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Background: Data on geographical variations in dual antiplatelet therapy (DAPT) cessation and the impact on outcomes after percutaneous coronary intervention (PCI) are limited. We sought to evaluate geographical patterns of DAPT cessation and associated outcomes in patients undergoing PCI in the United States versus Europe., Methods: Analyzing data from the PARIS registry, we studied 3,660 U.S. patients (72.9%) and 1,358 European patients (27.1%) that underwent PCI with stent implantation. DAPT cessation was classified as physician-recommended discontinuation, interruption (< 14 days), or disruption due to bleeding or noncompliance. The primary endpoint was 2-year major adverse cardiovascular events (MACE) defined as a composite of cardiac death, stent thrombosis, myocardial infarction, or target lesion revascularization., Results: Cardiovascular risk factors were more common in the United States, whereas procedural complexity was greater in Europe. The incidence of 2-year DAPT discontinuation was significantly lower in U.S. versus European patients (30.7% vs. 65.6%; p  < 0.001); however, rates of interruption (13.7% vs. 1.5%, p  < 0.001) and disruption (17.7% vs. 5.1%, p  < 0.001) were higher. DAPT discontinuation was associated with lower adjusted risk, whereas DAPT disruption was associated with greater risk for 2-year MACE, without interaction by region. After adjustment for baseline characteristics and DAPT cessation, 2-year MACE risk was not statistically different between regions (10.3% for Europe vs. 11.9% for U.S., adjusted hazard ratio 0.81, 95% confidence interval 0.65-1.01, p  = 0.065)., Conclusion: DAPT cessation patterns, along with clinical and angiographic risk, vary substantially between PCI patients in the U.S. versus Europe. Despite such differences, cardiovascular risk associated with DAPT cessation remains uniform., Competing Interests: D.C. has received research grant support from Eli Lilly and Astra Zeneca, consulting fees from Eli Lilly, Astra Zeneca, and speaking honoraria from Astra Zeneca. T.H. has received research grant support from Eli Lilly & Company and Daiichi-Sankyo. G.D. has received consulting fees and honoraria from Johnson & Johnson, Sanofi, Covidien, The Medicines Company, Merck, CSL Behring, AstraZeneca, Medtronic, Abbott, Bayer, Boston Scientific, Osprey Medical, and GE Healthcare; and research grant support from Sanofi, Bristol-Myers Squibb, and Eli Lilly & Company/Daiichi-Sankyo. M.G. has received research grant support from Angel Medical Corporation, Atrium Medical Systems, Bayer Corporation, Ikaria, Janssen/Johnson & Johnson Corporation, Lantheus Medical Imaging, Merck & Company, Portola Pharmaceuticals, Roche Diagnostics, Sanofi, Stealth Peptides, St. Jude Medical, Volcano Corporation, and Walk Vascular; consulting fees from AstraZeneca, Baxter Healthcare, Bayer Corporation, CRF, Consensus Medical Communications, CSL Behring, Cytori Therapeutics, Eli Lilly & Company/Daiichi Sankyo, Exeter Group, Genentech, GlaxoSmithKline, Janssen/Johnson & Johnson Corporation, Ortho McNeil, St. Jude Medical, and The Medicines Company; and royalty fees from UpToDate in Cardiovascular Medicine. D.M. has received institutional research grant support from AstraZeneca. M.K. has received consulting fees from Abbott Vascular, Abbott Laboratories, OrbusNeich, Angelmed, Volcano, Biosensors, Svelte, OrbusNeich, Medtronic, and Terumo; and research grant support from Abbott, Terumo, Angelmed, Ikaria, OrbusNeich, Cardiovascular Systems, Inc. (CSI), Eli Lilly & Company, and Medtronic. A.C. has received consulting fees and honoraria from Carbostent and Implantable Devices (CID); and other fees from Direct Flow Medical. A.K. serves on the speaker's bureau of the American College of Cardiology; and has received consulting fees from WebMD. P.G.S. discloses the following relationship: research grant from Bayer, Merck, Sanofi, and Servier, speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer-Ingelheim, Bristol-Myers-Squibb, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi, and Servier, received personal fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Medtronic, Servier, Janssen, CSL Behring, and Regeneron; grants and personal fees from Sanofi; and personal fees and nonfinancial support from The Medicines Company, outside the submitted work. R.M. has received institutional research grant support from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers-Squibb, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis Pharmaceuticals, and OrbusNeich; has served as a consultant for Abbott Vascular, American College of Cardiology, AstraZeneca, Boston Scientific, CardioKinetix, CSL Behring, Medscape, Shanghai Bracco Sine Pharmaceutical, and Spectranetics; has served on the advisory board for Bristol Myers-Squibb; has received institutional advisory board funding from Bristol-Myers Squibb; has received institutional funding from Claret Medical; owns equity in Claret Medical and Elixir Medical; has served on the executive committee for Janssen Pharmaceuticals and Osprey Medical; has served on the data safety monitoring board for Watermark Research Partners; and has a spouse who has served as a consultant for Abiomed and The Medicines Company., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Balancing ischemic and bleeding risk is an evolving framework., Methods and Results: Our objectives were to simulate changes in risks for adverse events and event-driven costs with use of ticagrelor or prasugrel versus clopidogrel according to varying levels of ischemic and bleeding risk. Using the validated PARIS risk functions, we estimated 1-year ischemic (myocardial infarction or stent thrombosis) and bleeding (Bleeding Academic Research Consortium types 3 or 5) event rates among PARIS study participants who underwent percutaneous coronary intervention with drug-eluting stent implantation for an acute coronary syndrome and were discharged with aspirin and clopidogrel (n=1497). Simulated changes in adverse events with ticagrelor or prasugrel were calculated by applying treatment effects from randomized trials for a 1-year time horizon. Event costs were estimated using National Inpatient Sample data. Net costs were calculated between antiplatelet therapy groups according to level of ischemic and bleeding risk. After weighting events for quality-of-life impact, we calculated event rates and costs for risk-tailored treatment versus clopidogrel under multiple drug pricing assumptions. One-year rates (per 1000 person-years) for ischemic events were 12.6, 24.1, and 66.1, respectively, among those at low (n=630), intermediate (n=536), and high (n=331) ischemic risk. Analogous bleeding rates were 11.0, 23.9, and 66.2, respectively, among low (n=728), intermediate (n=634), and high (n=135) bleeding risk patients. Mean per event costs were $22 174 (ischemic) and $12 203 (bleeding). When risks for ischemia matched or exceeded bleeding, simulated utility-weighted event rates favored ticagrelor/prasugrel, whereas clopidogrel reduced utility-weighted events when bleeding exceeded ischemic risk. One-year costs were sensitive to drug pricing assumptions, and risk-tailored treatment with either agent progressed from cost incurring to cost saving with increasing generic market share., Conclusions: Tailoring antiplatelet therapy intensity to patient risk may improve health utility and could produce cost savings in the first year after percutaneous coronary intervention., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00998127.

Background: Patients with chronic kidney disease (CKD) experience high rates of ischemic and bleeding events after percutaneous coronary intervention (PCI), complicating decisions surrounding dual antiplatelet therapy (DAPT). This study aims to determine the pattern and impact of various modes of DAPT cessation for patients with CKD undergoing PCI., Methods and Results: Patients from the PARIS registry (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients) were grouped based on the presence of CKD defined as creatinine clearance <60 mL/min. After index PCI, time and mode of DAPT cessation (discontinuation, interruption, and disruption) and clinical outcomes (major adverse cardiac events, stent thrombosis, myocardial infarction, and major bleeding [Bleeding Academic Research Consortium type 3 or 5]) were reported. Over 2 years, patients with CKD (n=839) had higher adjusted risks for death (hazard ratio, 3.16; 95% confidence interval, 2.26-4.41), myocardial infarction (hazard ratio, 2.43; 95% confidence interval, 1.65-3.57), and major bleeding (hazard ratio, 2.21; 95% confidence interval, 1.53-3.19) compared with patients without CKD (n=3745). Rates of DAPT discontinuation within the first year after PCI and disruption were significantly higher for patients with CKD. However, DAPT interruption occurred with equal frequency. Associations between DAPT cessation mode and subsequent risk were not modified by CKD status. Findings were unchanged after propensity matching., Conclusions: Patients with CKD display high and comparable risks for both ischemic and bleeding events after PCI. Physicians are more likely to discontinue DAPT within the first year after PCI among patients with CKD, likely reflecting clinical preferences to avoid bleeding. Risks after DAPT cessation, irrespective of underlying mode, are not modified by the presence or absence of CKD., (© 2018 American Heart Association, Inc.)

The therapeutic potential of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unknown. This prespecified analysis of a postrandomization subgroup evaluated the effects of vorapaxar compared with placebo among Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) participants undergoing PCI, focusing on the implanted stent type (drug-eluting stent [DES] vs bare-metal stent [BMS]). Among 12,944 recruited patients, 7,479 (57.8%) underwent PCI during index hospitalization, and 3,060 (40.9%) of those patients received exclusively BMS, whereas 4,015 (53.7%) received DES. The median (twenty-fifth, seventy-fifth percentiles) duration of thienopyridine therapy was 133 days (47, 246) with BMS and 221 days (88, 341) with DES. At 2 years among patients undergoing PCI, the primary (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) and secondary (cardiovascular death, myocardial infarction, or stroke) end points did not differ between vorapaxar and placebo groups, which was consistent with the treatment effect observed in the overall study population (p value for interaction = 0.540). However, the treatment effect trended greater (p value for interaction = 0.069) and the risk for bleeding in patients taking vorapaxar versus placebo appeared attenuated in BMS-only recipients. After adjustment for confounders, the interaction was no longer significant (p value = 0.301). The covariate that mostly explained the stent-type-by-treatment interaction was the duration of clopidogrel therapy. In conclusion, among patients with PCI, the effect of vorapaxar is consistent with the overall TRACER results. Patients who received a BMS underwent shorter courses of clopidogrel therapy and displayed trends toward greater ischemic benefit from vorapaxar and lesser bleeding risk, compared with patients who received a DES., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.