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Background: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis., Objectives: This study sought to determine the effect of ticagrelor on limb events., Methods: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline., Results: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; P interaction  = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (P interaction  = 0.40) or TIMI major bleeding (P interaction  = 0.3239)., Conclusions: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795)., Competing Interests: Funding Support and Author Disclosures THEMIS was funded and sponsored by AstraZeneca Research & Development. Dr Bonaca is the Executive Director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, Anthos, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cleerly, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, EverlyWell, Faraday, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group; has stock in Medtronic and Pfizer; and has received consulting fees from Audentes. Dr Bhatt serves as the co-chair of THEMIS and THEMIS-PCI with research funding from AstraZeneca paid to Brigham and Women’s Hospital. He discloses the following relationships: Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; and Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, and 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, Svelte, and Vascular Solutions; Trustee: American College of Cardiology; and Unfunded Research: FlowCo, Takeda. Dr Leiter has received research funding from, has provided CME on behalf of, and/or has received research funding from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, HLS, Kowa, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier. Dr Himmelmann is an employee of AstraZeneca. Drs Ridderstråle, Andersson, and Chen are employees of AstraZeneca. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on the advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has stock options in Artera Health and Saghmos Therapeutics. Dr McGuire has received honoraria for trial leadership from Boehringer Ingelheim, Sanofi, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, and CSL Behring; and has received consulting fees from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, CSL Behring, Bayer, Altimmune, Intercept, and Pfizer. Dr Steg has received grants and nonfinancial support (cochair of the ODYSSEY OUTCOMES trial [Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab]; as such, he has received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (Steering Committee MARINER [A Study of Rivaroxaban (JNJ-39039039) on the Venous Thromboembolic Risk of Post-Hospital Discharge Patients], grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (cochair of the ODYSSEY OUTCOMES trial; cochair of the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk); has received consulting and speaker fees from Servier (Chair of the CLARIFY registry [Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease]; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial]; consulting); has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron Pharmaceuticals, Lilly, and AstraZeneca; and has a European application number/patent number, issued on October 26, 2016 (No. 15712241.7), for a method for reducing cardiovascular risk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations., Methods: REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes., Results: A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; P <0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; P <0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; P <0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; P =0.0005)., Conclusions: Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Background: In the CHAMPION PHOENIX trial, cangrelor reduced the primary composite end point of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis at 48 hours. This study aimed to explore the impact of event adjudication and the prognostic importance of MI reported by a clinical events committee (CEC) or site investigators (SIs)., Methods and Results: Data from the CHAMPION PHOENIX trial of patients undergoing elective or nonelective percutaneous coronary intervention were analyzed. A CEC systematically identified and adjudicated MI using predefined criteria, a computer algorithm to identify suspected events, and semilogarithmic plots to review biomarker changes. Thirty-day death was modeled using baseline characteristics. Of 10 942 patients, 462 (4.2%) patients had at least 1 MI by 48 hours identified by the CEC (207 [3.8%] cangrelor; 255 [4.7%] clopidogrel; odds ratio [OR] 0.80; 95% CI, 0.67-0.97; P=0.022), and 143 patients had at least 1 MI by 48 hours reported by the SI (60 [1.1%] cangrelor; 83 [1.5%] clopidogrel; OR, 0.72; 95% CI, 0.52-1.01; P=0.053). Of the 462 MIs identified by the CEC, 92 (20%) were reported by SI, and 370 (80%) were not. Of the 143 MI reported by the SI, 51 (36%) were not confirmed by CEC. All categories were associated with an increased adjusted risk for 30-day death (CEC: OR, 5.35; 95% CI, 2.56-11.2; P<0.001; SI: 9.08 [4.01-20.5]; P<0.001; CEC and SI: 10.9 [3.23-36.6]; P<0.001; CEC but not SI: 4.69 [1.94-11.3]; P<0.001; SI but not CEC: 15.4 [5.26-44.9]; P<0.001)., Conclusions: In patients undergoing percutaneous coronary intervention, CEC procedures identified 3 times as many MIs as the SI reported. Compared with clopidogrel, cangrelor significantly reduced MIs identified by the CEC with a qualitatively similar relative risk reduction in MIs reported by the SI. MIs identified by CEC or reported by SI were independently associated with worse 30-day death. Central adjudication identified additional, prognostically important events., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

Background: In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. These patients are at risk for not only first but also subsequent ischemic events., Objectives: Pre-specified analyses determined the extent to which icosapent ethyl reduced total ischemic events., Methods: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dl (median baseline of 216 mg/dl) and low-density lipoprotein cholesterol >40 and ≤100 mg/dl (median baseline of 75 mg/dl), and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4 g/day or placebo. The main outcomes were total (first and subsequent) primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). As a pre-specified statistical method, we determined differences in total events using negative binomial regression. We also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint frailty analysis., Results: In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%) first primary endpoint events and 1,303 (44.8%) subsequent primary endpoint events occurred (which included 762 second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 vs. 89 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.70; 95% confidence interval: 0.62 to 0.78; p < 0.0001). Icosapent ethyl also reduced totals for each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 vs. 44 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.72; 95% confidence interval: 0.63 to 0.82; p < 0.0001)., Conclusions: Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events. (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial [REDUCE-IT]; NCT01492361)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To describe the characteristics and outcomes of patients receiving bailout glycoprotein IIb/IIIa inhibitors (GPI) for thrombotic complications of percutaneous coronary intervention (PCI) in a large, contemporary trial., Methods and Results: In the CHAMPION PHOENIX trial, the use of GPI was restricted to bailout for thrombotic complications. We describe the characteristics and outcomes of patients requiring bailout GPI compared to patients not receiving GPIs, with adjustment through propensity-score. A multivariable model was constructed to identify independent correlates associated with bailout GPI use. A total of 380 out of 10,942 patients received GPI (3.5%); GPI patients were younger, more frequently male, more likely to present with ST segment elevation myocardial infarction and less frequently treated with cangrelor. At 48 h, GPI patients experienced higher rates of the primary composite outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) (19.2% vs 4.8%; adjusted OR: 5.65(4.08, 7.82), p < 0.0001) and a higher rate of GUSTO severe or moderate bleeding (2.6% vs 0.4% adjusted OR: 4.90 (1.98, 12.18), p = 0.0006) compared with non GPI patients. Independent correlates of GPI use were STEMI, use of unfractionated heparin, drug-eluting stents and longer procedure duration., Conclusions: In a large contemporary trial, patients receiving bailout GPI for thrombotic complications of PCI experienced very high risks of both ischemic and bleeding complications, suggesting that prevention of periprocedural complications rather than bailout GPI may be preferable., Clinical Trial Registration: http://www.clinicaltrials.gov identifier: NCT01156571., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events., Objectives: The authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial., Methods: Patients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months., Results: A total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HR adj ]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HR adj : 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p < 0.0001), including a 36% reduction in coronary death (HR: 0.64; 95% confidence interval: 0.48 to 0.85; p = 0.002). In this subgroup, ticagrelor increased the risk of TIMI major bleeding (2.52% vs. 1.08%, HR: 2.67; p < 0.0001), but not ICH or fatal bleeds., Conclusions: Patients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients who have had a prior myocardial infarction (MI) are at increased risk for adverse outcomes after subsequent percutaneous coronary intervention (PCI)., Objective: The objective of this study is to examine the efficacy and safety of cangrelor, a potent intravenous P2Y 12 inhibitor, in patients with prior MI., Methods: Pooled data from the CHAMPION trials were examined. Prior MI was defined as a history of MI, excluding MI events at baseline. The primary endpoint was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48-h post-randomization. The primary safety endpoint was GUSTO-defined severe bleeding at 48h., Results: Out of 24,691 patients, 5699 (23%) had a prior MI. The primary endpoint was higher in patients with vs. without prior MI (4.9% vs. 4.0%, p=0.002). The primary endpoint was 4.2% with cangrelor vs. 5.7% with clopidogrel (absolute risk reduction=1.5%; OR 0.72 [95%CI 0.57-0.92]) in patients with prior MI and 3.7% with cangrelor vs. 4.3% with clopidogrel (absolute risk reduction=0.6%; OR 0.85 [95%CI 0.74-0.99]) in patients without prior MI (P-interaction=0.25). The rate of GUSTO-defined severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR 1.39 [95%CI 0.31-6.24]) in patients with prior MI, and 0.2% with cangrelor vs. 0.2% with clopidogrel (OR 1.18 [95%CI 0.65-2.14]) in patients without prior MI (P-interaction=0.84)., Conclusion: In the CHAMPION trials, patients with prior MI had higher rates of ischemic outcomes within 48h after PCI. Cangrelor reduced ischemic events with no significant increase in GUSTO-defined severe bleeding in patients with or without prior MI., (Copyright © 2017. Published by Elsevier B.V.)

Background: Older patients treated with percutaneous coronary intervention are at increased risk of periprocedural events., Methods and Results: CHAMPION (cangrelor versus standard therapy to achieve optimal management of platelet inhibition) PHOENIX randomized 11 145 patients to cangrelor or clopidogrel. We sought to determine the outcomes in the prespecified subgroup of patients ≥75 years old (n=2010; 18%). Cangrelor resulted in directionally consistent effects on the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) in patients ≥75 years old (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.50-1.02) and in those <75 years old (OR, 0.81; 95% CI, 0.67-0.98; P [interaction]=0.55). Age ≥75 years was an independent predictor of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate/severe bleeding (1.0% versus 0.3%; adjusted OR, 2.94; 95% CI, 1.28-6.77; P =0.01) when compared with patients <75 years old. There was no significant difference in GUSTO moderate/severe bleeding with cangrelor versus clopidogrel (1.1% versus 1.0%; OR, 1.07; 95% CI 0.45-2.53) in patients ≥75 years old or in those <75 years old (0.4% versus 0.2%; OR, 2.24; 95% CI, 1.02-4.93; P [interaction]=0.21). For the net composite end point of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis plus GUSTO moderate/severe bleeding, the OR for cangrelor in those ≥75 years old was 0.75 (6.4% versus 8.3%; 95% CI, 0.54-1.05; P =0.09). The effects were similar in those <75 years old (4.9% versus 5.8%; OR, 0.85; 95% CI, 0.70-1.02; P =0.08; P [interaction]=0.53)., Conclusions: Patients ≥75 years old have an overall ≈3-fold increased odds of moderate/severe bleeding. Cangrelor, when compared with clopidogrel, provides similar efficacy and in patients ≥75 years old as in those <75 years old but does not increase the risk of major bleeding., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01156571., (© 2017 American Heart Association, Inc.)

Background: Cangrelor, an intravenous, reversible P2Y 12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI)., Objectives: This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs)., Methods: This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator's discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization., Results: Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; P int  = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; P int  = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms., Conclusions: Cangrelor's efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cangrelor is a potent intravenous adenosine diphosphate-receptor antagonist that in the CHAMPION trials reduced the 48-hour and 30-day rates of ischemic events during percutaneous coronary intervention without an increase in severe bleeding., Methods and Results: CHAMPION PCI (A Clinical Trial to Demonstrate the Efficacy of Cangrelor), CHAMPION PLATFORM (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), and CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) were 3 randomized, double-blind, double-dummy trials in which cangrelor was compared with clopidogrel during percutaneous coronary intervention. The effect of cangrelor on ischemic events and bleeding was analyzed in the subgroup of patients with a history of cerebrovascular events at least 1 year prior to randomization; the Breslow-Day test was used to test for interaction of treatment effect in subgroups with and without such a history. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Among 24 910 randomized patients, 1270 patients (5.1%) had a cerebrovascular event >1 year old, including 650 assigned to cangrelor and 620 assigned to clopidogrel. Consistent with the overall trial results, the rate of the primary efficacy end point was 4.3% in the cangrelor group versus 5.3% in the clopidogrel group (odds ratio 0.80; 95% confidence interval 0.48-1.34; P=0.40; P for interaction =0.97), and the rate of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding was 0.3% in both groups (P=0.97; P for interaction =0.81)., Conclusions: Among patients in the CHAMPION trials with a prior cerebrovascular event at least 1 year before the percutaneous coronary intervention, the efficacy and bleeding profile of cangrelor compared with clopidogrel was similar to that in the overall trial., (© 2016 American Heart Association, Inc.)

Antithrombotic management of patients with atrial fibrillation (AF) undergoing coronary stenting is complicated by the need for anticoagulant therapy for stroke prevention and dual antiplatelet therapy for prevention of stent thrombosis and coronary events. Triple antithrombotic therapy, typically comprising warfarin, aspirin, and clopidogrel, is associated with a high risk of bleeding. A modest-sized trial of oral anticoagulation with warfarin and clopidogrel without aspirin showed improvements in both bleeding and thrombotic events compared with triple therapy, but large trials are lacking. The RE-DUAL PCI trial (NCT 02164864) is a phase 3b, a strategy of prospective, randomized, open-label, blinded-endpoint trial. The main objective is to evaluate dual antithrombotic therapy with dabigatran etexilate (110 or 150 mg twice daily) and a P2Y12 inhibtor (either clopidogrel or ticagrelor) compared with triple antithrombotic therapy with warfarin, a P2Y12 inhibtor (either clopidogrel or ticagrelor, and low-dose aspirin (for 1 or 3 months, depending on stent type) in nonvalvular AF patients who have undergone percutaneous coronary intervention with stenting. The primary endpoint is time to first International Society of Thrombosis and Hemostasis major bleeding event or clinically relevant nonmajor bleeding event. Secondary endpoints are the composite of all cause death or thrombotic events (myocardial infarction, or stroke/systemic embolism) and unplanned revascularization; death or thrombotic events; individual outcome events; death, myocardial infarction, or stroke; and unplanned revascularization. A hierarchical procedure for multiple testing will be used. The plan is to randomize ∼ 2500 patients at approximately 550 centers worldwide to try to identify new treatment strategies for this patient population., (© 2016 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

Background: Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel., Methods: PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours., Results: A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05)., Conclusions: In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX trial demonstrated superiority of cangrelor in reducing ischemic events at 48 hours in patients undergoing percutaneous coronary intervention compared with clopidogrel., Methods and Results: We analyzed all patients included in the modified intention-to-treat analysis in US (n=4097; 37.4%) and non-US subgroups (n=6845; 62.6%). The US cohort was older, had a higher burden of cardiovascular risk factors, and had more frequently undergone prior cardiovascular procedures. US patients more frequently underwent percutaneous coronary intervention for stable angina (77.9% versus 46.2%). Almost all US patients (99.1%) received clopidogrel loading doses of 600 mg, whereas 40.5% of non-US patients received 300 mg. Bivalirudin was more frequently used in US patients (56.7% versus 2.9%). At 48 hours, rates of the primary composite end point were comparable in the US and non-US cohorts (5.5% versus 5.2%; P=0.53). Cangrelor reduced rates of the primary composite end point compared with clopidogrel in US (4.5% versus 6.4%; odds ratio 0.70 [95% confidence interval 0.53-0.92]) and in non-US patients (4.8% versus 5.6%; odds ratio 0.85 [95% confidence interval 0.69-1.05]; interaction P=0.26). Similarly, rates of the key secondary end point, stent thrombosis, were reduced by cangrelor in both regions. Rates of Global Use of Strategies to Open Occluded Arteries (GUSTO)-defined severe bleeding were low and not significantly increased by cangrelor in either region., Conclusions: Despite broad differences in clinical profiles and indications for percutaneous coronary intervention by region in a large global cardiovascular clinical trial, cangrelor consistently reduced rates of ischemic end points compared with clopidogrel without an excess in severe bleeding in both the US and non-US subgroups., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571., (© 2016 The Authors.)

Background: Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed., Methods and Results: The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11,145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48-0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70-1.05; P interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20-0.77) and 16% in men (OR, 0.84; 95% CI, 0.53-1.33; P interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%, P=0.30 [women]; 0.1% versus 0.1%, P=0.41 [men]; P interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%, P=0.02), but not in men (0.2% versus 0.2%, P=0.68; P interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50-0.92) and men (OR, 0.87; 95% CI, 0.71-1.06; P interaction=0.26)., Conclusions: In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571., (© 2016 The Authors.)

Background: Patients with chronic obstructive pulmonary disease (COPD) experiencing acute coronary syndromes (ACS) are at high risk for clinical events. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor versus clopidogrel reduced the primary endpoint of death from vascular causes, myocardial infarction, or stroke after ACS, but increased the incidence of dyspnea, which may lead clinicians to withhold ticagrelor from COPD patients., Methods and Results: In 18 624 patients with ACS randomized to treatment with ticagrelor or clopidogrel, history of COPD was recorded in 1085 (5.8%). At 1 year, the primary endpoint occurred in 17.7% of patients with COPD versus 10.4% in those without COPD (P<0.001). The 1-year event rate for the primary endpoint in COPD patients treated with ticagrelor versus clopidogrel was 14.8% versus 20.6% (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.54 to 0.97), for death from any cause 8.4% versus 12.4% (HR=0.70; 95% CI: 0.47 to 1.04), and for PLATO-defined major bleeding rates at 1 year 14.6% versus 16.6% (HR=0.85; 95% CI: 0.61 to 1.17). Dyspnea occurred more frequently with ticagrelor (26.1% vs. 16.3%; HR=1.71; 95% CI: 1.28 to 2.30). There was no differential increase in the relative risk of dyspnea compared to non-COPD patients (HR=1.85). No COPD status-by-treatment interactions were found, showing consistency with the main trial results., Conclusions: In this post-hoc analysis, COPD patients experienced high rates of ischemic events. Ticagrelor versus clopidogrel reduced and substantially decreased the absolute risk of ischemic events (5.8%) in COPD patients, without increasing overall major bleeding events. The benefit-risk profile supports the use of ticagrelor in patients with ACS and concomitant COPD., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Few data are available regarding the use of antithrombotic strategies in coronary artery disease patients with atrial fibrillation (AF) in everyday practice. We sought to describe the prevalence of AF and its antithrombotic management in a contemporary population of patients with stable coronary artery disease., Methods and Findings: CLARIFY is an international, prospective, longitudinal registry of outpatients with stable coronary artery disease, defined as prior (≥12 months) myocardial infarction, revascularization procedure, coronary stenosis >50%, or chest pain associated with evidence of myocardial ischemia. Overall, 33,428 patients were screened, of whom 32,954 had data available for analysis at baseline; of these 2,229 (6.7%) had a history of AF. Median (interquartile range) CHA2DS2-VASc score was 4 (3, 5). Oral anticoagulation alone was used in 25.7%, antiplatelet therapy alone in 52.8% (single 41.8%, dual 11.0%), and both in 21.5%. OAC use was independently associated with permanent AF (p<0.001), CHA2DS2-VASc score (p=0.006), pacemaker (p<0.001), stroke (p=0.04), absence of angina (p=0.004), decreased left ventricular ejection fraction (p<0.001), increased waist circumference (p=0.005), and longer history of coronary artery disease (p=0.008). History of percutaneous coronary intervention (p=0.004) and no/partial reimbursement for cardiovascular medication (p=0.01, p<0.001, respectively) were associated with reduced oral anticoagulant use., Conclusions: In this contemporary cohort of patients with stable coronary artery disease and AF, most of whom are theoretical candidates for anticoagulation, oral anticoagulants were used in only 47.2%. Half of the patients received antiplatelet therapy alone and one-fifth received both antiplatelets and oral anticoagulants. Efforts are needed to improve adherence to guidelines in these patients., Trial Registration: ISRCTN registry of clinical trials: ISRCTN43070564.

Objectives: The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin., Background: Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis., Methods: In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm., Results: At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29)., Conclusions: Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES)., Methods and Results: Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥ 3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43)., Conclusion: A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: The aim of this study was to assess the relationship between sex and clinical outcomes and treatment-related complications in patients with ST-elevation or non-ST-elevation acute coronary syndromes (ACS) randomized to treatment with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial., Methods: The associations between sex subgroup and the primary composite outcomes, secondary outcomes, and major bleeding endpoints as well as interaction of sex subgroup with treatment effects were analysed using Cox proportional-hazards models., Results: Sex was not significantly associated with the probability of the primary composite endpoint [adjusted hazard ratio (HR): 1.02 (0.91-1.16)], or other adverse cardiovascular endpoints. Ticagrelor was similarly more effective than clopidogrel in reducing rates of the primary endpoint in women 11.2 vs. 13.2% [adjusted HR: 0.88 (0.74-1.06)] and men 9.4 vs. 11.1% [adjusted HR: 0.86 (0.76-0.97)] (interaction P-value 0.78), all-cause death in women 5.8 vs. 6.8% [adjusted HR: 0.90 (0.69-1.16)] and men 4.0 vs. 5.7% [adjusted HR: 0.80 (0.67-0.96)] (interaction P-value 0.49), and definite stent thrombosis in women 1.2 vs. 1.4% [adjusted HR: 0.71 (0.36-1.38)] and men 1.4 vs. 2.1% [adjusted HR: 0.63 (0.45-0.89)] (interaction P-value 0.78). The treatments did not differ for PLATO-defined overall major bleeding complications in women [adjusted HR: 1.01 (0.83-1.23)] or men [adjusted HR: 1.10 (0.98-1.24)]. Sex had no significant association with these outcomes (interactions P = 0.43-0.88)., Conclusion: Female sex is not an independent risk factor for adverse clinical outcomes in moderate-to-high risk ACS patients. Ticagrelor has a similar efficacy and safety profile in men and women., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as "on-treatment". Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment (p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.

Background: Although nonadherence with evidence-based secondary prevention medications is common in patients with established atherothrombotic disease, long-term outcomes studies are scant. We assessed the prevalence and long-term outcomes of nonadherence to secondary prevention (antiplatelet agents, statins, and antihypertensive agents) medications in stable outpatients with established atherothrombosis (coronary, cerebrovascular, or peripheral artery disease) enrolled in the international REduction of Atherothrombosis for Continued Health registry., Methods: Adherence with these medications in eligible patients at baseline and 1-year follow-up was assessed. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke at 4 years., Results: A total of 37,154 patients with established atherothrombotic disease were included. Adherence rates with all evidence-based medications at baseline and 1 year were 46.7% and 48.2%, respectively. Nonadherence with any medication at baseline (hazard ratio, 1.18; 95% confidence interval, 1.11-1.25) and at 1 year (hazard ratio, 1.19; 95% confidence interval, 1.11-1.28) were both significantly associated with an increased risk of the primary end point. The risk of all-cause mortality was similarly elevated. Corresponding numbers needed to treat were 31 and 25 patients for the composite end point and total mortality, respectively. This also was true for each disease-specific subgroup. Patients who were fully adherent at both time points had the lowest incidence of adverse outcomes, whereas patients who were nonadherent at both time points had the worst outcomes (P < .01)., Conclusions: Our analysis of a large international registry demonstrates that nonadherence with evidence-based secondary prevention therapies in patients with established atherothrombosis is associated with a significant increase in long-term adverse events, including mortality., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome., Background: Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment., Methods: The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI., Results: In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100])., Conclusions: Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: To describe aspirin use in primary and secondary prevention and to determine the incremental costs-effectiveness ratio (ICER) per life year gain (LYG) of aspirin use among subjects with, or at high risk of atherothrombotic disease., Design and Subjects: To project the cost-effectiveness of aspirin over 5 years of follow-up, a Markov state transition model was developed with yearly cycles and the following health states: "Alive" (post-CAD) and "Dead." The model compared current coverage observed among 2361 subjects using the prospective Australian subset of Reduction of Atherothrombosis for continued Health (REACH) registry, and hypothetical situation whereby all subjects assumed to be treated. Costs were calculated based on the Australian government reimbursed data for 2010., Main Outcome Measures: ICER per LYG for increased use of aspirin., Results: The use of aspirin in current group varied from 67% to 70%. The base-case analysis showed that increasing aspirin use among subjects with existing CAD in outpatient settings was cost saving, while increasing use of aspirin in primary prevention equated to an ICER of AUD 7126 per LYG., Conclusion: Among subjects with existing CAD aspirin use was shown to be a dominant choice of treatment. However, among patients without existing cardiovascular disease (primary prevention), increased uptake of aspirin was cost effective but with uncertain benefit, with two hemorrhagic bleeding events occurring for every life saved., (© 2011 Blackwell Publishing Ltd.)

Objective: To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy., Design: Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial., Setting: 862 centres in 43 countries., Participants: 5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management., Interventions: Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615)., Main Outcome Measurements: Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year., Results: 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel., Conclusions: In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy., Trial Registration: Clinical trials NCT00391872.

Objectives: The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes., Background: Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes., Methods: Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days)., Results: A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses ≥3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest., Conclusions: In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Smoking induces CYP1A2, thereby enhancing clopidogrel conversion to its active metabolite. We sought to determine the association between clopidogrel use and clinical outcomes in smokers versus nonsmokers with a broad spectrum of acute coronary syndrome (ACS)., Methods: We examined the association between early clopidogrel use in-hospital and 6-month outcomes among 44,426 patients with ACS in relation to smoking status in the Global Registry of Acute Coronary Events. We tested for heterogeneity of clopidogrel effect among smokers versus nonsmokers in separate multivariable models that adjusted for (1) established prognosticators in the Global Registry of Acute Coronary Events risk score and (2) independent predictors of major bleeding., Results: Rates of in-hospital mortality, death/myocardial infarction, and major bleeding were 4.3%, 5.9%, and 2.5%, respectively. Current smokers (n = 12,149) were more likely to be younger men without documented vascular disease; had lower rates of hypertension, hyperlipidemia, and diabetes; and more frequently presented with ST elevation (all P < .0001). Early clopidogrel use (55%) was associated with a reduction in the composite endpoint of mortality and myocardial infarction both in-hospital and at 6 months among current smokers and nonsmokers. There was no interaction between current smoking and clopidogrel use for ischemic endpoints. Major bleeding associated with early clopidogrel use was actually lower among current smokers compared with nonsmokers., Conclusions: Despite prior observations of smoking-enhanced clopidogrel effects, early clopidogrel use among smokers presenting with ACS compared with nonsmokers was not independently associated with a greater reduction in cardiovascular events. In contrast with nonsmokers, clopidogrel use among smokers was not associated with excess bleeding, perhaps because of unmeasured confounders., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Background: There are limited contemporary data on the early use of clopidogrel or glycoprotein (Gp) IIb/IIIa inhibitors, alone versus combination therapies, in non-ST-elevation acute coronary syndrome (NSTE-ACS)., Methods: This study included 5,806 Canadian NSTE-ACS patients with elevated cardiac biomarker and/or ST deviation on presentation in the prospective GRACE between 2003-2007. We stratified the study population according to the management strategy (non-invasive vs invasive) and into low-(GRACE risk score or=141)., Results: Overall, 3,893 patients (67.1%) received early (

Objectives: We sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs)., Background: Administration of a 300-mg clopidogrel LD is beneficial in situations requiring rapid platelet inhibition. Whether higher LDs can provide further benefits remains unknown., Methods: Patients (n = 103) with non-ST-segment elevation acute coronary syndromes were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including acetylsalicylic acid). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated., Results: Compared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 micromol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y(12) receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group., Conclusions: In low-to-moderate risk patients with non-ST-elevation acute coronary syndromes, clopidogrel LDs >300 mg provide a faster onset of action, a higher IPA plateau, and greater reductions in platelet activation during the first 24 h. A 900-mg LD may induce a greater antiplatelet effect than 600 mg, when compared with the standard 300-mg regimen. These findings require further clinical confirmation.

Background: Many agents are available to treat acute coronary syndromes (ACS), yet limited information is available about their use from a multinational perspective. The objective of this report was to describe patterns of use of antithrombotic and antiplatelet therapies in patients with the spectrum of ACS through the use of data from the Global Registry of Acute Coronary Events (GRACE)., Methods: Data from 12,665 patients with ACS were analyzed. Baseline characteristics, clinical presentation, and medication use were compared. Regional differences in the administration of antiplatelet and antithrombotic therapies were analyzed. Multivariable logistic regression was implemented to determine independent variables indicating the use of various hospital therapies., Results: Overall, unfractionated heparin was used in 57% of patients and low-molecular-weight heparin in 47% (P <.0001). More than 90% of patients received aspirin, but approximately 13% were not discharged on aspirin. Overall, 30% of patients received thienopyridines (with percutaneous coronary intervention [PCI] in 79%). Of those who did not receive aspirin, 31% received thienopyridines. Intravenous glycoprotein inhibitors were given to 17% of patients. Among those treated with PCI, only 47% received glycoprotein inhibitors, and 21% of those given glycoprotein inhibitors did not undergo PCI. Significant geographic variation was apparent in the use of unfractionated heparin, low-molecular-weight heparin, thienopyridines, and glycoprotein inhibitors., Conclusions: Despite the availability of guidelines, striking geographic and practice variations are apparent in the use of antithrombotic and antiplatelet therapies. There remains significant room for improvement in the use of these therapies in patients with ACS, which should lead to improvement in care and outcomes.

Background: In randomized trials, cangrelor reduced periprocedural ischemic events related to percutaneous coronary intervention without increasing GUSTO severe bleeding. However, some antiplatelet agents have shown a differential treatment effect by body mass index (BMI). Methods: Patients from the 3 CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) who were randomized to cangrelor versus clopidogrel during percutaneous coronary intervention were stratified by BMI. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis within 48 hours. The principal safety outcome was GUSTO moderate or severe bleeding at 48 hours, although more sensitive bleeding measures such as Thrombolysis in Myocardial Infarction major bleeding were also assessed. We examined obese patients (defined as BMI≥30) versus nonobese patients. Results: There were 24 893 patients, with 8979 (36.1%) having BMI of ≥30. There was no significant difference in the primary efficacy end point among obese versus nonobese patients (4.3% versus 4.2%; rate ratio, 1.01 [95% CI, 0.89–1.15]; P =0.82). There was a consistent benefit in the primary efficacy end point in patients who received cangrelor versus placebo who were obese (3.9% versus 4.7%, rate ratio, 0.83 [95% CI, 0.68–1.02]; P =0.07) and not obese (3.8% versus 4.7%; rate ratio, 0.81 [95% CI, 0.69–0.94]; P =0.0053); interaction P =0.77. There was no difference in GUSTO moderate or severe bleeding among patients who received cangrelor versus placebo who were obese (0.6% versus 0.6%; rate ratio, 0.99 [95% CI, 0.58–1.67]; P =0.96). Conclusions: Cangrelor at the time of percutaneous coronary intervention is effective and safe in obese and nonobese patients. There was no difference in short-term efficacy between obese and nonobese patients. Periprocedural cangrelor is an effective and safe antiplatelet agent, irrespective of BMI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01156571, NCT00385138, NCT00305162. [ABSTRACT FROM AUTHOR]

Background: Cangrelor is an intravenous P2Y12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention not pretreated with a P2Y12 inhibitor.Methods: A total of 11 145 patients were randomized to cangrelor or clopidogrel in the CHAMPION PHOENIX trial (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). We explored the effects of cangrelor on myocardial infarction (MI) using different definitions and performed sensitivity analyses on the primary end point of the trial.Results: A total of 462 patients (4.2%) undergoing percutaneous coronary intervention had an MI as defined by the second universal definition. The majority of these MIs (n=433, 93.7%) were type 4a. Treatment with cangrelor reduced the incidence of MI at 48 hours (3.8% versus 4.7%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.67-0.97; P=0.02). When the Society of Coronary Angiography and Intervention definition of periprocedural MI was applied to potential ischemic events, there were fewer total MIs (n=134); however, the effects of cangrelor on MI remained significant (OR, 0.65; 95% CI, 0.46-0.92; P=0.01). Similar effects were seen in the evaluation of the effects of cangrelor on MIs with peak creatinine kinase-MB ≥10 times the upper limit of normal (OR, 0.64; 95% CI, 0.45-0.91) and those with peak creatinine kinase-MB ≥10 times the upper limit of normal, ischemic symptoms, or ECG changes (OR, 0.63; 95% CI, 0.48-0.84). MIs defined by any of these definitions were associated with increased risk of death at 30 days. Treatment with cangrelor reduced the composite end point of death, MI (Society of Coronary Angiography and Intervention definition), ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis (1.4% versus 2.1%; OR, 0.69; 95% CI, 0.51-0.92).Conclusions: MI in patients undergoing percutaneous coronary intervention, regardless of definition, remains associated with increased risk of death in the current era. Cangrelor compared with clopidogrel significantly reduces MI regardless of the definition.Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT01156571. [ABSTRACT FROM AUTHOR]

Background: Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI).Objectives: This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI.Methods: PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up.Results: A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663; 19.3% vs. 8.4%; p < 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval: 0.44 to 0.95; p = 0.026).Conclusions: Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54]; NCT01225562). [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes appear to be at elevated risk of atherothrombotic events.Objectives: The purpose of this study was to determine the effect of antiplatelet therapy with ticagrelor on recurrent ischemic events in patients with diabetes and prior myocardial infarction (MI).Methods: We examined the subgroups of patients with diabetes (n = 6,806) and without diabetes (n = 14,355) from PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54), in which 21,162 patients with a history of MI 1 to 3 years prior and with additional risk factors were randomized to ticagrelor (90 or 60 mg twice daily) or placebo. Patients were followed for a median of 33 months. The primary efficacy endpoint was major adverse cardiovascular events (MACE) (cardiovascular death, MI, stroke) and the primary safety endpoint was TIMI (Thrombolysis In Myocardial Infarction) major bleeding.Results: The relative risk reduction in MACE with ticagrelor was consistent for the pooled doses versus placebo in patients with diabetes (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.72 to 0.99; p = 0.035) and without diabetes (HR: 0.84; 95% CI: 0.74 to 0.96; p = 0.013; p interaction = 0.99). As patients with diabetes were at higher risk of MACE, the absolute risk reduction tended to be greater in patients with versus without diabetes (1.5% vs. 1.1%, with corresponding 3-year number needed to treat of 67 vs. 91). In patients with diabetes requiring pharmacological therapy (n = 5,960), the absolute risk reduction was 1.9% with a 3-year number needed to treat of 53. Additionally, in patients with diabetes, ticagrelor reduced cardiovascular death by 22% and coronary heart disease death by 34%. Similar to patients without diabetes, there was increased TIMI major bleeding in patients with diabetes (HR: 2.56; 95% CI: 1.52 to 4.33; p = 0.0004).Conclusions: In patients with diabetes with prior MI, adding ticagrelor to aspirin significantly reduces the risk of recurrent ischemic events, including cardiovascular and coronary heart disease death. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562). [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the differences in specific causes of post–coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Background: In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality. Methods: In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death. Results: Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively). Conclusions: The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872) [ABSTRACT FROM AUTHOR]