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Background: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) who had an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is not known., Objectives: The authors sought to determine which antithrombotic regimen best balances safety and efficacy., Methods: AUGUSTUS, a multicenter 2 × 2 factorial design randomized trial compared apixaban with vitamin K antagonist (VKA) and aspirin with placebo in patients with AF with recent ACS and/or PCI treated with a P2Y 12 inhibitor. We conducted a 4-way analysis comparing safety and efficacy outcomes in the 4 randomized groups. The primary outcome was a composite of all-cause death, major or clinically relevant nonmajor bleeding, or hospitalization for cardiovascular causes over 6-month follow-up. Secondary outcomes included individual components of the primary endpoint., Results: A total of 4,614 patients were enrolled. All patients were treated with a P2Y 12 inhibitor. The primary endpoint occurred in 21.9% of patients randomized to apixaban plus placebo, 27.3% randomized to apixaban plus aspirin, 28.0% randomized to VKA plus placebo, and 33.3% randomized to VKA plus aspirin. Rates of major or clinically relevant nonmajor bleeding and hospitalization for cardiovascular causes were lower with apixaban and placebo compared with the other 3 antithrombotic strategies. There was no difference between the 4 randomized groups with respect to all-cause death., Conclusions: In patients with AF and a recent ACS and/or PCI, an antithrombotic regimen that included a P2Y 12 inhibitor and apixaban without aspirin resulted in a lower incidence of the composite of death, bleeding, or cardiovascular hospitalization than regimens including VKA, aspirin, or both. (An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; NCT02415400)., Competing Interests: Funding Support and Author Disclosures The AUGUSTUS study and this analysis were funded by Bristol Myers Squibb and Pfizer. Dr Berwanger has received research grants from AstraZeneca, Pfizer, Bayer, Amgen, Novartis, Servier, and Boehringer Ingelheim. Dr Fanaroff has received research grants from the American Heart Association and National Institutes of Health; and has received consulting fees from Abbott Laboratories. Dr Granger has received research grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, U.S. Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc, and Novartis; and has received consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, and Rho Pharmaceuticals. Dr Mehran has received institutional research grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis, and OrbusNeich; has received consulting fees from Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Roivant Sciences Inc, and Sanofi; has consulted (no fees) for Regeneron Pharmaceuticals Inc; has received institutional consulting fees from Abbott Vascular, Spectranetics/Phillips/Volcano Corporation, Bristol Myers Squibb, Novartis, and Watermark Research; is an executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb; and has <1% equity in Claret Medical and Elixir Medical. Dr Aronson is an employee of Bristol Myers Squibb. Dr Windecker has received institutional research and educational grants from Abbott, Amgen, Bayer, Bristol Myers Squibb, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. Dr Goodman has received research grant support and/or speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Eli Lilly, Esperion, Fenix Group International, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson and Johnson, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Novo Nordisk A/C, Pfizer, Regeneron, Sanofi, Servier, Tenax Therapeutics, Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Duke Clinical Research Institute, and PERFUSE. Dr Alexander has received research grants from Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, CryoLife, CSL Behring, U.S. Food and Drug Administration, National Institutes of Health, Sanofi, and VoluMetrix; and has received consulting fees from Pfizer, Bristol Myers Squibb, AbbVie Pharmaceuticals, CSL Behring, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies, and Zafgen. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. 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: The use of apixaban instead of vitamin K antagonists (VKA) as well as dropping aspirin results in less bleeding and comparable ischemic events in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention treated with a P2Y 12 inhibitor., Objectives: The authors assessed the safety and efficacy of antithrombotic regimens according to HAS-BLED and CHA 2 DS 2 -VASc scores in AUGUSTUS (The Open-Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention)., Methods: In AUGUSTUS, 4,614 patients were randomized in a 2-by-2 factorial design to open-label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor bleeding over 6 months of follow-up. Cox proportional hazards models were used to assess treatment effects by baseline HAS-BLED (≤2 vs ≥3) and CHA 2 DS 2 -VASc (≤2 vs ≥3) scores., Results: Of 4,386 (95.1%) patients with calculable scores, 66.8% had HAS-BLED ≥3 and 81.7% had CHA 2 DS 2 -VASc ≥3. Bleeding rates were lower with apixaban than VKA irrespective of baseline risk (HR: 0.57; 95% CI: 0.41-0.78 [HAS-BLED ≤2]; HR: 0.72; 95% CI: 0.59-0.88 [HAS-BLED ≥3]; interaction P = 0.23). Aspirin increased bleeding irrespective of baseline risk (HR: 1.86; 95% CI: 1.36-2.56 [HAS-BLED ≤2]; HR: 1.81; 95% CI: 1.47-2.23 [HAS-BLED ≥3]; interaction P = 0.88). Apixaban resulted in a lower risk of death or hospitalization than VKA without a significant interaction with baseline stroke risk (HR: 0.92; 95% CI: 0.67-1.25 [CHA 2 DS 2 -VASc ≤2]; HR: 0.82; 95% CI: 0.73-0.94 [CHA 2 DS 2 -VASc ≥3]; interaction P = 0.53)., Conclusions: Our findings support the use of apixaban and a P2Y 12 inhibitor without aspirin for most patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention, irrespective of a patient's baseline bleeding and stroke risk (NCT02415400)., Competing Interests: Funding Support and Author Disclosures The AUGUSTUS trial and this analysis were supported by Bristol Myers Squibb and Pfizer. Dr Fanaroff has received research grants and consulting fees from the American Heart Association; and has received research grants from Boston Scientific. Dr Lopes has received institutional research grants and consulting fees from Bristol Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC, and Sanofi; and has received consulting fees from Amgen, Bayer, and Boehringer Ingelheim. Dr Goodman has received research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, JAMP Pharma, Janssen/Johnson and Johnson, Merck, Novartis, Novo Nordisk A/C, Pendopharm, Pfizer, Regeneron, Sanofi, Servier, and Valeo Pharma; and has received salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) (Chair), Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, and PERFUSE Research Institute. Dr Thomas has received institutional research grants from Akili Interactive Labs Inc, Amgen Inc, Gilead, and Novartis. Dr Aronson is an employee of Bristol Myers Squibb. Dr Windecker has received Institutional research and educational grants from Abbott, Amgen, Bayer, Bristol Myers Squibb, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. Dr Mehran has received institutional research grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis, and OrbusNeich; has received consulting fees from Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Roivant Sciences Inc, and Sanofi; has performed consulting (no fees) for Regeneron Pharmaceuticals; has received institutional consulting fees from Abbott Vascular, Spectranetics/Phillips/Volcano Corporation, Bristol Myers Squibb, Novartis, and Watermark Research; has served as an executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb; and has <1% equity in Claret Medical and Elixir Medical. Dr Granger has received research grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, the U.S. Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc, and Novartis; and has received consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, and Rho Pharmaceuticals. Dr Alexander has received institutional research grants and consulting fees/honoraria from Bristol Myers Squibb and CSL Behring; has received institutional research grants from AstraZeneca, CryoLife, the U.S. Food and Drug Administration, National Institutes of Health, Sanofi, VoluMetrix, and Boehringer Ingelheim; and has received consulting fees/honoraria from Pfizer, AbbVie Pharmaceuticals, NovoNordisk, Portola Pharmaceuticals, Quantum Genetics, Teikoku Pharmaceuticals, VA Cooperative Studies Program, and Zafgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Older adults with atrial fibrillation (AF) are often treated with the shortest possible duration of antiplatelet/anticoagulant therapy after myocardial infarction (MI) or percutaneous coronary intervention (PCI) due to concern for bleeding. However, the risk of recurrent MI or PCI prompting antiplatelet therapy extension is unknown in this population., Methods: Using the National Cardiovascular Data Registry linked to Medicare claims, we described the cumulative incidence of recurrent MI or PCI over a median of 7-year follow-up for patients ≥65 years old with AF discharged alive after acute MI between 2008 and 2017. We used pharmacy fill data to describe the proportion of patients filling prescriptions for both oral anticoagulants and P2Y 12 inhibitors for ≥50% of the indicated duration after MI or PCI., Results: Of 187 622 older patients discharged alive after MI, 50 539 (26.9%) had AF. Over a median of 7-year follow-up in patients with AF, the cumulative incidence was 14.5% for recurrent MI, 12.1% for PCI, 7.9% for stroke, and 9.5% for bleeding hospitalization. Among 7998 patients with AF and recurrent MI or PCI, 1668 (20.9%) had >1 MI or PCI during follow-up. Assuming each MI or PCI should be followed by 6 months of P2Y 12 inhibitor therapy, patients with AF who had a recurrent MI/PCI had a median estimated indication for antiplatelet/anticoagulant treatment of 287 days (194, 358), but filled both P2Y 12 inhibitor and oral anticoagulant for a median of 0 days (0, 21). In this cohort, 12.2% of patients filled prescriptions for both a P2Y 12 inhibitor and oral anticoagulant for ≥50% of the indicated duration., Conclusions: Older adults with AF and MI have high incidences of downstream recurrent MI or PCI requiring extended antiplatelet/anticoagulant therapy durations, yet many appear to be under-treated. These results highlight the need for better thrombosis prevention strategies in this group of patients.

Dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel forms the backbone of secondary prevention in patients with acute coronary syndromes (ACS) or who undergo percutaneous coronary intervention (PCI), but in patients with atrial fibrillation (AF), oral anticoagulation (OAC) is superior to antiplatelet therapy for the prevention of stroke and systemic embolism. Patients with AF who undergo PCI or have an ACS event therefore have an indication for both OAC and DAPT, so-called triple antithrombotic therapy. However, observational analyses have shown that the annual rate of major bleeding on triple therapy exceeds 10%. For this reason, five major randomized clinical trials have compared double antithrombotic therapy with OAC and a P2Y 12 inhibitor versus triple therapy in patients with AF who underwent PCI or had an ACS event. Each of the trials showed that double antithrombotic therapy reduced the rate of major and clinically relevant non-major bleeding compared with triple therapy and was non-inferior for prevention of ischemic events, including cardiovascular death, myocardial infarction, or stroke. In the one trial that directly compared warfarin with a non-vitamin K antagonist oral anticoagulant (NOAC), apixaban reduced the rate of major or clinically relevant non-major bleeding compared with warfarin and was non-inferior with respect to prevention of ischemic events. As a result of these trials, consensus guidelines recommend that patients with AF who undergo PCI or have an ACS event should be treated with triple antithrombotic therapy (OAC + P2Y 12 inhibitor + aspirin) for 7 days or less, followed by double antithrombotic therapy (OAC + P2Y 12 inhibitor) for 6 to 12 months., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Patients with atrial fibrillation (AF) who have undergone mitral valve repair are at risk for thromboembolic strokes. Prior to 2019, only vitamin K antagonists were recommended for patients with AF who had undergone mitral valve repair despite the introduction of direct oral anticoagulants (DOAC) in 2010., Objective: To characterize the use of anticoagulants in patients with AF who underwent surgical mitral valve repair (sMVR) or transcatheter mitral valve repair (tMVR)., Methods: We performed a retrospective cohort analysis of patients with AF undergoing sMVR or tMVR between 04/2014 and 12/2018 using Optum's de-identified Clinformatics® Data Mart Database. We identified anticoagulants prescribed within 90 days of discharge from hospitalization., Results: Overall, 1997 patients with AF underwent valve repair: 1560 underwent sMVR, and 437 underwent tMVR. The mean CHA 2 DS 2 -VASc score among all patients was 4.1 (SD 1.9). The overall use of anticoagulation was unchanged between 2014 (72.2%) and 2018 (70.0%) (P = .49). Among patients who underwent sMVR or tMVR between April 2014 and December 2018, the use of VKA therapy decreased from 62.9% to 32.1% (P < .01 for trend) and the use of DOACs increased from 12.4% to 37.3% (P < .01 for trend)., Conclusions: Among patients with AF who underwent sMVR or tMVR between 2014 and 2018, roughly 30% of patients were not treated with any anticoagulant within 90 days of discharge, despite an elevated stroke risk in the cohort. The rate of DOAC use increased steadily over the study period but did not significantly increase the rate of overall anticoagulant use in this high-risk cohort., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy.

Real-world data (RWD) has been defined as data generated outside of traditional randomized clinical trials (RCTs). Though RWD has received increasing attention from regulatory authorities and professional societies, dividing evidence into that derived from 'real-world' vs. 'non-real-world' sources provides only one element of a much larger framework for evidence evaluation. Evidence should be evaluated on the source of the data, the method of treatment allocation (whether any intervention being evaluated was assigned or simply observed as used in practice) and the context in which the evidence was generated (overall study design). Under this framework, RWD refers only to data source, and a study incorporates RWD when it primarily uses data collected for non-research purposes, such as insurance claims data or the electronic health record, regardless of study design. Separation of study design, data source, and context enables parallel evaluation of two critical elements: (i) whether a study can support claims of causal inference, which can be assured with a high degree of confidence only in studies where patients are assigned treatments by protocol; and (ii) whether the study population and clinical context mirror clinical practice, a strength of observational studies using data from clinical practice or administrative claims. In this review, we describe the strengths and weaknesses of observational and non-observational studies, and studies involving RWD and non-RWD, through the lens of anticoagulation for atrial fibrillation (AF). Observational studies employing RWD are useful for describing how oral anticoagulants are used in clinical practice, but generally cannot be used to make claims regarding comparative treatment effects. Questions regarding treatment effect generally are best answered through an RCT, and additional pragmatic RCTs are needed to compare different antithrombotic agents for the prevention of thrombotic events in AF.

The RCTs of AF-PCI/ACS patients lack such information (Table 1).[[5], [7]] A subgroup analysis of the REDUAL PCI trial showed that only 9.9% of included patients had high-risk procedural factors and only 10% had both high-risk procedural and clinical complexity factors.[13] Although high-risk procedural features were not explicit exclusion criteria, the dearth of procedural details and the absence of statistically powered outcome stratification by PCI complexity prevent generalization of the four RCT results to PCI patients with high ischaemic risk PCI, which may represent up to 60% of cases according to a recent study.[12] Sub-analyses and specific high-risk subgroups. These patients made up only a fraction of the patients enrolled in WOEST (27%), PIONEER AF-PCI (29%), RE-DUAL (50%), AUGUSTUS (51%), and ENTRUST-AF PCI (52%), and individual trials were not powered to detect a treatment by subgroup interaction. The low thrombogenicity of new stent platforms, together with the increasing awareness of the prognostic impact of bleeding events have prompted the design of many RCTs testing a de-escalation or shortening of antithrombotic therapy, aiming at reducing bleeding without any trade-off in ischaemic events (Table 1).[38] Among them, the RCTs including patients with AF-PCI/ACS were the only ones in which: (i) the primary endpoints did not include ischaemic outcomes; (ii) procedural details were not reported; (iii) ACS patients were not well represented, as none focused entirely on the acute setting; (iv) "de-escalation" was started very early after PCI (Table 1). [Extracted from the article]

Background: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed.Methods: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model.Results: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause.Conclusions: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research. [ABSTRACT FROM AUTHOR]