Faculty Bibliography

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

BACKGROUND: Despite compelling evidence that aspirin reduces fatal and nonfatal vascular events among the overall population in various settings, women have frequently been underrepresented and their data underreported. We sought to evaluate the relationship between aspirin use, dose (81 or 325 mg), and clinical outcomes among postmenopausal women with stable cardiovascular disease (CVD). METHODS AND RESULTS: Women with CVD (n=8928) enrolled in the Women's Health Initiative Observational Study were used for this analysis. The primary outcome was the incidence of all-cause mortality and cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Among 8928 women with stable CVD, 4101 (46%) reported taking aspirin, of whom 30% were on 81 mg and 70% were on 325 mg. At 6.5 years of follow-up, no significant association was noted for aspirin use and all-cause mortality or cardiovascular events. However, after multivariate adjustment, aspirin use was associated with a significantly lower all-cause (adjusted hazard ratio, 0.86 [0.75 to 0.99]; P=0.04) and cardiovascular-related mortality (adjusted hazard ratio, 0.75 [0.60 to 0.95]; P=0.01) compared with no aspirin. Aspirin use was associated with a lower risk of cardiovascular events (adjusted hazard ratio, 0.90 [0.78 to 1.04]; P=0.14), which did not meet statistical significance. Compared with 325 mg, use of 81 mg was not significantly different for all-cause mortality, cardiovascular events, or any individual end point. CONCLUSIONS: After multivariate adjustment, aspirin use was associated with significantly lower risk of all-cause mortality, specifically, cardiovascular mortality, among postmenopausal women with stable CVD. No significant difference was noted between 81 mg and 325 mg of aspirin. Overall, aspirin use was low in this cohort of women with stable CVD

BACKGROUND: Differences in pathophysiology, diagnosis, and treatment of women with cardiovascular disease compared with men has become a major focus during the past decade. Nevertheless, little attention has focused on improving the quality of healthcare in women compared with other areas of cardiovascular medicine. METHODS: To address this deficit, Duke University Medical Center convened a national Duke Clinical Research Institute (DCRI) Think Tank meeting, including basic science and clinical researchers, payers, legislators, clinical experts, government regulators, and members of the pharmaceutical and device industries. This report provides an overview of the discussions and proposed solutions. RESULTS: Discussion concentrated on the development of strategies to improve the quality of health care for women with heart disease. Key components to improve quality care include: (1) enhance the quantity and quality of evidence-based medicine to guide care in women through improvements in trial design, enrollment and retention of women subjects, results analysis and reporting, and better incentives to perform research in women; (2) provide incentives to develop better data in women through mandating changes in the drug and device development and approval processes; (3) incorporate specific recommendations for women into guidelines when data are sufficient; and (4) apply proven sex-based differences in risk stratification, diagnostic testing, and drug usage and dosing in clinical care. Examples of possible strategies are included. CONCLUSION: The above approach represents a necessary, but not sufficient, platform to improve the overall quality of healthcare in women with cardiovascular disease

OBJECTIVES: The purpose of our multicenter study was to examine the impact of pre-operative administration of clopidogrel on reoperation rates, incidence of life-threatening bleeding, inpatient length of stay, and other bleeding-related outcomes in acute coronary syndrome (ACS) patients requiring cardiopulmonary bypass (coronary artery bypass graft surgery [CABG]) in a broad cross section of U.S. hospitals. BACKGROUND: There is relative uncertainty about the relationship between clopidogrel and CABG-associated outcomes in the setting of ACS. METHODS: A retrospective cohort analysis was performed of randomly selected ACS patients requiring CABG in 14 hospitals across the U.S. Patients exposed to clopidogrel were compared with those not exposed to clopidogrel within 5 days prior to surgery. RESULTS: Of the 596 patients enrolled in the study, 298 had been exposed to clopidogrel within 5 days (Group A). Patients in Group A were more than 3-fold more likely to require reoperation for assessment of bleeding than patients not exposed to clopidogrel (6.4% vs. 1.7% Group B, p = 0.004). Major bleeding occurred in 35% of Group A patients versus 26% of Group B patients (p = 0.049). Length of stay was greater in Group A compared with Group B (9.7 +/- 6.0 days vs. 8.6 +/- 4.7 days, unadjusted p = 0.016). After logistic regression analysis, clopidogrel exposure within 5 days of CABG was the strongest predictor of reoperation (odds ratio [OR]: 4.60, 95% confidence interval [CI]: 1.45 to 14.55) and major bleeding (OR: 1.824, 95% CI: 1.106 to 3.008). CONCLUSIONS: After ACS, patients who undergo CABG within 5 days of receiving clopidogrel are at increased risk for reoperation, major bleeding, and increased length of stay. These risks must be balanced by the clinical benefits of clopidogrel use demonstrated in randomized clinical trials

OBJECTIVE: Sustained ventricular arrhythmias complicate 2% to 20% of acute myocardial infarctions (MIs) and are associated with increased in-hospital mortality. However, it remains unclear whether successful mechanical revascularization improves outcomes in these patients. The objective of this analysis was to identify predictors of sustained ventricular arrhythmias after acute MI and to determine the influence of successful revascularization on in-hospital mortality. METHODS: We conducted a retrospective cohort study of all patients who underwent percutaneous coronary intervention for acute MI in New York State between 1997 and 1999. RESULTS: Of the 9015 patients who underwent percutaneous coronary intervention for acute MI, 472 (5.2%) developed sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) before revascularization. After multivariable adjustment, independent predictors of sustained VT/VF included cardiogenic shock (odds ratio [OR], 4.10; 95% confidence interval [CI], 3.20-5.58; P <.001), heart failure (OR, 2.86; 95% CI, 2.24-3.67: P <.001), chronic kidney disease (OR, 2.58; 95% CI, 1.27-5.23; P=.009), and presentation within 6 hours of symptom onset (OR, 1.46; 95% CI, 1.18-1.81; P=.001). Patients with sustained VT/VF had greater in-hospital mortality (16.3% vs 3.7%, P <.001). Although successful percutaneous coronary intervention was associated with decreased in-hospital mortality in patients with VT/VF (P <.001), patients with sustained VT/VF and successful revascularization experienced increased mortality compared with patients without sustained ventricular arrhythmias (P <.001). CONCLUSION: Among patients undergoing percutaneous coronary intervention for acute MI, sustained VT/VF remains a significant complication associated with a 4-fold increased risk of in-hospital mortality. Early mortality is reduced after successful percutaneous coronary intervention, but remains elevated in this high-risk group

Few studies have investigated the role of elevated lipoprotein-associated phospholipase A2 (Lp-PLA(2)) with stroke risk, and those that have are based on small numbers of strokes. No study has evaluated the effect of hormone therapy use on the association of Lp-PLA(2) and stroke. We assessed the relationship between Lp-PLA(2) and the risk of incident ischemic stroke in 929 stroke patients and 935 control subjects in the Hormones and Biomarkers Predicting Stroke Study, a nested case-control study from the Women's Health Initiative Observational Study. Mean (SD) levels of Lp-PLA(2) were significantly higher among case subjects (309.0 [97.1]) than control subjects (296.3 [87.3]; P<0.01). Odds ratio for ischemic stroke for the highest quartile of Lp-PLA(2), compared with lowest, controlling for multiple covariates, was 1.08 (95% CI: 0.75 to 1.55). However, among 1137 nonusers of hormone therapy at baseline, the corresponding odds ratio was 1.55 (95% CI: 1.05 to 2.28),whereas there was no significant association among 737 hormone users (odds ratio: 0.70; 95% CI: 0.42 to 1.17; P for interaction=0.055). Moreover, among nonhormone users, women with high C-reactive protein and high Lp-PLA2 had more than twice the risk of stroke (odds ratio: 2.26; 95% CI: 1.55 to 3.35) compared with women low levels in both biomarkers. Furthermore, different stroke cases were identified as high risk by Lp-PLA(2) rather than by C-reactive protein. Lp-PLA(2) was associated with incident ischemic stroke independently of C-reactive protein and traditional cardiovascular risk factors among nonusers of hormone therapy with highest risk in those who had both high C-reactive protein and high Lp-PLA(2)

BACKGROUND: Although treatment with immediate aspirin reduces morbidity and mortality in ST-elevation myocardial infarction, the optimal dose is unclear. We therefore compared the acute mortality and bleeding risks associated with the initial use of 162 versus 325 mg aspirin in fibrinolytic-treated ST-elevation myocardial infarction patients. METHODS AND RESULTS: Using combined data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) trials (n=48 422 ST-elevation myocardial infarction patients), we compared the association between initial aspirin dose of 162 versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding. Results were adjusted for previously identified mortality and bleeding risk factors. Overall, 24.4% of patients (n=11 828) received an initial aspirin dose of 325 mg, and 75.6% (n=36 594) received 162 mg. The 24-hour mortality rates were 2.9% versus 2.8% (P=0.894) for those receiving an initial aspirin dose of 325 versus 162 mg. Mortality rates at 7 and 30 days were 5.2% versus 4.9% (P=0.118) and 7.1% versus 6.5% (P=0.017) among patients receiving the 325 versus 162 mg aspirin. After adjustment, aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for myocardial infarction or the composite of death or myocardial infarction between groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P<0.001). After adjustment, 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P=0.003). CONCLUSIONS: These data suggest that an initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST-elevation myocardial infarction

We examined risk factors associated with failure of arterial catheterization in the medical intensive care unit of a large urban teaching hospital. We analyzed 92 consecutive arterial catheterizations by internal medicine house staff and critical care fellows. Of the 92 attempts, 26.1% were done on femoral arteries, and 73.9% were done on radial arteries. Failure, which occurred in 28% of attempts, was more common in female patients (P < .001). The failure rate was 50.0% for attempts on femoral arteries and 20.6% on radial arteries. Systolic blood pressure was significantly lower in patients where the attempt failed (P = .024). In univariate analyses, hemoglobin values were lower (P = .028) and number of percutaneous punctures were higher (P = .019) in patients where catheterization failed. After multivariate analysis, only gender and systolic blood pressure remained statistically significant. The strongest predictor of failure was female gender. A possible explanation not explored here could be smaller arterial size in female patients