/coronary death, thromboembolism, and serious bleeding, respectively. Relative to VKA monotherapy, the risk of myocardial infarction/coronary death was similar for VKA plus aspirin (hazard ratio, 1.12 [95% confidence interval, 0.94-1.34]) and VKA plus clopidogrel (hazard ratio, 1.53 [95% confidence interval, 0.93-2.52]). The risk of thromboembolism was comparable in all regimens that included VKA, whereas the risk of bleeding increased when aspirin (hazard ratio, 1.50 [95% confidence interval, 1.23-1.82]) or clopidogrel (hazard ratio, 1.84 [95% confidence interval, 1.11-3.06]) was added to VKA. CONCLUSIONS:In atrial fibrillation patients with stable coronary artery disease, the addition of antiplatelet therapy to VKA therapy is not associated with a reduction in risk of recurrent coronary events or thromboembolism, whereas risk of bleeding is increased significantly. The common practice of adding antiplatelet therapy to oral VKA anticoagulation in patients with atrial fibrillation and stable coronary artery disease warrants reassessment.
10.1161/CIRCULATIONAHA.113.004834
Vorapaxar in patients with diabetes mellitus and previous myocardial infarction: findings from the thrombin receptor antagonist in secondary prevention of atherothrombotic ischemic events-TIMI 50 trial.
Cavender Matthew A,Scirica Benjamin M,Bonaca Marc P,Angiolillo Dominick J,Dalby Anthony J,Dellborg Mikael,Morais Joao,Murphy Sabina A,Ophuis Ton Oude,Tendera Michal,Braunwald Eugene,Morrow David A
Circulation
BACKGROUND:Vorapaxar reduces cardiovascular death, myocardial infarction (MI), or stroke in patients with previous MI while increasing bleeding. Patients with diabetes mellitus (DM) are at high risk of recurrent thrombotic events despite standard therapy and may derive particular benefit from antithrombotic therapies. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 trial was a randomized, double-blind, placebo-controlled trial of vorapaxar in patients with stable atherosclerosis. METHODS AND RESULTS:We examined the efficacy of vorapaxar in patients with and without DM who qualified for the trial with a previous MI. Because vorapaxar is contraindicated in patients with a history of stroke or transient ischemic attack, the analysis (n=16 896) excluded such patients. The primary end point of cardiovascular death, MI, or stroke occurred more frequently in patients with DM than in patients without DM (rates in placebo group: 14.3% versus 7.6%; adjusted hazard ratio, 1.47; P<0.001). In patients with DM (n=3623), vorapaxar significantly reduced the primary end point (11.4% versus 14.3%; hazard ratio, 0.73 [95% confidence interval, 0.60-0.89]; P=0.002) with a number needed to treat to avoid 1 major cardiovascular event of 29. The incidence of moderate/severe bleeding was increased with vorapaxar in patients with DM (4.4% versus 2.6%; hazard ratio, 1.60 [95% confidence interval, 1.07-2.40]). However, net clinical outcome integrating these 2 end points (efficacy and safety) was improved with vorapaxar (hazard ratio, 0.79 [95% confidence interval, 0.67-0.93]). CONCLUSIONS:In patients with previous MI and DM, the addition of vorapaxar to standard therapy significantly reduced the risk of major vascular events with greater potential for absolute benefit in this group at high risk of recurrent ischemic events. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.
10.1161/CIRCULATIONAHA.114.013774
Stenting versus medical treatment in patients with symptomatic vertebral artery stenosis: a randomised open-label phase 2 trial.
Compter Annette,van der Worp H Bart,Schonewille Wouter J,Vos Jan Albert,Boiten Jelis,Nederkoorn Paul J,Uyttenboogaart Maarten,Lo Rob T,Algra Ale,Kappelle L Jaap,
The Lancet. Neurology
BACKGROUND:Patients with a recent vertebrobasilar transient ischaemic attack or ischaemic stroke and vertebral artery stenosis of at least 50% have a high risk of future vertebrobasilar stroke. Stenting of vertebral artery stenosis is promising, but of uncertain benefit. We investigated the safety and feasibility of stenting of symptomatic vertebral artery stenosis of at least 50%, and assessed the rate of vascular events in the vertebrobasilar supply territory to inform the design of a phase 3 trial. METHODS:Between Jan 22, 2008, and April 8, 2013, patients with a recent transient ischaemic attack or minor stroke associated with an intracranial or extracranial vertebral artery stenosis of at least 50% were enrolled from seven hospitals in the Netherlands in a phase 2 open-label trial with masked assessment of outcome. Patients were randomly allocated in a 1:1 ratio to stenting plus best medical treatment or best medical treatment alone by the local investigators using a web-based randomisation system. The primary outcome was the composite of vascular death, myocardial infarction, or any stroke within 30 days after the start of treatment. The secondary outcomes were stroke in the supply territory of the symptomatic vertebral artery during follow-up, the composite outcome during follow-up, and the degree of stenosis in the symptomatic vertebral artery at 12 months. The trial is registered, number ISRCTN29597900. FINDINGS:The trial was stopped after inclusion of 115 patients because of new regulatory requirements, including the use of a few prespecified stent types and external monitoring, for which no funding was available. 57 patients were assigned to stenting and 58 to medical treatment alone. Three patients in the stenting group had vascular death, myocardial infarction, or any stroke within 30 days after the start of treatment (5%, 95% CI 0-11) versus one patient in the medical treatment group (2%, 0-5). During a median follow-up of 3 years (IQR 1·3-4·1), seven (12%, 95% CI 6-24) patients in the stenting group and four (7%, 2-17) in the medical treatment group had a stroke in the territory of the symptomatic vertebral artery; 11 (19%) patients in the stenting group and ten (17%) in the medical treatment group had vascular death, myocardial infarction, or any stroke. The small size of the vertebral artery and stent artifacts did not allow exact grading of restenosis on CT angiography. During the complete period of follow-up, there were 60 serious adverse events (eight strokes) in the stenting group and 56 (seven strokes) in the medical treatment alone group. INTERPRETATION:Stenting of symptomatic vertebral artery stenosis is associated with a major periprocedural vascular complication in about one in 20 patients. In the population we studied, the risk of recurrent vertebrobasilar stroke under best medical treatment alone was low, questioning the need for and feasibility of a phase 3 trial. FUNDING:Dutch Heart Foundation.
10.1016/S1474-4422(15)00017-4
Incidence, Management, and Immediate- and Long-Term Outcomes After Iatrogenic Aortic Dissection During Diagnostic or Interventional Coronary Procedures.
Núñez-Gil Iván J,Bautista Daniel,Cerrato Enrico,Salinas Pablo,Varbella Ferdinando,Omedè Pierluigi,Ugo Fabrizio,Ielasi Alfonso,Giammaria Massimo,Moreno Raúl,Pérez-Vizcayno María José,Escaned Javier,De Agustin José Alberto,Feltes Gisela,Macaya Carlos,Fernández-Ortiz Antonio,
Circulation
BACKGROUND:Aortic dissection type A is a disease with high mortality. Iatrogenic aortic dissection after interventional procedures is infrequent, and prognostic data are scarce. Our objective was to analyze its incidence, patient profile, and long-term prognosis. METHODS AND RESULTS:Between 2000 and 2014, we retrospectively analyzed 74 patients with dissection of the ascending aorta. Clinical and procedural data were reviewed, and later, we performed a prospective clinical follow-up by telephone or in the office. The incidence of aortic dissection was 0.06%. Our patients, predominantly male (67.6%), had a mean age of 66.9±10.8 years. With multiple cardiovascular risk factors, the main reason for cardiac catheterization was an acute coronary syndrome (n=54). The complication was detected acutely in all, trying to engage the right coronary artery in 47 and the left main artery in 30 and after other maneuvers in 2, mostly complex therapeutic procedures (78.4%). A coronary artery was involved in 45 patients (60.8%). Thirty-five patients underwent an angioplasty and stent implantation; 3 had cardiac surgery; and 36 were managed conservatively. Two patients died of cardiogenic shock after the dissection. After a median follow-up of 51.2 months (range, 16.4-104.8 months), none of the remaining patients developed complications as a result of the dissection, progression, ischemia, pain, or dissection recurrence. CONCLUSIONS:Iatrogenic catheter dissection of the aorta is a rare complication that carries an excellent short- and long-term prognosis with the adoption of a conservative approach. When a coronary artery is involved as an entry point, it usually can be safely sealed with a stent with good long-term outcomes.
10.1161/CIRCULATIONAHA.115.015334
Early invasive versus non-invasive treatment in patients with non-ST-elevation acute coronary syndrome (FRISC-II): 15 year follow-up of a prospective, randomised, multicentre study.
Wallentin Lars,Lindhagen Lars,Ärnström Elisabet,Husted Steen,Janzon Magnus,Johnsen Søren Paaske,Kontny Frederic,Kempf Tibor,Levin Lars-Åke,Lindahl Bertil,Stridsberg Mats,Ståhle Elisabeth,Venge Per,Wollert Kai C,Swahn Eva,Lagerqvist Bo,
Lancet (London, England)
BACKGROUND:The FRISC-II trial was the first randomised trial to show a reduction in death or myocardial infarction with an early invasive versus a non-invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome. Here we provide a remaining lifetime perspective on the effects on all cardiovascular events during 15 years' follow-up. METHODS:The FRISC-II prospective, randomised, multicentre trial was done at 58 Scandinavian centres in Sweden, Denmark, and Norway. Between June 17, 1996, and Aug 28, 1998, we randomly assigned (1:1) 2457 patients with non-ST-elevation acute coronary syndrome to an early invasive treatment strategy, aiming for revascularisation within 7 days, or a non-invasive strategy, with invasive procedures at recurrent symptoms or severe exercise-induced ischaemia. Plasma for biomarker analyses was obtained at randomisation. For long-term outcomes, we linked data with national health-care registers. The primary endpoint was a composite of death or myocardial infarction. Outcomes were compared as the average postponement of the next event, including recurrent events, calculated as the area between mean cumulative count-of-events curves. Analyses were done by intention to treat. FINDINGS:At a minimum of 15 years' follow-up on Dec 31, 2014, data for survival status and death were available for 2421 (99%) of the initially recruited 2457 patients, and for other events after 2 years for 2182 (89%) patients. During follow-up, the invasive strategy postponed death or next myocardial infarction by a mean of 549 days (95% CI 204-888; p=0·0020) compared with the non-invasive strategy. This effect was larger in non-smokers (mean gain 809 days, 95% CI 402-1175; p=0·0182), patients with elevated troponin T (778 days, 357-1165; p=0·0241), and patients with high concentrations of growth differentiation factor-15 (1356 days, 507-1650; p=0·0210). The difference was mainly driven by postponement of new myocardial infarction, whereas the early difference in mortality alone was not sustained over time. The invasive strategy led to a mean of 1128 days (95% CI 830-1366) postponement of death or next readmission to hospital for ischaemic heart disease, which was consistent in all subgroups (p<0·0001). INTERPRETATION:During 15 years of follow-up, an early invasive treatment strategy postponed the occurrence of death or next myocardial infarction by an average of 18 months, and the next readmission to hospital for ischaemic heart disease by 37 months, compared with a non-invasive strategy in patients with non-ST-elevation acute coronary syndrome. This remaining lifetime perspective supports that an early invasive treatment strategy should be the preferred option in most patients with non-ST-elevation acute coronary syndrome. FUNDING:Swedish Heart-Lung Foundation, Swedish Foundation for Strategic Research, and Uppsala Clinical Research Center.
10.1016/S0140-6736(16)31276-4
Implanted Monitor Alerting to Reduce Treatment Delay in Patients With Acute Coronary Syndrome Events.
Holmes David R,Krucoff Mitchell W,Mullin Chris,Mikdadi Ghiath,Presser Dale,Wohns David,Kaplan Andrew,Ciuffo Allen,Eberly Arthur L,Iteld Bruce,Fischell David R,Fischell Tim,Keenan David,John M Sasha,Gibson C Michael
Journal of the American College of Cardiology
BACKGROUND:Increased pre-hospital delay during acute coronary syndrome (ACS) events contributes to worse outcome. OBJECTIVES:The purpose of this study was to assess the effectiveness of an implanted cardiac monitor with real-time alarms for abnormal ST-segment shifts to reduce pre-hospital delay during ACS events. METHODS:In the ALERTS (AngeLmed Early Recognition and Treatment of STEMI) pivotal study, subjects at high risk for recurrent ACS events (n = 907) were randomized to control (Alarms OFF) or treatment groups for 6 months, after which alarms were activated in all subjects (Alarms ON). Emergency department (ED) visits with standard-of-care cardiac test results were independently adjudicated as true- or false-positive ACS events. Alarm-to-door (A2D) and symptom-to-door (S2D) times were calculated for true-positive ACS ED visits triggered by 3 possible prompts: alarm only, alarms + symptoms, or symptoms only. RESULTS:The Alarms ON group showed reduced delays, with 55% (95% confidence interval [CI]: 46% to 63%) of ED visits for ACS events <2 h compared with 10% (95% CI: 2% to 27%) in the Alarms OFF group (p < 0.0001). Results were similar when restricted to myocardial infarction (MI) events. Median pre-hospital delay for MI was 12.7 h for Alarms OFF and 1.6 h in Alarms ON subjects (p < 0.0089). Median A2D delay was 1.4 h for asymptomatic MI. Median S2D delay for symptoms-only MI (no alarm) in Alarms ON was 4.3 h. CONCLUSIONS:Intracardiac monitoring with real-time alarms for ST-segment shift that exceeds a subject's self-normative ischemia threshold level significantly reduced the proportion of pre-hospital delays >2 h for ACS events, including asymptomatic MI, compared with symptoms-only ED visits in Alarms OFF. (AngeLmed for Early Recognition and Treatment of STEMI [ALERTS]; NCT00781118).
10.1016/j.jacc.2019.07.084
Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial.
Amarenco Pierre,Albers Gregory W,Denison Hans,Easton J Donald,Evans Scott R,Held Peter,Hill Michael D,Jonasson Jenny,Kasner Scott E,Ladenvall Per,Minematsu Kazuo,Molina Carlos A,Wang Yongjun,Wong K S Lawrence,Johnston S Claiborne,
The Lancet. Neurology
BACKGROUND:Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial. METHODS:SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov, number NCT01994720. FINDINGS:Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 [50%] to ticagrelor and 6610 [50%] to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 [95% CI 0·53-0·88]; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 [0·84-1·13]; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group. INTERPRETATION:In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention. FUNDING:AstraZeneca.
10.1016/S1474-4422(17)30038-8
Outcomes in Women and Minorities Compared With White Men 1 Year After Everolimus-Eluting Stent Implantation: Insights and Results From the PLATINUM Diversity and PROMUS Element Plus Post-Approval Study Pooled Analysis.
JAMA cardiology
Importance:There exist limited outcomes data for women and minorities after contemporary percutaneous coronary intervention (PCI). Objective:To examine 1-year outcomes in women and minorities vs white men after PCI with everolimus-eluting stents. Design, Settings, and Participants:The PLATINUM Diversity study was a single-arm study enrolling women and minorities. Patient-level pooling with the PROMUS Element Plus Post-Approval Study was prespecified. Data on social determinants of health and language were collected in the PLATINUM Diversity cohort, which included 1501 patients at 52 US sites. The PROMUS Element Plus Post-Approval study enrolled 2681 patients at 52 US sites with some site overlap and included an "all-comers" population. All patients were enrolled beginning in October 2014 and were followed for 12 months. Analyses began in August 2016. Interventions:Patients received 1 or more everolimus-eluting stent implantation. Main Outcomes and Measures:The primary end point was 1-year major adverse cardiac events (MACE), which included death/myocardial infarction (MI)/target vessel revascularization. Secondary ischemic end points were also evaluated. Results:The pooled study consisted of 4182 patients: 1635 white men (39.1%), 1863 women (white and minority) (44.5%), and 1059 minority patients (women and men) (25.3%). Women and minorities had a higher prevalence of diabetes, prior stroke, hypertension, renal disease, and congestive heart failure than white men but lower rates of multivessel disease, prior coronary artery bypass graft surgery, prior MI, and smoking. Unadjusted 1-year MACE rates (white men, 7.6%; women, 8.6%; minorities, 9.6%) were similar between groups with no significant differences after risk adjustment. The adjusted risk of death/MI was higher among women (odds ratio, 1.6; 95% CI, 1.1-2.4) and minorities (odds ratio, 1.9; 95% CI, 1.2-2.8) compared with white men and the adjusted risk of MI was higher in minorities (odds ratio, 2.6; 95% CI, 1.4-4.8). These differences were driven primarily by nonstent-related MIs. Within the PLATINUM Diversity cohort, the independent predictors of MACE were cardiogenic shock, renal disease, history of peripheral vascular disease, multivessel disease, widowhood, and lack of private insurance. Conclusions and Relevance:After contemporary everolimus-eluting stent implantation, women and minorities experience a similar risk of 1-year MACE but a higher adjusted risk of recurrent ischemic events primarily because of nonstent-related MIs. Both clinical and angiographic factors and social determinants of health, including widowhood and insurance status, contribute to 1-year MACE among women and minorities.
10.1001/jamacardio.2017.3802
A randomized trial of deferred stenting versus immediate stenting to prevent no- or slow-reflow in acute ST-segment elevation myocardial infarction (DEFER-STEMI).
Carrick David,Oldroyd Keith G,McEntegart Margaret,Haig Caroline,Petrie Mark C,Eteiba Hany,Hood Stuart,Owens Colum,Watkins Stuart,Layland Jamie,Lindsay Mitchell,Peat Eileen,Rae Alan,Behan Miles,Sood Arvind,Hillis W Stewart,Mordi Ify,Mahrous Ahmed,Ahmed Nadeem,Wilson Rebekah,Lasalle Laura,Généreux Philippe,Ford Ian,Berry Colin
Journal of the American College of Cardiology
OBJECTIVES:The aim of this study was to assess whether deferred stenting might reduce no-reflow and salvage myocardium in primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND:No-reflow is associated with adverse outcomes in STEMI. METHODS:This was a prospective, single-center, randomized, controlled, proof-of-concept trial in reperfused STEMI patients with ≥1 risk factors for no-reflow. Randomization was to deferred stenting with an intention-to-stent 4 to 16 h later or conventional treatment with immediate stenting. The primary outcome was the incidence of no-/slow-reflow (Thrombolysis In Myocardial Infarction ≤2). Cardiac magnetic resonance imaging was performed 2 days and 6 months after myocardial infarction. Myocardial salvage was the final infarct size indexed to the initial area at risk. RESULTS:Of 411 STEMI patients (March 11, 2012 to November 21, 2012), 101 patients (mean age, 60 years; 69% male) were randomized (52 to the deferred stenting group, 49 to the immediate stenting). The median (interquartile range [IQR]) time to the second procedure in the deferred stenting group was 9 h (IQR: 6 to 12 h). Fewer patients in the deferred stenting group had no-/slow-reflow (14 [29%] vs. 3 [6%]; p = 0.006), no reflow (7 [14%] vs. 1 [2%]; p = 0.052) and intraprocedural thrombotic events (16 [33%] vs. 5 [10%]; p = 0.010). Thrombolysis In Myocardial Infarction coronary flow grades at the end of PCI were higher in the deferred stenting group (p = 0.018). Recurrent STEMI occurred in 2 patients in the deferred stenting group before the second procedure. Myocardial salvage index at 6 months was greater in the deferred stenting group (68 [IQR: 54% to 82%] vs. 56 [IQR: 31% to 72%]; p = 0.031]. CONCLUSIONS:In high-risk STEMI patients, deferred stenting in primary PCI reduced no-reflow and increased myocardial salvage. (Deferred Stent Trial in STEMI; NCT01717573).
10.1016/j.jacc.2014.02.530
Relationship Between Infarct Size and Outcomes Following Primary PCI: Patient-Level Analysis From 10 Randomized Trials.
Stone Gregg W,Selker Harry P,Thiele Holger,Patel Manesh R,Udelson James E,Ohman E Magnus,Maehara Akiko,Eitel Ingo,Granger Christopher B,Jenkins Paul L,Nichols Melissa,Ben-Yehuda Ori
Journal of the American College of Cardiology
BACKGROUND:Prompt reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) reduces infarct size and improves survival. However, the intuitive link between infarct size and prognosis has not been convincingly demonstrated in the contemporary era. OBJECTIVES:This study sought to determine the strength of the relationship between infarct size assessed early after primary percutaneous coronary intervention (PCI) in STEMI and subsequent all-cause mortality, reinfarction, and hospitalization for heart failure. METHODS:We performed a pooled patient-level analysis from 10 randomized primary PCI trials (total 2,632 patients) in which infarct size was assessed within 1 month after randomization by either cardiac magnetic resonance (CMR) imaging or technetium-99m sestamibi single-photon emission computed tomography (SPECT), with clinical follow-up for ≥ 6 months. RESULTS:Infarct size was assessed by CMR in 1,889 patients (71.8%) and by SPECT in 743 patients (28.2%). Median (25th, 75th percentile) time to infarct size measurement was 4 days (3, 10 days) after STEMI. Median infarct size (% left ventricular myocardial mass) was 17.9% (8.0%, 29.8%), and median duration of clinical follow-up was 352 days (185, 371 days). The Kaplan-Meier estimated 1-year rates of all-cause mortality, reinfarction, and HF hospitalization were 2.2%, 2.5%, and 2.6%, respectively. A strong graded response was present between infarct size (per 5% increase) and subsequent mortality (Cox-adjusted hazard ratio: 1.19 [95% confidence interval: 1.18 to 1.20]; p < 0.0001) and hospitalization for heart failure (adjusted hazard ratio: 1.20 [95% confidence interval: 1.19 to 1.21]; p < 0.0001), independent of age, sex, diabetes, hypertension, hyperlipidemia, current smoking, left anterior descending versus non-left anterior descending infarct vessel, symptom-to-first device time, and baseline TIMI (Thrombolysis In Myocardial Infarction) flow 0/1 versus 2/3. Infarct size was not significantly related to subsequent reinfarction. CONCLUSIONS:Infarct size, measured by CMR or technetium-99m sestamibi SPECT within 1 month after primary PCI, is strongly associated with all-cause mortality and hospitalization for HF within 1 year. Infarct size may, therefore, be useful as an endpoint in clinical trials and as an important prognostic measure when caring for patients with STEMI.
10.1016/j.jacc.2016.01.069
Randomized trial of primary PCI with or without routine manual thrombectomy.
Jolly Sanjit S,Cairns John A,Yusuf Salim,Meeks Brandi,Pogue Janice,Rokoss Michael J,Kedev Sasko,Thabane Lehana,Stankovic Goran,Moreno Raul,Gershlick Anthony,Chowdhary Saqib,Lavi Shahar,Niemelä Kari,Steg Philippe Gabriel,Bernat Ivo,Xu Yawei,Cantor Warren J,Overgaard Christopher B,Naber Christoph K,Cheema Asim N,Welsh Robert C,Bertrand Olivier F,Avezum Alvaro,Bhindi Ravinay,Pancholy Samir,Rao Sunil V,Natarajan Madhu K,ten Berg Jurriën M,Shestakovska Olga,Gao Peggy,Widimsky Petr,Džavík Vladimír,
The New England journal of medicine
BACKGROUND:During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results. METHODS:We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days. RESULTS:The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P=0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P=0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P=0.02). CONCLUSIONS:In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research; TOTAL ClinicalTrials.gov number, NCT01149044.).
10.1056/NEJMoa1415098
Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: Analysis From FOURIER.
Sabatine Marc S,De Ferrari Gaetano M,Giugliano Robert P,Huber Kurt,Lewis Basil S,Ferreira Jorge,Kuder Julia F,Murphy Sabina A,Wiviott Stephen D,Kurtz Christopher E,Honarpour Narimon,Keech Anthony C,Sever Peter S,Pedersen Terje R
Circulation
BACKGROUND:The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab. METHODS:The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared. RESULTS:A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22-1.53), 1.78 (95% CI, 1.59-1.99), and 1.39 (95% CI, 1.24-1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71-0.91), 18% (HR, 0.82; 95% CI, 0.72-0.93), and 21% (HR, 0.79; 95% CI, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85-1.05), 8% (HR, 0.92; 95% CI, 0.84-1.02), and 7% (HR, 0.93; 95% CI, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%). CONCLUSIONS:Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
10.1161/CIRCULATIONAHA.118.034309
Atherothrombotic Risk Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart Disease and Previous Myocardial Infarction.
Bohula Erin A,Bonaca Marc P,Braunwald Eugene,Aylward Philip E,Corbalan Ramon,De Ferrari Gaetano M,He Ping,Lewis Basil S,Merlini Piera A,Murphy Sabina A,Sabatine Marc S,Scirica Benjamin M,Morrow David A
Circulation
BACKGROUND:Patients with stable ischemic heart disease and previous myocardial infarction (MI) vary in their risk for recurrent cardiovascular events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential to benefit from more intensive secondary preventive therapy such as treatment with vorapaxar. METHODS:We identified independent clinical indicators of atherothrombotic risk among 8598 stable, placebo-treated patients with a previous MI followed up for 2.5 years (median) in TRA 2°P-TIMI 50 [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50]. The efficacy and safety of vorapaxar (SCH 530348; MK-5348) were assessed by baseline risk among patients with previous MI without prior stroke or transient ischemic attack for whom there is a clinical indication for vorapaxar. End points were cardiovascular death, MI, or ischemic stroke and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding. RESULTS:The 9 independent risk predictors were age, diabetes mellitus, hypertension, smoking, peripheral arterial disease, previous stroke, previous coronary bypass grafting, heart failure, and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rate of cardiovascular death/MI/ischemic stroke and the individual components (P for trend <0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction in cardiovascular disease/MI/ischemic stroke with vorapaxar, and intermediate-risk patients (1-2 risk indicators; 61%) had a 2.1% absolute risk reduction (P<0.001 each), translating to a number needed to treat of 31 and 48. Bleeding increased across risk groups (P for trend<0.01); however, net clinical outcome was increasingly favorable with vorapaxar across risk groups. Fatal bleeding or intracranial hemorrhage was 0.9% with both treatments in high-risk patients. CONCLUSIONS:Stratification of baseline atherothrombotic risk can assist with therapeutic decision making for vorapaxar use for secondary prevention after MI. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00526474.
10.1161/CIRCULATIONAHA.115.019861
Assessment of Cardiovascular Risk in Older Patients With Gout Initiating Febuxostat Versus Allopurinol: Population-Based Cohort Study.
Zhang MaryAnn,Solomon Daniel H,Desai Rishi J,Kang Eun Ha,Liu Jun,Neogi Tuhina,Kim Seoyoung C
Circulation
BACKGROUND:Hyperuricemia and gout are associated with an increased risk of cardiovascular disease. Xanthine oxidase inhibitors, allopurinol and febuxostat, are the mainstay of urate-lowering treatment for gout and may have different effects on cardiovascular risk in patients with gout. METHODS:Using US Medicare claims data (2008-2013), we conducted a cohort study for comparative cardiovascular safety of initiating febuxostat versus allopurinol among patients with gout ≥65 years of age. The primary outcome was a composite end point of hospitalization for myocardial infarction or stroke. Secondary outcomes were individual end points of hospitalization for myocardial infarction, stroke, coronary revascularization, new and recurrent heart failure, and all-cause mortality. We used propensity score matching with a ratio of 1:3 to control for confounding. We estimated incidence rates and hazard ratios for primary and secondary outcomes in the propensity score-matched cohorts of febuxostat and allopurinol initiators. RESULTS:We included 24 936 febuxostat initiators propensity score-matched to 74 808 allopurinol initiators. The median age was 76 years, 52% were male, and 12% had cardiovascular disease at baseline. The incidence rate per 100 person-years for the primary outcome was 3.43 in febuxostat and 3.36 in allopurinol initiators. The hazard ratio for the primary outcome was 1.01 (95% CI, 0.94-1.08) in the febuxostat group compared with the allopurinol group. Risk of secondary outcomes including all-cause mortality was similar in both groups, except for a modestly decreased risk of heart failure exacerbation (hazard ratio, 0.94; 95% CI, 0.91-0.99) in febuxostat initiators. The hazard ratio for all-cause mortality associated with long-term use of febuxostat (>3 years) was 1.25 (95% CI, 0.56-2.80) versus allopurinol. Subgroup and sensitivity analyses consistently showed similar cardiovascular risk in both groups. CONCLUSIONS:Among a cohort of 99 744 older Medicare patients with gout, overall there was no difference in the risk of myocardial infarction, stroke, new-onset heart failure, coronary revascularization, or all-cause mortality between patients initiating febuxostat compared with allopurinol. However, there seemed to be a trend toward an increased, albeit not statistically significant, risk for all-cause mortality in patients who used febuxostat for >3 years versus allopurinol for >3 years. The risk of heart failure exacerbation was slightly lower in febuxostat initiators.
10.1161/CIRCULATIONAHA.118.033992
Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery.
Goodman Shaun G,Aylward Philip E,Szarek Michael,Chumburidze Vakhtang,Bhatt Deepak L,Bittner Vera A,Diaz Rafael,Edelberg Jay M,Hanotin Corinne,Harrington Robert A,Jukema J Wouter,Kedev Sasko,Letierce Alexia,Moryusef Angele,Pordy Robert,Ramos López Gabriel Arturo,Roe Matthew T,Viigimaa Margus,White Harvey D,Zeiher Andreas M,Steg Ph Gabriel,Schwartz Gregory G,
Journal of the American College of Cardiology
BACKGROUND:Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death. OBJECTIVES:This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). METHODS:Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003). RESULTS:In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]). CONCLUSIONS:Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).
10.1016/j.jacc.2019.07.015
Accuracy of Medical Claims for Identifying Cardiovascular and Bleeding Events After Myocardial Infarction : A Secondary Analysis of the TRANSLATE-ACS Study.
Guimarães Patricia O,Krishnamoorthy Arun,Kaltenbach Lisa A,Anstrom Kevin J,Effron Mark B,Mark Daniel B,McCollam Patrick L,Davidson-Ray Linda,Peterson Eric D,Wang Tracy Y
JAMA cardiology
Importance:Pragmatic clinical trial designs have proposed the use of medical claims data to ascertain clinical events; however, the accuracy of billed diagnoses in identifying potential events is unclear. Objectives:To compare the 1-year cumulative incidences of events when events were identified by medical claims vs by physician adjudication and to assess the accuracy of bill-identified events using physician adjudication as the criterion standard. Design, Setting, and Participants:This post hoc analysis of a clinical trial assessed the medical claims forms and records for all rehospitalizations at 233 US hospitals within 1 year of the index acute myocardial infarction (MI) of 12 365 patients enrolled in the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study between April 1, 2010, and October 31, 2012. Fourteen patients (0.1%) died during the index hospitalization and were excluded from analysis. Recurrent MI, stroke, and bleeding events were identified per the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedural codes in medical bills. These events were independently adjudicated by study physicians through medical record reviews using the prespecified criteria of recurrent MI and stroke and the bleeding definition by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scale. Medical claims were reported on a Uniform Bill-04 claims form; claims were collected from all hospitals visited by patients enrolled in TRANSLATE-ACS. Agreement between medical claims-identified events and physician-adjudicated events over the 12 months after discharge was assessed with the κ statistic. Data were analyzed from January 30, 2015, to March 2, 2017. Main Outcomes and Measures:Event rates within 1 year after MI. Results:Among 12 365 patients with acute MI, 8890 (71.9%) were men and mean (SD) age was 60 (11.6) years. The cumulative 1-year incidence of events identified by medical claims was 4.3% for MI, 0.9% for stroke, and 5.0% for bleeding. Incidence rates based on physician adjudication were 4.7% for MI, 0.9% for stroke, and 5.4% for bleeding. Agreement between medical claims-identified and physician-adjudicated events was modest, with a κ of 0.76 (95% CI, 0.73 to 0.79) for MI and 0.55 (95% CI, 0.41 to 0.68) for stroke events. In contrast, agreement between medical claims-identified and physician-adjudicated bleeding events was poor, with a κ of 0.24 (95% CI, 0.19 to 0.30) for any hospitalized bleeding event and 0.15 (95% CI, 0.11 to 0.20) for moderate or severe bleeding on the GUSTO scale. Conclusions and Relevance:Event rates at 1 year after MI were lower for MI, stroke, and bleeding when medical claims were used to identify events than when adjudicated by physicians. Medical claims diagnoses were only modestly accurate in identifying MI and stroke admissions but had limited accuracy for bleeding events. An alternative approach may be needed to ensure good safety surveillance in cardiovascular studies. Trial Registration:clinicaltrials.gov Identifier: NCT01088503.
10.1001/jamacardio.2017.1460
Long-term outcomes of secondary atrial fibrillation in the community: the Framingham Heart Study.
Lubitz Steven A,Yin Xiaoyan,Rienstra Michiel,Schnabel Renate B,Walkey Allan J,Magnani Jared W,Rahman Faisal,McManus David D,Tadros Thomas M,Levy Daniel,Vasan Ramachandran S,Larson Martin G,Ellinor Patrick T,Benjamin Emelia J
Circulation
BACKGROUND:Guidelines have proposed that atrial fibrillation (AF) can occur as an isolated event, particularly when precipitated by a secondary, or reversible, condition. However, knowledge of long-term AF outcomes after diagnosis during a secondary precipitant is limited. METHODS AND RESULTS:In 1409 Framingham Heart Study participants with new-onset AF, we examined associations between first-detected AF episodes occurring with and without a secondary precipitant and both long-term AF recurrence and morbidity. We selected secondary precipitants based on guidelines (surgery, infection, acute myocardial infarction, thyrotoxicosis, acute alcohol consumption, acute pericardial disease, pulmonary embolism, or other acute pulmonary disease). Among 439 patients (31%) with AF diagnosed during a secondary precipitant, cardiothoracic surgery (n=131 [30%]), infection (n=102 [23%]), noncardiothoracic surgery (n=87 [20%]), and acute myocardial infarction (n=78 [18%]) were most common. AF recurred in 544 of 846 eligible individuals without permanent AF (5-, 10-, and 15-year recurrences of 42%, 56%, and 62% with versus 59%, 69%, and 71% without secondary precipitants; multivariable-adjusted hazard ratio, 0.65 [95% confidence interval, 0.54-0.78]). Stroke risk (n=209/1262 at risk; hazard ratio, 1.13 [95% confidence interval, 0.82-1.57]) and mortality (n=1098/1409 at risk; hazard ratio, 1.00 [95% confidence interval, 0.87-1.15]) were similar between those with and without secondary precipitants, although heart failure risk was reduced (n=294/1107 at risk; hazard ratio, 0.74 [95% confidence interval, 0.56-0.97]). CONCLUSIONS:AF recurs in most individuals, including those diagnosed with secondary precipitants. Long-term AF-related stroke and mortality risks were similar between individuals with and without secondary AF precipitants. Future studies may determine whether increased arrhythmia surveillance or adherence to general AF management principles in patients with reversible AF precipitants will reduce morbidity.
10.1161/CIRCULATIONAHA.114.014058
Bioabsorbable Intracoronary Matrix for Prevention of Ventricular Remodeling After Myocardial Infarction.
Rao Sunil V,Zeymer Uwe,Douglas Pamela S,Al-Khalidi Hussein,White Jennifer A,Liu Jingyu,Levy Howard,Guetta Victor,Gibson C Michael,Tanguay Jean-Francois,Vermeersch Paul,Roncalli Jérôme,Kasprzak Jaroslaw D,Henry Timothy D,Frey Norbert,Kracoff Oscar,Traverse Jay H,Chew Derek P,Lopez-Sendon Jose,Heyrman Reinilde,Krucoff Mitchell W
Journal of the American College of Cardiology
BACKGROUND:Bioabsorbable cardiac matrix (BCM) is a novel device that attenuates adverse left ventricular (LV) remodeling after large myocardial infarctions in experimental models. OBJECTIVES:This study aimed to analyze whether BCM, compared with saline control, would result in less LV dilation and fewer adverse clinical events between baseline and 6 months. METHODS:In an international, randomized, double-blind, controlled trial, 303 subjects with large areas of infarction despite successful primary percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) were randomized 2:1 to BCM or saline injected into the infarct-related artery 2 to 5 days after primary PCI. The primary outcome was mean change from baseline in LV end-diastolic volume index (LVEDVI) at 6 months. Secondary outcomes included change in Kansas City Cardiomyopathy Questionnaire score, 6-minute walk time, and New York Heart Association functional class at 6 months. The primary safety endpoint was a composite of cardiovascular death, recurrent MI, target-vessel revascularization, stent thrombosis, significant arrhythmia requiring therapy, or myocardial rupture through 6 months. RESULTS:In total, 201 subjects were assigned to BCM and 102 to saline control. There was no significant difference in change in LVEDVI from baseline to 6 months between the groups (mean change ± SD: BCM 14.1 ± 28.9 ml/m(2) vs. saline 11.7 ± 26.9 ml/m(2); p = 0.49). There was also no significant difference in the secondary endpoints. The rates of the primary safety outcome were similar between the 2 groups (BCM 11.6% vs. saline 9.1%; p = 0.37). CONCLUSIONS:Intracoronary deployment of BCM 2 to 5 days after successful reperfusion in subjects with large myocardial infarction did not reduce adverse LV remodeling or cardiac clinical events at 6 months. (IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction [PRESERVATION I]; NCT01226563).
10.1016/j.jacc.2016.05.053
Pro-substance p for evaluation of risk in acute myocardial infarction.
Ng Leong L,Sandhu Jatinderpal K,Narayan Hafid,Quinn Paulene A,Squire Iain B,Davies Joan E,Struck Joachim,Bergmann Andreas,Maisel Alan,Jones Donald J L
Journal of the American College of Cardiology
BACKGROUND:Pro-substance P (ProSP) is a stable surrogate marker for labile substance P, which has pro-inflammatory effects, increases platelet aggregation and clot strength, and reduces fibrinolysis. OBJECTIVES:This study assessed whether ProSP was associated with poor prognosis after acute myocardial infarction (AMI) to identify novel pathophysiological mechanisms. METHODS:ProSP was measured in 1,148 AMI patients (825 men, mean age 66.2 ± 12.8 years). Endpoints were major adverse cardiac events (composite of death, reinfarction, and heart failure [HF] hospitalization), death/reinfarction, and death/HF. GRACE (Global Registry of Acute Coronary Events) scores were compared with ProSP for death and/or reinfarction at 6 months. RESULTS:During 2-year follow-up, there were 140 deaths, 112 HF hospitalizations, and 149 re-AMI. ProSP levels were highest on the first 2 days after admission and related to estimated glomerular filtration rate, age, history of diabetes, ischemic heart disease or hypertension, Killip class, left ventricular wall motion index, and sex. Multivariate Cox regression models showed ProSP level was a predictor of major adverse events (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.10 to 1.54; p < 0.002), death and/or AMI (HR: 1.42; 95% CI: 1.20 to 1.68; p < 0.0005), death and/or HF (HR: 1.38; 95% CI: 1.14 to 1.67; p < 0.001). ProSP levels with GRACE scores were independent predictors of 6-month death and/or reinfarction (p < 0.0005 for both). ProSP-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement of 31.6 (95% CI: 14.3 to 49.0; p < 0.0005) mainly by down-classifying those without endpoints. CONCLUSIONS:ProSP levels post-AMI are prognostic for death, recurrent AMI, or HF, and they improve risk prediction of GRACE scores, predominantly by down-classifying risk in those without events.
10.1016/j.jacc.2014.05.074
Percutaneous Transcatheter Mitral Valve Replacement: First-in-Human Experience With a New Transseptal System.
Webb John G,Murdoch Dale J,Boone Robert H,Moss Robert,Attinger-Toller Adrian,Blanke Philipp,Cheung Anson,Hensey Mark,Leipsic Jonathon,Ong Kevin,Sathananthan Janarthanan,Wood David A,Ye Jian,Tartara Paolo
Journal of the American College of Cardiology
BACKGROUND:Severe mitral regurgitation (MR) conveys significant morbidity and mortality, and surgical repair or replacement may not be a desirable option. OBJECTIVES:The purpose of this study was to evaluate the feasibility of a percutaneous transseptal transcatheter mitral valve replacement (TMVR) system. METHODS:This first-in-human study was conducted between August 2017 and August 2018. The system comprises a nitinol dock, which encircles the chordae tendineae, and a balloon-expandable transcatheter heart valve. The dock and transcatheter heart valve form an ensemble, with the native mitral valve leaflets secured in between, thereby abolishing MR. Key inclusion criteria were severe symptomatic MR and high surgical risk; exclusion criteria included left ventricular ejection fraction <30% or screening suggesting unfavorable anatomy. The primary endpoint was technical success as defined by Mitral Valve Academic Research Consortium (MVARC) criteria at completion of the index procedure. The secondary endpoint was freedom from mortality, stroke, and device dysfunction (MR grade >1, mitral gradient >6 mm Hg, left ventricular outflow tract gradient >20 mm Hg) at 30 days. RESULTS:Ten patients with severe MR of various etiologies (4 degenerative, 4 functional, and 2 mixed) were treated. The device was successfully implanted and the primary endpoint was achieved in 9 of 10 patients (90%). By transesophageal echocardiography, total MR was reduced to ≤ trivial in all implanted patients, and mean transmitral gradient was 2.3 ± 1.4 mm Hg. A pericardial effusion occurred in 1 patient: pericardiocentesis was performed, and the device was not implanted. Median length of hospital stay was 1.5 days. At 30 days, there was no stroke, myocardial infarction, rehospitalization, left ventricular outflow tract obstruction, device migration, embolization, or conversion to mitral surgery. One patient had recurrent regurgitation due to a paravalvular leak, treated with a closure device. All other treated patients had ≤1+ MR. No patients died. CONCLUSIONS:Percutaneous transvenous transseptal TMVR is feasible and safe in patients with severe MR who are at high risk for mitral valve surgery. Further evaluation is warranted.
10.1016/j.jacc.2018.12.065
Catheter Ablation of Refractory Ventricular Fibrillation Storm After Myocardial Infarction.
Komatsu Yuki,Hocini Mélèze,Nogami Akihiko,Maury Philippe,Peichl Petr,Iwasaki Yu-Ki,Masuda Keita,Denis Arnaud,Voglimacci-Stephanopoli Quentin,Wichterle Dan,Kawamura Mitsuharu,Fukamizu Seiji,Yokoyama Yasuhiro,Mukai Yasushi,Harada Tomoo,Yoshida Kentaro,Yasuoka Ryobun,Igawa Masayuki,Ohira Koji,Shimizu Wataru,Aonuma Kazutaka,Kautzner Josef,Haïssaguerre Michel,Ieda Masaki
Circulation
BACKGROUND:Ventricular fibrillation (VF) storm after myocardial infarction (MI) is a life-threatening condition that necessitates multiple defibrillations. Catheter ablation is a potentially effective treatment strategy for VF storm refractory to optimal medical treatment. However, its impact on patient survival has not been verified in a large population. METHODS:We conducted a multicenter, retrospective observational study involving consecutive patients who underwent catheter ablation of post-MI refractory VF storm without preceding monomorphic ventricular tachycardia. The target of ablation was the Purkinje-related ventricular extrasystoles triggering VF. The primary outcome was in-hospital and long-term mortalities. Univariate logistic regression and Cox proportional-hazards analysis were used to evaluate clinical characteristics associated with in-hospital and long-term mortalities, respectively. RESULTS:One hundred ten patients were enrolled (age, 65±11years; 92 men; left ventricular ejection fraction, 31±10%). VF storm occurred at the acute phase of MI (4.5±2.5 days after the onset of MI during the index hospitalization for MI) in 43 patients (39%), the subacute phase (>1 week) in 48 (44%), and the remote phase (>6 months) in 19 (17%). The focal triggers were found to originate from the scar border zone in 88 patients (80%). During in-hospital stay after ablation, VF storm subsided in 92 patients (84%). Overall, 30 (27%) in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality (odds ratio for each 1-day increase, 1.11 [95% CI, 1.03-1.20]; P=0.008). During follow-up after discharge from hospital, only 1 patient developed recurrent VF storm. However, 29 patients (36%) died, with a median survival time of 2.2 years (interquartile range, 1.2-5.5 years). Long-term mortality was associated with left ventricular ejection fraction <30% (hazard ratio, 2.54 [95% CI, 1.21-5.32]; P=0.014), New York Heart Association class ≥III (hazard ratio, 2.68 [95% CI, 1.16-6.19]; P=0.021), a history of atrial fibrillation (hazard ratio, 3.89 [95% CI, 1.42-10.67]; P=0.008), and chronic kidney disease (hazard ratio, 2.74 [95% CI, 1.15-6.49]; P=0.023). CONCLUSIONS:In patients with MI presenting with focally triggered VF storm, catheter ablation of culprit triggers is lifesaving and appears to be associated with short- and long-term freedom from recurrent VF storm. Mortality over the long-term follow-up is associated with the severity of underlying cardiovascular disease and comorbidities in this specific patient population.
10.1161/CIRCULATIONAHA.118.037997
Three-Year Outcomes With the Absorb Bioresorbable Scaffold: Individual-Patient-Data Meta-Analysis From the ABSORB Randomized Trials.
Ali Ziad A,Gao Runlin,Kimura Takeshi,Onuma Yoshinobu,Kereiakes Dean J,Ellis Stephen G,Chevalier Bernard,Vu Minh-Thien,Zhang Zhen,Simonton Charles A,Serruys Patrick W,Stone Gregg W
Circulation
BACKGROUND:The Absorb bioresorbable vascular scaffold (BVS) completely resorbs within 3 years after coronary artery implantation. The safety and effectiveness of BVS through this critical 3-year period have not been characterized. METHODS:We performed an individual-patient-data pooled meta-analysis of the 4 randomized ABSORB trials in which 3389 patients with coronary artery disease were randomly assigned to everolimus-eluting Absorb BVS (n=2164) or cobalt-chromium everolimus-eluting stents (n=1225). The primary efficacy outcome measure was target lesion failure (cardiac mortality, target vessel myocardial infarction, or ischemia-driven target lesion revascularization), and the primary safety outcome measure was device thrombosis. RESULTS:BVS compared with cobalt-chromium everolimus-eluting stents resulted in higher 3-year rates of target lesion failure (11.7% versus 8.1%; risk ratio [RR], 1.38; 95% confidence interval [CI], 1.10-1.73; =0.006), driven by greater target vessel myocardial infarction (7.8% versus 4.2%; RR, 1.72; 95% CI, 1.26-2.35; =0.0006) and ischemia-driven target lesion revascularization (6.6% versus 4.4%; RR, 1.44; 95% CI, 1.05-1.98; =0.02), with comparable cardiac mortality (1.1% versus 1.1%; RR, 0.93; 95% CI, 0.47-1.88; =0.85). Device thrombosis rates through 3 years were also higher with BVS (2.4% versus 0.6%; RR, 3.71; 95% CI, 1.70-8.11; =0.001). Between 1 and 3 years, target lesion failure rates (6.1% versus 3.9%; =0.02) and device thrombosis rates (1.1% versus 0.0%; <0.0001) were higher with BVS than cobalt-chromium everolimus-eluting stents. CONCLUSIONS:In the present individual-patient-data pooled meta-analysis of the ABSORB trials, BVS was associated with increased rates of target lesion failure and device thrombosis between 1 and 3 years and cumulatively through 3 years of follow-up compared with everolimus-eluting stents. CLINICAL TRIAL REGISTRATION:URL: https://clinicaltrials.gov. Unique identifiers: NCT01751906, NCT01844284, NCT01923740, and NCT01425281.
10.1161/CIRCULATIONAHA.117.031843
Biomarkers and Clinical Cardiovascular Outcomes With Ezetimibe in the IMPROVE-IT Trial.
Qamar Arman,Giugliano Robert P,Bohula Erin A,Park Jeong-Gun,Jarolim Petr,Murphy Sabina A,Blazing Michael A,Califf Robert M,Cannon Christopher P,Braunwald Eugene,Morrow David A
Journal of the American College of Cardiology
BACKGROUND:Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown. OBJECTIVES:This study sought to evaluate the role of established CV biomarkers in assessing likely benefit with ezetimibe added to statin therapy in post-ACS patients. METHODS:In a pre-specified nested analysis within a randomized, double-blind trial of ezetimibe/simvastatin versus placebo/simvastatin (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, growth-differentiation factor-15, and high-sensitivity C-reactive protein was measured in 7,195 patients stabilized (1 month post-randomization) after ACS. A multimarker approach based on biomarker values was used to examine the risk of recurrent CV events and clinical benefit with ezetimibe. RESULTS:Elevated levels of each biomarker were independently associated with higher risks of CV death/myocardial infarction/stroke and CV death/heart failure (p < 0.001 for each). There was a pattern of greater absolute risk reduction in CV death/myocardial infarction/stroke with the addition of ezetimibe to statin therapy in patients at higher risk on the basis of biomarker levels. High-risk patients (≥3 biomarkers "positive"; n = 1,437) had an absolute risk difference of -7.3% (95% confidence interval: -13.8% to -0.8%; p = 0.02) with ezetimibe, and intermediate-risk patients (1 to 2 biomarkers positive; n = 3,842) had an absolute risk difference of -4.4% (95% confidence interval: -9.7% to 0.8%), translating into numbers needed to treat at 7 years of 14 and 23, respectively. Low-risk patients (0 biomarkers positive; n = 1,916) did not appear to benefit from the addition of ezetimibe to statin therapy. CONCLUSIONS:A biomarker-based strategy identifies a gradient of risk among patients post-ACS, offering the potential to identify higher-risk patients with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy.
10.1016/j.jacc.2019.06.038
Characterization of the Average Daily Ischemic and Bleeding Risk After Primary PCI for STEMI.
Giustino Gennaro,Mehran Roxana,Dangas George D,Kirtane Ajay J,Redfors Björn,Généreux Philippe,Brener Sorin J,Prats Jayne,Pocock Stuart J,Deliargyris Efthymios N,Stone Gregg W
Journal of the American College of Cardiology
BACKGROUND:The risk of recurrent ischemic and bleeding events after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) may not be uniform over time, which may affect the benefit-to-risk ratio of guideline-recommended antithrombotic therapies in different intervals. OBJECTIVES:This study sought to characterize the average daily ischemic rates (ADIRs) and average daily bleeding rates (ADBRs) within the first year after primary PCI for STEMI. METHODS:Among 3,602 patients with STEMI who were enrolled in the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, all ischemic and bleeding events, including recurrent events, were classified according to the timing of their occurrence as acute (≤24 h after PCI), subacute (1 day to 30 days), and late (30 days to 1 year). Patients were treated with aspirin and clopidogrel for the entire year. ADIRs included cardiac death, reinfarction, and definite stent thrombosis. ADBRs included non-coronary artery bypass graft-related Thrombolysis In Myocardial Infarction major and minor bleeding. ADIRs and ADBRs were calculated as the total number of events divided by the number of patient-days of follow-up in each interval assuming a Poisson distribution. Generalized estimating equations were used to test the absolute least square mean differences (LSMD) between ADIRs and ADBRs. RESULTS:The ADIR and ADBR both exponentially decreased from the acute to the late periods (p < 0.0001). Although there were no significant differences in ADIR and ADBR in the acute phase (LSMD: +0.11%; 95% confidence interval [CI]: -0.35% to 0.58%; p = 0.63), the ADBR was greater than the ADIR in the subacute phase (LSMD: -0.39%; 95% CI: -0.58% to -0.20%; p < 0.0001). In the late phase, the ADIR exceeded the ADBR (LSMD: +1.51%; 95% CI: 1.04% to 1.98%; p < 0.0001). CONCLUSIONS:After primary PCI, the ADIR and ADBR both markedly decreased over time. Although the rates for bleeding exceeded those for ischemia within 30 days, the daily risk of ischemia significantly exceeded the daily risk of bleeding beyond 30 days, supporting the use of intensified platelet inhibition during the first year after STEMI.
10.1016/j.jacc.2017.08.018
Occurence of First and Recurrent Major Adverse Cardiovascular Events With Liraglutide Treatment Among Patients With Type 2 Diabetes and High Risk of Cardiovascular Events: A Post Hoc Analysis of a Randomized Clinical Trial.
Verma Subodh,Bain Stephen C,Buse John B,Idorn Thomas,Rasmussen Søren,Ørsted David D,Nauck Michael A
JAMA cardiology
Importance:After the occurrence of nonfatal cardiovascular events, recurrent events are highly likely. Most cardiovascular outcomes trials analyze first events only; extending analyses to first and recurrent (total) events can provide clinically meaningful information. Objective:To investigate whether liraglutide is associated with reduced first and recurrent total major adverse cardiovascular events (MACE) compared with placebo among patients with type 2 diabetes and high risk of cardiovascular events. Design, Setting, and Participants:This post hoc analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) randomized, double-blind, clinical trial included data from patients with type 2 diabetes who had established or were at high risk for cardiovascular disease at 410 sites in 32 countries from August 2010, to December 2015. Data analysis was performed from August 15, 2016, to July 5, 2019. Interventions:Patients were randomized 1:1 to receive liraglutide (up to 1.8 mg per day) or placebo, both with standard care, for 3.5 to 5.0 years. Main Outcomes and Measures:Assessed outcomes were MACE (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), expanded MACE (primary MACE plus coronary revascularization and hospitalization for heart failure or unstable angina pectoris), and the individual end points. Results:The 9340 LEADER trial participants (6003 [64.3%] male; mean [SD] age, 64.3 [7.2] years) experienced 1605 total MACE (1302 first and 303 recurrent events; median follow-up, 3.8 years [range, 0-5.2 years]). Patients who experienced any MACE were older (1 MACE: mean [SD] age, 65.6 [8.0] years; >1 MACE: 65.7 [7.9] years) and had diabetes for longer duration (1 MACE: mean [SD] duration, 13.4 [8.3] years; >1 MACE: 14.4 [8.7] years) compared with patients without MACE (mean [SD] age, 64.1 [7.1] years; mean [SD] duration, 12.7 [7.9] years). Fewer first and recurrent MACE occurred in the liraglutide group (n = 4668; 608 first and 127 recurrent events) than in the placebo group (n = 4672; 694 first and 176 recurrent events). Liraglutide was associated with a 15.7% relative risk reduction in total MACE (hazard ratio [HR], 0.84; 95% CI, 0.76-0.93) and a 13.4% reduction in total expanded MACE (HR, 0.87; 95% CI, 0.81-0.93) compared with placebo. For most individual cardiovascular end points, liraglutide was associated with lower risk vs placebo. Conclusions and Relevance:These results suggest that liraglutide treatment is associated with reduced total MACE compared with placebo among patients with type 2 diabetes and high risk of cardiovascular events. This analysis supports the findings of an absolute benefit of liraglutide treatment with respect to the overall burden of cardiovascular events in this high-risk patient population. Trial Registration:ClinicalTrials.gov identifier: NCT01179048.
10.1001/jamacardio.2019.3080
Cyclosporine before PCI in Patients with Acute Myocardial Infarction.
Cung Thien-Tri,Morel Olivier,Cayla Guillaume,Rioufol Gilles,Garcia-Dorado David,Angoulvant Denis,Bonnefoy-Cudraz Eric,Guérin Patrice,Elbaz Meier,Delarche Nicolas,Coste Pierre,Vanzetto Gerald,Metge Marc,Aupetit Jean-François,Jouve Bernard,Motreff Pascal,Tron Christophe,Labeque Jean-Noel,Steg Philippe Gabriel,Cottin Yves,Range Grégoire,Clerc Jérome,Claeys Marc J,Coussement Patrick,Prunier Fabrice,Moulin Frédéric,Roth Olivier,Belle Loïc,Dubois Philippe,Barragan Paul,Gilard Martine,Piot Christophe,Colin Patrice,De Poli Fabien,Morice Marie-Claude,Ider Omar,Dubois-Randé Jean-Luc,Unterseeh Thierry,Le Breton Hervé,Béard Thierry,Blanchard Didier,Grollier Gilles,Malquarti Vincent,Staat Patrick,Sudre Arnaud,Elmer Eskil,Hansson Magnus J,Bergerot Cyrille,Boussaha Inesse,Jossan Claire,Derumeaux Geneviève,Mewton Nathan,Ovize Michel
The New England journal of medicine
BACKGROUND:Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS:In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS:A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS:In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).
10.1056/NEJMoa1505489
Cost-effectiveness of Canakinumab for Prevention of Recurrent Cardiovascular Events.
Sehested Thomas S G,Bjerre Jenny,Ku Seul,Chang Andrew,Jahansouz Alison,Owens Douglas K,Hlatky Mark A,Goldhaber-Fiebert Jeremy D
JAMA cardiology
Importance:In the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, the anti-inflammatory monoclonal antibody canakinumab significantly reduced the risk of recurrent cardiovascular events in patients with previous myocardial infarction (MI) and high-sensitivity C-reactive protein (hs-CRP) levels of 2 mg/L or greater. Objective:To estimate the cost-effectiveness of adding canakinumab to standard of care for the secondary prevention of major cardiovascular events over a range of potential prices. Design, Setting, and Participants:A state-transition Markov model was constructed to estimate costs and outcomes over a lifetime horizon by projecting rates of recurrent MI, coronary revascularization, infection, and lung cancer with and without canakinumab treatment. We used a US health care sector perspective, and the base case used the current US market price of canakinumab of $73 000 per year. A hypothetical cohort of patients after MI aged 61 years with an hs-CRP level of 2 mg/L or greater was constructed. Interventions:Canakinumab, 150 mg, administered every 3 months plus standard of care compared with standard of care alone. Main Outcomes and Measures:Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results:Adding canakinumab to standard of care increased life expectancy from 11.31 to 11.36 years, QALYs from 9.37 to 9.50, and costs from $242 000 to $1 074 000, yielding an incremental cost-effectiveness ratio of $6.4 million per QALY gained. The price would have to be reduced by more than 98% (to $1150 per year or less) to meet the $100 000 per QALY willingness-to-pay threshold. These results were generally robust across alternative assumptions, eg, substantially lower health-related quality of life after recurrent cardiovascular events, lower infection rates while receiving canakinumab, and reduced all-cause mortality while receiving canakinumab. Including a potential beneficial effect of canakinumab on lung cancer incidence improved the incremental cost-effectiveness ratio to $3.5 million per QALY gained. A strategy of continuing canakinumab selectively in patients with reduction in hs-CRP levels to less than 2 mg/L would have a cost-effectiveness ratio of $819 000 per QALY gained. Conclusions and Relevance:Canakinumab is not cost-effective at current US prices for prevention of recurrent cardiovascular events in patients with a prior MI. Substantial price reductions would be needed for canakinumab to be considered cost-effective.
10.1001/jamacardio.2018.4566
Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention.
Bohula Erin A,Morrow David A,Giugliano Robert P,Blazing Michael A,He Ping,Park Jeong-Gun,Murphy Sabina A,White Jennifer A,Kesaniemi Y Antero,Pedersen Terje R,Brady Adrian J,Mitchel Yale,Cannon Christopher P,Braunwald Eugene
Journal of the American College of Cardiology
BACKGROUND:Ezetimibe improves cardiovascular (CV) outcomes in patients stabilized after acute coronary syndrome (ACS) when added to statin therapy. After ACS, patients vary considerably in their risk for recurrent CV events. OBJECTIVES:This study tested the hypothesis that atherothrombotic risk stratification may be useful to identify post-ACS patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy. METHODS:The TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2°P) is a simple 9-point risk stratification tool, previously developed in a large population with atherothrombosis to predict CV death, myocardial infarction (MI), and ischemic stroke (CV death/MI/ischemic cerebrovascular accident [iCVA]). The current study applied this tool prospectively to 17,717 post-ACS patients randomized either to ezetimibe and simvastatin or to placebo and simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Treatment efficacy was assessed by baseline risk for CV death/MI/iCVA, the IMPROVE-IT composite endpoints (CE), and individual component endpoints at 7 years. RESULTS:All 9 clinical variables in the TRS 2°P were independent risk indicators for CV death/MI/iCVA (p < 0.001). The integer-based scheme showed a strong graded relationship with the rate of CV death/MI/iCVA, the trial CE, and the individual components (p trend <0.0001 for each). High-risk patients (n = 4,393; 25%), defined by ≥3 risk indicators, had a 6.3% (95% confidence interval: 2.9% to 9.7%) absolute risk reduction in CV death/MI/iCVA at 7 years with ezetimibe/simvastatin, thus translating to a number-needed-to-treat of 16. Intermediate-risk patients (2 risk indicators; n = 5,292; 30%) had a 2.2% (95% confidence interval: -0.3% to 4.6%) absolute risk reduction. Low-risk patients (0 to 1 risk indicators; n = 8,032; 45%) did not appear to derive benefit from the addition of ezetimibe (p interaction = 0.010). Similar findings were observed for the IMPROVE-IT primary CE. CONCLUSIONS:Atherothrombotic risk stratification using the TRS 2°P identifies high-risk patients who derive greatest benefit from the addition of ezetimibe to statin therapy for secondary prevention after ACS. (Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878).
10.1016/j.jacc.2016.11.070
Aldosterone Antagonist Therapy and Mortality in Patients With ST-Segment Elevation Myocardial Infarction Without Heart Failure: A Systematic Review and Meta-analysis.
Dahal Khagendra,Hendrani Aditya,Sharma Sharan P,Singireddy Sampath,Mina George,Reddy Pratap,Dominic Paari,Modi Kalgi
JAMA internal medicine
Importance:Treatment with aldosterone antagonists is recommended and has been shown to have beneficial effects in patients with ST-segment elevation myocardial infarction (STEMI) and left ventricular ejection fraction (LVEF) less than 40%. However, the role of aldosterone antagonists in patients with ejection fraction greater than 40% or without congestive heart failure is not well known. Objectives:To perform a systematic review and meta-analysis using standard techniques to determine the role of therapy with aldosterone antagonists in this patient population. Data Sources:PubMed, Embase, CINAHL, and Cochrane Central databases were searched and a manual search for relevant references from the selected articles and published reviews was performed from database inception through June 2017. Study Selection:Randomized clinical trials that evaluated treatment with aldosterone antagonists in patients with STEMI without clinical heart failure or LVEF greater than 40% were included. Data Extraction and Synthesis:Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to conduct and report the meta-analysis, which used a random-effects model. Two investigators independently performed the database search and agreed on the final study selection. A manual search was performed for relevant references from the selected articles and published reviews. Main Outcomes and Measures:The outcomes analyzed were mortality, new congestive heart failure, recurrent myocardial infarction, ventricular arrhythmia, and changes in LVEF, serum potassium level, and creatinine level at follow-up. Results:In all, 10 randomized clinical trials with a total of 4147 unique patients were included in the meta-analysis. In patients who presented with STEMI without heart failure, treatment with aldosterone antagonists compared with control was associated with lower risk of mortality (2.4% vs 3.9%; odds ratio [OR], 0.62; 95% CI, 0.42-0.91; P = .01) and similar risks of myocardial infarction (1.6% vs 1.5%; OR, 1.03; 95% CI, 0.57-1.86; P = .91), new congestive heart failure (4.3% vs 5.4%; OR, 0.82; 95% CI, 0.56-1.20; P = .31), and ventricular arrhythmia (4.1% vs 5.1%; OR, 0.76; 95% CI, 0.45-1.31; P = .33). Similarly, treatment with aldosterone antagonists compared with control was associated with a small yet significant increase in LVEF (mean difference, 1.58%; 95% CI, 0.18%-2.97%; P = .03), a small increase in serum potassium level (mean difference, 0.07 mEq/L; 95% CI, 0.01-0.13 mEq/L; P = .02), and no change in serum creatinine level (standardized mean difference, 1.4; 95% CI, -0.43 to 3.24; P = .13). Conclusions and Relevance:Treatment with aldosterone antagonists is associated with a mortality benefit in patients with STEMI with LVEF greater than 40% or without heart failure.
10.1001/jamainternmed.2018.0850
Efficacy and Safety of Vorapaxar With and Without a Thienopyridine for Secondary Prevention in Patients With Previous Myocardial Infarction and No History of Stroke or Transient Ischemic Attack: Results from TRA 2°P-TIMI 50.
Bohula Erin A,Aylward Philip E,Bonaca Marc P,Corbalan Ramon L,Kiss Robert G,Murphy Sabina A,Scirica Benjamin M,White Harvey,Braunwald Eugene,Morrow David A
Circulation
BACKGROUND:Vorapaxar antagonizes protease-activated receptor 1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a previous myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with vorapaxar was modified by concurrent thienopyridine use. METHODS AND RESULTS:The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26,449 patients with previous atherothrombosis. This prespecified analysis included 16,897 patients who qualified with a MI in the preceding 2 weeks to 12 months and was restricted to patients without a history of stroke or transient ischemic attack given its contraindication in that population. Randomization was stratified on the basis of planned thienopyridine use. Thienopyridine was planned at randomization in 12,410 (73%). Vorapaxar significantly reduced the composite of cardiovascular death, MI, and stroke in comparison with placebo regardless of planned thienopyridine therapy (planned thienopyridine, hazard ratio, 0.80, 0.70-0.91, P<0.001; no planned thienopyridine, hazard ratio, 0.75; 0.60-0.94, P=0.011; P-interaction=0.67). Findings were similar when patients were stratified by actual thienopyridine use at baseline (P-interaction=0.82) and through 18 months (P-interaction=0.44). Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding risk was increased with vorapaxar and was not significantly altered by planned thienopyridine (planned, hazard ratio, 1.50; 1.18-1.89, P<0.001; no planned, hazard ratio, 1.90, 1.17-3.07, P=0.009; P-interaction=0.37) or actual thienopyridine use (P-interaction=0.24). CONCLUSIONS:Vorapaxar reduced cardiovascular death, MI, or stroke in stable patients with a history of previous MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.
10.1161/CIRCULATIONAHA.114.015042
Sudden Cardiac Death After Non-ST-Segment Elevation Acute Coronary Syndrome.
Hess Paul L,Wojdyla Daniel M,Al-Khatib Sana M,Lokhnygina Yuliya,Wallentin Lars,Armstrong Paul W,Roe Matthew T,Ohman E Magnus,Harrington Robert A,Alexander John H,White Harvey D,Van de Werf Frans,Piccini Jonathan P,Held Claes,Aylward Philip E,Moliterno David J,Mahaffey Kenneth W,Tricoci Pierluigi
JAMA cardiology
IMPORTANCE:In the current therapeutic era, the risk for sudden cardiac death (SCD) after non-ST-segment elevation acute coronary syndrome (NSTE ACS) has not been characterized completely. OBJECTIVE:To determine the cumulative incidence of SCD during long-term follow-up after NSTE ACS, to develop a risk model and risk score for SCD after NSTE ACS, and to assess the association between recurrent events after the initial ACS presentation and the risk for SCD. DESIGN, SETTING, AND PARTICIPANTS:This pooled cohort analysis merged individual data from 48 286 participants in 4 trials: the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2), Study of Platelet Inhibition and Patient Outcomes (PLATO), Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER), and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trials. The cumulative incidence of SCD and cardiovascular death was examined according to time after NSTE ACS. Using competing risk and Cox proportional hazards models, clinical factors at baseline and after the index event that were associated with SCD after NSTE ACS were identified. Baseline factors were used to develop a risk model. Data were analyzed from January 2, 2014, to December 11, 2015. MAIN OUTCOMES AND MEASURES:Sudden cardiac death. RESULTS:Of the initial 48 286 patients, 37 555 patients were enrolled after NSTE ACS (67.4% men; 32.6% women; median [interquartile range] age, 65 [57-72] years). Among these, 2109 deaths occurred after a median follow-up of 12.1 months. Of 1640 cardiovascular deaths, 513 (31.3%) were SCD. At 6, 18, and 30 months, the cumulative incidence estimates of SCD were 0.79%, 1.65%, and 2.37%, respectively. Reduced left ventricular ejection fraction, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior myocardial infarction, peripheral artery disease, Asian race, male sex, and high Killip class were significantly associated with SCD. A model developed to calculate the risk for SCD in trials with systematic collection of left ventricular ejection fraction had a C index of 0.77. An integer-based score was developed from this model and yielded a calculated SCD probability ranging from 0.1% to 56.7% (C statistic, 0.75). In a multivariable model that included time-dependent clinical events occurring after the index hospitalization for ACS, SCD was associated with recurrent myocardial infarction (hazard ratio [HR], 2.95; 95% CI, 2.29-3.80; P < .001) and any hospitalization (HR, 2.45; 95% CI, 1.98-3.03; P < .001), whereas coronary revascularization had a negative relationship with SCD (HR, 0.75; 95% CI, 0.58-0.98; P = .03). CONCLUSIONS AND RELEVANCE:In the current therapeutic era, SCD accounts for about one-third of cardiovascular deaths after NSTE ACS. Risk stratification can be performed with good accuracy using commonly collected clinical variables. Clinical events occurring after the index hospitalization are underappreciated but important risk factors.
10.1001/jamacardio.2015.0359
Quinidine-Responsive Polymorphic Ventricular Tachycardia in Patients With Coronary Heart Disease.
Viskin Sami,Chorin Ehud,Viskin Dana,Hochstadt Aviram,Halkin Amir,Tovia-Brodie Oholi,Lee John K,Asher Elad,Laish-Farkash Avishag,Amit Guy,Havakuk Ofer,Belhassen Bernard,Rosso Raphael
Circulation
BACKGROUND:Polymorphic ventricular tachycardia (VT) without QT prolongation is well described in patients without structural heart disease (mainly idiopathic ventricular fibrillation and Brugada syndrome) and in patients with acute ST-elevation myocardial infarction. METHODS:Retrospective study of patients with polymorphic VT related to coronary artery disease, but without evidence of acute myocardial ischemia. RESULTS:The authors identified 43 patients in whom polymorphic VT developed within days of an otherwise uncomplicated myocardial infarction or coronary revascularization procedure. The polymorphic VT events were invariably triggered by extrasystoles with short (364±36 ms) coupling interval. Arrhythmic storms (4-16 events of polymorphic VT deteriorating to ventricular fibrillation) occurred in 23 (53%) patients. These arrhythmic storms were always refractory to conventional antiarrhythmic therapy, including intravenous amiodarone, but invariably responded to quinidine therapy. In-hospital mortality was 17% for patients with arrhythmic storm. Patients treated with quinidine invariably survived to hospital discharge. During long-term follow-up (of 5.6±6 years; range, 1 month to 18 years), 3 (16%) of patients discharged without quinidine developed recurrent polymorphic VT. There were no recurrent arrhythmias during quinidine therapy Conclusions: Arrhythmic storm with recurrent polymorphic VT in patients with coronary disease responds to quinidine therapy when other antiarrhythmic drugs (including intravenous amiodarone) fail.
10.1161/CIRCULATIONAHA.118.038036
Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration.
Simes John,Becattini Cecilia,Agnelli Giancarlo,Eikelboom John W,Kirby Adrienne C,Mister Rebecca,Prandoni Paolo,Brighton Timothy A,
Circulation
BACKGROUND:In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued. The Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed that aspirin reduces this risk, but they were not individually powered to detect treatment effects for particular outcomes or subgroups. METHODS AND RESULTS:An individual patient data analysis of these trials was planned, before their results were known, to assess the effect of aspirin versus placebo on recurrent VTE, major vascular events (recurrent VTE, myocardial infarction, stroke, and cardiovascular disease death) and bleeding, overall and within predefined subgroups. The primary analysis, for VTE, was by intention to treat using time-to-event data. Of 1224 patients, 193 had recurrent VTE over 30.4 months' median follow-up. Aspirin reduced recurrent VTE (7.5%/yr versus 5.1%/yr; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90; P=0.008), including both deep-vein thrombosis (HR, 0.66; 95% CI, 0.47-0.92; P=0.01) and pulmonary embolism (HR, 0.66; 95% CI, 0.41-1.06; P=0.08). Aspirin reduced major vascular events (8.7%/yr versus 5.7%/yr; HR, 0.66; 95% CI, 0.50-0.86; P=0.002). The major bleeding rate was low (0.4%/yr for placebo and 0.5%/yr for aspirin). After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR, 0.58; 95% CI, 0.40-0.85; P=0.005). Prespecified subgroup analyses indicate similar relative, but larger absolute, risk reductions in men and older patients. CONCLUSIONS:Aspirin after anticoagulant treatment reduces the overall risk of recurrence by more than a third in a broad cross-section of patients with a first unprovoked VTE, without significantly increasing the risk of bleeding. CLINICAL TRIAL REGISTRATION URL:www.anzctr.org.au. Unique identifier: ACTRN12611000684921.
10.1161/CIRCULATIONAHA.114.008828
Diabetes Mellitus and Prevention of Late Myocardial Infarction After Coronary Stenting in the Randomized Dual Antiplatelet Therapy Study.
Meredith Ian T,Tanguay Jean-François,Kereiakes Dean J,Cutlip Donald E,Yeh Robert W,Garratt Kirk N,Lee David P,Steg P Gabriel,Weaver W Douglas,Holmes David R,Brindis Ralph G,Trebacz Jaroslaw,Massaro Joseph M,Hsieh Wen-Hua,Mauri Laura,
Circulation
BACKGROUND:Patients with diabetes mellitus (DM) are at high risk for recurrent ischemic events after coronary stenting. We assessed the effects of continued thienopyridine among patients with DM participating in the Dual Antiplatelet Therapy (DAPT) Study as a prespecified analysis. METHODS AND RESULTS:After coronary stent placement and 12 months treatment with open-label thienopyridine plus aspirin, 11 648 patients free of ischemic or bleeding events and who were medication compliant were randomly assigned to continued thienopyridine or placebo, in addition to aspirin, for 18 more months. After randomization, patients with DM (n=3391), in comparison with patients without DM (n=8257), had increased composite outcome of death, myocardial infarction (MI), or stroke (6.8% versus 4.3%, P<0.001), increased death (2.5% versus 1.4%, P<0.001), and MI (4.2% versus 2.6%, P<0.001). Among patients with DM, in a comparison of continued thienopyridine versus placebo, rates of stent thrombosis were 0.5% versus 1.1%, P=0.06, and rates of MI were 3.5% versus 4.8%, P=0.058; and among patients without DM the rates were 0.4% versus 1.4%, P<0.001 (stent thrombosis, P interaction=0.21) and 1.6% versus 3.6%, P<0.001 (MI, P interaction=0.02). Bleeding risk with continued thienopyridine was similar among patients with or without DM (interaction P=0.61). CONCLUSIONS:In patients with DM, continued thienopyridine beyond 1 year after coronary stenting is associated with reduced risk of MI, although this benefit is attenuated in comparison with patients without DM. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00977938.
10.1161/CIRCULATIONAHA.115.016783
Long-term Safety and Efficacy of New-Generation Drug-Eluting Stents in Women With Acute Myocardial Infarction: From the Women in Innovation and Drug-Eluting Stents (WIN-DES) Collaboration.
Giustino Gennaro,Harari Rafael,Baber Usman,Sartori Samantha,Stone Gregg W,Leon Martin B,Windecker Stephan,Serruys Patrick W,Kastrati Adnan,Von Birgelen Clemens,Kimura Takeshi,Stefanini Giulio G,Dangas George D,Wijns William,Steg P Gabriel,Morice Marie-Claude,Camenzind Edoardo,Weisz Giora,Smits Pieter C,Sorrentino Sabato,Sharma Madhav,Farhan Serdar,Faggioni Michela,Kandzari David,Galatius Soren,Jeger Raban V,Valgimigli Marco,Itchhaporia Dipti,Mehta Laxmi,Kim Hyo-Soo,Chieffo Alaide,Mehran Roxana
JAMA cardiology
Importance:Women with acute myocardial infarction (MI) undergoing mechanical reperfusion remain at increased risk of adverse cardiac events and mortality compared with their male counterparts. Whether the benefits of new-generation drug-eluting stents (DES) are preserved in women with acute MI remains unclear. Objective:To investigate the long-term safety and efficacy of new-generation DES vs early-generation DES in women with acute MI. Design, Setting, and Participants:Collaborative, international, individual patient-level data of women enrolled in 26 randomized clinical trials of DES were analyzed between July and December 2016. Only women presenting with an acute coronary syndrome were included. Study population was categorized according to presentation with unstable angina (UA) vs acute MI. Acute MI included non-ST-segment elevation MI (NSTEMI) or ST-segment elevation MI (STEMI). Interventions:Randomization to early- (sirolimus- or paclitaxel-eluting stents) vs new-generation (everolimus-, zotarolimus-, or biolimus-eluting stents) DES. Main Outcomes and Measures:Composite of death, MI or target lesion revascularization, and definite or probable stent thrombosis at 3-year follow-up. Results:Overall, the mean age of participants was 66.8 years. Of 11 577 women included in the pooled data set, 4373 (37.8%) had an acute coronary syndrome as clinical presentation. Of these 4373 women, 2176 (49.8%) presented with an acute MI. In women with acute MI, new-generation DES were associated with lower risk of death, MI or target lesion revascularization (14.9% vs 18.4%; absolute risk difference, -3.5%; number needed to treat [NNT], 29; adjusted hazard ratio, 0.78; 95% CI, 0.61-0.99), and definite or probable stent thrombosis (1.4% vs 4.0%; absolute risk difference, -2.6%; NNT, 46; adjusted hazard ratio, 0.36; 95% CI, 0.19-0.69) without evidence of interaction for both end points compared with women without acute MI (P for interaction = .59 and P for interaction = .31, respectively). A graded absolute benefit with use of new-generation DES was observed in the transition from UA, to NSTEMI, and to STEMI (for death, MI, or target lesion revascularization: UA, -0.5% [NNT, 222]; NSTEMI, -3.1% [NNT, 33]; STEMI, -4.0% [NNT, 25] and for definite or probable ST: UA, -0.4% [NNT, 278]; NSTEMI, -2.2% [NNT, 46]; STEMI, -4.0% [NNT, 25]). Conclusions and Relevance:New-generation DES are associated with consistent and durable benefits over 3 years in women presenting with acute MI. The magnitude of these benefits appeared to be greater per increase in severity of acute coronary syndrome.
10.1001/jamacardio.2017.1978
Thrombus Aspiration in ST-Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration.
Jolly Sanjit S,James Stefan,Džavík Vladimír,Cairns John A,Mahmoud Karim D,Zijlstra Felix,Yusuf Salim,Olivecrona Goran K,Renlund Henrik,Gao Peggy,Lagerqvist Bo,Alazzoni Ashraf,Kedev Sasko,Stankovic Goran,Meeks Brandi,Frøbert Ole
Circulation
BACKGROUND:Thrombus aspiration during percutaneous coronary intervention (PCI) for the treatment of ST-segment-elevation myocardial infarction (STEMI) has been widely used; however, recent trials have questioned its value and safety. In this meta-analysis, we, the trial investigators, aimed to pool the individual patient data from these trials to determine the benefits and risks of thrombus aspiration during PCI in patients with ST-segment-elevation myocardial infarction. METHODS:Included were large (n≥1000), randomized, controlled trials comparing manual thrombectomy and PCI alone in patients with ST-segment-elevation myocardial infarction. Individual patient data were provided by the leadership of each trial. The prespecified primary efficacy outcome was cardiovascular mortality within 30 days, and the primary safety outcome was stroke or transient ischemic attack within 30 days. RESULTS:The 3 eligible randomized trials (TAPAS [Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction], TASTE [Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia], and TOTAL [Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI]) enrolled 19 047 patients, of whom 18 306 underwent PCI and were included in the primary analysis. Cardiovascular death at 30 days occurred in 221 of 9155 patients (2.4%) randomized to thrombus aspiration and 262 of 9151 (2.9%) randomized to PCI alone (hazard ratio, 0.84; 95% confidence interval, 0.70-1.01; P=0.06). Stroke or transient ischemic attack occurred in 66 (0.8%) randomized to thrombus aspiration and 46 (0.5%) randomized to PCI alone (odds ratio, 1.43; 95% confidence interval, 0.98-2.10; P=0.06). There were no significant differences in recurrent myocardial infarction, stent thrombosis, heart failure, or target vessel revascularization. In the subgroup with high thrombus burden (TIMI [Thrombolysis in Myocardial Infarction] thrombus grade ≥3), thrombus aspiration was associated with fewer cardiovascular deaths (170 [2.5%] versus 205 [3.1%]; hazard ratio, 0.80; 95% confidence interval, 0.65-0.98; P=0.03) and with more strokes or transient ischemic attacks (55 [0.9%] versus 34 [0.5%]; odds ratio, 1.56; 95% confidence interval, 1.02-2.42, P=0.04). However, the interaction P values were 0.32 and 0.34, respectively. CONCLUSIONS:Routine thrombus aspiration during PCI for ST-segment-elevation myocardial infarction did not improve clinical outcomes. In the high thrombus burden group, the trends toward reduced cardiovascular death and increased stroke or transient ischemic attack provide a rationale for future trials of improved thrombus aspiration technologies in this high-risk subgroup. CLINICAL TRIAL REGISTRATION:URLs: http://www.ClinicalTrials.gov http://www.crd.york.ac.uk/prospero/. Unique identifiers: NCT02552407 and CRD42015025936.
10.1161/CIRCULATIONAHA.116.025371
Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.
Journal of the American College of Cardiology
BACKGROUND:Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES:This study sought to test the association between the rs9349379 genotype and SCAD. METHODS:Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS:The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS:The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
10.1016/j.jacc.2018.09.085
Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease.
Bansilal Sameer,Bonaca Marc P,Cornel Jan H,Storey Robert F,Bhatt Deepak L,Steg Ph Gabriel,Im Kyungah,Murphy Sabina A,Angiolillo Dominick J,Kiss Robert G,Parkhomenko Alexander N,Lopez-Sendon Jose,Isaza Daniel,Goudev Assen,Kontny Frederic,Held Peter,Jensen Eva C,Braunwald Eugene,Sabatine Marc S,Oude Ophuis A J
Journal of the American College of Cardiology
BACKGROUND:Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events. OBJECTIVES:The authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial. METHODS:Patients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months. RESULTS:A total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HR]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HR: 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p < 0.0001), including a 36% reduction in coronary death (HR: 0.64; 95% confidence interval: 0.48 to 0.85; p = 0.002). In this subgroup, ticagrelor increased the risk of TIMI major bleeding (2.52% vs. 1.08%, HR: 2.67; p < 0.0001), but not ICH or fatal bleeds. CONCLUSIONS:Patients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562).
10.1016/j.jacc.2017.11.050
Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes.
Nanchen David,Gencer Baris,Muller Olivier,Auer Reto,Aghlmandi Soheila,Heg Dik,Klingenberg Roland,Räber Lorenz,Carballo David,Carballo Sebastian,Matter Christian M,Lüscher Thomas F,Windecker Stephan,Mach François,Rodondi Nicolas
Circulation
BACKGROUND:Patients with heterozygous familial hypercholesterolemia (FH) and coronary heart disease have high mortality rates. However, in an era of high-dose statin prescription after acute coronary syndrome (ACS), the risk of recurrent coronary and cardiovascular events associated with FH might be mitigated. We compared coronary event rates between patients with and without FH after ACS. METHODS:We studied 4534 patients with ACS enrolled in a multicenter, prospective cohort study in Switzerland between 2009 and 2013 who were individually screened for FH on the basis of clinical criteria according to 3 definitions: the American Heart Association definition, the Simon Broome definition, and the Dutch Lipid Clinic definition. We used Cox proportional models to assess the 1-year risk of first recurrent coronary events defined as coronary death or myocardial infarction and adjusted for age, sex, body mass index, smoking, hypertension, diabetes mellitus, existing cardiovascular disease, high-dose statin at discharge, attendance at cardiac rehabilitation, and the GRACE (Global Registry of Acute Coronary Events) risk score for severity of ACS. RESULTS:At the 1-year follow-up, 153 patients (3.4%) had died, including 104 (2.3%) of fatal myocardial infarction. A further 113 patients (2.5%) experienced nonfatal myocardial infarction. The prevalence of FH was 2.5% with the American Heart Association definition, 5.5% with the Simon Broome definition, and 1.6% with the Dutch Lipid Clinic definition. Compared with patients without FH, the risk of coronary event recurrence after ACS was similar in patients with FH in unadjusted analyses, although patients with FH were >10 years younger. However, after multivariable adjustment including age, the risk was greater in patients with FH than without, with an adjusted hazard ratio of 2.46 (95% confidence interval, 1.07-5.65; P=0.034) for the American Heart Association definition, 2.73 (95% confidence interval, 1.46-5.11; P=0.002) for the Simon Broome definition, and 3.53 (95% confidence interval, 1.26-9.94; P=0.017) for the Dutch Lipid Clinic definition. Depending on which clinical definition of FH was used, between 94.5% and 99.1% of patients with FH were discharged on statins and between 74.0% and 82.3% on high-dose statins. CONCLUSIONS:Patients with FH and ACS have a >2-fold adjusted risk of coronary event recurrence within the first year after discharge than patients without FH despite the widespread use of high-intensity statins.
10.1161/CIRCULATIONAHA.116.023007
Treatment, Outcomes, and Adherence to Medication Regimens Among Dual Medicare-Medicaid-Eligible Adults With Myocardial Infarction.
Doll Jacob A,Hellkamp Anne S,Goyal Abhinav,Sutton Nadia R,Peterson Eric D,Wang Tracy Y
JAMA cardiology
Importance:Patients with dual Medicare-Medicaid eligibility have a higher burden of chronic disease conditions and increased health care utilization compared with patients with Medicare coverage alone, but the treatment patterns and outcomes of dual-eligible patients with myocardial infarction (MI) are unknown. Objective:To examine the association of dual-eligible status with clinical outcomes and adherence to medication regimens (hereinafter "medication adherence") among older adults after MI. Design, Setting, and Participants:In this retrospective study conducted from February 2015 to April 2016, we linked patients 65 years or older enrolled in a national myocardial infarction registry (the Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines [ACTION Registry-GWTG]) from July 1, 2007, to December 31, 2009, to Medicare claims data to obtain 1-year follow-up and medication adherence data. The ACTION Registry-GWTG is the largest quality-improvement registry of patients with MI in the United States. Included patients were all 65 years or older; had Medicare Parts A, B, and D; presented with MI; and survived to hospital discharge. Exposures:Dual Medicare and Medicaid eligibility. Main Outcomes and Measures:Death, readmission, major adverse cardiovascular events (death, recurrent MI, stroke), and medication adherence at 1 year. Results:Of 17 419 Medicare patients discharged alive after MI, 4674 (27%) were dual eligible. Dual-eligible patients were more likely to be female (64% vs 49%) and nonwhite (29% vs 6%), with a higher prevalence of comorbid conditions and more frequent presentation with non-ST elevation MI (non-STEMI) (75% vs 69%). Dual-eligible patients were less likely to receive primary percutaneous coronary intervention for STEMI (77% vs 81%), revascularization for non-STEMI (58% vs 65%), and prescription of secondary prevention medications at discharge. After multivariable adjustment, dual eligibility status was associated with a higher risk of readmission at 30 days (hazard ratio [HR], 1.16; 95% CI, 1.06-1.26), death at 1 year (HR, 1.24; 95% CI, 1.14-1.36), and major adverse cardiac events at 1 year (HR, 1.21; 95% CI, 1.12-1.31). Dual-eligible patients had higher 1-year adherence to medications prescribed at discharge (HR, 1.55; 95% CI, 1.39-1.74) than Medicare-only patients. Conclusions and Relevance:Compared with Medicare-only patients, older adults with dual Medicare-Medicaid eligibility presenting with MI have superior rates of medication adherence but higher rates of postdischarge readmission and adverse cardiovascular outcomes.
10.1001/jamacardio.2016.2724
Percutaneous Coronary Intervention at Centers With and Without On-Site Surgical Backup: An Updated Meta-Analysis of 23 Studies.
Lee Joo Myung,Hwang Doyeon,Park Jonghanne,Kim Kyung-Jin,Ahn Chul,Koo Bon-Kwon
Circulation
BACKGROUND:Emergency coronary artery bypass grafting for unsuccessful percutaneous coronary intervention (PCI) is now rare. We aimed to evaluate the current safety and outcomes of primary PCI and nonprimary PCI at centers with and without on-site surgical backup. METHODS AND RESULTS:We performed an updated systematic review and meta-analysis by using mixed-effects models. We included 23 high-quality studies that compared clinical outcomes and complication rates of 1 101 123 patients after PCI at centers with or without on-site surgery. For primary PCI for ST-segment-elevation myocardial infarction (133 574 patients), all-cause mortality (without on-site surgery versus with on-site surgery: observed rates, 4.8% versus 7.2%; pooled odds ratio [OR], 0.99; 95% confidence interval, 0.91-1.07; P=0.729; I(2)=3.4%) or emergency coronary artery bypass grafting rates (observed rates, 1.5% versus 2.4%; pooled OR, 0.76; 95% confidence interval, 0.56-1.01; P=0.062; I(2)=42.5%) did not differ by presence of on-site surgery. For nonprimary PCI (967 549 patients), all-cause mortality (observed rates, 1.6% versus 2.1%; pooled OR, 1.15; 95% confidence interval, 0.94-1.41; P=0.172; I(2)=67.5%) and emergency coronary artery bypass grafting rates (observed rates, 0.5% versus 0.8%; pooled OR, 1.14; 95% confidence interval, 0.62-2.13; P=0.669; I(2)=81.7%) were not significantly different. PCI complication rates (cardiogenic shock, stroke, aortic dissection, tamponade, recurrent infarction) also did not differ by on-site surgical capability. Cumulative meta-analysis of nonprimary PCI showed a temporal decrease of the effect size (OR) for all-cause mortality after 2007. CONCLUSIONS:Clinical outcomes and complication rates of PCI at centers without on-site surgery did not differ from those with on-site surgery, for both primary and nonprimary PCI. Temporal trends indicated improving clinical outcomes in nonprimary PCI at centers without on-site surgery.
10.1161/CIRCULATIONAHA.115.016137
Sex-Specific Thresholds of High-Sensitivity Troponin in Patients With Suspected Acute Coronary Syndrome.
Lee Kuan Ken,Ferry Amy V,Anand Atul,Strachan Fiona E,Chapman Andrew R,Kimenai Dorien M,Meex Steven J R,Berry Colin,Findlay Iain,Reid Alan,Cruickshank Anne,Gray Alasdair,Collinson Paul O,Apple Fred S,McAllister David A,Maguire Donogh,Fox Keith A A,Newby David E,Tuck Chris,Keerie Catriona,Weir Christopher J,Shah Anoop S V,Mills Nicholas L,
Journal of the American College of Cardiology
BACKGROUND:Major disparities between women and men in the diagnosis, management, and outcomes of acute coronary syndrome are well recognized. OBJECTIVES:The aim of this study was to evaluate the impact of implementing a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome. METHODS:Consecutive patients with suspected acute coronary syndrome were enrolled in a stepped-wedge, cluster-randomized controlled trial across 10 hospitals. Myocardial injury was defined as high-sensitivity cardiac troponin I concentration >99th centile of 16 ng/l in women and 34 ng/l in men. The primary outcome was recurrent myocardial infarction or cardiovascular death at 1 year. RESULTS:A total of 48,282 patients (47% women) were included. Use of the high-sensitivity cardiac troponin I assay with sex-specific thresholds increased myocardial injury in women by 42% and in men by 6%. Following implementation, women with myocardial injury remained less likely than men to undergo coronary revascularization (15% vs. 34%) and to receive dual antiplatelet (26% vs. 43%), statin (16% vs. 26%), or other preventive therapies (p < 0.001 for all). The primary outcome occurred in 18% (369 of 2,072) and 17% (488 of 2,919) of women with myocardial injury before and after implementation, respectively (adjusted hazard ratio: 1.11; 95% confidence interval: 0.92 to 1.33), compared with 18% (370 of 2,044) and 15% (513 of 3,325) of men (adjusted hazard ratio: 0.85; 95% confidence interval: 0.71 to 1.01). CONCLUSIONS:Use of sex-specific thresholds identified 5 times more additional women than men with myocardial injury. Despite this increase, women received approximately one-half the number of treatments for coronary artery disease as men, and outcomes were not improved. (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]; NCT01852123).
10.1016/j.jacc.2019.07.082
Spontaneous Coronary Artery Dissection Associated With Pregnancy.
Tweet Marysia S,Hayes Sharonne N,Codsi Elisabeth,Gulati Rajiv,Rose Carl H,Best Patricia J M
Journal of the American College of Cardiology
BACKGROUND:Spontaneous coronary artery dissection (SCAD) is the most common cause of pregnancy-associated myocardial infarction and remains poorly characterized. OBJECTIVES:This study sought to assess presentation, clinical factors, and outcomes of pregnancy-associated spontaneous coronary artery dissection (P-SCAD) compared with spontaneous coronary artery dissection not associated with pregnancy (NP-SCAD). METHODS:A Mayo Clinic registry was established in 2010 to include comprehensive retrospective and prospective SCAD data. Records were reviewed to identify women who were pregnant or ≤12 weeks postpartum at time of SCAD. Complete records were available for 323 women; 54 women met criteria for P-SCAD (4 during pregnancy) and they were compared with 269 women with NP-SCAD. RESULTS:Most events occurred within the first month postpartum (35 of 50). Compared with NP-SCAD, P-SCAD patients more frequently presented with ST-segment elevation myocardial infarction (57% vs. 36%; p = 0.009), left main or multivessel SCAD (24% vs. 5%; p < 0.0001; and 33% vs. 14%; p = 0.0027, respectively), and left ventricular function ≤35% (26% vs. 10%; p = 0.0071). Among women with imaging of other vascular territories, P-SCAD was less likely with a diagnosis of fibromuscular dysplasia and extracoronary vascular abnormalities (42% vs. 64%; p = 0.047; and 46% vs. 77%; p = 0.0032, respectively). Compared with U.S. birth data, women with P-SCAD were more often multiparous (p = 0.0167), had a history of infertility therapies (p = 0.0004), and had pre-eclampsia (p = 0.001). On long-term follow-up (median 2.3 years) recurrent SCAD occurred in 51 patients, with no difference in the Kaplan Meier 5-year recurrence rates (10% vs. 23%; p = 0.18). CONCLUSIONS:P-SCAD patients had more acute presentations and high-risk features than women with NP-SCAD did. The highest frequency of P-SCAD occurred during the first postpartum month and P-SCAD patients less often had extracoronary vascular abnormalities. Hormonal, hemodynamic variations, and yet-undefined mechanisms might be significant contributors to P-SCAD. (The "Virtual" Multicenter Spontaneous Coronary Artery Dissection [SCAD] Registry [SCAD]; NCT01429727; Genetic Investigations in Spontaneous Coronary Artery Dissection [SCAD]; NCT01427179).
10.1016/j.jacc.2017.05.055
Prevalence, Clinical Features, and Prognosis of Acute Myocardial Infarction Attributable to Coronary Artery Embolism.
Shibata Tatsuhiro,Kawakami Shoji,Noguchi Teruo,Tanaka Tomotaka,Asaumi Yasuhide,Kanaya Tomoaki,Nagai Toshiyuki,Nakao Kazuhiro,Fujino Masashi,Nagatsuka Kazuyuki,Ishibashi-Ueda Hatsue,Nishimura Kunihiro,Miyamoto Yoshihiro,Kusano Kengo,Anzai Toshihisa,Goto Yoichi,Ogawa Hisao,Yasuda Satoshi
Circulation
BACKGROUND:Coronary artery embolism (CE) is recognized as an important nonatherosclerotic cause of acute myocardial infarction. Its prevalence, clinical features, and prognosis remain insufficiently characterized. METHODS AND RESULTS:We screened 1776 consecutive patients who presented with de novo acute myocardial infarction between 2001 and 2013. CE was diagnosed based on criteria encompassing histological, angiographic, and other diagnostic imaging findings. The prevalence, clinical characteristics, treatment strategies, in-hospital outcomes, and long-term risk of CE recurrence or major adverse cardiac and cerebrovascular events (cardiac death, fatal arrhythmia, or recurrent thromboembolism) were evaluated. The prevalence of CE was 2.9% (n=52), including 8 (15%) patients with multivessel CE. Atrial fibrillation was the most common cause (n=38, 73%). Only 39% of patients with CE were treated with vitamin K antagonists, and the median international normalized ratio was 1.42 (range, 0.95-1.80). Eighteen of the 30 CE patients with nonvalvular atrial fibrillation had a CHADS2 score of 0 or 1. When those patients were reevaluated using CHA2DS2-VASc, 61% were reassigned to a higher risk category. During a median follow-up of 49 months, CE and thromboembolism recurred in 5 atrial fibrillation patients. The 5-year rate of major adverse cardiac and cerebrovascular events was 27.1%. In the propensity score-matched cohorts (n=45 each), Kaplan-Meier analysis showed a significantly higher incidence of cardiac death in the CE group than in the non-CE group (hazard ratio, 9.29; 95% confidence interval, 1.13-76.5; P<0.001). CONCLUSIONS:Atrial fibrillation is the most frequent cause of CE. Patients with CE represent a high-risk subgroup of patients with acute myocardial infarction and require close follow-up.
10.1161/CIRCULATIONAHA.114.015134
Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography.
Gaggin Hanna K,Liu Yuyin,Lyass Asya,van Kimmenade Roland R J,Motiwala Shweta R,Kelly Noreen P,Mallick Aditi,Gandhi Parul U,Ibrahim Nasrien E,Simon Mandy L,Bhardwaj Anju,Belcher Arianna M,Harisiades Jamie E,Massaro Joseph M,D'Agostino Ralph B,Januzzi James L
Circulation
BACKGROUND:Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome. METHODS:A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection. RESULTS:One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P<0.001; all-cause death, 23.3 versus 3.3, P<0.001; cardiovascular death, 17.5 versus 2.6, P<0.001; heart failure events, 22.4 versus 7.4, P<0.001); these rates are similar to those seen in patients with type 1 MI. Incident diagnosis of T2MI strongly predicted risk for subsequent MACE (adjusted hazard ratio, 1.90; 95% confidence interval, 1.46-2.48; P<0.001), all-cause death (adjusted hazard ratio, 2.96; 95% confidence interval, 2.01-4.36; P<0.001), and cardiovascular death (adjusted hazard ratio, 2.16; 95% confidence interval, 1.36-3.43; P=0.001). CONCLUSIONS:T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842868.
10.1161/CIRCULATIONAHA.116.023052
Statin Intolerance and Risk of Coronary Heart Events and All-Cause Mortality Following Myocardial Infarction.
Serban Maria-Corina,Colantonio Lisandro D,Manthripragada Angelika D,Monda Keri L,Bittner Vera A,Banach Maciej,Chen Ligong,Huang Lei,Dent Ricardo,Kent Shia T,Muntner Paul,Rosenson Robert S
Journal of the American College of Cardiology
BACKGROUND:Many patients report adverse reactions to, and may not tolerate, statin therapy. These patients may be at increased risk for coronary heart disease (CHD) events and mortality. OBJECTIVES:This study evaluated the risk for recurrent myocardial infarction (MI), CHD events, and all-cause mortality in Medicare beneficiaries with statin intolerance and in those with high adherence to statin therapy. METHODS:We studied 105,329 Medicare beneficiaries who began a moderate- or high-intensity statin dosage after hospitalization for MI between 2007 and 2013. Statin intolerance was defined as down-titrating statins and initiating ezetimibe therapy, switching from statins to ezetimibe monotherapy, having International Classification of Diseases, 9th revision, diagnostic codes for rhabdomyolysis or an antihyperlipidemic adverse event, followed by statin down-titration or discontinuation, or switching between ≥3 types of statins within 1 year after initiation. High statin adherence over the year following hospital discharge was defined as proportion of days covered ≥80%. Recurrent MI, CHD events (recurrent MI or a coronary revascularization procedure), and mortality were identified from 1 year after hospital discharge through December 2014. RESULTS:Overall, 1,741 patients (1.65%) had statin intolerance, and 55,567 patients (52.8%) had high statin adherence. Over a median of 1.9 to 2.3 years of follow-up, there were 4,450 recurrent MIs, 6,250 CHD events, and 14,311 deaths. Compared to beneficiaries with high statin adherence, statin intolerance was associated with a 36% higher rate of recurrent MI (41.1 vs. 30.1 per 1,000 person-years, respectively), a 43% higher rate of CHD events (62.5 vs. 43.8 per 1,000 person-years, respectively), and a 15% lower rate of all-cause mortality (79.9 vs. 94.2 per 1,000 person-years, respectively). The multivariate-adjusted hazard ratios (HR) comparing beneficiaries with statin intolerance versus those with high statin adherence were 1.50 (95% confidence interval [CI]: 1.30 to 1.73) for recurrent MI, 1.51 (95% CI: 1.34 to 1.70) for CHD events, and 0.96 (95% CI: 0.87 to 1.06) for all-cause mortality. CONCLUSIONS:Statin intolerance was associated with an increased risk for recurrent MI and CHD events but not all-cause mortality.
10.1016/j.jacc.2016.12.036
Long-Term Evolution of Premature Coronary Artery Disease.
Collet Jean-Philippe,Zeitouni Michel,Procopi Niki,Hulot Jean-Sébastien,Silvain Johanne,Kerneis Mathieu,Thomas Daniel,Lattuca Benoit,Barthelemy Olivier,Lavie-Badie Yoan,Esteve Jean-Baptiste,Payot Laurent,Brugier Delphine,Lopes Izolina,Diallo Abdourahmane,Vicaut Eric,Montalescot Gilles,
Journal of the American College of Cardiology
BACKGROUND:The long-term evolution of premature coronary artery disease (CAD) is unknown. OBJECTIVES:The objective of this study was to describe the evolution of coronary atherosclerosis in young patients and identify the risk factors of poor outcomes. METHODS:Participants age ≤45 years with acute or stable obstructive CAD were prospectively enrolled and followed. The primary endpoint was all-cause death, myocardial infarction (MI), refractory angina requiring coronary revascularization, and ischemic stroke. RESULTS:Eight hundred-eighty patients with premature CAD were included. They were age 40.1 ± 5.7 years, mainly men, smokers, with a family history of CAD or hypercholesterolemia. At baseline presentation, 91.2% underwent coronary revascularization, predominantly for acute MI (78.8%). Over a follow-up of 20 years, one-third (n = 264) of patients presented with a total of 399 ischemic events, and 36% had at least a second recurrent event. MI was the most frequent first recurrent event (n = 131 of 264), mostly related to new coronary lesions (17.3% vs. 7.8%; p = 0.01; hazard ratio [HR]:1.45; 95% confidence interval [CI]: 1.09 to 1.93 for new vs. initial culprit lesion). All-cause death (n = 55; 6.3%) occurred at 8.4 years (median time). Ethnic origin (sub-Saharan African vs. Caucasian, adjusted hazard ratio [adjHR]: 1.95; 95% CI: 1.13 to 3.35; p = 0.02), inflammatory disease (adjHR: 1.58; 95% CI: 1.05 to 2.36; p = 0.03), and persistent smoking (adjHR: 2.32; 95% CI: 1.63 to 3.28; p < 0.01) were the strongest correlates of a first recurrent event. When considering all recurrent events, the same factors and Asian ethnicity predicted poor outcome, but persistent smoking had the greatest impact on prognosis. CONCLUSIONS:Premature CAD is an aggressive disease despite the currently recommended prevention measures, with high rates of recurrent events and mortality. Ethnicity and concomitant inflammatory disease are associated with poor prognoses, along with insufficient control of risk factors.
10.1016/j.jacc.2019.08.1002
Atherosclerotic Burden and Heart Failure After Myocardial Infarction.
Gerber Yariv,Weston Susan A,Enriquez-Sarano Maurice,Manemann Sheila M,Chamberlain Alanna M,Jiang Ruoxiang,Roger Véronique L
JAMA cardiology
IMPORTANCE:Whether the extent of coronary artery disease (CAD) is associated with the occurrence of heart failure (HF) after myocardial infarction (MI) is not known. Furthermore, whether this association might differ by HF type according to preserved or reduced ejection fraction (EF) has yet to be determined. OBJECTIVES:To evaluate in a community cohort of patients with incident (first-ever) MI the association of angiographic CAD with subsequent HF and to examine the prognostic role of CAD according to HF subtypes: HF with reduced EF and HF with preserved EF. DESIGN, SETTING, AND PARTICIPANTS:A population-based cohort study was conducted in 1922 residents of Olmsted County, Minnesota, with incident MI diagnosed between January 1, 1990, and December 31, 2010, and no prior HF; study participants were followed up through March 31, 2013. The extent of angiographic CAD was determined at baseline and categorized according to the number of major epicardial coronary arteries with 50% or more lumen diameter obstruction. MAIN OUTCOMES AND MEASURES:The primary end point was time to incident HF. The primary exposure variable was the extent of CAD as expressed by the number of major coronary arteries with significant obstruction (0-, 1-, 2-, or 3-vessel disease) obtained from coronary angiograms performed no more than 1 day after the MI. Heart failure was ascertained by the Framingham criteria and classified by type according to EF (50% cutoff). RESULTS:Of the 1922 participants, 1258 (65.4%) were men (mean [SD] age, 64 [13] years). During a mean follow-up period of 6.7 (5.9) years, 588 patients (30.6%) developed HF. With death and recurrent MI modeled as competing risks, the cumulative incidence rates of post-MI HF among patients with 0 or 1, 2, and 3 diseased vessels were 10.7%, 14.6%, and 23.0% at 30 days; and 14.7%, 20.6%, and 29.8% at 5 years, respectively (P < .001 for trend). After adjustment for clinical characteristics in a Cox proportional hazards regression model, the hazard ratios (95% CIs) for HF were 1.25 (0.99-1.59) and 1.75 (1.40-2.20) in patients with 2 and 3 vessels vs 0 or 1 occluded vessel, respectively (P < .001 for trend). The increased risk with a greater number of occluded vessels was independent of the occurrence of a recurrent MI and did not differ appreciably by HF type. CONCLUSIONS AND RELEVANCE:The extent of angiographic CAD is an indicator of post-MI HF regardless of HF type and independent of recurrent MI. These data underscore the need to further investigate the processes taking place in the transition from myocardial injury to HF.
10.1001/jamacardio.2016.0074
Galectin-3 Levels and Outcomes After Myocardial Infarction: A Population-Based Study.
Asleh Rabea,Enriquez-Sarano Maurice,Jaffe Allan S,Manemann Sheila M,Weston Susan A,Jiang Ruoxiang,Roger Véronique L
Journal of the American College of Cardiology
BACKGROUND:Galectin-3 (Gal-3) is implicated in cardiac fibrosis, but its association with adverse outcomes after myocardial infarction (MI) is unknown. OBJECTIVES:The purpose of this study was to examine the prognostic value of Gal-3 in a community cohort of incident MI. METHODS:A population-based incidence MI cohort was prospectively assembled in Olmsted County, Minnesota, between 2002 and 2012. Gal-3 levels were measured at the time of MI. Patients were followed for heart failure (HF) and death. RESULTS:A total of 1,342 patients were enrolled (mean age 67.1 years; 61.3% male; 78.8% non-ST-segment elevation MI). Patients with elevated Gal-3 were older and had more comorbidities. Over a mean follow-up of 5.4 years, 484 patients (36.1%) died and 368 (27.4%) developed HF. After adjustment for age, sex, comorbidities, and troponin, patients with Gal-3 values in tertiles 2 and 3 had a 1.3-fold (95% confidence interval [CI]: 0.9-fold to 1.7-fold) and a 2.4-fold (95% CI: 1.8-fold to 3.2-fold) increased risk of death, respectively (p < 0.001) compared with patients with Gal-3 values in tertile 1. Patients with Gal-3 values in tertiles 2 and 3 had a higher risk of HF with hazard ratios of 1.4 (95% CI: 1.0 to 2.0) and 2.3 (95% CI: 1.6 to 3.2), respectively (p < 0.001). With further adjustment for soluble suppression of tumorigenicity-2, elevated Gal-3 remained associated with increased risk of death and HF. The increased risk of HF did not differ by HF type and was independent of the occurrence of recurrent MI. CONCLUSIONS:Gal-3 is an independent predictor of mortality and HF post-MI. These findings suggest a role for measuring Gal-3 levels for risk stratification post-MI.
10.1016/j.jacc.2019.02.046
Proenkephalin and prognosis after acute myocardial infarction.
Ng Leong L,Sandhu Jatinderpal K,Narayan Hafid,Quinn Paulene A,Squire Iain B,Davies Joan E,Bergmann Andreas,Maisel Alan,Jones Donald J L
Journal of the American College of Cardiology
OBJECTIVES:The goal of this research was to assess the prognostic value of proenkephalin (PENK) levels in acute myocardial infarction (AMI) by using N-terminal pro-B-type natriuretic peptide and Global Registry of Acute Coronary Events (GRACE) scores as comparators and to identify levels that might be valuable in clinical decision making. BACKGROUND:PENK is a stable analyte of labile enkephalins. Few biomarkers predict recurrent AMI. METHODS:We measured PENK in 1,141 patients (820 male subjects; mean age 66.2 ± 12.8 years) with AMI. Endpoints were major adverse events (composite of death, myocardial infarction [MI], and heart failure [HF] hospitalization) and recurrent MI at 2 years. GRACE scoring was used for comparisons with PENK for the death and/or MI endpoint at 6 months. RESULTS:During follow-up, 139 patients died, and there were 112 HF hospitalizations and 149 recurrent AMIs. PENK levels were highest on admission and were related to estimated glomerular filtration rate, left ventricular wall motion index, sex, blood pressure, and age. Multivariable Cox regression models found that the PENK level was a predictor of major adverse events (hazard ratio [HR]: 1.52 [95% confidence interval (CI): 1.19 to 1.94]), death and/or AMI (HR: 1.76 [95% CI: 1.34 to 2.30]), and death and/or HF (HR: 1.67 [95% CI: 1.24 to 2.25]) (all comparisons p < 0.001), as well as recurrent AMI (HR: 1.43 [95% CI: 1.07 to 1.91]; p < 0.01). PENK levels were independent predictors of 6-month death and/or MI compared with GRACE scores. PENK-adjusted GRACE scores reclassified patients significantly (overall category-free net reclassification improvement [>0] of 21.9 [95% CI: 4.5 to 39.4]; p < 0.014). PENK levels <48.3 pmol/l and >91 pmol/l detected low- and high-risk patients, respectively. CONCLUSIONS:PENK levels reflect cardiorenal status post-AMI and are prognostic for death, recurrent AMI, or HF. Cutoff values define low- and high-risk groups and improve risk prediction of GRACE scores.
10.1016/j.jacc.2013.09.037
Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial.
Gershlick Anthony H,Khan Jamal Nasir,Kelly Damian J,Greenwood John P,Sasikaran Thiagarajah,Curzen Nick,Blackman Daniel J,Dalby Miles,Fairbrother Kathryn L,Banya Winston,Wang Duolao,Flather Marcus,Hetherington Simon L,Kelion Andrew D,Talwar Suneel,Gunning Mark,Hall Roger,Swanton Howard,McCann Gerry P
Journal of the American College of Cardiology
BACKGROUND:The optimal management of patients found to have multivessel disease while undergoing primary percutaneous coronary intervention (P-PCI) for ST-segment elevation myocardial infarction is uncertain. OBJECTIVES:CvLPRIT (Complete versus Lesion-only Primary PCI trial) is a U.K. open-label randomized study comparing complete revascularization at index admission with treatment of the infarct-related artery (IRA) only. METHODS:After they provided verbal assent and underwent coronary angiography, 296 patients in 7 U.K. centers were randomized through an interactive voice-response program to either in-hospital complete revascularization (n = 150) or IRA-only revascularization (n = 146). Complete revascularization was performed either at the time of P-PCI or before hospital discharge. Randomization was stratified by infarct location (anterior/nonanterior) and symptom onset (≤ 3 h or >3 h). The primary endpoint was a composite of all-cause death, recurrent myocardial infarction (MI), heart failure, and ischemia-driven revascularization within 12 months. RESULTS:Patient groups were well matched for baseline clinical characteristics. The primary endpoint occurred in 10.0% of the complete revascularization group versus 21.2% in the IRA-only revascularization group (hazard ratio: 0.45; 95% confidence interval: 0.24 to 0.84; p = 0.009). A trend toward benefit was seen early after complete revascularization (p = 0.055 at 30 days). Although there was no significant reduction in death or MI, a nonsignificant reduction in all primary endpoint components was seen. There was no reduction in ischemic burden on myocardial perfusion scintigraphy or in the safety endpoints of major bleeding, contrast-induced nephropathy, or stroke between the groups. CONCLUSIONS:In patients presenting for P-PCI with multivessel disease, index admission complete revascularization significantly lowered the rate of the composite primary endpoint at 12 months compared with treating only the IRA. In such patients, inpatient total revascularization may be considered, but larger clinical trials are required to confirm this result and specifically address whether this strategy is associated with improved survival.
10.1016/j.jacc.2014.12.038
Unloading the Left Ventricle Before Reperfusion in Patients With Anterior ST-Segment-Elevation Myocardial Infarction.
Kapur Navin K,Alkhouli Mohamad A,DeMartini Tony J,Faraz Haroon,George Zachary H,Goodwin Mark J,Hernandez-Montfort Jaime A,Iyer Vijay S,Josephy Noam,Kalra Sanjog,Kaki Amir,Karas Richard H,Kimmelstiel Carey D,Koenig Gerald C,Lau Evan,Lotun Kapildeo,Madder Ryan D,Mannino Salvatore F,Meraj Perwaiz M,Moreland Jason A,Moses Jeffrey W,Kim Raymond L,Schreiber Theodore L,Udelson James E,Witzke Christian,Wohns David H W,O'Neill William W
Circulation
BACKGROUND:In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. METHODS:In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. RESULTS:All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53). CONCLUSIONS:We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270.
10.1161/CIRCULATIONAHA.118.038269
Randomized Trial Evaluating Percutaneous Coronary Intervention for the Treatment of Chronic Total Occlusion.
Lee Seung-Whan,Lee Pil Hyung,Ahn Jung-Min,Park Duk-Woo,Yun Sung-Cheol,Han Seungbong,Kang Heejun,Kang Soo-Jin,Kim Young-Hak,Lee Cheol Whan,Park Seong-Wook,Hur Seung Ho,Rha Seung-Woon,Her Sung-Ho,Choi Si Wan,Lee Bong-Ki,Lee Nae-Hee,Lee Jong-Young,Cheong Sang-Sig,Kim Moo Hyun,Ahn Young-Keun,Lim Sang Wook,Lee Sang-Gon,Hiremath Shirish,Santoso Teguh,Udayachalerm Wasan,Cheng Jun Jack,Cohen David J,Muramatsu Toshiya,Tsuchikane Etsuo,Asakura Yasushi,Park Seung-Jung
Circulation
BACKGROUND:Procedural results for percutaneous coronary intervention (PCI) in coronary vessels with chronic total occlusion (CTO) have improved in recent years, and PCI strategies have moved toward more complete revascularization with more liberal use of CTO-PCI. However, evidence evaluating CTO-PCI is limited to observational studies and small clinical trials. METHODS:In this open-label, multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either 1 of 2 strategies: PCI or no PCI for the qualifying de novo CTO lesion with the option for PCI of obstructive non-CTO lesions at the discretion of the operator. The primary end point was a composite of death, myocardial infarction, stroke, or any revascularization. Health-related quality of life was assessed at baseline and at 1, 6, 12, 24, and 36 months. Because of slow recruitment, the trial was stopped before completion of the 1284 planned enrollments. RESULTS:Between March 2010 and September 2016, 834 patients were randomly assigned to the CTO-PCI (n=417) or no CTO-PCI (n=398) strategy. Among the patients assigned to the no CTO-PCI strategy, 78 (19.6%) crossed over to receive staged CTO-PCI within 3 days of randomization. The overall CTO-PCI success rate was 90.6%. Serious nonfatal complications associated with CTO-PCI occurred in 3 patients (1 stroke, 1 cardiac tamponade, and 1 patient with recurrent episodes of ventricular tachyarrhythmia induced by intracoronary thrombus). Approximately half of the patients in each group underwent PCI for an average of 1.3 non-CTO lesions, resulting in a comparable residual SYNTAX score (Synergy Between PCI With TAXUS and Cardiac Surgery; 3.7±5.4 versus 4.0±5.9, P=0.42) confined to non-CTO vessels. During a median follow-up of 4.0 years (interquartile range, 2.4 to 5.1 years), there was no significant difference between the CTO-PCI and the no CTO-PCI strategies in the incidence of the primary end point (22.3% versus 22.4%, hazard ratio, 1.03; 95% CI, 0.77 to 1.37; P=0.86). Both CTO-PCI and no CTO-PCI strategy were associated with significant improvements but without between-group differences in disease-specific health status that was sustained through 36 months. CONCLUSIONS:CTO-PCI was feasible with high success rates. There was no difference in the incidence of major adverse cardiovascular events with CTO-PCI versus no CTO-PCI, but the study was limited by low power for clinical end points and high crossover rates between groups. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT01078051.
10.1161/CIRCULATIONAHA.118.031313
Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial.
Murphy Sabina A,Pedersen Terje R,Gaciong Zbigniew A,Ceska Richard,Ezhov Marat V,Connolly Derek L,Jukema J Wouter,Toth Kalman,Tikkanen Matti J,Im Kyungah,Wiviott Stephen D,Kurtz Christopher E,Honarpour Narimon,Giugliano Robert P,Keech Anthony C,Sever Peter S,Sabatine Marc S
JAMA cardiology
Importance:The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events. Objective:To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists. Design, Setting, and Participants:Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019. Main Outcomes and Measures:The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms. Results:The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P < .001) including both first events (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001) and subsequent events (RR, 0.74; 95% CI, 0.65-0.85). There were 2192 total primary events in the evolocumab group and 2714 total events in the placebo group. For every 1000 patients treated for 3 years, evolocumab prevented 22 first PEP events and 52 total PEP events. Reductions in total events were driven by fewer total myocardial infarctions (RR, 0.74; 95% CI, 0.65-0.84; P < .001), strokes (RR, 0.77; 95% CI, 0.64-0.93; P = .007), and coronary revascularizations (RR, 0.78; 95% CI, 0.71-0.87; P < .001). Conclusions and Relevance:The addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes, with significant reductions in total PEP events, driven by decreases in myocardial infarction, stroke, and coronary revascularization. More than double the number of events were prevented with evolocumab vs placebo as compared with the analysis of only first events. These data provide further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events. Trial Registration:ClinicalTrials.gov identifier: NCT01764633.
10.1001/jamacardio.2019.0886
Rivaroxaban Plus Aspirin Versus Aspirin in Relation to Vascular Risk in the COMPASS Trial.
Anand Sonia S,Eikelboom John W,Dyal Leanne,Bosch Jackie,Neumann Christoph,Widimsky Petr,Avezum Alvaro A,Probstfield Jeffrey,Cook Bruns Nancy,Fox Keith A A,Bhatt Deepak L,Connolly Stuart J,Yusuf Salim,
Journal of the American College of Cardiology
BACKGROUND:The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease. OBJECTIVES:The purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy. METHODS:COMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit. RESULTS:High-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months. CONCLUSIONS:In patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.
10.1016/j.jacc.2019.02.079
Intraaortic Balloon Pump in Cardiogenic Shock Complicating Acute Myocardial Infarction: Long-Term 6-Year Outcome of the Randomized IABP-SHOCK II Trial.
Thiele Holger,Zeymer Uwe,Thelemann Nathalie,Neumann Franz-Josef,Hausleiter Jörg,Abdel-Wahab Mohamed,Meyer-Saraei Roza,Fuernau Georg,Eitel Ingo,Hambrecht Rainer,Böhm Michael,Werdan Karl,Felix Stephan B,Hennersdorf Marcus,Schneider Steffen,Ouarrak Taoufik,Desch Steffen,de Waha-Thiele Suzanne, ,
Circulation
BACKGROUND:The role of intraaortic balloon counterpulsation (IABP) in cardiogenic shock is still a subject of intense debate despite the neutral results of the IABP-SHOCK II trial (Intraaortic Balloon Pump in Cardiogenic Shock II) with subsequent downgrading in international guidelines. So far, randomized data on the impact of IABP on long-term clinical outcomes in patients with cardiogenic shock complicating acute myocardial infarction are lacking. Furthermore, only limited evidence is available on general long-term outcomes of patients with cardiogenic shock treated by contemporary practice. METHODS:The IABP-SHOCK II trial is a multicenter, randomized, open-label trial. Between 2009 and 2012, 600 patients with cardiogenic shock complicating acute myocardial infarction undergoing early revascularization were randomized to IABP versus control. RESULTS:Long-term follow-up was performed 6.2 years (interquartile range 5.6-6.7) after initial randomization. Follow-up was completed for 591 of 600 patients (98.5%). Mortality was not different between the IABP and the control group (66.3% versus 67.0%; relative risk, 0.99; 95% CI, 0.88-1.11; =0.98). There were also no differences in recurrent myocardial infarction, stroke, repeat revascularization, or rehospitalization for cardiac reasons (all >0.05). Survivors' quality of life as assessed by the EuroQol 5D questionnaire and the New York Heart Association class did not differ between groups. CONCLUSIONS:IABP has no effect on all-cause mortality at 6-year long-term follow-up. Mortality is still very high, with two thirds of patients with cardiogenic shock dying despite contemporary treatment with revascularization therapy. CLINICAL TRIAL REGISTRATION:URL: https://www. CLINICALTRIALS:gov/. Unique identifier: NCT00491036.
10.1161/CIRCULATIONAHA.118.038201
One-Year Outcomes after PCI Strategies in Cardiogenic Shock.
Thiele Holger,Akin Ibrahim,Sandri Marcus,de Waha-Thiele Suzanne,Meyer-Saraei Roza,Fuernau Georg,Eitel Ingo,Nordbeck Peter,Geisler Tobias,Landmesser Ulf,Skurk Carsten,Fach Andreas,Jobs Alexander,Lapp Harald,Piek Jan J,Noc Marko,Goslar Tomaž,Felix Stephan B,Maier Lars S,Stepinska Janina,Oldroyd Keith,Serpytis Pranas,Montalescot Gilles,Barthelemy Olivier,Huber Kurt,Windecker Stephan,Hunziker Lukas,Savonitto Stefano,Torremante Patrizia,Vrints Christiaan,Schneider Steffen,Zeymer Uwe,Desch Steffen,
The New England journal of medicine
BACKGROUND:Among patients with acute myocardial infarction, cardiogenic shock, and multivessel coronary artery disease, the risk of a composite of death from any cause or severe renal failure leading to renal-replacement therapy at 30 days was found to be lower with percutaneous coronary intervention (PCI) of the culprit lesion only than with immediate multivessel PCI. We evaluated clinical outcomes at 1 year. METHODS:We randomly assigned 706 patients to either culprit-lesion-only PCI or immediate multivessel PCI. The results for the primary end point of death or renal-replacement therapy at 30 days have been reported previously. Prespecified secondary end points at 1 year included death from any cause, recurrent myocardial infarction, repeat revascularization, rehospitalization for congestive heart failure, the composite of death or recurrent infarction, and the composite of death, recurrent infarction, or rehospitalization for heart failure. RESULTS:As reported previously, at 30 days, the primary end point had occurred in 45.9% of the patients in the culprit-lesion-only PCI group and in 55.4% in the multivessel PCI group (P=0.01). At 1 year, death had occurred in 172 of 344 patients (50.0%) in the culprit-lesion-only PCI group and in 194 of 341 patients (56.9%) in the multivessel PCI group (relative risk, 0.88; 95% confidence interval [CI], 0.76 to 1.01). The rate of recurrent infarction was 1.7% with culprit-lesion-only PCI and 2.1% with multivessel PCI (relative risk, 0.85; 95% CI, 0.29 to 2.50), and the rate of a composite of death or recurrent infarction was 50.9% and 58.4%, respectively (relative risk, 0.87; 95% CI, 0.76 to 1.00). Repeat revascularization occurred more frequently with culprit-lesion-only PCI than with multivessel PCI (in 32.3% of the patients vs. 9.4%; relative risk, 3.44; 95% CI, 2.39 to 4.95), as did rehospitalization for heart failure (5.2% vs. 1.2%; relative risk, 4.46; 95% CI, 1.53 to 13.04). CONCLUSIONS:Among patients with acute myocardial infarction and cardiogenic shock, the risk of death or renal-replacement therapy at 30 days was lower with culprit-lesion-only PCI than with immediate multivessel PCI, and mortality did not differ significantly between the two groups at 1 year of follow-up. (Funded by the European Union Seventh Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).
10.1056/NEJMoa1808788
Comparison of prasugrel and clopidogrel in patients with non-cardioembolic ischaemic stroke: a phase 3, randomised, non-inferiority trial (PRASTRO-I).
Ogawa Akira,Toyoda Kazunori,Kitagawa Kazuo,Kitazono Takanari,Nagao Takehiko,Yamagami Hiroshi,Uchiyama Shinichiro,Tanahashi Norio,Matsumoto Masayasu,Minematsu Kazuo,Nagata Izumi,Nishikawa Masakatsu,Nanto Shinsuke,Abe Kenji,Ikeda Yasuo,
The Lancet. Neurology
BACKGROUND:The effect of prasugrel in terms of the prevention of recurrence of ischaemic stroke is unknown. We investigated the non-inferiority of prasugrel to clopidogrel for prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes in Japanese patients with non-cardioembolic stroke. METHODS:In this phase 3 randomised, double-blind, non-inferiority trial, patients aged 20-74 years who had had a non-cardioembolic stroke in the previous 1-26 weeks were recruited from 224 hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive prasugrel (3·75 mg/day) or clopidogrel (75 mg/day) orally for 96-104 weeks. Randomisation was stratified according to stroke subtype. The randomisation schedule was generated by an independent statistician who created a computer-generated random number sequence. Patients, investigators, and the funder were masked to treatment allocation. The primary endpoint was combined incidence of ischaemic stroke (fatal and non-fatal), myocardial infarction (fatal and non-fatal), and death from other vascular causes in the intention-to-treat population. The safety endpoint was incidence of bleeding events, comprising life-threatening bleeding, major bleeding, and clinically relevant bleeding. The safety analysis was done in the population excluding trial patients with serious Good Clinical Practice violations, and those who had not taken the trial drug. The predefined non-inferiority margin was an upper 95% CI limit for the risk ratio (RR) of 1·35. The trial was registered with the Japan Pharmaceutical Information Center (JapicCTI-111582). FINDINGS:Patients were recruited between Sept 1, 2011, and June 12, 2015. 3747 patients (797 [21%] women) were enrolled, with a mean age of 62·1 (SD 8·5) years. 3753 patients were randomly assigned to treatment and, of these patients, 1885 in the prasugrel group and 1862 in the clopidogrel group were confirmed to have taken the trial drug at least once, and six patients withdrew from the trial before administration of the trial drug. Thus, a total of 3747 patients were included in the full analysis set. 73 (4%) of 1885 patients in the prasugrel group and 69 (4%) of 1862 patients in the clopidogrel group reached the primary endpoint (RR 1·05, 95% CI 0·76-1·44). The incidence of bleeding events was not significantly different between treatment groups; life-threatening bleeding was observed in 18 (1%) patients in the prasugrel group and 23 (1%) patients in the clopidogrel group (RR 0·77, 0·41-1·42). INTERPRETATION:The non-inferiority of prasugrel to clopidogrel for the prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes was not confirmed in Japanese patients with non-cardioembolic stroke. No safety concerns were identified. FUNDING:Daiichi Sankyo.
10.1016/S1474-4422(18)30449-6
Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs.
Sapp John L,Wells George A,Parkash Ratika,Stevenson William G,Blier Louis,Sarrazin Jean-Francois,Thibault Bernard,Rivard Lena,Gula Lorne,Leong-Sit Peter,Essebag Vidal,Nery Pablo B,Tung Stanley K,Raymond Jean-Marc,Sterns Laurence D,Veenhuyzen George D,Healey Jeff S,Redfearn Damian,Roux Jean-Francois,Tang Anthony S L
The New England journal of medicine
BACKGROUND:Recurrent ventricular tachycardia among survivors of myocardial infarction with an implantable cardioverter-defibrillator (ICD) is frequent despite antiarrhythmic drug therapy. The most effective approach to management of this problem is uncertain. METHODS:We conducted a multicenter, randomized, controlled trial involving patients with ischemic cardiomyopathy and an ICD who had ventricular tachycardia despite the use of antiarrhythmic drugs. Patients were randomly assigned to receive either catheter ablation (ablation group) with continuation of baseline antiarrhythmic medications or escalated antiarrhythmic drug therapy (escalated-therapy group). In the escalated-therapy group, amiodarone was initiated if another agent had been used previously. The dose of amiodarone was increased if it had been less than 300 mg per day or mexiletine was added if the dose was already at least 300 mg per day. The primary outcome was a composite of death, three or more documented episodes of ventricular tachycardia within 24 hours (ventricular tachycardia storm), or appropriate ICD shock. RESULTS:Of the 259 patients who were enrolled, 132 were assigned to the ablation group and 127 to the escalated-therapy group. During a mean (±SD) of 27.9±17.1 months of follow-up, the primary outcome occurred in 59.1% of patients in the ablation group and 68.5% of those in the escalated-therapy group (hazard ratio in the ablation group, 0.72; 95% confidence interval, 0.53 to 0.98; P=0.04). There was no significant between-group difference in mortality. There were two cardiac perforations and three cases of major bleeding in the ablation group and two deaths from pulmonary toxic effects and one from hepatic dysfunction in the escalated-therapy group. CONCLUSIONS:In patients with ischemic cardiomyopathy and an ICD who had ventricular tachycardia despite antiarrhythmic drug therapy, there was a significantly lower rate of the composite primary outcome of death, ventricular tachycardia storm, or appropriate ICD shock among patients undergoing catheter ablation than among those receiving an escalation in antiarrhythmic drug therapy. (Funded by the Canadian Institutes of Health Research and others; VANISH ClinicalTrials.gov number, NCT00905853.).
10.1056/NEJMoa1513614
Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a malignant neoplasm of predominantly salivary gland origin for which effective therapies are lacking. We conducted a phase II trial evaluating the multitargeted tyrosine kinase inhibitor lenvatinib in patients with R/M ACC. PATIENTS AND METHODS:This study was conducted with a two-stage minimax design. Patients with histologically confirmed R/M ACC of any primary site with radiographic and/or symptomatic progression were eligible. Any prior therapy was allowed except previous lenvatinib. Patients received lenvatinib 24 mg orally per day. The primary end point was overall response rate. Secondary end points were progression-free survival and safety. An exploratory analysis of how expression and genomic alterations relate to outcomes was conducted. RESULTS:Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response. Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed. Patients otherwise were removed for toxicity (n = 5), as a result of withdrawal of consent (n = 9), or at the treating physician's discretion (n = 6). Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1). CONCLUSION:This trial met the prespecified overall response rate primary end point, demonstrating antitumor activity with lenvatinib in R/M ACC patients. Toxicity was comparable to previous studies, requiring monitoring and management.
10.1200/JCO.18.01859
Spontaneous Coronary Artery Dissection: Clinical Outcomes and Risk of Recurrence.
Saw Jacqueline,Humphries Karin,Aymong Eve,Sedlak Tara,Prakash Roshan,Starovoytov Andrew,Mancini G B John
Journal of the American College of Cardiology
BACKGROUND:Spontaneous coronary artery dissection (SCAD) is underdiagnosed and an important cause of myocardial infarction (MI), especially in young women. Long-term cardiovascular outcomes, including recurrent SCAD, are inadequately reported. OBJECTIVES:This study sought to describe the acute and long-term cardiovascular outcomes and assess the predictors of recurrent SCAD. METHODS:Nonatherosclerotic SCAD patients were prospectively followed at Vancouver General Hospital systematically to ascertain baseline, predisposing and precipitating stressors, angiographic features, revascularization, use of medication, and in-hospital and long-term cardiovascular events. Clinical predictors for recurrent de novo SCAD were tested using univariate and multivariate Cox regression models. RESULTS:The authors prospectively followed 327 SCAD patients. Average age was 52.5 ± 9.6 years, and 90.5% were women (56.9% postmenopausal). All presented with MI; 25.7% had ST-segment elevation MI, 74.3% had non-ST-segment elevation MI, and 8.9% had ventricular tachycardia/ventricular fibrillation. Precipitating emotional stressors were reported in 48.3% and physical stressors in 28.1%. Fibromuscular dysplasia was present in 62.7%, connective tissue disorder in 4.9%, and systemic inflammatory disease in 11.9%. The majority (83.1%) were initially treated medically, with only 16.5% or 2.2% undergoing in-hospital percutaneous coronary intervention or coronary artery bypass graft surgery, respectively. The majority of SCAD patients were taking aspirin and beta-blocker therapy at discharge and at follow-up. Median hospital stay was 3.0 days, and the overall major adverse event rate was 7.3%. Median long-term follow-up was 3.1 years, and overall major adverse cardiac event rate was 19.9% (death rate: 1.2%; recurrent MI: 16.8%; stroke/transient ischemic attack: 1.2%; revascularization: 5.8%). Recurrent SCAD occurred in 10.4% of patients. In multivariate modeling, only hypertension increased (hazard ratio: 2.46; p = 0.011) and beta-blocker use diminished (hazard ratio: 0.36; p = 0.004) recurrent SCAD. CONCLUSIONS:In our large prospectively followed SCAD cohort, long-term cardiovascular events were common. Hypertension increased the risk of recurrent SCAD, whereas beta-blocker therapy appeared to be protective.
10.1016/j.jacc.2017.06.053
Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT.
Bhatt Deepak L,Steg Ph Gabriel,Miller Michael,Brinton Eliot A,Jacobson Terry A,Ketchum Steven B,Doyle Ralph T,Juliano Rebecca A,Jiao Lixia,Granowitz Craig,Tardif Jean-Claude,Gregson John,Pocock Stuart J,Ballantyne Christie M,
Journal of the American College of Cardiology
BACKGROUND:In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. These patients are at risk for not only first but also subsequent ischemic events. OBJECTIVES:Pre-specified analyses determined the extent to which icosapent ethyl reduced total ischemic events. METHODS:REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dl (median baseline of 216 mg/dl) and low-density lipoprotein cholesterol >40 and ≤100 mg/dl (median baseline of 75 mg/dl), and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4 g/day or placebo. The main outcomes were total (first and subsequent) primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). As a pre-specified statistical method, we determined differences in total events using negative binomial regression. We also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint frailty analysis. RESULTS:In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%) first primary endpoint events and 1,303 (44.8%) subsequent primary endpoint events occurred (which included 762 second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 vs. 89 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.70; 95% confidence interval: 0.62 to 0.78; p < 0.0001). Icosapent ethyl also reduced totals for each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 vs. 44 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.72; 95% confidence interval: 0.63 to 0.82; p < 0.0001). CONCLUSIONS:Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events. (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial [REDUCE-IT]; NCT01492361).
10.1016/j.jacc.2019.02.032
Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.
Johnston S Claiborne,Amarenco Pierre,Albers Gregory W,Denison Hans,Easton J Donald,Evans Scott R,Held Peter,Jonasson Jenny,Minematsu Kazuo,Molina Carlos A,Wang Yongjun,Wong K S Lawrence,
The New England journal of medicine
BACKGROUND:Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia. METHODS:We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. RESULTS:During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%. CONCLUSIONS:In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01994720.).
10.1056/NEJMoa1603060
Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction.
Furtado Remo H M,Bonaca Marc P,Raz Itamar,Zelniker Thomas A,Mosenzon Ofri,Cahn Avivit,Kuder Julia,Murphy Sabina A,Bhatt Deepak L,Leiter Lawrence A,McGuire Darren K,Wilding John P H,Ruff Christian T,Nicolau Jose C,Gause-Nilsson Ingrid A M,Fredriksson Martin,Langkilde Anna Maria,Sabatine Marc S,Wiviott Stephen D
Circulation
BACKGROUND:Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. METHODS:DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. RESULTS:In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). CONCLUSIONS:Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.
10.1161/CIRCULATIONAHA.119.039996
Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction.
Stub Dion,Smith Karen,Bernard Stephen,Nehme Ziad,Stephenson Michael,Bray Janet E,Cameron Peter,Barger Bill,Ellims Andris H,Taylor Andrew J,Meredith Ian T,Kaye David M,
Circulation
BACKGROUND:Oxygen is commonly administered to patients with ST-elevation-myocardial infarction despite previous studies suggesting a possible increase in myocardial injury as a result of coronary vasoconstriction and heightened oxidative stress. METHODS AND RESULTS:We conducted a multicenter, prospective, randomized, controlled trial comparing oxygen (8 L/min) with no supplemental oxygen in patients with ST-elevation-myocardial infarction diagnosed on paramedic 12-lead ECG. Of 638 patients randomized, 441 patients had confirmed ST-elevation-myocardial infarction and underwent primary end-point analysis. The primary end point was myocardial infarct size as assessed by cardiac enzymes, troponin I, and creatine kinase. Secondary end points included recurrent myocardial infarction, cardiac arrhythmia, and myocardial infarct size assessed by cardiac magnetic resonance imaging at 6 months. Mean peak troponin was similar in the oxygen and no oxygen groups (57.4 versus 48.0 μg/L; ratio, 1.20; 95% confidence interval, 0.92-1.56; P=0.18). There was a significant increase in mean peak creatine kinase in the oxygen group compared with the no oxygen group (1948 versus 1543 U/L; means ratio, 1.27; 95% confidence interval, 1.04-1.52; P=0.01). There was an increase in the rate of recurrent myocardial infarction in the oxygen group compared with the no oxygen group (5.5% versus 0.9%; P=0.006) and an increase in frequency of cardiac arrhythmia (40.4% versus 31.4%; P=0.05). At 6 months, the oxygen group had an increase in myocardial infarct size on cardiac magnetic resonance (n=139; 20.3 versus 13.1 g; P=0.04). CONCLUSION:Supplemental oxygen therapy in patients with ST-elevation-myocardial infarction but without hypoxia may increase early myocardial injury and was associated with larger myocardial infarct size assessed at 6 months. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01272713.
10.1161/CIRCULATIONAHA.114.014494
Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis: TREAT Trial.
Berwanger Otavio,Lopes Renato D,Moia Diogo D F,Fonseca Francisco A,Jiang Lixin,Goodman Shaun G,Nicholls Stephen J,Parkhomenko Alexander,Averkov Oleg,Tajer Carlos,Malaga Germán,Saraiva Jose F K,Guimaraes Helio P,de Barros E Silva Pedro G M,Damiani Lucas P,Santos Renato H N,Paisani Denise M,Miranda Tamiris A,Valeis Nanci,Piegas Leopoldo S,Granger Christopher B,White Harvey D,Nicolau Jose C
Journal of the American College of Cardiology
BACKGROUND:The efficacy of ticagrelor in the long-term post-ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain. OBJECTIVES:The purpose of this study was to evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. METHODS:This international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3,799 patients (age <75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, myocardial infarction, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months. RESULTS:The combined outcome of cardiovascular mortality, myocardial infarction, or stroke occurred in 129 of 1,913 patients (6.7%) receiving ticagrelor and in 137 of 1,886 patients (7.3%) receiving clopidogrel (hazard ratio: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53). The composite of cardiovascular mortality, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1,886 patients (9.1%) receiving clopidogrel (hazard ratio: 0.88; 95% confidence interval: 0.71 to 1.09; p = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups. CONCLUSION:Among patients age <75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not significantly reduce the frequency of cardiovascular events when compared with clopidogrel. (Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis [TREAT]; NCT02298088).
10.1016/j.jacc.2019.03.011
Coronary Angiography after Cardiac Arrest without ST-Segment Elevation.
Lemkes Jorrit S,Janssens Gladys N,van der Hoeven Nina W,Jewbali Lucia S D,Dubois Eric A,Meuwissen Martijn,Rijpstra Tom A,Bosker Hans A,Blans Michiel J,Bleeker Gabe B,Baak Rémon,Vlachojannis Georgios J,Eikemans Bob J W,van der Harst Pim,van der Horst Iwan C C,Voskuil Michiel,van der Heijden Joris J,Beishuizen Albertus,Stoel Martin,Camaro Cyril,van der Hoeven Hans,Henriques José P,Vlaar Alexander P J,Vink Maarten A,van den Bogaard Bas,Heestermans Ton A C M,de Ruijter Wouter,Delnoij Thijs S R,Crijns Harry J G M,Jessurun Gillian A J,Oemrawsingh Pranobe V,Gosselink Marcel T M,Plomp Koos,Magro Michael,Elbers Paul W G,van de Ven Peter M,Oudemans-van Straaten Heleen M,van Royen Niels
The New England journal of medicine
BACKGROUND:Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography and percutaneous coronary intervention (PCI) in the treatment of patients who have been successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains uncertain. METHODS:In this multicenter trial, we randomly assigned 552 patients who had cardiac arrest without signs of STEMI to undergo immediate coronary angiography or coronary angiography that was delayed until after neurologic recovery. All patients underwent PCI if indicated. The primary end point was survival at 90 days. Secondary end points included survival at 90 days with good cerebral performance or mild or moderate disability, myocardial injury, duration of catecholamine support, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, major bleeding, occurrence of acute kidney injury, need for renal-replacement therapy, time to target temperature, and neurologic status at discharge from the intensive care unit. RESULTS:At 90 days, 176 of 273 patients (64.5%) in the immediate angiography group and 178 of 265 patients (67.2%) in the delayed angiography group were alive (odds ratio, 0.89; 95% confidence interval [CI], 0.62 to 1.27; P = 0.51). The median time to target temperature was 5.4 hours in the immediate angiography group and 4.7 hours in the delayed angiography group (ratio of geometric means, 1.19; 95% CI, 1.04 to 1.36). No significant differences between the groups were found in the remaining secondary end points. CONCLUSIONS:Among patients who had been successfully resuscitated after out-of-hospital cardiac arrest and had no signs of STEMI, a strategy of immediate angiography was not found to be better than a strategy of delayed angiography with respect to overall survival at 90 days. (Funded by the Netherlands Heart Institute and others; COACT Netherlands Trial Register number, NTR4973.).
10.1056/NEJMoa1816897
Complete Revascularization with Multivessel PCI for Myocardial Infarction.
The New England journal of medicine
BACKGROUND:In patients with ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) of the culprit lesion reduces the risk of cardiovascular death or myocardial infarction. Whether PCI of nonculprit lesions further reduces the risk of such events is unclear. METHODS:We randomly assigned patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI to a strategy of either complete revascularization with PCI of angiographically significant nonculprit lesions or no further revascularization. Randomization was stratified according to the intended timing of nonculprit-lesion PCI (either during or after the index hospitalization). The first coprimary outcome was the composite of cardiovascular death or myocardial infarction; the second coprimary outcome was the composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. RESULTS:At a median follow-up of 3 years, the first coprimary outcome had occurred in 158 of the 2016 patients (7.8%) in the complete-revascularization group as compared with 213 of the 2025 patients (10.5%) in the culprit-lesion-only PCI group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.91; P = 0.004). The second coprimary outcome had occurred in 179 patients (8.9%) in the complete-revascularization group as compared with 339 patients (16.7%) in the culprit-lesion-only PCI group (hazard ratio, 0.51; 95% CI, 0.43 to 0.61; P<0.001). For both coprimary outcomes, the benefit of complete revascularization was consistently observed regardless of the intended timing of nonculprit-lesion PCI (P = 0.62 and P = 0.27 for interaction for the first and second coprimary outcomes, respectively). CONCLUSIONS:Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. (Funded by the Canadian Institutes of Health Research and others; COMPLETE ClinicalTrials.gov number, NCT01740479.).
10.1056/NEJMoa1907775
Updates on Acute Coronary Syndrome: A Review.
Eisen Alon,Giugliano Robert P,Braunwald Eugene
JAMA cardiology
IMPORTANCE:Acute coronary syndrome (ACS), the acute manifestation of ischemic heart disease, remains a major cause of morbidity and mortality worldwide and is responsible for more than 1 million hospital admissions in the United States annually. Considerable research is being conducted in the field. This review provides a contemporary overview of key new findings on the pathophysiology, diagnosis, treatment, and prognosis of ACS. OBSERVATIONS:While plaque rupture is the most frequent cause of coronary thrombosis, studies with optical coherence tomography demonstrate that superficial plaque erosion is more common than previously thought. High-sensitivity troponin assays (not yet available in the United States) and cardiac computed tomographic angiography are being increasingly used in diagnosis and risk stratification of patients with suspected ACS. New data from long-term dual antiplatelet therapy studies and investigations of anticoagulants provide important insights into the balance between ischemic and bleeding risks. The added benefit of percutaneous coronary intervention in non-infarct-related arteries in patients with ST-segment elevation myocardial infarction has been demonstrated in randomized trials, and the radial approach has become the standard of care in patients with ACS undergoing angiography. Promising old and new adjunctive therapies, such as pretreatment with β-blockers, ezetimibe, and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, are discussed. New guidelines on the management of non-ST-segment elevation ACS were published in the last 2 years, as well as scientific documents on ACS in understudied populations, such as women and patients with renal dysfunction. CONCLUSIONS AND RELEVANCE:Substantial progress in the prevention, diagnosis, and management of patients with ACS has been accomplished in recent years. Despite optimal pharmacological and invasive therapies, the burden of recurrent ischemic events and mortality remains high, and future research is ongoing to prevent and improve the outcome of patients with ACS.
10.1001/jamacardio.2016.2049
Cryptogenic Stroke and High-Risk Patent Foramen Ovale: The DEFENSE-PFO Trial.
Lee Pil Hyung,Song Jae-Kwan,Kim Jong S,Heo Ran,Lee Sahmin,Kim Dae-Hee,Song Jong-Min,Kang Duk-Hyun,Kwon Sun U,Kang Dong-Wha,Lee Dongwhane,Kwon Hyuk Sung,Yun Sung-Cheol,Sun Byung Joo,Park Jae-Hyeong,Lee Jae-Hwan,Jeong Hye Seon,Song Hee-Jung,Kim Jei,Park Seung-Jung
Journal of the American College of Cardiology
BACKGROUND:Recent reports showing the favorable role of patent foramen ovale (PFO) closure in patients with cryptogenic stroke have raised the issue of selecting optimal candidates. OBJECTIVES:This study, DEFENSE-PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale), evaluated whether the benefits of PFO closure can be determined on the basis of the morphologic characteristics of the PFO, as evaluated by transesophageal echocardiography. METHODS:Patients with cryptogenic stroke and high-risk PFO were divided between a transcatheter PFO closure and a medication-only group. High-risk PFO included PFO with atrial septal aneurysm, hypermobility (phasic septal excursion into either atrium ≥10 mm), or PFO size (maximum separation of the septum primum from the secundum) ≥2 mm. The primary endpoint was a composite of stroke, vascular death, or Thrombolysis In Myocardial Infarction-defined major bleeding during 2 years of follow-up. RESULTS:From September 2011 until October 2017, 120 patients (mean age: 51.8 years) underwent randomization. PFO size, frequency of septal aneurysm (13.3% vs. 8.3%; p = 0.56), and hypermobility (45.0% vs. 46.7%; p > 0.99) were similar between the groups. All PFO closures were successful. The primary endpoint occurred exclusively in the medication-only group (6 of 60 patients; 2-year event rate: 12.9% [log-rank p = 0.013]; 2-year rate of ischemic stroke: 10.5% [p = 0.023]). The events in the medication-only group included ischemic stroke (n = 5), cerebral hemorrhage (n = 1), Thrombolysis In Myocardial Infarction-defined major bleeding (n = 2), and transient ischemic attack (n = 1). Nonfatal procedural complications included development of atrial fibrillation (n = 2), pericardial effusion (n = 1), and pseudoaneurysm (n = 1). CONCLUSIONS:PFO closure in patients with high-risk PFO characteristics resulted in a lower rate of the primary endpoint as well as stroke recurrence. (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale [DEFENSE-PFO]; NCT01550588).
10.1016/j.jacc.2018.02.046
Intravenous Iron in Patients Undergoing Maintenance Hemodialysis.
Macdougall Iain C,White Claire,Anker Stefan D,Bhandari Sunil,Farrington Kenneth,Kalra Philip A,McMurray John J V,Murray Heather,Tomson Charles R V,Wheeler David C,Winearls Christopher G,Ford Ian,
The New England journal of medicine
BACKGROUND:Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited. METHODS:In a multicenter, open-label trial with blinded end-point evaluation, we randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 μg per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 μg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25. RESULTS:A total of 2141 patients underwent randomization (1093 patients to the high-dose group and 1048 to the low-dose group). The median follow-up was 2.1 years. Patients in the high-dose group received a median monthly iron dose of 264 mg (interquartile range [25th to 75th percentile], 200 to 336), as compared with 145 mg (interquartile range, 100 to 190) in the low-dose group. The median monthly dose of an erythropoiesis-stimulating agent was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group (median difference, -7539 IU; 95% confidence interval [CI], -9485 to -5582). A total of 320 patients (29.3%) in the high-dose group had a primary end-point event, as compared with 338 (32.3%) in the low-dose group (hazard ratio, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). In an analysis that used a recurrent-events approach, there were 429 events in the high-dose group and 507 in the low-dose group (rate ratio, 0.77; 95% CI, 0.66 to 0.92). The infection rate was the same in the two groups. CONCLUSIONS:Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered. (Funded by Kidney Research UK; PIVOTAL EudraCT number, 2013-002267-25 .).
10.1056/NEJMoa1810742
Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association.
Circulation
Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden death, particularly among young women and individuals with few conventional atherosclerotic risk factors. Patient-initiated research has spurred increased awareness of SCAD, and improved diagnostic capabilities and findings from large case series have led to changes in approaches to initial and long-term management and increasing evidence that SCAD not only is more common than previously believed but also must be evaluated and treated differently from atherosclerotic myocardial infarction. High rates of recurrent SCAD; its association with female sex, pregnancy, and physical and emotional stress triggers; and concurrent systemic arteriopathies, particularly fibromuscular dysplasia, highlight the differences in clinical characteristics of SCAD compared with atherosclerotic disease. Recent insights into the causes of, clinical course of, treatment options for, outcomes of, and associated conditions of SCAD and the many persistent knowledge gaps are presented.
10.1161/CIR.0000000000000564
Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.
Johnston S Claiborne,Easton J Donald,Farrant Mary,Barsan William,Conwit Robin A,Elm Jordan J,Kim Anthony S,Lindblad Anne S,Palesch Yuko Y,
The New England journal of medicine
BACKGROUND:Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS:In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS:A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS:In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).
10.1056/NEJMoa1800410
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.
The New England journal of medicine
BACKGROUND:Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS:We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS:The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS:Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).
10.1056/NEJMoa1801174
Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction.
Tardif Jean-Claude,Kouz Simon,Waters David D,Bertrand Olivier F,Diaz Rafael,Maggioni Aldo P,Pinto Fausto J,Ibrahim Reda,Gamra Habib,Kiwan Ghassan S,Berry Colin,López-Sendón José,Ostadal Petr,Koenig Wolfgang,Angoulvant Denis,Grégoire Jean C,Lavoie Marc-André,Dubé Marie-Pierre,Rhainds David,Provencher Mylène,Blondeau Lucie,Orfanos Andreas,L'Allier Philippe L,Guertin Marie-Claude,Roubille François
The New England journal of medicine
BACKGROUND:Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. METHODS:We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. RESULTS:A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). CONCLUSIONS:Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).
10.1056/NEJMoa1912388
ST-segment elevation myocardial infarction.
Vogel Birgit,Claessen Bimmer E,Arnold Suzanne V,Chan Danny,Cohen David J,Giannitsis Evangelos,Gibson C Michael,Goto Shinya,Katus Hugo A,Kerneis Mathieu,Kimura Takeshi,Kunadian Vijay,Pinto Duane S,Shiomi Hiroki,Spertus John A,Steg P Gabriel,Mehran Roxana
Nature reviews. Disease primers
ST-segment elevation myocardial infarction (STEMI) is the most acute manifestation of coronary artery disease and is associated with great morbidity and mortality. A complete thrombotic occlusion developing from an atherosclerotic plaque in an epicardial coronary vessel is the cause of STEMI in the majority of cases. Early diagnosis and immediate reperfusion are the most effective ways to limit myocardial ischaemia and infarct size and thereby reduce the risk of post-STEMI complications and heart failure. Primary percutaneous coronary intervention (PCI) has become the preferred reperfusion strategy in patients with STEMI; if PCI cannot be performed within 120 minutes of STEMI diagnosis, fibrinolysis therapy should be administered to dissolve the occluding thrombus. The initiation of networks to provide around-the-clock cardiac catheterization availability and the generation of standard operating procedures within hospital systems have helped to reduce the time to reperfusion therapy. Together with new advances in antithrombotic therapy and preventive measures, these developments have resulted in a decrease in mortality from STEMI. However, a substantial amount of patients still experience recurrent cardiovascular events after STEMI. New insights have been gained regarding the pathophysiology of STEMI and feed into the development of new treatment strategies.
10.1038/s41572-019-0090-3
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.
Ridker Paul M,Everett Brendan M,Thuren Tom,MacFadyen Jean G,Chang William H,Ballantyne Christie,Fonseca Francisco,Nicolau Jose,Koenig Wolfgang,Anker Stefan D,Kastelein John J P,Cornel Jan H,Pais Prem,Pella Daniel,Genest Jacques,Cifkova Renata,Lorenzatti Alberto,Forster Tamas,Kobalava Zhanna,Vida-Simiti Luminita,Flather Marcus,Shimokawa Hiroaki,Ogawa Hisao,Dellborg Mikael,Rossi Paulo R F,Troquay Roland P T,Libby Peter,Glynn Robert J,
The New England journal of medicine
BACKGROUND:Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS:We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS:At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS:Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).
10.1056/NEJMoa1707914