Faculty Bibliography

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: Prior randomized trials have shown reduced bleeding with bivalirudin compared with unfractionated heparin (UFH) in patients undergoing percutaneous coronary intervention (PCI). However, it is not known if this benefit is also present when UFH doses are more tightly controlled (as measured by activated clotting time, ACT). METHODS AND RESULTS: Patients enrolled in the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry, were divided into 3 groups, based on the antithrombotic drug used during PCI (UFH monotherapy, UFH+glycoprotein IIb-IIIa receptor inhibitor [GPI], or bivalirudin alone). Propensity score matching was used to adjust for measured covariates (89 variables) and to compare bivalirudin versus UFH monotherapy and bivalirudin versus UFH+GPI groups. The UFH groups were stratified based on ACT achieved (optimal ACT defined as 250-300 for UFH monotherapy and 200-250 when GPI was also used). The primary bleeding outcome was in-hospital composite bleeding, defined as events of access site bleeding, Thrombolysis In Myocardial Infarction major/minor bleeding, or transfusion. Primary (in-hospital death/myocardial infarction) and secondary ischemic outcomes (death/MI/unplanned repeat revascularization at 12 months) were also evaluated. Propensity score matching yielded 3022 patients for the UFH monotherapy versus bivalirudin comparison and 3520 patients for the UFH+GPI versus bivalirudin comparison. Bivalirudin use was associated with numerically lower bleeding rates at all categories of achieved ACT when compared with UFH (low, optimal, high ACT: 2.5% versus 4.7%, 1.9% versus 6.0%, 3.1% versus 4.8%, respectively) or heparin+GPI groups (low, optimal, high ACT: 0.0% versus 2.7%, 2.7% versus 5.2%, 2.4% versus 6.1%, respectively) and was not associated with any statistically significant increase in either primary or secondary ischemic outcomes. CONCLUSIONS: Among unselected patients undergoing PCI, bivalirudin use during PCI was associated with a lower risk of bleeding at all comparator ACT levels without an increase in ischemic outcomes

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:Chronic kidney disease (CKD) is a risk factor for coronary heart disease and bleeding with antithrombotic therapy in patients with acute coronary syndromes (ACS). We evaluated the effect of renal function on efficacy and outcomes in high-risk patients with NSTE ACS in the SYNERGY trial. METHODS:Creatinine clearance (CrCl) at the time of randomization was analyzed as a continuous variable added to multivariable logistic regression models for 30-day death or MI, non-CABG-associated TIMI major bleeding, GUSTO severe bleeding, and transfusion in the overall study population, patients undergoing coronary angiography, and patients undergoing PCI. RESULTS:Of 9838 patients with a CrCl value, 70.6% (N=6950) had CrCl≥60 mL/min, 27.8% (N=2732) had CrCl 30-59 mL/min, and 1.6% (N=156) had CrCl<30 mL/min. No randomized treatment by CrCl interaction test was found to be statistically significant, suggesting renal insufficiency affected enoxaparin and unfractionated heparin outcomes similarly. After adjustment, CrCl was an independent predictor of 30-day death or MI (OR 1.06, 95% CI 1.03-1.09), TIMI major bleeding (OR 1.06, 95% CI 1.02-1.10), GUSTO severe bleeding (OR 1.10, 95% CI 1.03-1.17), and transfusion (OR 1.07, 95% CI 1.04-1.11). CONCLUSIONS:Patients with CKD had higher rates of 30-day death or MI and bleeding than those without CKD, regardless of randomized antithrombin therapy. While this analysis suggests that there is a rise in bleeding events as CrCl falls for patients in either treatment group, it is unknown whether a reduction in dose would decrease bleeding risk.

AIMS/OBJECTIVE:To correlate inhibition of platelet aggregation (IPA) with bleeding events assessed by TIMI, GUSTO, and BleedScore scales in a large cohort of patients with coronary artery disease (CAD) and ischaemic stroke (IS) treated with chronic low-dose aspirin plus clopidogrel. Data from recent trials and registries suggest a link between increased risk of bleeding and cardiovascular mortality. However, the potential association of bleeding risk and IPA is not established. It may play a critical role for the safety of more aggressive platelet inhibition or/and individual tailoring of antiplatelet strategies. METHODS AND RESULTS/RESULTS:Secondary post hoc analyses of 5 microM ADP-induced IPA and bleeding complications assessed by TIMI, GUSTO, and BleedScore scales in a combined data set consisting of patients with documented CAD (n = 246) and previous IS (n = 117). Demographic characteristics differ substantially depending on the underlying vascular disease; however, IPA and bleeding risks were similar between CAD and IS. All three bleeding scales adequately captured serious haemorrhagic events, where the TIMI scale was the most exclusive, whereas BleedScore was the most inclusive. Over half of all patients experienced superficial event(s), most commonly occurring during two to three distinct bleeding episodes. There was no correlation between IPA and duration of antiplatelet therapy. Inhibition of platelet aggregation >50% strongly correlates with minor (r(2) = 0.58, P < 0.001; c-statistic = 0.92), but not severe (r(2) = 0.11, P = 0.038; c-statistic = 0.57), bleeding events. CONCLUSION/CONCLUSIONS:Chronic oral combination antiplatelet regimens are associated with a very high (56.5-60.7%) prevalence of superficial bleeding episodes, which are grossly underestimated in trials and registries. The role of such frequent mild complications for the overall benefit of antiplatelet therapy is entirely unknown, as is their effect on compliance. Although IPA is well suited for defining the risk of minor complications, prediction of more severe bleeding events may be challenging.

BACKGROUND:Previous data on bleeding after percutaneous coronary intervention (PCI) have been obtained primarily from randomized trials that focused on in-hospital bleeding. The incidence of late bleeding after PCI, its independent predictors, and its prognostic importance in clinical practice has not been fully addressed. METHODS AND RESULTS/RESULTS:We evaluated 22 798 patients aged >65 years who underwent PCI from December 1, 2003, to March 31, 2007, in Ontario, Canada. Cox proportional hazard models were used to determine factors associated with late bleeding, which was defined as hospitalization for bleeding after discharge from the index PCI, and to estimate risk of death or myocardial infarction associated with late bleeding. We found that 2.5% of patients were hospitalized for bleeding in the year after PCI, with 56% of bleeding episodes due to gastrointestinal bleed. The most significant predictor of late bleeding was warfarin use after PCI (hazard ratio [HR], 3.12). Other significant predictors included age (HR, 1.41 per 10 years), male sex (HR, 1.24), cancer (HR, 1.80), previous bleeding (HR, 2.42), chronic kidney disease (HR, 1.93), and nonsteroidal antiinflammatory drug use (HR, 1.73). After adjusting for baseline covariates, hospitalization for a bleeding episode was associated with a significantly increased 1-year hazard of death or myocardial infarction (HR, 2.39; 95% CI, 1.93 to 2.97) and death (HR, 3.38; 95% CI, 2.60 to 4.40). CONCLUSIONS:Hospitalization for late bleeding after PCI is associated with substantially increased risk of death and myocardial infarction. The use of triple therapy (i.e., aspirin, thienopyridine, and warfarin) is associated with the highest risk of late bleeding.

BACKGROUND:Factor Xa and factor IIa (thrombin) play roles in thrombotic complications after percutaneous coronary intervention. M118 is a novel low-molecular-weight heparin that has been rationally designed to capture the desired attributes of unfractionated heparin (UFH) and low-molecular-weight heparin: Potent activity against factor Xa and IIa, predictable pharmacokinetics after both intravenous and subcutaneous administration, ability to be monitored by use of point-of-care coagulation assays, and reversibility with protamine sulfate. We performed a phase 2 randomized trial to evaluate the safety and feasibility of M118 in the setting of elective percutaneous coronary intervention. METHODS AND RESULTS/RESULTS:Overall, 503 patients undergoing elective percutaneous coronary intervention at 43 centers in the United States and Canada were randomized in an open-label fashion to 1 of 4 arms: UFH 70 U/kg, M118 50 IU/kg IV, M118 75 IU/kg IV, or M118 100 IU/kg IV. The primary outcome was the composite of death, myocardial infarction, repeat revascularization, stroke, thrombocytopenia, catheter thrombus, bailout use of glycoprotein IIb/IIIa inhibitor, or any bleeding through 30 days. The primary end point occurred in 31.1% of patients randomized to UFH and in 22.7%, 28.3%, and 30.1% of patients randomized to M118 50, 75, and 100 IU/kg, respectively. The primary analysis comparing the rates of the primary end points between the pooled M118 groups versus UFH demonstrated that M118 was noninferior to UFH at preventing percutaneous coronary intervention-related complications (28.4% pooled M118 arms versus 31.1% UFH). The adverse event profiles of M118 and UFH were comparable. CONCLUSIONS:This phase 2 randomized trial demonstrates that M118 is well tolerated and feasible to use as an anticoagulant in patients undergoing elective percutaneous coronary intervention and forms the basis for further investigation of this agent in ischemic heart disease. CLINICAL TRIAL REGISTRATION/BACKGROUND:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00543400.

OBJECTIVES/OBJECTIVE:We sought to create contemporary models for predicting mortality risk following percutaneous coronary intervention (PCI). BACKGROUND:There is a need to identify PCI risk factors and accurately quantify procedural risks to facilitate comparative effectiveness research, provider comparisons, and informed patient decision making. METHODS:Data from 181,775 procedures performed from January 2004 to March 2006 were used to develop risk models based on pre-procedural and/or angiographic factors using logistic regression. These models were independently evaluated in 2 validation cohorts: contemporary (n = 121,183, January 2004 to March 2006) and prospective (n = 285,440, March 2006 to March 2007). RESULTS:Overall, PCI in-hospital mortality was 1.27%, ranging from 0.65% in elective PCI to 4.81% in ST-segment elevation myocardial infarction patients. Multiple pre-procedural clinical factors were significantly associated with in-hospital mortality. Angiographic variables provided only modest incremental information to pre-procedural risk assessments. The overall National Cardiovascular Data Registry (NCDR) model, as well as a simplified NCDR risk score (based on 8 key pre-procedure factors), had excellent discrimination (c-index: 0.93 and 0.91, respectively). Discrimination and calibration of both risk tools were retained among specific patient subgroups, in the validation samples, and when used to estimate 30-day mortality rates among Medicare patients. CONCLUSIONS:Risks for early mortality following PCI can be accurately predicted in contemporary practice. Incorporation of such risk tools should facilitate research, clinical decisions, and policy applications.