Faculty Bibliography

The aim of the present study was to analyze the effect of drug exposure patterns of clopidogrel and proton pump inhibitors (PPIs) on the clinical outcomes after percutaneous coronary intervention (PCI). Previous analyses predominantly included discharge medications and did not explore the effect of the drug exposure patterns. We analyzed all-cause death, nonfatal myocardial infarction, repeat revascularization, and major adverse cardiovascular events (MACE) in a cohort of 23,200 post-PCI patients (January 2003 to December 2008) using a multivariate adjusted Cox model and propensity-matched case-control analysis. The adjusted hazard ratio for MACE on PPI according to the exposure patterns of clopidogrel after PCI for 6 years was 1.24 (95% confidence interval [CI] 1.11 to 1.38) and 1.12 (95% CI 1.03 to 1.22) for "continuous" (consistent clopidogrel with or without PPIs) and "switched" (clopidogrel with or without varying PPIs) respectively. However, the propensity score adjusted odds ratios for MACE on PPI use was 0.97 (95% CI 0.65 to 1.44) for "continuous" and 1.04 (95% CI 0.87 to 1.25) for "switched." Moreover, in the first year after PCI, the use of "rescue" (≤30 days before MACE) nitroglycerin was greater in the patients taking clopidogrel and PPIs than in those taking clopidogrel alone, as was the overall use of rescue PPIs (p <0.001). In conclusion, PPI use in clopidogrel-treated post-PCI patients was not associated with an increased risk of MACE after controlling for the confounding effect of PPI use with propensity matching. A potential for the misdiagnosis of angina symptoms and rescue use of nitroglycerin and PPIs in post-PCI patients exists, a finding that might have confounded previous observational analyses.

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

OBJECTIVES: The aim of this study was to evaluate the relative frequency of access and nonaccess site bleeding, the association of these events with 1-year mortality, and the impact of randomized antithrombotic therapy. BACKGROUND: Post-percutaneous coronary intervention (PCI) bleeding has been strongly associated with subsequent mortality. The extent to which access versus nonaccess site bleeding contributes to this poor prognosis and the role of antithrombotic therapies remains poorly understood. METHODS: The incidence and impact of Thrombolysis In Myocardial Infarction (TIMI) major/minor 30-day bleeding and randomized antithrombotic therapy were examined in a combined dataset from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events), Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials in 17,393 PCI patients. RESULTS: The TIMI major/minor bleeding occurred in 5.3% of patients, 61.4% of which (3.3%) were nonaccess site bleeds. After multivariable adjustment, TIMI bleeding was associated with an increased risk of 1-year mortality (hazard ratio [HR]: 3.17, 95% confidence interval [CI]: 2.51 to 4.00, p < 0.0001). The HR of a nonaccess site bleed was approximately 2-fold that of an access site bleed: HR: 3.94, 95% CI: 3.07 to 5.15, p < 0.0001 versus HR: 1.82, 95% CI: 1.17 to 2.83, p = 0.008, respectively. Randomization to bivalirudin versus heparin + a glycoprotein IIb/IIIa inhibitor resulted in 38% and 43% relative reductions in TIMI major/minor and TIMI major bleeding, respectively (p < 0.0001 for both), with significant reductions in both access and nonaccess site bleeding. CONCLUSIONS: Nonaccess site bleeding after PCI is common, representing approximately two-thirds of all TIMI bleeding events, and is associated with a 4-fold increase in 1-year mortality. Use of bivalirudin rather than heparin + a glycoprotein IIb/IIIa inhibitor significantly decreases both nonaccess site as well as access site bleeding events by approximately 40%

BACKGROUND:Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes. OBJECTIVES/OBJECTIVE:The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy. DESIGN/METHODS:This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) non-coronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites. CONCLUSIONS:The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS.

BACKGROUND:studies have shown higher bleeding and mortality rates among African Americans who receive fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) compared with whites; however, the relationship of bleeding risk to mortality has not been evaluated. METHODS:we studied data from 32,260 STEMI patients receiving fibrinolysis enrolled in the US in 5 clinical trials. Bleeding was defined according to criteria from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries study. Main outcome measure was adjusted 1-year mortality. RESULTS:despite younger age (median: 57 years vs 61 years) and fewer comorbidities, moderate or severe bleeding occurred more frequently among African-Americans than whites (16.3% vs 14.1%; P=.0147, adjusted OR 1.36; 95% confidence interval [CI], 1.14-1.62; P=.0006) as did 1-year mortality (11.5% vs 9.4%). African-American race and moderate or severe bleeding were independently related to 1-year mortality (χ(2) 9.02, P=.0003 and 148.58, P<.0001, respectively). Mortality was highest among African Americans with bleeding (hazard ratio [HR] 2.83; 95% CI, 2.08-3.86) followed by whites with bleeding (HR 1.99; 95% CI, 1.78-2.22) and African Americans without bleeding (HR 1.33; 95% CI, 1.02-1.73) (referent whites without bleeding). CONCLUSIONS:in STEMI patients receiving fibrinolysis, moderate or severe bleeding and mortality were significantly higher in African Americans compared with whites. Bleeding was associated with similarly increased mortality risk in both groups.

OBJECTIVES/OBJECTIVE:This study sought to develop a tool for predicting an individual's risk of mortality following rescue percutaneous coronary intervention (PCI). BACKGROUND:Although fibrinolytic therapy is appropriate and improves survival for certain ST-segment elevation myocardial infarction patients, a substantial proportion suffer ongoing myocardial ischemia, a class I indication for emergent percutaneous coronary intervention (rescue PCI). METHODS:Using the National Cardiovascular Data Registry (NCDR), rescue PCI was defined as nonelective PCI following failed fibrinolysis in patients with continuing or recurrent myocardial ischemia. Multivariable logistic regression was used to determine mortality predictors and the C-statistic for model discrimination. The NCDR-RESCUE (Real-World Estimator of Survival in Catheterized STEMI Patients Following Unsuccessful Earlier Fibrinolysis) score was developed using a shortened list of 6 pre-angiographic variables and 70% of the cohort; performance was subsequently validated against the remaining 30%. RESULTS:Among 166,516 PCI procedures on patients with an admission diagnosis of ST-segment elevation myocardial infarction, 8,007 (4.8%) represented rescue PCI. In-hospital mortality occurred in 464 (5.8%). Factors in the final model were age, glomerular filtration rate, history of congestive heart failure, insulin-treated diabetes, cardiogenic shock, and salvage status. The NCDR-RESCUE score effectively segregated individuals into 6 clinically meaningful risk categories, with 0.4% (0.0% to 1.3%), 1.6% (0.9% to 2.4%), 7.6% (5.3% to10.4%), 27.5% (20.7% to 35.1%), 64.2% (49.8% to 76.9%), or 100% (59.0% to 100.0%) risk, respectively, of in-hospital mortality (mean ± 95% confidence interval, C-index = 0.88, Hosmer-Lemeshow p = 0.898). CONCLUSIONS:In-hospital mortality risk among individuals undergoing rescue PCI varies from minimal to extreme and can be easily calculated using the NCDR-RESCUE score. This information can be of value in counseling patients, families, and referring caregivers.