Abstract 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 )
Bleeding, a common complication of acute myocardial infarction (AMI) treatment, is associated with worse outcomes. A contemporary model for major bleeding associated with AMI treatment can stratify ...patients at elevated risk for bleeding and is needed to risk-adjust AMI practice and outcomes. Using the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines (ACTION Registry–GWTG) database, an in-hospital major bleeding risk model was developed in a population of patients with ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction. The model used only baseline variables and was developed (n = 72,313) and validated (n = 17,960) in patients with AMI (at 251 United States centers from January 2007 to December 2008). The 12 most statistically and clinically significant variables were incorporated into the final regression model. The calibration plots are shown, and the model discrimination is demonstrated in derivation and validation cohorts, as well as across key subgroups. The rate of major bleeding in the overall population was 10.8%. The 12 factors associated with major bleeding in the model were heart rate, baseline hemoglobin, female gender, baseline serum creatinine, age, electrocardiographic changes, heart failure or shock, diabetes, peripheral artery disease, body weight, systolic blood pressure, and home warfarin use. The risk model discriminated well in the derivation (C-statistic = 0.73) and validation (C-statistic = 0.71) cohorts. A risk score for major bleeding corresponded well with observed bleeding: very low risk (3.9%), low risk (7.3%), moderate risk (16.1%), high risk (29.0%), and very high risk (39.8%). In conclusion, the ACTION Registry–GWTG in-hospital major bleeding model stratifies risk for major bleeding using variables at presentation and enables risk-adjusted bleeding outcomes for quality improvement initiatives and clinical decision making.
Background The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is evaluating the potential benefit for reduction in major cardiovascular (CV) events from the ...addition of ezetimibe versus placebo to 40 mg/d of simvastatin therapy in patients who present with acute coronary syndromes and have low-density lipoprotein cholesterol (LDL-C) ≤125 mg/dL. Methods The primary composite end point is CV death, nonfatal myocardial infarction (MI), nonfatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization (≥30 days postrandomization). The simvastatin monotherapy arm’s LDL-C target is <70 mg/dL. Ezetimibe was assumed to further lower LDL-C by 15 mg/dL and produce an estimated ~8% to 9% treatment effect. The targeted number of events is 5,250. Results We enrolled 18,144 patients with either ST-segment elevation MI (STEMI, n = 5,192) or UA/non–ST-segment elevation MI (UA/NSTEMI, n = 12,952) from October 2005 to July 2010. Western Europe (40%) and North America (38%) were the leading enrolling regions. The STEMI cohort was younger and had a higher percentage of patients naive to lipid-lowering treatment compared with the UA/NSTEMI cohort. The UA/NSTEMI group had a higher prevalence of diabetes, hypertension, and prior MI. Median LDL-C at entry was 100 mg/dL for STEMI and 93 mg/dL for UA/NSTEMI patients. Conclusions This trial is evaluating LDL-C lowering beyond previously targeted LDL-C levels. The results depend on achieving the desired separation of LDL-C with ezetimibe and on the assumption that ezetimibe’s lowering of LDL-C will have similar event reduction efficacy as the LDL-C lowering from a statin. The results could affect future therapies and guidelines.
Background Accurate risk adjustment is needed to guide quality improvement initiatives and research to improve care of patients with acute myocardial infarction (MI). We developed and validated a ...model to predict the risk of in-hospital mortality for contemporary patients with acute MI treated in routine clinical practice. Methods The Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry® –Get With The Guidelines (GWTG)™ database of patients with acute MI was used to derive (n = 65,668 from 248 US sites) and validate (n = 16,336) a multivariable logistic regression model to predict the likelihood of in-hospital mortality (4.9% in each cohort). Results Factors with the highest independent significance in terms of mortality prediction included age, baseline serum creatinine, systolic blood pressure, troponin elevation, heart failure and/or cardiogenic shock at presentation, ST-segment changes, heart rate, and prior peripheral arterial disease. The model showed very good discrimination, with c statistics of 0.85 and 0.84 in the derivation and validation cohorts, respectively. The model calibrated well overall and in key patient subgroups including males versus females, age <75 versus ≥75 years, diabetes versus no diabetes, and ST-elevation MI versus non–ST-elevation MI. The ACTION Registry® –GWTG™ in-hospital mortality risk score was also developed from the model. Patients with a risk score of ≤40 had an observed mortality rate of <4% compared with those with a risk score of 41–50 (12%) and risk scores >50 (34%). Conclusion The ACTION Registry® –GWTG™ in-hospital mortality model and risk score represent simple, accurate risk adjustment tools for contemporary patients with acute MI.
Summary Background Upper gastrointestinal safety of cyclo-oxygenase (COX)-2 selective inhibitors versus traditional non-steroidal anti-inflammatory drugs (NSAIDs) has not been assessed in trials that ...simulate standard clinical practice. Our aim was to assess the effects of these drugs on gastrointestinal outcomes in a population that includes patients taking gastrointestinal protective therapy. Methods A prespecified pooled intent-to-treat analysis of three double-blind randomised comparisons of etoricoxib (60 or 90 mg daily) and diclofenac (150 mg daily) in 34 701 patients with osteoarthritis or rheumatoid arthritis was done for upper gastrointestinal clinical events (bleeding, perforation, obstruction, or ulcer) and the subset of complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). We also assessed such outcomes in patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin. These trials are registered with ClinicalTrials.gov , with the numbers NCT00092703 , NCT00092742 , and NCT00250445. Findings Overall upper gastrointestinal clinical events were significantly less common with etoricoxib than with diclofenac (hazard ratio HR 0·69, 95% CI 0·57–0·83; p=0·0001). There were significantly fewer uncomplicated gastrointestinal events with etoricoxib than there were with diclofenac (0·57, 0·45–0·74; p<0·0001); there was no difference in complicated events (0·91, 0·67–1·24; p=0·561). PPIs were used concomitantly for at least 75% of the study period by 13 862 (40%) and low-dose aspirin by 11 418 (33%) patients; treatment effects did not differ significantly in these individuals. Interpretation There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events. The reduction in uncomplicated events with etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.
Background Higher levels of lipoprotein-associated phospholipase A2 (Lp-PLA2 ) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib ...inhibits Lp-PLA2 activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events. Study Design The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, individual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years. Conclusions The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA2 activity with darapladib in patients after an acute coronary syndrome.
Background The ODYSSEY COMBO I study ( http://clinicaltrials.gov/show/NCT01644175 ) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or ...without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia. Methods This multicenter, phase 3, randomized (2:1 alirocumab vs placebo), double-blind, 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia. Alirocumab (75 mg every 2 weeks Q2W) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen. The alirocumab dose was increased to 150 mg Q2W (also 1 mL) at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 (intention-to-treat analysis). Results At week 24, estimated mean (95% CI) changes in LDL-C from baseline were −48.2% (−52.0% to −44.4%) and −2.3% (−7.6% to 3.1%) for alirocumab and placebo, respectively, an estimated mean (95% CI) difference of −45.9% (−52.5% to −39.3%) ( P < .0001). Low-density lipoprotein cholesterol <70 mg/dL was achieved by 75% alirocumab versus 9% placebo patients at week 24. At week 12, 83.2% of evaluable alirocumab-treated patients remained on 75-mg Q2W. Treatment-emergent adverse events were comparable between groups. Conclusions Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals, versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy. The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups.
Background Non–ST-segment myocardial infarction (NSTEMI) can be complicated by high-degree atrioventricular (AV) block, asystole, or electromechanical dissociation (EMD), but these events are not ...well characterized in the contemporary era. This analysis assesses the incidence of and factors associated with these dysrhythmias in acute NSTEMIs. Methods Patients with NSTEMI in the EARLY ACS, PLATO, and TRACER trials were included in the pooled cohort (N = 29,677). Logistic regression was used to identify factors associated with in-hospital high-degree AV block and asystole or EMD, and Kaplan-Meier methods were used to assess mortality. Results High-degree AV block occurred in 112 (0.4%) patients, asystole in 157 (0.5%), and EMD in 38 (0.1%). Pacemakers were inserted in 241 patients (0.8%) during the index hospitalization: 30 (12%) for AV block. Among patients with high-degree AV block, we observed more frequent right coronary artery lesions (47% vs 29%). Age, diabetes, lower heart rate, and lower blood pressure were associated with high-degree AV block. Higher Killip class, ST-segment depression, prior myocardial infarction, and peripheral vascular disease were most strongly associated with asystole or EMD. Ten-day unadjusted survival was 90% for patients with high-degree AV block and 43% for those with asystole or EMD. Conclusions Although high-degree AV block, asystole, and EMD were infrequent complications of NSTEMI, they were associated with substantial short-term mortality. Only 1 in 8 pacemakers placed in NSTEMI patients during the acute hospitalization was for high-degree AV block.
Abstract Background We aimed to determine the efficacy and safety of adding ezetimibe (Ez) to simvastatin (S) in a post-acute coronary syndrome (ACS) population in a prespecified on-treatment ...analysis. Methods We evaluated 17,706 post-ACS patients from the IMPROVE-IT trial who had low-density lipoprotein cholesterol (LDL-C) values between 50 and 125 mg/dL and who received Ez 10 mg/day with S 40 mg/day (Ez/S) or placebo with simvastatin 40 mg/day (P/S). The primary composite endpoint was cardiovascular death, myocardial infarction, unstable angina, coronary revascularization ≥30 days post randomization, or stroke. The on-treatment analysis included patients who received study drug for the duration of the trial or experienced a primary endpoint or non-cardiovascular death within 30 days of drug discontinuation. Results Mean LDL-C values at 1 year were 71 mg/dL for P/S and 54 mg/dL for Ez/S (absolute difference− 17 mg/dL = −24%; P < .001). The 7-year Kaplan–Meier estimate of the primary endpoint occurred in 32.4% in the P/S arm and 29.8% in the Ez/S arm (absolute difference 2.6%; HRadj 0.92 95% CI 0.87–0.98; P = .01). The absolute treatment effect favoring Ez/S was 30% greater than in the intention-to-treat analysis of IMPROVE-IT. Conclusions This analysis provides additional support for the efficacy and safety of adding Ez to S in this high-risk, post-ACS population.
Since the original publication of the IMPROVE-IT Trial design,1 controversy over the impact of ezetimibe on the risk of cardiovascular events, as well as the drug's effect on the balance of benefit ...and risk for overall health outcomes, has persisted.2,3 This controversy has kept IMPROVE-IT in the public awareness,4 and questions have been raised about whether the trial will be completed.5 The purpose of this report is 2-fold: first, to describe the rationale for helping to ensure that IMPROVE-IT will accurately detect the effect of ezetimibe on cardiovascular events as a function of the expected relationship between low-density lipoprotein cholesterol (LDL-C) and cardiovascular outcomes seen with statin drugs, and second, to provide an update on the trial's expected completion date. ...IMPROVE-IT is focused on patients with relatively low LDL-C values at incident ACS, in whom treatment with simvastatin 40 mg + placebo is likely to result in achievement of the 2004 NCEP ATP III Update LDL-C goals.7 Although it is not absolutely known whether the relationship between LDL-C lowering and change in CVD risk is log-linear at the lowest LDL-C levels (due to limited amounts of data gathered from the lower range of measurements), it is reasonable to assume that this relationship holds at lower LDL-C ranges. Because available systematic reviews consistently demonstrate a log-linear relationship on a relative scale (curvilinear on an absolute scale) between absolute reduction in LDL-C levels and reduction in cardiovascular events,8 and because the expected LDL-C treatment group difference is smaller than in placebo-controlled trials, the expected difference in event rates at the lower end of LDL-C values addressed by this trial is likely to be relatively modest in absolute terms, compared with most other CVD outcomes trials.
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