Faculty Bibliography

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

CONTEXT: Randomized trials have shown that aspirin decreases the risk of cardiovascular events in patients with symptomatic coronary and cerebrovascular disease. Despite guideline recommendations for secondary prevention in peripheral artery disease (PAD), the effect of aspirin in this population is not well established. OBJECTIVE: To investigate the effect of aspirin on cardiovascular event rates in patients with PAD. DATA SOURCES AND STUDY SELECTION: MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Science Citation Index (1966 to December 2008), and unpublished studies from the supplemental index of the Antithrombotic Trialists' Collaboration. Eligible studies were prospective, randomized controlled trials of aspirin therapy, with or without dipyridamole that reported cardiovascular event rates. Eighteen trials involving 5269 individuals were identified. DATA EXTRACTION: Studies were reviewed to determine the number of participants, mean follow-up, and the primary end point of cardiovascular events (nonfatal myocardial infarction [MI], nonfatal stroke, and cardiovascular death). Data on the secondary end points of all-cause mortality, major bleeding, and the individual components of the primary outcome measure were also abstracted. For the primary end point, the analysis had 88% power to detect a 25% reduction and 70% power to detect a 20% reduction in cardiovascular events in the aspirin group compared with the control group. DATA SYNTHESIS: Among 5269 participants, cardiovascular events were experienced by 251 (8.9%) of 2823 patients taking aspirin (alone or with dipyridamole) and by 269 (11.0%) of 2446 in the control group (pooled relative risk [RR], 0.88; 95% confidence interval [CI], 0.76-1.04). Aspirin therapy was associated with a reduction in the secondary outcome of nonfatal stroke (52 of 2823 vs 76 of 2446; RR, 0.66; 95% CI, 0.47-0.94) but was not associated with significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. In the subset of 3019 participants taking aspirin alone vs control, aspirin was associated with a nonsignificant reduction in cardiovascular events (125 of 1516 vs 144 of 1503; RR, 0.75; 95% CI, 0.48-1.18), a significant reduction in nonfatal stroke (32 of 1516 vs 51 of 1503; RR, 0.64; 95% CI, 0.42-0.99), but no statistically significant reductions in all-cause or cardiovascular mortality, MI, or major bleeding. CONCLUSIONS: In patients with PAD, treatment with aspirin alone or with dipyridamole resulted in a statistically nonsignificant decrease in the primary end point of cardiovascular events and a significant reduction in nonfatal stroke. Results for the primary end point may reflect limited statistical power. Additional randomized controlled trials of aspirin therapy are needed to establish the net benefit and bleeding risks in PAD

Many patients with systolic dysfunction undergo elective percutaneous coronary intervention (PCI) despite the unknown risk and limited data supporting its use. Therefore, the aim of this study was to evaluate the association between the severity of left ventricular (LV) systolic dysfunction and hospital mortality in patients who undergo elective PCI. A retrospective cohort study was conducted of all patients who underwent elective PCI in New York State in 1998 and 1999. Patients were stratified into 5 groups on the basis of their LV ejection fractions (EFs) before PCI (>55%, 46% to 55%, 36% to 45%, 26% to 35%, and < or =25%). Comparisons of demographic, procedural, and outcome variables were performed, and adjusted odds ratios (ORs) were calculated to evaluate the relation between the EF and hospital mortality. Among 55,709 patients who underwent elective PCI, EFs < or =25%, 26% to 35% and 36% to 45% were present in 3.4%, 7.6%, and 17.4%, respectively. Hospital mortality was 0.3%, 0.2%, 0.6%, 1.2%, and 2.7% in the groups with EFs >55%, 46% to 55%, 36% to 45%, 26% to 35%, and < or =25%, respectively (p <0.001). After multivariate adjustment, an increased risk for hospital mortality was significant for EF groups of 36% to 45% (OR 1.56, 95% confidence interval 1.06 to 2.30), 26% to 35% (OR 2.17, 95% confidence interval 1.42 to 3.31), and < or =25% (OR 3.85, 95% confidence interval 2.46 to 6.01) compared with EF >55%, respectively. In conclusion, this analysis demonstrates that elective PCI is commonly performed in patients with reduced EFs, and the risk for hospital mortality increases as the EF decreases. For patients who undergo elective PCI, an EF < or =45% is associated with higher adjusted hospital mortality. Whether elective PCI in patients with low EFs reduces morbidity and/or mortality over medical therapy alone is unknown

AIMS: Not all patients at risk for sudden cardiac death (SCD) are eligible for, or have access to implantable cardioverter defibrillator (ICD) implantation. There are conflicting data regarding the efficacy and safety of amiodarone for the prevention of SCD. METHODS AND RESULTS: We conducted a meta-analysis of all randomized controlled trials examining the use of amiodarone vs. placebo/control for the prevention of SCD. We identified 15 trials, which randomized 8522 patients to amiodarone or placebo/control. Amiodarone decreased the incidence of SCD [7.1 vs. 9.7%; OR 0.71 (0.61-0.84), P < 0.001] and cardiovascular death (CVD) [14.0 vs. 16.3%; OR 0.82 (0.71-0.94), P = 0.004]. There was a 1.5% absolute risk reduction in all-cause mortality which did not meet statistical significance (P = 0.093). Amiodarone therapy increased the risk of pulmonary [2.9 vs. 1.5%; OR 1.97, (1.27-3.04), P = 0.002], and thyroid [3.6 vs. 0.4%; OR 5.68, (2.94-10.98), P < 0.001] toxicity. CONCLUSION: Amiodarone reduces the risk of SCD by 29% and CVD by 18%, and therefore, represents a viable alternative in patients who are not eligible for or who do not have access to ICD therapy for the prevention of SCD. However, amiodarone therapy is neutral with respect to all-cause mortality and is associated with a two- and five-fold increased risk of pulmonary and thyroid toxicity

Platelet-initiated acute thrombosis and coronary embolization are fundamental to the pathophysiology of acute coronary syndromes. Pharmacotherapies aimed at disrupting platelet function via the P2Y(12) receptor have been successful at reducing the incidence of vascular events in randomized clinical trials. However, with the emergence of third and fourth generation drugs, several important considerations remain, including metabolism, timing of onset, variability in platelet response or 'resistance', monitoring ability, and off-target effects. These fundamental properties and distinct profiles may shape the future of cardiovascular therapeutics. Investigation of practical ex vivo platelet performance measurement tools is actively proceeding and may provide important information for patient management

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

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

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