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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.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Background: Novel P2Y12 inhibitors prasugrel and ticagrelor were approved for patients with acute coronary syndrome (ACS) in 2009 and 2011, respectively. We assessed the association of racial, ethnic, and socioeconomic factors with initiation of and adherence to novel P2Y12 inhibitors in a commercially insured population., Methods: We performed a retrospective cohort analysis of adults undergoing percutaneous coronary intervention with placement of a drug-eluting stent, stratified by ACS status, between January 2008 and December 2016 using Clinformatics Data Mart (OptumInsight). We estimated multivariable logistic regression models to identify factors associated with the initiation of clopidogrel vs novel P2Y12 inhibitors as well as subsequent 6-month medication adherence, assessed via pharmacy records., Results: A total of 55,664 patients were included in the analysis. Hispanic ethnicity was independently associated with the initiation of clopidogrel compared with novel P2Y12 inhibitors among ACS patients (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.04-1.36; P<.01). ACS patients with an annual median household income of over $100,000 were less likely to be started on clopidogrel when compared with those who earned less than $40,000 (OR, 0.67; 95% CI, 0.61-0.75; P<.01). Black race, Hispanic ethnicity, and lower household income were each associated with significantly reduced odds of P2Y12 inhibitor adherence., Conclusion: Hispanic ethnicity and lower household income were associated with novel P2Y12 inhibitor initiation, and non-White race and ethnicity were associated with lower P2Y12 inhibitor adherence over 6-month follow-up. These findings highlight continued inequity of care, even in an insured population, and point to a need for new strategies to close these gaps.

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.)

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 Cardiovascular clinical trials have traditionally incorporated separate time-to-first-event analyses for their primary efficacy and safety comparisons, but this framework has a number of limitations, including limited patient-centeredness and a traditional requirement for central adjudication. Days alive and out of the hospital (DAOH) has the potential to provide additional insight. Methods and Results TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) was a randomized, multinational clinical trial that compared the effect of prasugrel versus clopidogrel in patients stabilized after non-ST segment elevation acute coronary syndrome treated without revascularization; the trial had a neutral result. DAOH was calculated for each patient using site-submitted adverse event reporting data. We described patterns of DAOH overall, and among younger adults (<75 years old), older adults (≥75 years old), and frail/prefrail patients over 12 months follow-up and used Poisson regression to compare DAOH for patients randomized to prasugrel versus clopidogrel. Of 9249 patients in the overall trial population, 500 (5.4%) died, and 2504 (27.1%) were hospitalized 4150 times over 12 months' follow-up; the mean±SD DAOH was 317±86. The distribution of DAOH over 12 months was left-skewed, with median DAOH 363 days. Among younger adults, older adults, and frail/prefrail patients, mean DAOH were 323, 293, and 304 days, respectively. There were no differences in DAOH by treatment arm in the overall population (rate ratio, 1.00; 95% CI, 0.99-1.01) or any subgroup. Conclusions These results support the feasibility of determining DAOH, a patient-centered outcome that can potentially overcome many of the disadvantages of the traditional time-to-composite-event framework in the clinical trial setting. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00699998.

Background: Guidelines recommend P2Y 12 inhibitor therapy for 1 year after myocardial infarction (MI), yet little guidance is provided on antiplatelet management for patients with recurrent ischemic events during that year. We describe changes in P2Y 12 inhibitor type among patients with recurrent ischemic events in the first year after MI., Methods and Results: The TRANSLATE-ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study enrolled 12 365 patients with MI treated with percutaneous coronary intervention. We examined whether P2Y 12 inhibitor choice changed among patients with recurrent MI, stent thrombosis, and/or unplanned revascularization during the first year after MI, and modeled factors associated with P2Y 12 inhibitor intensification (changing clopidogrel to prasugrel or ticagrelor). In the first year after MI, 1414 patients (11%) had a total of 1740 recurrent ischemic events (771 recurrent MIs, 969 unplanned revascularizations, and 165 stent thromboses). Median time to the first recurrent ischemic event was 154 days (25th-75th percentiles, 55-287 days). Of those with recurrent ischemic events, 101 of 1092 (9.3%) occurring in clopidogrel-treated patients led to P2Y 12 inhibitor intensification. Recurrent events involving stent thrombosis or MI were the strongest factors associated with P2Y 12 inhibitor intensification, yet only 40% of patients with stent thrombosis and 14% of patients with recurrent MI had P2Y 12 inhibitor intensification. Increasing age and longer time from the index MI were associated with lower likelihood for intensification., Conclusions: Few patients after MI with a recurrent ischemic event who were taking clopidogrel switched to a more potent P2Y 12 inhibitor, even after stent thrombosis events. Specific guidance is needed for patients who have recurrent ischemic events, particularly when closely spaced., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01088503., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Understanding the relative risk of cardiovascular versus noncardiovascular death is important for designing clinical trials. These risks may differ depending on patient age, sex, and type of acute coronary syndrome (ACS)., Methods and Results: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized controlled trial of simvastatin plus either ezetimibe or placebo following stabilized ACS. Cause of death was adjudicated by an independent committee. We compared the cumulative incidence of cardiovascular and noncardiovascular death for patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) and ST-segment elevation myocardial infarction (STEMI), in those <65 and ≥65 years old, and males and females, over 7 years of follow-up. Of 18 131 patients, the presenting event was STEMI for 5190 (29%) and UA/NSTEMI for 12 941 (71%); 10 173 (56%) patients were <65 years old and 7971 (44%) were ≥65 years old at presentation. UA/NSTEMI patients were older than STEMI patients, with more cardiovascular and noncardiovascular risk factors. In STEMI patients, the cumulative incidence of cardiovascular death was higher for ∼4 years following the index event, after which noncardiovascular death predominated. In UA/NSTEMI patients, the cumulative incidence of cardiovascular death remained higher than noncardiovascular death over the full follow-up period. Patients ≥65 years old and <65 years old had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow-up. Female patients had a higher incidence of cardiovascular death than noncardiovascular death for ∼6 years following the index event; male patients had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow-up., Conclusions: Among post-ACS patients enrolled in a long-term clinical trial, the relative incidence of cardiovascular and noncardiovascular death differed based on type of ACS presentation and sex, but not age. These findings further delineate long-term prognosis after ACS and should inform the design of future cardiovascular outcomes trials., (© 2017 The Authors and Merck Sharp & Dohme Corp. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Nine oral antithrombotic medications currently available in the United States and Europe have been studied in clinical trials for secondary prevention of cardiac events following acute coronary syndrome (ACS). Few combinations of these medications have been directly compared, and studies have used multiple different comparator regimens., Methods: We performed a systematic review and network meta-analysis of randomized controlled trials evaluating one or more available oral antithrombotic therapies in patients with ACS or prior myocardial infarction (MI). Co-primary outcomes were all-cause and cardiovascular mortality compared with imputed placebo and aspirin monotherapy., Results: Forty-seven studies (196,057 subjects) met inclusion criteria and were included in the systematic review. Almost all studies tested either aspirin monotherapy compared with placebo or a combination of antithrombotic agents that included aspirin. Nearly all regimens reduced all-cause and cardiovascular mortality compared with imputed placebo. However, compared with imputed aspirin monotherapy, only combination therapy with aspirin plus ticagrelor was associated with lower cardiovascular mortality (OR 0.80, 95% CI 0.68-0.93), and triple therapy with aspirin, clopidogrel, and very low dose rivaroxaban was associated with lower all-cause mortality (OR 0.67, 95% CI 0.49-0.90). Major bleeding was increased 45-95% with dual antithrombotic therapy, and 2-6-fold with triple therapy., Conclusion: Few combinations of antithrombotic therapy were associated with a reduction in mortality compared with aspirin monotherapy, highlighting the difficulty in clinical interpretation of composite ischemic endpoints. Future studies may need to focus on limiting the number of antithrombotic therapies tested in combination to best balance ischemic event reduction and bleeding., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Platelets play a key role in mediating stent thrombosis, which is the major cause of ischemic events immediately after percutaneous coronary intervention (PCI). Antiplatelet therapy is therefore the cornerstone of antithrombotic therapy after PCI. However, the use of antiplatelet agents increases bleeding risk, with more potent antiplatelet agents further increasing bleeding risk. In the past 5 years, potent and fast-acting P2Y 12 inhibitors have augmented the antiplatelet armamentarium available to interventional cardiologists. This article reviews the preclinical and clinical data surrounding these new agents, and discusses the significant questions and controversies that still exist regarding the optimal antiplatelet strategy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: It is unclear whether diagnostic protocols based on cardiac markers to identify low-risk chest pain patients suitable for early release from the emergency department can be applied to patients older than 65 years or with traditional cardiac risk factors., Methods and Results: In a single-center retrospective study of 231 consecutive patients with high-risk factor burden in which a first cardiac troponin (cTn) level was measured in the emergency department and a second cTn sample was drawn 4 to 14 hours later, we compared the performance of a modified 2-Hour Accelerated Diagnostic Protocol to Assess Patients with Chest Pain Using Contemporary Troponins as the Only Biomarker (ADAPT) rule to a new risk classification scheme that identifies patients as low risk if they have no known coronary artery disease, a nonischemic electrocardiogram, and 2 cTn levels below the assay's limit of detection. Demographic and outcome data were abstracted through chart review. The median age of our population was 64 years, and 75% had Thrombosis In Myocardial Infarction risk score ≥2. Using our risk classification rule, 53 (23%) patients were low risk with a negative predictive value for 30-day cardiac events of 98%. Applying a modified ADAPT rule to our cohort, 18 (8%) patients were identified as low risk with a negative predictive value of 100%. In a sensitivity analysis, the negative predictive value of our risk algorithm did not change when we relied only on undetectable baseline cTn and eliminated the second cTn assessment., Conclusions: If confirmed in prospective studies, this less-restrictive risk classification strategy could be used to safely identify chest pain patients with more traditional cardiac risk factors for early emergency department release., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Importance: About 10% of patients with acute chest pain are ultimately diagnosed with acute coronary syndrome (ACS). Early, accurate estimation of the probability of ACS in these patients using the clinical examination could prevent many hospital admissions among low-risk patients and ensure that high-risk patients are promptly treated., Objective: To review systematically the accuracy of the initial history, physical examination, electrocardiogram, and risk scores incorporating these elements with the first cardiac-specific troponin., Study Selection: MEDLINE and EMBASE were searched (January 1, 1995-July 31, 2015), along with reference lists from retrieved articles, to identify prospective studies of diagnostic test accuracy among patients admitted to the emergency department with symptoms suggesting ACS., Data Extraction and Synthesis: We identified 2992 unique articles; 58 met inclusion criteria., Main Outcomes and Measures: Sensitivity, specificity, and likelihood ratio (LR) of findings for the diagnosis of ACS. The reference standard for ACS was either a final hospital diagnosis of ACS or occurrence of a cardiovascular event within 6 weeks., Results: The clinical findings and risk factors most suggestive of ACS were prior abnormal stress test (specificity, 96%; LR, 3.1 [95% CI, 2.0-4.7]), peripheral arterial disease (specificity, 97%; LR, 2.7 [95% CI, 1.5-4.8]), and pain radiation to both arms (specificity, 96%; LR, 2.6 [95% CI, 1.8-3.7]). The most useful electrocardiogram findings were ST-segment depression (specificity, 95%; LR, 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia (specificity, 91%; LR, 3.6 [95% CI,1.6-5.7]). Both the History, Electrocardiogram, Age, Risk Factors, Troponin (HEART) and Thrombolysis in Myocardial Infarction (TIMI) risk scores performed well in diagnosing ACS: LR, 13 (95% CI, 7.0-24) for the high-risk range of the HEART score (7-10) and LR, 6.8 (95% CI, 5.2-8.9) for the high-risk range of the TIMI score (5-7). The most useful for identifying patients less likely to have ACS were the low-risk range HEART score (0-3) (LR, 0.20 [95% CI, 0.13-0.30]), low-risk range TIMI score (0-1) (LR, 0.31 [95% CI, 0.23-0.43]), or low to intermediate risk designation by the Heart Foundation of Australia and Cardiac Society of Australia and New Zealand risk algorithm (LR, 0.24 [95% CI, 0.19-0.31])., Conclusions and Relevance: Among patients with suspected ACS presenting to emergency departments, the initial history, physical examination, and electrocardiogram alone did not confirm or exclude the diagnosis of ACS. Instead, the HEART or TIMI risk scores, which incorporate the first cardiac troponin, provided more diagnostic information.

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]

Aspirin has been the cornerstone of therapy for the secondary prevention treatment of patients with cardiovascular disease since landmark trials were completed in the late 1970s and early 1980s that demonstrated the efficacy of aspirin for reducing the risk of ischemic events. Notwithstanding the consistent benefits demonstrated with aspirin for both acute and chronic cardiovascular disease, there are a number of toxicities associated with aspirin that have been showcased by recent long-term clinical trials that have included an aspirin monotherapy arm. As an inhibitor of cyclooxygenase (COX), aspirin impairs gastric mucosal protective mechanisms. Previous trials have shown that up to 15-20 % of patients developed gastrointestinal symptoms with aspirin monotherapy, and approximately 1 % of patients per year had a clinically significant bleeding event, including 1 in 1000 patients who suffered an intracranial or fatal bleed. These risks have been shown to be compounded for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) who are also treated with other antithrombotic agents during the acute care/procedural period, as well as for an extended time period afterwards. Given observations of substantial increases in bleeding rates from many prior long-term clinical trials that have evaluated aspirin together with other oral platelet inhibitors or oral anticoagulants, the focus of contemporary research has pivoted towards tailored antithrombotic regimens that attempt to either shorten the duration of exposure to aspirin or replace aspirin with an alternative antithrombotic agent. While these shifts are occurring, the safety profile of aspirin when used for the secondary prevention treatment of patients with established cardiovascular disease deserves further consideration. [ABSTRACT FROM AUTHOR]