Faculty Bibliography

BACKGROUND: Adequate representation by sex in trials allows generalizability of results. We examined representation of women in clinical trials during a 17-year period in which inclusion criteria were broadened and federal mandates for representativeness were launched. METHODS AND RESULTS: Using mixed models, we studied sex-stratified temporal trends in enrollment, clinical characteristics, treatment, and outcomes among 76 148 non-ST-segment elevation acute coronary syndrome patients using patient-level data merged from 11 phase III trials conducted from 1994 to 2010. Overall, 33.3% of patients were women, which changed minimally over time. Women were consistently 4 to 5 years older than men (median age 68 [interquartile range 61-75] versus 64 [interquartile range 56-72] years) and more frequently had diabetes mellitus, hypertension, and heart failure; men more frequently had prior myocardial infarction and revascularization. GRACE risk scores increased over time for both sexes with the inclusion of older patients with more comorbidities. Use of percutaneous coronary intervention, in-hospital and discharge angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, beta-blockers, and lipid-lowering drugs also increased among both sexes. Kaplan-Meier estimates of 6-month mortality declined from 7.0% [95% confidence interval 6.5%-7.6%] to 4.5% [95% confidence interval 4.0%-5.0%] among women and 6.3% [95% confidence interval 6.0%-6.7%] to 3.1% [95% confidence interval 2.9%-3.4%] among men during the 17-year period. CONCLUSIONS: The relative proportion of women in non-ST-segment elevation acute coronary syndrome trials changed minimally over time. Nevertheless, in parallel with men, use of evidence-based care and outcomes improved significantly over time among women.

AIMS: Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side. METHODS AND RESULTS: The traditional time-to-first-event, Andersen-Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen-Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72-0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen-Gill and WCE methods used all events in all participants; however, with the Andersen-Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events. CONCLUSION: This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common. CLINICAL TRIAL REGISTRATION: NCT00699998.

BACKGROUND: In the SHOCK trial an invasive strategy of early revascularization was associated with a significant mortality benefit at 6-months when compared with initial stabilization in patients with cardiogenic shock complicating acute myocardial infarction. Our objectives were to evaluate the data on real world practice and outcomes of invasive vs. conservative management in patients with cardiogenic shock. METHODS: We analyzed data from the Nationwide Inpatient Sample (NIS) between 2002 to 2011 with primary discharge diagnosis of acute myocardial infarction and secondary diagnosis of cardiogenic shock. Propensity score matching was used to assemble a cohort of patients managed invasively (with cardiac catheterization, percutaneous coronary intervention or coronary artery bypass graft surgery) vs. conservatively with similar baseline characteristics. The primary outcome was in-hospital mortality. RESULTS: We identified 60833 patients with cardiogenic shock of which 20644 patients (10322 in each group) with similar propensity scores, including 11,004 elderly patients (>/= 75 years), were in the final analysis. Patients who underwent invasive management had a 59% lower odds of in-hospital mortality (37.7% vs. 59.7%; OR=0.41; 95% CI 0.39-0.43; P<0.0001) when compared with those managed conservatively. This lower mortality was consistently seen across all tested subgroups; specifically in the elderly (>/= 75 years) (44.0% vs. 63.6%; OR=0.45; 95% CI 0.42-0.49; P<0.0001) and those younger than 75 years (30.6% vs. 55.1%; OR=0.36; 95% CI 0.33-0.39; P<0.0001) although the magnitude of risk reduction differed (Pinteraction <0.0001). CONCLUSIONS: In this largest cohort of patients with cardiogenic shock complicating acute myocardial infarction, patients managed invasively had significantly lower mortality when compared with those managed conservatively, even in the elderly. Our results emphasize the need for aggressive management in this high-risk subgroup.

AIMS/OBJECTIVE:Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD. METHODS AND RESULTS/RESULTS:We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (OR(adj) 0.15; 95% CI, 0.11-0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (OR(adj) 0.19 (0.14-0.25) and 0.37 (0.28-0.49), respectively). CONCLUSION/CONCLUSIONS:Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.

INTRODUCTION: There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, is a significant risk factor for CVD. METHODS: We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy (TACT) strengthen the link between atherosclerosis and xenobiotic metal contamination in humans. CONCLUSIONS: There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor.

IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000727.