Abstract Background The effect of saxagliptin on cardiovascular outcomes according to different hemoglobin A1c (HbA1c) levels has not been described. Thus, we analyzed the SAVOR-TIMI 53 trial to ...compare the cardiovascular effects of saxagliptin vs placebo according to baseline HbA1c. Methods A total of 16,492 patients with type 2 diabetes (HbA1c 6.5%-12.0% in the 6 months before randomization) and either a history of established cardiovascular disease or multiple risk factors for atherosclerosis were randomized to saxagliptin or placebo in addition to usual care. Patients were followed for a median of 2.1 years. The primary endpoint was cardiovascular death, myocardial infarction, or ischemic stroke. Results Patients were stratified by HbA1c at randomization into the following prespecified groups: <7%, 7%-<8%, 8%-<9%, and ≥9%. Baseline HbA1c ≥7% was associated with increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (adjusted hazard ratio HRadj 1.35; 95% confidence interval CI, 1.17-1.58) but not hospitalization for heart failure (HRadj 1.09; 95% CI, 0.88-1.36). Saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke in patients with HbA1c <7% (HR 1.01; 95% CI, 0.78-1.31), 7%-<8% (HR 0.98; 95% CI, 0.80-1.20), 8%-<9% (HR 1.09; 95% CI, 0.85-1.39), ≥9% (HR 0.95; 95% CI, 0.77-1.18) ( P -interaction = .89). Conclusions Baseline HbA1c is associated with increased risk of macrovascular events but not hospitalization for heart failure. There was no heterogeneity in the effect of saxagliptin on cardiovascular events by baseline HbA1c, with cardiovascular death, myocardial infarction, or ischemic stroke neither increased nor decreased across the spectrum of baseline HbA1c values.
Abstract Background Prediction models for cardiovascular events and cardiovascular death in patients with established cardiovascular disease are not generally available. Methods Participants from the ...prospective REduction of Atherothrombosis for Continued Health (REACH) Registry provided a global outpatient population with known cardiovascular disease at entry. Cardiovascular prediction models were estimated from the 2-year follow-up data of 49,689 participants from around the world. Results A developmental prediction model was estimated from 33,419 randomly selected participants (2394 cardiovascular events with 1029 cardiovascular deaths) from the pool of 49,689. The number of vascular beds with clinical disease, diabetes, smoking, low body mass index, history of atrial fibrillation, cardiac failure, and history of cardiovascular event(s) <1 year before baseline examination increased risk of a subsequent cardiovascular event. Statin (hazard ratio 0.75; 95% confidence interval, 0.69-0.82) and acetylsalicylic acid therapy (hazard ratio 0.90; 95% confidence interval, 0.83-0.99) also were significantly associated with reduced risk of cardiovascular events. The prediction model was validated in the remaining 16,270 REACH subjects (1172 cardiovascular events, 494 cardiovascular deaths). Risk of cardiovascular death was similarly estimated with the same set of risk factors. Simple algorithms were developed for prediction of overall cardiovascular events and for cardiovascular death. Conclusions This study establishes and validates a risk model to predict secondary cardiovascular events and cardiovascular death in outpatients with established atherothrombotic disease. Traditional risk factors, burden of disease, lack of treatment, and geographic location all are related to an increased risk of subsequent cardiovascular morbidity and cardiovascular mortality.
Abstract Background Anemia is a predictor of adverse outcomes in acute myocardial infarction. We studied the relationship of hemoglobin, or its change over time, and outcomes in patients with stable ...coronary artery disease. Methods CLARIFY is a prospective, cohort study of outpatients with stable coronary artery disease (32,901 in 45 countries 2009-2010); 21,829 with baseline hemoglobin levels. They were divided into hemoglobin quintiles and anemia status (anemic A or normal N) at baseline/follow-up: N/N; A/N; N/A; A/A. All-cause mortality, cardiovascular events, and major bleeding at 4-year follow-up were assessed. Results Low baseline hemoglobin was an independent predictor of all-cause, cardiovascular, and noncardiovascular mortality, the composite of cardiovascular death/myocardial infarction or stroke and major bleeds (all P <.001; unadjusted models). Anemia at follow-up was independently associated with all-cause mortality (hazard ratio HR, 1.90; 95% confidence interval CI, 1.55-2.33 for A/A; 1.87; 1.54-2.28 for N/A; both P <.001), noncardiovascular mortality ( P <.001), and cardiovascular mortality ( P = .001). Patients whose baseline anemia normalized (A/N) were not at increased risk of death (HR, 1.02; 95% CI, 0.77-1.35), although risk of major bleeding was greater (HR, 2.06; 95% CI, 1.23-3.44; P = .013) than in those with normal hemoglobin throughout. Sensitivity analyses excluding patients with heart failure and chronic kidney disease at baseline yielded qualitatively similar results. Conclusion In this large stable coronary artery disease population, low hemoglobin was an independent predictor of mortality, cardiovascular events, and major bleeds. Persisting or new-onset anemia is a powerful predictor of cardiovascular and noncardiovascular mortality.
Objectives This study investigated the differences in specific causes of post–coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial. ...Background In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality. Methods In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death. Results Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively). Conclusions The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes PLATO; NCT00391872 )
Abstract Background Nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin have been linked to heart failure, salt retention, adverse ventricular remodeling, and thrombosis. We therefore ...sought to assess their impact on cardiovascular events in outpatients with stable atherothrombotic disease. Methods We analyzed 44,095 patients in the REduction of Atherothrombosis for Continued Health (REACH) registry with information on NSAID use and 4-year follow-up. Cox proportional hazard models, including NSAID use as a time-dependent covariate, were constructed and adjusted for key baseline characteristics. End points of interest included multivariate adjusted: cardiovascular death/myocardial infarction/stroke/ischemic hospitalizations; cardiovascular death/myocardial infarction/stroke; hospitalization for heart failure; and individual components of the composite end points. Results Compared with NSAID nonusers (n = 39,675), NSAID users (n = 4420) were older (70 vs 68 years), more frequently female and white, and had more baseline heart failure and atherosclerotic risk factors (hypertension, dyslipidemia, diabetes, reduced creatinine clearance) (all P < .001). NSAID use was associated with an increased hazard for cardiovascular death/myocardial infarction/stroke/ischemic hospitalizations (adjusted hazard ratio adj. HR 1.12; 95% confidence interval CI, 1.04-1.21; P = .003) and for cardiovascular death/myocardial infarction/stroke (adj. HR 1.16; 95% CI, 1.03-1.30; P = .02). There also was a higher risk of myocardial infarction (adj. HR 1.37; 95% CI, 1.12-1.68; P = .002), stroke (adj. HR 1.21; 95% CI, 1.00-1.45; P = .048), heart failure hospitalizations (adj. HR 1.18; 95% CI, 1.03-1.34; P = .013), and ischemic hospitalizations (adj. HR 1.17; 95% CI, 1.07-1.27; P = .001). Conclusion Among patients with stable atherothrombosis, NSAID use is associated with a higher risk of myocardial infarction, stroke, and hospitalizations for both ischemia and heart failure.
Objectives Saxagliptin, a dipeptidyl peptidase 4 inhibitor, improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by increasing endogenous active, intact glucagon-like peptide 1 ...and glucose-dependent insulinotropic polypeptide in response to food, which augments insulin secretion and decreases glucagon release. Research Design and Methods SAVOR-TIMI 53 is a phase 4, randomized, double-blind, placebo-controlled trial conducted in 25 countries that is designed to evaluate the safety and efficacy of saxagliptin during long-term treatment of approximately 16,500 patients with T2DM. Eligible patients who are either treatment naive or on any background antidiabetic treatment (except incretin therapy) with history of established cardiovascular (CV) disease or multiple risk factors are randomized 1:1 to saxagliptin 5 mg QD (2.5 mg in subjects with moderate/severe renal impairment) or matching placebo, stratified by qualifying disease state. The primary end point is the composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke. The trial will continue until approximately 1,040 primary end points accrue, providing 85% power to identify a 17% relative reduction of the primary end point with saxagliptin versus placebo and 98% power to test for noninferiority of saxagliptin versus placebo (reject the upper limit of 95% CI for a hazard ratio <1.3 at a 1-sided α of .025). Conclusion SAVOR-TIMI 53 is testing the hypothesis that treatment with saxagliptin is safe and reduces CV events in high-risk patients with T2DM.
Abstract OBJECTIVE To determine whether ethnic-specific differences in the prevalence of cardiovascular risk factors and outcomes exist worldwide among individuals with stable arterial disease. ...PATIENTS AND METHODS From December 1, 2003, to June 30, 2004, the prospective, observational REduction of Atherothrombosis for Continued Health (REACH) Registry enrolled 49,602 outpatients with coronary artery disease, cerebrovascular disease, and/or peripheral arterial disease from 7 predefined ethnic/racial groups: white, Hispanic, East Asian, South Asian, Other Asian, black, and Other (comprising any race distinct from those specified). The baseline demographic and risk factor profiles, medication use, and 2-year cardiovascular outcomes were assessed among these groups. RESULTS The prevalence of traditional atherothrombotic risk factors varied significantly among the ethnic/racial groups. The use of medical therapies to reduce risk was comparable among all groups. At 2-year follow-up, the rate of cardiovascular death was significantly higher in blacks (6.1%) compared with all other ethnic/racial groups (3.9%; P=.01). Cardiovascular death rates were significantly lower in all 3 Asian ethnic/racial groups (overall, 2.1%) compared with the other groups (4.5%; P<.001). CONCLUSION The REACH Registry, a large international study of individuals with atherothrombotic disease, documents the important ethnic-specific differences in cardiovascular risk factors and variations in cardiovascular mortality that currently exist worldwide.
Objectives This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint. Background In the prospective, double-blind, active-controlled ...CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST. Methods An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee. Results IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction MI, ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis Academic Research Consortium) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points. Conclusions In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention PCI CHAMPION PHOENIX; NCT01156571 )
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.
Abstract Objectives This study sought to compare the outcomes of patients undergoing drug-eluting stent implantation according to lesion location within or outside the proximal left anterior ...descending (LAD) artery. Background Proximal LAD artery involvement is considered uniquely in revascularization guidelines. The impact of LAD lesion location on long-term outcomes after revascularization is poorly understood in context of current percutaneous coronary intervention and medical therapy. Methods Among 8,709 patients enrolled in PROTECT (Patient Related Outcomes with Endeavor Versus Cypher Stenting Trial), a multicenter percutaneous coronary intervention trial, we compared the outcomes of 2,534 patients (29.1%) (3,871 lesions 31.5%) with stents implanted in the proximal LAD to 6,172 patients (70.9%) (8,419 lesions 68.5%) with stents implanted outside the proximal LAD. Results At the 4-year follow-up, death rates were the same (5.8% vs. 5.8%; p > 0.999), but more myocardial infarctions occurred in the proximal LAD group (6.2% vs. 4.9%; p = 0.015). The rate of clinically driven target vessel failure (TVF) (14.8% vs. 13.5%; p = 0.109), major adverse cardiac event(s) (MACE) (15.0% vs. 13.7%; hazard ratio: 1.1; 95% confidence interval: 0.97 to 1.31; p = 0.139), and stent thrombosis (2.1% vs. 2.0%; p = 0.800) were similar. Drug-eluting stent type had no interaction with MACE or TVF. In multivariate analysis, the proximal LAD was a predictor of myocardial infarction (p = 0.038) but not of TVF (p = 0.149) or MACE (p = 0.069). Conclusions In this study of contemporary percutaneous coronary intervention, proximal LAD location was associated with higher rates of myocardial infarction during the long-term follow-up, but there were no differences in stent thrombosis, death, TVF, or overall MACE. This finding may suggest that, in the drug-eluting stent era, proximal LAD no longer confers a different prognosis than other lesion sites. (Randomized Study Comparing Endeavor With Cypher Stents PROTECT; NCT00476957 )
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