Faculty Bibliography

BACKGROUND:We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y(12) inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention. METHODS AND RESULTS/RESULTS:In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure. CONCLUSIONS:In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies. CLINICAL TRIAL REGISTRATION/BACKGROUND:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

BACKGROUND:Elinogrel is the only selective, competitive and reversible platelet P2Y(12) inhibitor available in both intravenous (IV) and oral formulations. METHODS AND RESULTS/RESULTS:This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300-600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens. CONCLUSIONS:Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation. CLINICAL TRIAL REGISTRATION/BACKGROUND:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

OBJECTIVES/OBJECTIVE:The purpose of this study was to examine temporal trends in post-percutaneous coronary intervention (PCI) bleeding among patients with elective PCI, unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). BACKGROUND:The impact of bleeding avoidance strategies on post-PCI bleeding rates over time is unknown. METHODS:Using the CathPCI Registry, we examined temporal trends in post-PCI bleeding from 2005 to 2009 among patients with elective PCI (n = 599,524), UA/NSTEMI (n = 836,103), and STEMI (n = 267,632). We quantified the linear time trend in bleeding using 3 sequential logistic regression models: 1) clinical factors; 2) clinical + vascular access strategies (femoral vs. radial, use of closure devices); and 3) clinical, vascular strategies + antithrombotic treatments (anticoagulant ± glycoprotein IIb/IIIa inhibitor [GPI]). Changes in the odds ratio for time trend in bleeding were compared using bootstrapping and converted to risk ratio. RESULTS:An approximate 20% reduction in post-PCI bleeding was seen (elective PCI: 1.4% to 1.1%; UA/NSTEMI: 2.3% to 1.8; STEMI: 4.9% to 4.5%). Radial approach remained low (<3%), and closure device use increased marginally from 44% to 49%. Bivalirudin use increased (17% to 30%), whereas any heparin + GPI decreased (41% to 28%). There was a significant 6% to 8% per year reduction in annual bleeding risk in UA/NSTEMI and elective PCI, but not in STEMI. Antithrombotic strategies were associated with roughly half of the reduction in annual bleeding risk: change in risk ratio from 7.5% to 4% for elective PCI, and 5.7% to 2.8% for UA/NSTEMI (both p <0.001). CONCLUSIONS:The nearly 20% reduction in post-PCI bleeding over time was largely due to temporal changes in antithrombotic strategies. Further reductions in bleeding complications may be possible as bleeding avoidance strategies evolve, especially in STEMI.

High residual platelet reactivity (HRPR) on clopidogrel is a predictor of recurrent ischemic events in patients undergoing percutaneous coronary interventions (PCI). Significant intraindividual variability in platelet aggregation on repeat testing has been reported. To understand factors contributing to the variability in platelet aggregation testing, we examined clinical and laboratory elements linked to HRPR in 255 consecutive patients tested ≥12 hours after PCI using light transmission aggregometry (LTA) in response to adenosine diphosphate 5 μmol/L and VerifyNow P2Y12 assay (VNP2Y12; Accumetrics). HRPR was defined as >46% residual aggregation for LTA and >236 P2Y12 response units (PRUs) for VNP2Y12. On multivariate analysis the only variable independently associated with HRPR with both LTA and VNP2Y12 was laboratory-defined anemia. Prevalences of HRPR by LTA were 34.3% in anemic patients, 15.6% in patients with normal hemoglobin levels, and 59.8% versus 25.9% by VNP2Y12 (p <0.005 for the 2 comparisons). In a subgroup of 50 patients, testing was done before and after the clopidogrel loading dose. At baseline there were no differences in platelet aggregation with either assay; however, absolute decrease in reactivity after the clopidogrel load was significantly less in anemic patients compared to patients with normal hemoglobin (change in residual aggregation by LTA 15.8 ± 5.8% vs 28.8 ± 3.2%, p <0.05; change in PRU by VNP2Y12 56.5 ± 35.5 vs 145.0 ± 14.2 PRUs, p <0.05, respectively). In conclusion, anemia is an important contributor to apparent HRPR on clopidogrel and may explain some of the intraindividual variability of platelet aggregation testing.

BACKGROUND:Prior studies have suggested that blacks with acute ST-segment-elevation myocardial infarction have increased bleeding risks with fibrinolysis relative to whites, yet these data were quite limited. Additionally, it is unknown whether there are racial differences in bleeding risks among patients with ST-segment-elevation myocardial infarction receiving primary percutaneous coronary intervention. METHODS AND RESULTS/RESULTS:We evaluated data on blacks and whites with ST-segment-elevation myocardial infarction treated with either fibrinolysis or primary percutaneous coronary intervention from the National Registry of Myocardial Infarction (NRMI)-4 and 5 participating centers between July 2000 and December 2006. We compared differences between the 2 groups in rates of in-hospital major bleeding and mortality, adjusted with logistic regression analyses. In fibrinolytic-treated patients with ST-segment-elevation myocardial infarction, the bleeding rates were higher among blacks (n=2283) than whites (n=42 243; 10.9% versus 10.3%; adjusted odds ratio, 1.21; 95% confidence interval, 1.02-1.43). Similarly, in patients receiving primary percutaneous coronary intervention, the bleeding rates were higher in blacks (n=2826) than in whites (n=46 332; 10.3% versus 7.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.13-1.56). Bleeding was associated with higher risk of death in both ethnic groups. However, there was no overall racial difference in in-hospital mortality among those with bleeding or without bleeding treated with either fibrinolysis or primary percutaneous coronary intervention. CONCLUSIONS:Blacks with ST-segment-elevation myocardial infarction treated with either fibrinolysis or primary percutaneous coronary intervention had a higher risk of bleeding events than their white counterparts. Bleeding was associated with a similar increased risk of death in both ethnic groups treated by either reperfusion strategy.

BACKGROUND:Despite lower risks of access site-related complications with transradial approach (TRA), its clinical benefit for percutaneous coronary intervention (PCI) is uncertain. We conducted a systematic review and meta-analysis of clinical studies comparing TRA and transfemoral approach (TFA) for PCI. METHODS:Randomized trials and observational studies (1993-2011) comparing TRA with TFA for PCI with reports of ischemic and bleeding outcomes were included. Crude and adjusted (for age and sex) odds ratios (OR) were estimated by a hierarchical Bayesian random-effects model with prespecified stratification for observational and randomized designs. The primary outcomes were rates of death, combined incidence of death or myocardial infarction, bleeding, and transfusions, early (≤ 30 days) and late after PCI. RESULTS:We collected data from 76 studies (15 randomized, 61 observational) involving a total of 761,919 patients. Compared with TFA, TRA was associated with a 78% reduction in bleeding (OR 0.22, 95% credible interval [CrI] 0.16-0.29) and 80% in transfusions (OR 0.20, 95% CrI 0.11-0.32). These findings were consistent in both randomized and observational studies. Early after PCI, there was a 44% reduction of mortality with TRA (OR 0.56, 95% CrI 0.45-0.67), although the effect was mainly due to observational studies (OR 0.52, 95% CrI 0.40-0.63, adjusted OR 0.49 [95% CrI 0.37-0.60]), with an OR of 0.80 (95% CrI 0.49-1.23) in randomized trials. CONCLUSION/CONCLUSIONS:Our results combining observational and randomized studies show that PCI performed by TRA is associated with substantially less risks of bleeding and transfusions compared with TFA. Benefit on the incidence of death or combined death or myocardial infarction is found in observational studies but remains inconclusive in randomized trials.

OBJECTIVES/OBJECTIVE:This study sought to assess percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) stenosis in routine U.S. clinical practice. BACKGROUND:Percutaneous coronary intervention for ULMCA stenosis is controversial; however, current use and outcomes of ULMCA PCI in routine U.S. clinical practice have not been described. METHODS:We evaluated 5,627 patients undergoing ULMCA PCI at 693 centers within the National Cardiovascular Data Registry Catheterization Percutaneous Coronary Intervention Registry for temporal trends in PCI use (2004 to 2008), patient characteristics, and in-hospital mortality. Thirty-month mortality and composite major adverse events (death, myocardial infarction, and revascularization) with drug-eluting versus bare-metal stents were compared using inverse probability weighted (IPW) hazard ratios (HRs) in a nonrandomized Medicare-linked (age ≥65 years) patient cohort (n = 2,765). RESULTS:ULMCA PCI was performed in 4.3% of patients with ULMCA stenosis. Unadjusted in-hospital mortality rates ranged from 2.9% for elective cases to 45.1% for emergent/salvage cases. By 30 months, 57.9% of the elderly ULMCA PCI population experienced death, myocardial infarction, or revascularization, and 42.7% died. Patients receiving drug-eluting stents (versus bare-metal stents) had a lower 30-month mortality (IPW HR: 0.84, 95% confidence interval [CI]: 0.73 to 0.96), but the composite of major adverse events were similar (IPW HR: 0.95, 95% CI: 0.84 to 1.06). CONCLUSIONS:In the United States, ULMCA PCI is performed in <5% of patients with ULMCA disease and is generally reserved for those at high procedural risk. Adverse events are common in elderly patients and are related to patient and procedural characteristics, including stent type.