Faculty Bibliography

Background The 2007 American Heart Association guidelines for cardiovascular disease prevention in women drew heavily on results from randomized clinical trials; however, representation of women in trials of cardiovascular disease prevention has not been systematically assessed. Methods and Results We abstracted 156 randomized clinical trials cited by the 2007 women's prevention guidelines to determine female representation over time and by clinical indication, prevention type, location of trial conduct, and funding source. Both women and men were represented in 135 of 156 (86.5%) trials; 20 trials enrolled only men; 1 enrolled only women. Among all trials, the proportion of women increased significantly over time, from 9% in 1970 to 41% in 2006. Considering only trials that enrolled both women and men, female enrollment was 18% in 1970 and increased to 34% in 2006. Female representation was higher in international versus United States\Nonly trials (32.7% versus 26.7%) and primary versus secondary prevention trials (42.6% versus 26.6%). Female enrollment was comparable in government/foundation-funded versus industry-funded trials (31.9% versus 31.5%). Representation of women was highest among trials in hypertension (44%), diabetes (40%), and stroke (38%) and lowest for heart failure (29%), coronary artery disease (25%), and hyperlipidemia (28%). By contrast, women accounted for 53% of all individuals with hypertension, 50% with diabetes, 51% with heart failure, 49% with hyperlipidemia, and 46% with coronary artery disease. Sex-specific results were discussed in only 31% of primary trial publications. Conclusions Enrollment of women in randomized clinical trials has increased over time but remains low relative to their overall representation in disease populations. Efforts are needed to reach a level of representation that is adequate to ensure evidence-based sex-specific recommendations

Summary Aim: To determine if an association exists between mean platelet volume (MPV) and acute myocardial infarction (AMI) and other cardiovascular events. Platelet activity is a major culprit in atherothrombotic events. Mean platelet volume, widely available in clinical practice, is a potentially useful biomarker of platelet activity in the setting of cardiovascular disease. Methods and Results: We performed a systematic review and meta-analysis investigating the association between MPV and AMI, all-cause mortality following MI, and restenosis following coronary angioplasty. Results were pooled using random effects modeling. Pooled results from 16 cross-sectional studies involving 2,809 patients investigating the association of MPV and AMI indicated that MPV was significantly higher in those with AMI than those without AMI (mean difference 0.92 fl, 95% confidence interval [CI] 0.67 to 1.16, P < 0.001). In subgroup analyses, significant differences in MPV existed between subjects with AMI versus stable coronary disease (P < 0.001) and versus stable controls (P < 0.001), but not versus unstable angina (P = 0.24). Pooled results from three cohort studies involving 3,184 patients evaluating the risk of death following AMI, demonstrated that an elevated MPV increased the odds of death compared with a normal MPV (11.5% versus 7.1%, odds ratio 1.65, 95% CI 1.12 to 2.52, P = 0.012). Pooled results from five cohort studies involving 430 patients who underwent coronary angioplasty revealed that MPV was significantly higher in patients who developed restenosis compared with those who did not develop restenosis (mean difference 0.98 fl, 95% CI 0.74 to 1.21, P < 0.001). Conclusions: Elevated MPV is associated with AMI, mortality following MI, and restenosis following coronary angioplasty. These data suggest that MPV is a potentially useful prognostic biomarker in patients with cardiovascular disease. Whether the relationship is causal, and whether MPV should influence practice or guide therapy remains unknown

BACKGROUND: Smoking increases platelet aggregability and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown. METHODS AND RESULTS: We evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status (P for interaction=0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 1.58). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P=0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P=0.15). CONCLUSIONS: Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility

BACKGROUND: Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, versus placebo when administered to STEMI patients before primary PCI. METHODS: The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated. RESULTS: Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between elinogrel and placebo. CONCLUSIONS: With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, as an adjunctive therapy for primary PCI for STEMI

OBJECTIVES: This study sought to investigate the efficacy and safety of clopidogrel in women and men. BACKGROUND: Previous analyses have shown sex-based differences in response to several antiplatelet medications. Little is known about the efficacy and safety of clopidogrel in women and men. METHODS: This study performed a meta-analysis of all blinded randomized clinical trials comparing clopidogrel and placebo (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events], CREDO [Clopidogrel for the Reduction of Events During Observation], CLARITY-TIMI 28 [Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28], COMMIT [Clopidogrel and Metoprolol in Myocardial Infarction Trial], and CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trials), involving a total of 79,613 patients, of whom 30% were women. The relative efficacy and safety of clopidogrel at reducing cardiovascular events (cardiovascular death, myocardial infarction [MI], or stroke) in women and men was estimated using random-effects modeling. RESULTS: Overall, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93), with no significant differences in treatment effect between women and men. Among the 23,533 women enrolled, there were fewer cardiovascular events in the clopidogrel group compared with the placebo group (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01). In women the risk reduction with clopidogrel seemed to be greatest for MI (OR: 0.81; 95% CI: 0.70 to 0.93), with the effects on stroke (OR: 0.91; 95% CI: 0.69 to 1.21) or total death (OR: 0.99; 95% CI: 0.90 to 1.08) not statistically significant. Among the 56,091 men enrolled, there were fewer cardiovascular events in those receiving clopidogrel compared with placebo (7.8% vs. 9.0%; OR: 0.84; 95% CI: 0.78 to 0.91), and the risk reduction was significant for MI (OR: 0.83; 95% CI: 0.76 to 0.92), stroke (OR: 0.83; 95% CI: 0.71 to 0.96), and total death (OR: 0.91; 95% CI: 0.84 to 0.97). Clopidogrel increased the risk of major bleeding in both women (OR: 1.43; 95% CI: 1.15 to 1.79) and men (OR: 1.22; 95% CI: 1.05 to 1.42). CONCLUSIONS: Clopidogrel reduces the risk of cardiovascular events in both women and men

BACKGROUND: Although adequate representation of specific subgroups (eg, women and the elderly) in randomized controlled trials (RCTs) has been under intense scrutiny, there are few data on representation by race. METHODS: Using all RCTs cited by the 2007 American Heart Association guidelines for cardiovascular disease prevention in women (although trials were included whether or not there were female participants), we explored the extent to which information on race was reported in the baseline characteristics. Race/ethnicity categories were whites, blacks, Asians, Hispanics, and 'others.' RESULTS: Overall, 156 trials were analyzed. Demographic data on race/ethnicity were reported in 55 (35%) trials and increased significantly over time (1970s, 12.5%; 1980s, 25%; 1990s, 30.5%; 2000s, 46.2%; P for trend = .011). Among the 55 trials reporting any race/ethnicity information, trial inclusion of whites, blacks, Asians, Hispanics, and 'others' was reported in 27%, 13%, 14%, 5%, and 10% of trials, respectively, and increased over time (P for trend < .05 for all). Trials enrolling subjects only in the United States or globally, including the US, were more likely to report race composition than trials that included no US sites (US only 64% vs global 62% vs non-US 21%, P < .01). Industry- and federal/foundation-funded RCTs reported race with similar frequency (industry 36% vs federal 34% vs both 24%, P = .44). When we isolated our analyses to trials that were funded by the National Institutes of Health, 12 (67%) of 18 RCTs reported race/ethnicity as a baseline characteristic. CONCLUSION: Although reporting the race/ethnic composition of study populations is increasing over time, two thirds of all RCTs supporting a recent American Heart Association () guideline failed to publish any information on race. A necessary first requirement in translating RCT evidence to patients of all races is information regarding racial demographics. Such information should be strongly encouraged in future publications

Coronary artery bypass grafting (CABG) is effective in reducing cardiovascular morbidity and mortality in certain high-risk groups. Despite improvement in surgical technique, hemorrhagic complications are a major concern and are likely to affect perioperative morbidity and mortality, length of stay, and hospital expenditures. The use of platelet-directed therapies in this setting is effective in decreasing ischemic complications, yet these agents simultaneously increase the risk of bleeding. Concern about potential hemorrhagic risk from antiplatelet agents in proximity to CABG may influence physicians to discontinue these agents. The benefit of low-dose aspirin given preoperatively is likely to outweigh any hemorrhagic risk. Dual antiplatelet therapy with aspirin and clopidogrel (or aspirin and prasugrel) is associated with a significant increased risk of bleeding and its complications. Additional research is needed to properly evaluate the ischemic benefit versus bleeding risk of aspirin and clopidogrel. Whether reversible P2Y(12) receptor antagonists will mitigate the bleeding risk is unclear at the present time and will require large prospective studies

CONTEXT: Conflicting information exists about whether sex differences modulate short-term mortality following acute coronary syndromes (ACS). OBJECTIVES: To investigate the relationship between sex and 30-day mortality in ACS, and to determine whether this relationship was modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates. DESIGN, SETTING, AND PARTICIPANTS: A convenience sample of patients pooled from 11 independent, international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained at the Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) were women; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29% women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina. MAIN OUTCOME MEASURE: Thirty-day mortality following ACS. RESULTS: Thirty-day mortality was 9.6% in women and 5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95% CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI, 30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI (adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women (adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, women more often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel (23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (P for interaction = .70). CONCLUSIONS: Sex-based differences existed in 30-day mortality among patients with ACS and vary depending on clinical presentation. However, these differences appear to be largely explained by clinical differences at presentation and severity of angiographically documented disease