Background Incomplete revascularization (ICR) after percutaneous coronary intervention (PCI) is common and is associated with increased rates of rehospitalization, revascularization, and mortality. ...Adjunctive pharmacotherapy with ranolazine, an inhibitor of the late sodium current with anti-ischemic properties, may be effective in reducing recurrent events after PCI in patients with ICR. Trial Design RIVER-PCI is a phase 3, randomized, double-blind, placebo-controlled, international event-driven clinical trial evaluating the efficacy of ranolazine in patients with a history of chronic angina and ICR after PCI. Approximately 2,600 participants with ICR post-PCI will be randomized in a 1:1 ratio to ranolazine or matched placebo within 14 days of an index PCI. The primary end point of the trial is time to the first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization. Participants will be followed up for a minimum of 1 year and until at least 720 confirmed primary end point events have occurred. Secondary end points include sudden cardiac death, cardiovascular death, myocardial infarction, and measures of quality of life and cost-effectiveness. The evaluation of long-term safety will include all-cause mortality, stroke, transient ischemic attack, and hospitalization for heart failure. Enrollment commenced in November 2011 and was completed in summer 2013. Conclusions RIVER-PCI is a novel, large-scale, international, randomized, double-blind, placebo-controlled clinical trial evaluating the role of ranolazine in the long-term medical management of patients with ICR post-PCI.
Gender-related differences in the incidence of bleeding and its relation to subsequent mortality in patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolysis are not ...well understood. We studied patients with STEMI receiving fibrinolysis enrolled in 6 clinical trials. Outcomes included moderate or severe bleeding defined using Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria and adjusted 1-year mortality (excluding deaths in first 24 hours). Moderate or severe bleeding was 1.9-fold higher in women compared to men (13.3% vs 7.1%, p <0.0001). Bleeding remained higher in women even after adjustment for baseline differences (odd ratios 1.52, 95% confidence interval CI 1.42 to 1.62). In fact, female gender was second most important prognostic factor (Wald chi-square 153.6) after older age (Wald chi-square 241.2) in the multivariable bleeding model. Overall 1-year mortality was similar in women and men after adjusting for prognostically important baseline differences (hazard ratio HR 1.06, 95% CI 0.97 to 1.17). However, after adjustment for baseline confounders and bleeding, female gender was associated with a lower risk of 1-year death. Thus, adjusted 1-year mortality was similar in women compared to men without bleeding (HR 1.08, 95% CI 0.97 to 1.19) but lower in women compared to men with bleeding (HR 0.85, 95% CI 0.73 to 0.98, p for interaction of gender by bleeding = 0.0016). The highest adjusted 1-year mortality was observed in men with bleeding (HR 2.42, 95% CI 2.20 to 2.66) followed by women with bleeding (HR 2.05, 95% CI 1.80 to 2.33) and women without bleeding (HR 1.08, 95% CI 0.97 to 1.19, referent men without bleeding). In conclusion, in patients with fibrinolytic-treated STEMI, women had a higher incidence but lower mortality with bleeding than men. These data highlight the importance of understanding factors associated with gender-related differences in bleeding and represent an opportunity for improving outcomes of women and men with fibrinolytic-treated STEMI.
PROVE IT-TIMI 22 randomized 4,162 patients to intensive (atorvastatin, 80 mg daily) versus moderate (pravastatin, 40 mg daily) statin after acute cardiac syndrome (4). cTn was measured using a ...research-use-only high-sensitivity assay (Erenna Singulex, Inc., Alameda, California), which has a limit of detection of 0.2 ng/l (0.0002 ng/ml), and a 99th percentile reference limit of 9 ng/l (0.009 ng/ml) (5). Compared with patients with low 30-day levels, those with a 30-day hsTnI >=9 ng/l had a higher hazard of CV death/HF (6.2% vs. 2.9%; adjusted hazard ratio HRadj: 1.27; 95% confidence interval CI: 0.84 to 1.92; p = 0.26). ...even among the 69.8% of patients with hsTnI below 9 ng/l, a significant gradient of risk of CV death/HF was present by hsTnI tertile (Figure 1A).
Abstract Background Anticoagulation is often avoided in patients with atrial fibrillation who are at an increased risk of falling. Objectives This study assessed the relative efficacy and safety of ...edoxaban versus warfarin in the ENGAGE AF–TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48) trial in patients with atrial fibrillation judged to be at increased risk of falling. Methods We performed a pre-specified analysis of the ENGAGE AF–TIMI 48, comparing patients with versus without increased risk of falling. Results Nine hundred patients (4.3%) were judged to be at increased risk of falling. These patients were older (median, 77 vs. 72 years; p < 0.001), and had a higher prevalence of comorbidities including prior stroke/transient ischemic attack, diabetes, and coronary artery disease. After multivariable adjustment, patients at increased risk of falling experienced more bone fractures caused by falling (adjusted hazard ratio HRadj : 1.88; 95% confidence interval CI: 1.49 to 2.38; p < 0.001), major bleeding (HRadj : 1.30; 95% CI: 1.04 to 1.64; p = 0.023), life-threatening bleeding (HRadj : 1.67; 95% CI: 1.11 to 2.50; p = 0.013), and all-cause death (HRadj : 1.45; 95% CI: 1.23 to 1.70; p < 0.001), but not ischemic events including stroke/systemic embolic event (HRadj : 1.16; 95% CI: 0.89 to 1.51; p = 0.27). No treatment interaction was observed between either dosing regimens of edoxaban and warfarin for the efficacy and safety outcomes. Treatment with edoxaban resulted in a greater absolute risk reduction in severe bleeding events and all-cause mortality compared with warfarin. Conclusions Edoxaban is an attractive alternative to warfarin in patients at increased risk of falling, because it is associated with an even greater absolute reduction in severe bleeding events and mortality. (Effective aNticaoGulation with factor xA next Generation in Atrial Fibrillation ENGAGE AF-TIMI 48; NCT00781391 )
Pharmacological Inhibition of Cannabinoid Receptor-1 Protects Against Doxorubicin-Induced Cardiotoxicity Partha Mukhopadhyay, Sándor Bátkai, Mohanraj Rajesh, Nora Czifra, Judith Harvey-White, György ...Haskó, Zsuzsanna Zsengeller, Norma P. Gerard, Lucas Liaudet, George Kunos, Pál Pacher Treatment with cannabinoid-1 (CB1 ) receptor antagonists (rimonabant and AM281) improved doxorubicin (DOX)-induced cardiac dysfunction and decreased myocardial apoptosis in a well-established mouse model of DOX-induced cardiotoxicity in vivo. Likewise, pharmacologic inhibition of CB1 receptor also protected H9c2 cardiac cells against DOX-induced cell death in vitro. Thus, CB1 receptor antagonists may offer a new cardioprotective strategy against DOX-induced cardiotoxicity.
Background The OAT study randomized 2,201 patients with a totally occluded infarct-related artery on days 3 to 28 (>24 hours) after myocardial infarction (MI) to percutaneous coronary intervention ...(PCI) or medical treatment (MED). There was no difference in the primary end point of death, reinfarction, or heart failure at 2.9 or 6-year mean follow-up. However, in patients randomized to PCI, there was a trend toward a higher rate of reinfarction. Methods We analyzed the characteristics and types of reinfarction according to the universal definition. Independent predictors of reinfarction were determined using Cox proportional hazard models with follow-up up to 9 years. Results There were 169 reinfarctions: 9.4% PCI vs 8.0% MED, hazard ratio 1.31, 95% CI 0.97-1.77, P = .08. Spontaneous reinfarction (type 1) occurred with similar frequency in the groups: 4.9% PCI vs 6.7% MED, hazard ratio 0.78, 95% CI 0.53-1.15, P = .21. Rates of type 2 (secondary) and 3 (sudden death) MI were similar in both groups. There was an increase in type 4a reinfarctions (related to protocol or other PCI) (0.8% PCI vs 0.1% MED, P = .01) and type 4b reinfarctions (stent thrombosis) (2.7% PCI vs 0.6% MED, P < .001). Multivariate predictors of reinfarction were history of PCI before study entry ( P = .001), diabetes ( P = .005), and absence of new Q waves with the index infarction ( P = .01). Conclusions There was a trend for reinfarctions to be more frequent with PCI. Opening an occluded infarct-related artery in stable patients with late post-MI may expose them to a risk of subsequent reinfarction related to reocclusion and stent thrombosis.
The accuracy of the 12-lead electrocardiogram in detecting coronary artery occlusion is limited. We sought to determine the incidence, distribution, and outcomes of patients who have total occlusion ...of the culprit artery but present with non–ST-segment elevation myocardial infarction (NSTEMI). The randomized Acute Catheterization and Urgent Intervention Triage Strategy trial enrolled 13,819 patients presenting with non–ST-segment elevation acute coronary syndromes who underwent an early invasive strategy. The present study includes 1,319 patients with baseline biomarker elevation (NSTEMI) and no history of coronary artery bypass graft who underwent percutaneous coronary intervention of a single culprit vessel. We compared the baseline characteristics and outcomes according to whether the culprit vessel was occluded (baseline Thrombolysis In Myocardial Infarction TIMI 0 to 1) or patent (TIMI 2 to 3 flow) by angiographic core laboratory assessment. TIMI 0 to 1 flow in the culprit artery was present in 262 of 1,319 (19.9%) patients. The incidence of coronary occlusion was 28.4%, 19.3%, and 12.6% in patients with NSTEMI because of right coronary, left circumflex, and left anterior descending artery disease, respectively. Patients with an occluded culprit artery were more commonly men and had ST-segment deviation ≥1 mm. One-year outcomes, including death (3.5% vs 3.0%, p = 0.68) and myocardial infarction (8.4% vs 9.6%, p = 0.47), did not differ significantly between patients with versus without occluded culprit arteries, respectively. In conclusion, the present study demonstrates that the culprit artery is totally occluded in approximately 1 in 5 patients presenting with NSTEMI and single-vessel disease; however, the presence of total occlusion in NSTEMI was not associated with an incremental hazard of death or reinfarction at 1 year.
Background To further explore the impact of smoking on antiplatelet activity and treatment response, we evaluated time-dependent relationships between smoking status with on-treatment platelet ...reactivity and clinical outcomes for prasugrel vs. clopidogrel in patients with acute coronary syndromes managed medically without revascularization. Methods and Results A total of 7062 patients aged <75 years from the primary TRILOGY ACS cohort randomized to prasugrel vs. clopidogrel were evaluated through 30 months by baseline and time-dependent smoking status with adjusted proportional-hazards models. A total of 1613 participants (23%) were included in a platelet function sub-study evaluating serial P2Y12 reaction unit (PRU) measurements. Current smokers (n = 1566 22%) at baseline had fewer comorbidities compared with non-smokers; nearly half quit smoking during follow-up. Although median on-treatment PRU values were lower with prasugrel vs. clopidogrel, persistent smokers had lower serial PRU values in both treatment groups compared with non-smokers, with no differential interaction of treatment response by smoking status. The frequency of cardiovascular death, myocardial infarction, or stroke in current smokers was significantly lower with prasugrel (11.7%) vs. clopidogrel (18.6%), but there was no difference in non-smokers (13.8% vs. 13.7%), with significant interaction between treatment and baseline smoking status ( P = .0002). Bleeding events occurred more frequently in prasugrel-treated patients with no significant interaction between treatment and baseline smoking status. Conclusions Among medically managed ACS patients <75 years of age, the risk of ischemic outcomes was significantly reduced with prasugrel vs. clopidogrel among smokers vs. non-smokers. No interaction between on-treatment platelet reactivity and smoking status was found.
Abstract Background We examined warfarin use at discharge (according to Congestive heart failure, Hypertension, Age > 75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding ...risk) and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation. Methods Of the 23,208 patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A, and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trials, 4.0% (917 patients) had atrial fibrillation as an in-hospital complication and were discharged alive. Cox proportional hazards models were performed to assess 6-month outcomes after discharge. Results Overall, 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin use among patients with atrial fibrillation had no relation with estimated stroke risk; similar rates were observed across Congestive heart failure, Hypertension, Age > 75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS2 ) scores (0, 13%; 1, 14%; ≥ 2, 13%) and across different bleeding risk categories (low risk, 11.9%; intermediate risk, 13.3%; high risk, 11.1%). Among patients with in-hospital atrial fibrillation, warfarin use at discharge was independently associated with a lower risk of death or myocardial infarction within 6 months of discharge (hazard ratio 0.39; 95% confidence interval, 0.15-0.98). Conclusion Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to CHADS2 score or bleeding risk.
Abstract Background Studies have shown higher bleeding and mortality rates among African Americans who receive fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) compared ...with whites; however, the relationship of bleeding risk to mortality has not been evaluated. Methods We studied data from 32,260 STEMI patients receiving fibrinolysis enrolled in the US in 5 clinical trials. Bleeding was defined according to criteria from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries study. Main outcome measure was adjusted 1-year mortality. Results Despite younger age (median: 57 years vs 61 years) and fewer comorbidities, moderate or severe bleeding occurred more frequently among African-Americans than whites (16.3% vs 14.1%; P = .0147, adjusted OR 1.36; 95% confidence interval CI, 1.14-1.62; P = .0006) as did 1-year mortality (11.5% vs 9.4%). African-American race and moderate or severe bleeding were independently related to 1-year mortality (χ2 9.02, P = .0003 and 148.58, P < .0001, respectively). Mortality was highest among African Americans with bleeding (hazard ratio HR 2.83; 95% CI, 2.08-3.86) followed by whites with bleeding (HR 1.99; 95% CI, 1.78-2.22) and African Americans without bleeding (HR 1.33; 95% CI, 1.02-1.73) (referent whites without bleeding). Conclusions In STEMI patients receiving fibrinolysis, moderate or severe bleeding and mortality were significantly higher in African Americans compared with whites. Bleeding was associated with similarly increased mortality risk in both groups.
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