Faculty Bibliography

BACKGROUND: A pooled analysis in cardiogenic shock due to acute coronary syndromes is desirable to assess the effect of early revascularization (ERV) across all ages and a wide spectrum of disease severity. METHODS: Only two randomized controlled trials (RCT), i.e. SMASH and SHOCK, met the inclusion criteria and were combined for a pooled analysis using individual patient data (n = 348). RESULTS: SMASH patients (n = 54, 16%) had more severe disease than SHOCK patients (n = 294, 84%). After adjustment for age, anoxic brain damage, non-inferior myocardial infarction, prior coronary artery bypass graft surgery, renal failure, systolic blood pressure, and selection for coronary angiography, one-year mortality was similar (relative risk SHOCK versus SMASH 0.87, 95% CI: 0.61-1.25). Relative risk of one-year death for ERV versus initial medical stabilization was 0.82 (95% CI: 0.70-0.96). There was no significant difference in the treatment effect by age (</=75 years relative risk at one year 0.79, 95% CI: 0.63-0.99; > 75 years relative risk at one year 0.93, 95% CI: 0.56-1.53; interaction P = 0.10). CONCLUSIONS: Only two RCT have been published emphasizing the difficulty of enrolling critically ill patients. Despite large differences in shock severity, ERV benefit is similar across all ages and not significantly different for the elderly

BACKGROUND: In the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study, patients assigned enoxaparin or unfractionated heparin (UFH) were treated with alternative anticoagulant therapy after randomization at physician discretion, a practice made possible because the trial was open label. Using SYNERGY as an example, we demonstrate the difficulty of evaluating the effect of postrandomization events in clinical trials and discuss possible methodology. METHODS AND RESULTS: Patients with and without postrandomization crossovers were characterized and event rates analyzed. Statistical modeling was performed using inverse probability weighting and landmark analyses to evaluate the potential impact of postrandomization crossovers on event rates and treatment effect. Of 9978 SYNERGY patients, 9613 (96.3%) received at least 1 dose of randomized therapy and are included in these analyses. Of these, 740 (7.7%; 554 enoxaparin; 186 UFH) had postrandomization crossover. Crossover patients had higher unadjusted rates of 30-day death/myocardial infarction (MI) (18.9% versus 14.0%), thrombolysis in MI (TIMI) bleeding (16.9% versus 7.6%), Global Use of Strategies to Open Occluded Coronary Arteries bleeding (4.5% versus 2.3%), and transfusions (32.3% versus 15.2%). Adjustment for timing of crossover relative to the events attenuated the difference noted in death/MI but accentuated the association with TIMI bleeding. After adjustment using the inverse probability weighting technique, only a modest difference in the absolute treatment effect was observed between enoxaparin and UFH on death/MI (0.6% [unadjusted] versus 0.8% [adjusted]) and TIMI major bleeding (1.5% [unadjusted] versus 1.0% [adjusted]). The landmark analysis indicated a significant association between crossover from enoxaparin to UFH and TIMI bleeding but not in the other direction, and no crossover association was found in death/MI. CONCLUSIONS: Postrandomization events in clinical trials are accompanied by substantial confounders that require careful consideration. In SYNERGY, postrandomization crossovers occurred in nearly 10% of patients, abetted by the open-label trial design. These patients had increased incidence of bleeding and death/MI, but after adjustment using several modeling techniques, only a modest impact of postrandomization crossovers on treatment effect was observed. The usual methods of analyzing end points cannot adequately address biases in changing treatment in these patients. The potential biases of membership in a postrandomization subgroup, as well as the methods used to account for the biases, should be considered when weighing the strength of results. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00043784

BACKGROUND: The Occluded Artery Trial (OAT) showed no difference in outcomes between percutaneous coronary intervention (PCI) versus optimal medical therapy (MED) in patients with persistent total occlusion of the infarct-related artery 3 to 28 days post-myocardial infarction. Whether PCI may benefit a subset of patients with preservation of infarct zone (IZ) viability is unknown. METHODS AND RESULTS: The OAT nuclear ancillary study hypothesized that (1) IZ viability influences left ventricular (LV) remodeling and that (2) PCI as compared with MED attenuates adverse remodeling in post-myocardial infarction patients with preserved viability. Enrolled were 124 OAT patients who underwent resting nitroglycerin-enhanced technetium-99m sestamibi single-photon emission computed tomography (SPECT) before OAT randomization, with repeat imaging at 1 year. All images were quantitatively analyzed for infarct size, IZ viability, LV volumes, and function in a core laboratory. At baseline, mean infarct size was 26% +/- 18 of the LV, mean IZ viability was 43% +/- 8 of peak uptake, and most patients (70%) had at least moderately retained IZ viability. There were no significant differences in 1-year end-diastolic or end-systolic volume change between those with severely reduced versus moderately retained IZ viability, or when compared by treatment assignment PCI versus MED. In multivariable models, increasing baseline viability independently predicted improvement in ejection fraction (P = .005). There was no interaction between IZ viability and treatment assignment for any measure of LV remodeling. CONCLUSIONS: In the contemporary era of MED, PCI of the infarct-related artery compared with MED alone does not impact LV remodeling irrespective of IZ viability

Ischemic heart disease (IHD) is a leading cause of morbidity in the United States and worldwide. In women, it is the leading cause of death in all age groups except young women who rarely have clinically evident disease. However, when young women less than age 50 develop IHD, they are at high risk for mortality. This may be due in part to delay in diagnosis or less aggressive treatment. Young women may be less aggressively treated with medical therapies and percutaneous or surgical interventions despite studies that have shown benefit in women as well as men. Young women are an especially important population to target for treatment and study since prevention of IHD during this stage of life can have great personal and societal health consequences. Epidemiological studies, including the INTERHEART study, have identified risk factors including hypertension, diabetes, metabolic syndrome, smoking, and sedentary lifestyle that explain much of IHD in women. Several factors, including diabetes, metabolic syndrome, and tobacco use, are stronger predictors of IHD in young women as compared with older women. Healthcare practitioners who encounter young women should aggressively treat risk factors, maintain an appropriate index of suspicion for IHD, and treat acute coronary syndromes promptly and intensively to reduce the burden of IHD in young women