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Aims: To estimate the incidence of major adverse cardiovascular events (MACE), expanded MACE, and MACE or Death across Fibrosis- 4 score (FIB-4) categories in people with type 2 diabetes and to determine whether efpeglenatide's effect varies with increasing FIB-4 severity., Materials and Methods: AMPLITUDE-O trial data were used to estimate the relationship of FIB-4 score categories to the hazard of MACE, expanded MACE, and MACE or death. Interactions on these outcomes between baseline FIB-4 score, and between FIB-4 score and efpeglenatide were also assessed., Results: Baseline FIB-4 score was available for 4059 participants (99.6%) allowing subdivision of the population in tertiles. During a median follow-up of 1.8 years, numerical increases in the incidence of all 3 outcomes did not change significantly across tertiles of FIB-4 score (P for trend ≥ 0.25) with negligible relationship of the score to incident outcomes (MACE HR, per 1 SD higher score, 95% CI: 1.00, 0.89-1.13). Efpeglenatide's effect on all MACE outcomes did not vary across FIB-4 tertiles (all interaction p values ≥ 0.64)., Conclusions: In high-risk people with type 2 diabetes, the degree of liver fibrosis, as estimated by FIB-4 score, was not related to incident cardiovascular outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of FIB-4 category., (© 2024. The Author(s).)

Aims: To estimate the incidence of a major adverse cardiovascular event (MACE) and a composite kidney outcome across estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) levels, and to determine whether efpeglenatide's effect varies with these indices., Materials and Methods: AMPLITUDE-O trial data were used to estimate the relationship of eGFR, UACR, and Kidney Disease Improving Global Outcomes (KDIGO) category to the hazard of MACE and the kidney composite. Interactions on these outcomes between eGFR and the UACR, and between each of these variables and efpeglenatide were also assessed., Results: Baseline eGFR and UACR were available for 3983 participants (mean age 64.5 years). During a median follow-up of 1.8 years, the hazards of MACE and the kidney composite for the lowest versus highest eGFR third were 1.6 (95% confidence interval [CI] 1.2, 2.2) and 2.3 (95% CI 1.9, 2.8), respectively. The hazards for the highest versus the lowest UACR third were 2.3 (95% CI 1.8, 3.1) and 18.0 (95% CI 12.7, 25.5), respectively, and for the high- versus low-risk KDIGO categories the hazards were 2.4 (95% CI 1.8, 3.1) and 16.0 (95% CI 11.6, 22.0), respectively. eGFR and UACR were independent determinants of both outcomes, but negatively interacted with each other for the kidney outcome. Efpeglenatide's effect on both outcomes did not vary with any kidney disease measure (all interaction p values ≥0.26)., Conclusions: In high-risk people with diabetes, eGFR, UACR, and KDIGO category have different relationships to incident cardiovascular and kidney outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of kidney-related risk category., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial infarction in patients with either stable coronary artery disease (CAD) or peripheral artery disease (PAD). The cost-effectiveness of this regimen in this population is essential for decision-makers to know., Methods: US direct healthcare system costs (in USD) were applied to hospitalized events, procedures and study drugs utilized by all patients. We determined the mean cost per participant for the full duration of the trial (mean follow-up of 23 months) plus quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) over a lifetime using a two-state Markov model with 1-year cycle length. Sensitivity analyses were performed on the price of rivaroxaban and the annual discontinuation rate., Results: The costs of events and procedures were reduced for Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) patients who received rivaroxaban 2.5 mg orally (BID) plus acetylsalicylic acid (ASA) compared with ASA alone. Total costs were higher for the combination group ($7426 versus $4173) after considering acquisition costs of the study drug. Over a lifetime, patients receiving rivaroxaban plus ASA incurred $27,255 more and gained 1.17 QALYs compared with those receiving ASA alone resulting in an ICER of $23,295/QALY. ICERs for PAD only and polyvascular disease subgroups were lower., Conclusion: Rivaroxaban 2.5 mg BID plus ASA compared with ASA alone was cost-effective (high value) in the USA. COMPASS ClinicalTrials.gov identifier: NCT01776424., (© 2023. The Author(s).)

Aims: The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial demonstrated that rivaroxaban 2.5 mg BID with aspirin 100 mg was more effective than aspirin 100 mg daily alone for the prevention of cardiovascular (CV) death, stroke, or myocardial infarction in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). We aimed to examine the cost-effectiveness of rivaroxaban using patient-level data from the COMPASS trial., Methods and Results: We performed an in-trial analysis and extrapolated our results for 33 years using a two-state Markov model with a 1-year cycle length. Hospitalization events, procedures, and study drugs were documented for patients. We applied country-specific (Canada, France, and Germany) direct healthcare system costs (in USD) to healthcare resources consumed by patients. Average cost per patient during the trial (mean follow-up of 23 months), quality-adjusted life years (QALYs), and lifetime cost-effectiveness were calculated. Costs of events and procedures were reduced with rivaroxaban 2.5 mg BID with aspirin. The addition of rivaroxaban 2.5 mg BID increased total costs for the combination group. Over a lifetime horizon (in trial +33 years), rivaroxaban plus aspirin was associated with 1.17 QALYs gained, yielding an incremental cost-effectiveness ratio (ICER) of $3946/QALY, $9962/QALY, and $10 264/QALY in Canada, France, and Germany, respectively. PAD and polyvascular disease subgroups had lower ICERs., Conclusion: Rivaroxaban 2.5 mg twice daily plus aspirin compared with aspirin alone reduces direct healthcare costs. After acquisition costs of rivaroxaban, the lifetime cost-effectiveness of 2.5 mg twice daily plus aspirin is highly cost-effective in Canada, France, and Germany.(COMPASS ClinicalTrials.gov identifier: NCT01776424)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: Our aim was to test whether a head-to-pelvis CT scan improves diagnostic yield and speed to identify causes for out of hospital circulatory arrest (OHCA)., Methods: CT FIRST was a prospective observational pre-/post-cohort study of patients successfully resuscitated from OHCA. Inclusion criteria included unknown cause for arrest, age >18 years, stability to undergo CT, and no known cardiomyopathy or obstructive coronary artery disease. A head-to-pelvis sudden death CT (SDCT) scan within 6 hours of hospital arrival was added to the standard of care for patients resuscitated from OHCA (post-cohort) and compared to standard of care (SOC) alone (pre-cohort). The primary outcome was SDCT diagnostic yield. Secondary outcomes included time to identifying OHCA cause and time-critical diagnoses, SDCT safety, and survival to hospital discharge., Results: Baseline characteristics between the SDCT (N = 104) and the SOC (N = 143) cohorts were similar. CT scans (either head, chest, and/or abdomen) were ordered in 74 (52%) of SOC patients. Adding SDCT scanning identified 92% of causes for arrest compared to 75% (SOC-cohort; p value < 0.001) and reduced the time to diagnosis by 78% (SDCT 3.1 hours, SOC alone 14.1 hours, p < 0.0001). Identification of critical diagnoses was similar between cohorts, but SDCT reduced delayed (>6 hours) identification of critical diagnoses by 81% (p < 0.001). SDCT safety endpoints were similar including acute kidney injury. Patient survival to discharge was similar between cohorts., Discussion: SDCT scanning early after OHCA resuscitation safely improved the efficiency and diagnostic yield for causes of arrest compared to the standard of care alone., Clinical Trials Number: NCT03111043., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Low dose rivaroxaban with aspirin reduced major cardiovascular events (MACE) compared to aspirin alone in patients with cardiovascular disease although effects on total events are unknown., Methods: The COMPASS clinical trial randomized 27,395 participants with chronic coronary and/or peripheral artery disease to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg daily. We analyzed total (first and recurrent) MACE outcomes of cardiovascular death, stroke, or myocardial infarction, and the primary safety outcome of major bleeding. Exploratory analyses included on-treatment and net clinical benefit. Total MACE and safety events were modeled for each treatment., Results: MACE events were lowest in rivaroxaban with aspirin (379 first MACE, 432 total MACE) compared with rivaroxaban (448 first, 508 total) or aspirin alone (496 first, 574 total). Rivaroxaban and aspirin reduced total MACE events compared with aspirin alone [HR 0.75, 95% CI 0.66-0.85, P < .0001, number needed to treat for 2 years (NNT 2y ) of 63]. Total major bleeding was higher for rivaroxaban with aspirin compared to aspirin, but severe bleeding was not increased. The net clinical benefit of rivaroxaban plus aspirin was 20% higher compared with aspirin alone [HR 0.80 (95% CI 16.3%-31.6%)]. Rivaroxaban alone had no benefit on MACE outcomes compared with aspirin alone. MACE outcomes were similar for those on and off randomized treatment., Conclusions: Low dose rivaroxaban with aspirin significantly reduces first and total cardiovascular events compared with aspirin alone with a NNT 2y of 63 and a 20% net clinical benefit., Trial Registration: NCT01776424. https://clinicaltrials.gov/ct2/show/NCT01776424., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain., Methods: Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ 2 statistic for trend., Results: During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5-0.86]; P =0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63-1.06]; P =0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg, P =0.011; HR, 0.85 for 4 mg, P =0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg, P <0.0001; HR, 0.73 for 4 mg, P =0.0009), MACE or any death (HR, 0.67 for 6 mg, P =0.0021; HR, 0.81 for 4 mg, P =0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg, P =0.0072; HR, 0.97 for 4 mg, P =0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg, P =0.0002; HR, 0.81 for 4 mg, P =0.067). A clear dose-response was noted for all primary and secondary outcomes (all P for trend ≤0.018)., Conclusions: The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03496298.

Aim: Current international guidelines recommend early echocardiography after resuscitated sudden death despite limited data. Our aim was to analyze published data on early post-resuscitation echocardiography to identify cardiac causes of sudden death and prognostic implications., Methods: We reviewed MEDLINE, EMBASE, and CENTRAL databases to December 2021 for echocardiographic studies of adult patients after resuscitation from non-traumatic sudden death. Studies were included if echocardiography was performed <48 hours after resuscitation and reported (1) diagnostic accuracy to detect cardiac etiologies of sudden death or (2) prognostic outcomes. Diagnostic endpoints were associations of regional wall motion abnormalities (RWMA), ventricular function, and structural abnormalities with cardiac etiologies of arrest. Prognostic endpoints were associations of echocardiographic findings with survival to hospital discharge and favorable neurological outcome., Results: Of 2877 articles screened, 16 (0.6%) studies met inclusion criteria, comprising 2035 patients. Two of six studies formally reported diagnostic accuracy for echocardiography identifying cardiac etiology of arrest; RWMA (in 5 of 6 studies) were associated with presumed cardiac ischemia in 17-89% of cases. Among 12 prognostic studies, there was no association of reduced left ventricular ejection fraction with hospital survival (v10) or favorable neurologic status (n = 5). Echocardiographic high mitral E/e' ratio (n = 1) and right ventricular systolic dysfunction (n = 2) were associated with poor survival., Conclusion: This scoping review highlights the limited data on early echocardiography in providing etiology of arrest and prognostic information after resuscitated sudden death. Further research is needed to refine the clinical application of early echocardiographic findings in post arrest care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE)., Methods and Results: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination., Conclusion: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: People with diabetes are at high risk for cardiovascular events including heart failure (HF). We examined the effect of the glucagon-like peptide 1 agonist dulaglutide on incident HF events and other cardiovascular outcomes in those with or without prior HF in the randomized placebo-controlled Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial., Methods and Results: The REWIND major adverse cardiovascular event (MACE) outcome was the first occurrence of a composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes). In this post-hoc analysis, a HF event was defined as an adjudication-confirmed hospitalization or urgent evaluation for HF. Of the 9901 participants studied over a median follow-up of 5.4 years, 213/4949 (4.3%) randomly assigned to dulaglutide and 226/4952 (4.6%) participants assigned to placebo experienced a HF event (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.77-1.12; p = 0.456). In the 853 (8.6%) participants with HF at baseline, there was no change in either MACE or HF events with dulaglutide as compared to participants without HF (p = 0.44 and 0.19 for interaction, respectively). Combined cardiovascular death and HF events were marginally reduced with dulaglutide compared to placebo (HR 0.88, 95% CI 0.78-1.00; p = 0.050) but unchanged in patients with and without HF at baseline (p = 0.31)., Conclusions: Dulaglutide was not associated with a reduction in HF events in patients with type 2 diabetes regardless of baseline HF status over 5.4 years of follow-up., (© 2022 European Society of Cardiology.)

Introduction: A wearable cardioverter defibrillator (WCD) is indicated in appropriate patients to reduce the risk for sudden cardiac death. Challenges for patients wearing a WCD have been frequent false shock alarms primarily due to electrocardiogram noise and wear discomfort. The objective of this study was to test a contemporary WCD designed for reduced false shock alarms and improved comfort., Methods: One hundred and thirty patients with left ventricular ejection fraction ≤40% and an active implantable cardioverter defibrillator (ICD) were fitted with the ASSURE WCD (Kestra Medical Technologies) and followed for 30 days. WCD detection was enabled and shock alarm markers recorded, but shocks and shock alarms were disabled. All WCD episodes and ICD ventricular tachycardia/ventricular fibrillation (VT/VF) episodes were adjudicated. The primary endpoint was the false-positive shock alarm rate with a performance goal of 1 every 3.4 days (0.29 per patient-day)., Results: Of 163 WCD episodes, 4 were VT/VF and 159 non-VT/VF (121 rhythms with noise, 32 uncertain with noise, 6 atrial flutter without noise). Only three false-positive shock alarm markers were recorded; one false-positive shock alarm every 1333 patient-days (0.00075 per patient-day, 95% confidence interval: 0.00015-0.00361; p < .001). No ICD recorded VT/VF episodes meeting WCD detection criteria (≥170 bpm for ≥20 s) were missed by the WCD during 3501 patient-days of use. Median wear was 31.0 days (interquartile range [IQR] 2.0) and median daily use 23.0 h (IQR 1.7). Adverse events were mostly mild: skin irritation (19.4%) and musculoskeletal discomfort (8.5%)., Conclusion: The ASSURE WCD demonstrated a low false-positive shock alarm rate, low patient-reported discomfort, and no serious adverse events., (© 2022 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes., Methods: Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term., Results: The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58-0.94] and 0.70 [0.37-1.30], respectively), expanded MACEs (0.77 [0.62-0.96] and 0.87 [0.51-1.48]), renal composite (0.70 [0.59-0.83] and 0.52 [0.33-0.83]), and MACEs or death (0.74 [0.59-0.93] and 0.65 [0.36-1.19]) did not differ by baseline SGLT2 inhibitor use ( P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P ≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use., Conclusions: The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298.

Background Patients resuscitated from out-of-hospital circulatory arrest (OHCA) frequently have cardiopulmonary resuscitation injuries identifiable by computed tomography, although the prevalence, types of injury, and effects on clinical outcomes are poorly characterized. Methods and Results We assessed the prevalence of resuscitation-associated injuries in a prospective, observational study of a head-to-pelvis sudden-death computed tomography scan within 6 hours of successful OHCA resuscitation. Primary outcomes included total injuries and time-critical injuries (such as organ laceration). Exploratory outcomes were injury associations with mechanical cardiopulmonary resuscitation and survival to discharge. Among 104 patients with OHCA (age 56±15 years, 30% women), 58% had bystander cardiopulmonary resuscitation, and total cardiopulmonary resuscitation time was 15±11 minutes. The prevalence of resuscitation-associated injury was high (81%), including 15 patients (14%) with time-critical findings. Patients with resuscitation injury were older (58±15 versus 46±13 years; P <0.001), but had otherwise similar baseline characteristics and survival compared with those without. Mechanical chest compression systems (27%) had more frequent sternal fractures (36% versus 12%; P =0.009), including displaced fractures (18% versus 1%; P =0.005), but no difference in survival (46% versus 41%; P =0.66). Conclusions In patients resuscitated from OHCA, head-to-pelvis sudden-death computed tomography identified resuscitation injuries in most patients, with nearly 1 in 7 with time-critical complications, and one-half with extensive rib-cage injuries. These data suggest that sudden-death computed tomography may have additional diagnostic utility and treatment implications beyond evaluating causes of OHCA. These important findings need to also be taken in context of the certain fatal outcome without resuscitation efforts. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03111043.

Background: GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes., Methods: We did a meta-analysis, including new data from AMPLITUDE-O, using a random effects model to estimate overall hazard ratio (HR) for MACE; its components; all-cause mortality; hospital admission for heart failure; a composite kidney outcome consisting of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change; and odds ratios for key safety outcomes (severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer). We also examined MACE outcome in patient subgroups on the basis of MACE incidence rates in the placebo group, presence or absence of cardiovascular disease, HbA 1c level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, BMI, age, and eGFR. We searched PubMed for eligible trials reporting MACE (ie, cardiovascular death, myocardial infarction, or stroke), up to June 9, 2021. We meta-analysed data from published randomised placebo-controlled trials testing either injectable or oral GLP-1 receptor agonists in patients with type 2 diabetes. We restricted the search to trials of more than 500 patients with a primary outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This meta-analysis was registered on PROSPERO, CRD42021259711., Findings: Of 98 articles screened, eight trials comprising 60 080 patients fulfilled the prespecified criteria and were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (HR 0·86 [95% CI 0·80-0·93]; p<0·0001), with no significant heterogeneity across GLP-1 receptor agonist structural homology or eight other examined subgroups (all p interaction ≥0·14). GLP-1 receptor agonists reduced all-cause mortality by 12% (HR 0·88 [95% CI 0·82-0·94]; p=0·0001), hospital admission for heart failure by 11% (HR 0·89 [95% CI 0·82-0·98]; p=0·013), and the composite kidney outcome by 21% (HR 0·79 [95% CI 0·73-0·87]; p<0·0001), with no increase in risk of severe hypoglycaemia, retinopathy, or pancreatic adverse effects. In sensitivity analyses removing the only trial restricted to patients with an acute coronary syndrome (ELIXA), all benefits marginally increased, including the outcome of worsening of kidney function, based on eGFR change (HR 0·82 [95% CI 0·69-0·98]; p=0·030)., Interpretation: GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with type 2 diabetes., Funding: None., Competing Interests: Declaration of interests NS has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi; and received grant support from Boehringer Ingelheim, outside the submitted work. MMYL's employer, the University of Glasgow, has received grant support from Boehringer Ingelheim. SLK reports speaker fees from AstraZeneca, outside the submitted work. KRHB reports research grant funding from Bayer, Sanofi, and Eli Lilly; and consultation fees from Amgen, Bayer, Janssen, Sana, and Kestra. RDL reports research grants and personal fees from Bristol-Myers Squibb and Pfizer; personal fees from Boehringer Ingelheim and Bayer; and research grants from Amgen, GlaxoSmithKline, Medtronic, and Sanofi Aventis, outside the submitted work. CSPL has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as consultant or on the advisory board, steering committee, or executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, Us2.ai, Janssen Research & Development, Medscape, MSD, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, and WebMD Global; and serves as co-founder and non-executive director of Us2.ai. SDP consulted for Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, and Sanofi; received grant support from AstraZeneca and Boehringer Ingelheim; and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, and Sanofi. JJVM acknowledges payments to his employer, the University of Glasgow, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Theracos; personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus. JR has participated in advisory panels for Boehringer Ingelheim, Intarcia Therapeutics, Applied Therapeutics, Eli Lilly, Hanmi, Novo Nordisk, Sanofi, Oramed, and Zealand Pharma; and has received research support from Applied Therapeutics, GlaxoSmithKline, Pfizer, Intarcia Therapeutics, Genentech, MSD, Eli Lilly, Novartis, Novo Nordisk, Sanofi, Hanmi, and Oramed. REP reports grants from Hanmi; grants from Janssen and Poxel SA; consulting fees from MSD, Scohia, and Sun Pharmaceutical Industries; grants, speaker fees, and consulting fees from Novo Nordisk; consulting fees from Pfizer; and grants and consulting fees from Sanofi. REP's services were paid for directly to AdventHealth, a non-profit organisation. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, MSD, Novo Nordisk, and Sanofi; honoraria for speaking from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, DKSH, and Zuellig; and consulting fees from Abbott, Covance, Eli Lilly, Novo Nordisk, Sanofi, Pfizer, Kowa, and Hanmi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The combination of 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily compared with 100 mg aspirin once daily reduces major adverse cardiovascular (CV) events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD)., Objectives: The aim of this work was to report the effects of the combination on overall and cause-specific mortality., Methods: The COMPASS trial enrolled 27,395 patients of whom 18,278 were randomized to the combination (n = 9,152) or aspirin alone (n = 9,126). Deaths were adjudicated by a committee blinded to treatment allocation. Previously identified high-risk baseline features were polyvascular disease, chronic kidney disease, mild or moderate heart failure, and diabetes., Results: During a median of 23 months of follow-up (maximum 47 months), 313 patients (3.4%) allocated to the combination and 378 patients (4.1%) allocated to aspirin alone died (hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.71-0.96; P = 0.01). Compared with aspirin, the combination reduced CV death (160 [1.7%] vs 203 [2.2%]; HR: 0.78; 95% CI: 0.64-0.96; P = 0.02) but not non-CV death. There were fewer deaths following MI, stroke, and CV procedures, as well as fewer sudden cardiac, other, and unknown causes of CV deaths and coronary heart disease deaths. Patients with 0, 1, 2, and 3 or 4 high-risk features at baseline had 4.2, 4.8, 25.0, and 53.9 fewer deaths, respectively, per 1000 patients treated for 30 months., Conclusions: The combination of rivaroxaban and aspirin compared with aspirin reduced overall and CV mortality with consistent reductions in cause specific CV mortality in patients with chronic CAD or PAD. The absolute mortality benefits are greater with increasing baseline risk. (Cardiovascular Outcomes for People Using Anticoagulant Strategies [COMPASS]; NCT01776424)., Competing Interests: Funding Support and Author Disclosures The COMPASS study was sponsored by Bayer. Dr. Eikelboom has received consulting fees and grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Eli-Lilly, GlaxoSmithKline, Pfizer, Janssen, Sanofi, and Servier. Dr. Bhatt discloses the following relationships: Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, and Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committee: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), 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), and Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, and ACC.org; Vice-Chair, ACC Accreditation Committee), 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), 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, 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), and WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. Dr. Fox has received grant support from Bayer and AstraZeneca; and has received consulting fees from Bayer/Janssen, Sanofi/Regeneron, and Verseon. Dr. Bosch has received fees for advisory board work for Bayer. Dr. Connolly has received lecture and consulting fees from BI, BMS, DSI, Medtronic, Pfizer, Portola, and Servier. Dr. Anand has received speaker fees and has provided consultation services for Bayer and Janssen. Dr. Avezum has received lecture fees from Bayer, Daiichi-Sankyo, Boehringer Ingelheim, Lilly, and NovoNordisk. Dr. Berkowitz is employed as a clinical research physician by Bayer US. Dr. Branch has received grant support from Bayer and Eli Lilly; and has provided consultation services for Janssen, Bayer, Sana, and Sanofi. Dr. Dagenais has received honoraria for lectures from Bayer and Eli Lilly. Dr. Guzik has received grants and speaking/consulting fees from Bayer during the conduct of the study. Dr. Hart participated in COMPASS and received research support and personal remuneration from Bayer. Dr. Maggioni has received personal fees for participation in committees of studies sponsored by Bayer, Fresenius, and Novartis outside the present work. Dr. Muehlhofer is employed as a global clinical lead by Bayer, Germany. Dr. Sharma has received grants and honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Daiichi. Dr. Yusuf has received grants and honoraria from Bayer, Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, and Cadila. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Patients resuscitated from an out-of-hospital circulatory arrest (OHCA) commonly present without an obvious etiology. We assessed the diagnostic capability and safety of early head-to-pelvis computed tomography (CT) imaging in such patients., Methods: From November 2015 to February 2018, we enrolled 104 patients resuscitated from OHCA without obvious cause (idiopathic OHCA) to an early sudden-death CT (SDCT) scan protocol within 6 h of hospital arrival. The SDCT protocol included a noncontrast CT head, an electrocardiogram-gated cardiac and thoracic CT angiogram, and a nongated venous-phase abdominopelvic CT angiogram. Patients needing urgent cardiac catheterization or hemodynamically unable to tolerate SDCT were excluded. Cardiac CT analyses were blinded, but other SDCT findings were clinically available. Primary endpoints were the number of OHCA causes identified by SDCT compared to the adjudicated cause and critical diagnoses identified by SDCT, including resuscitation complications. Safety endpoints were acute kidney injury (AKI) and inappropriate treatments based on SDCT findings. Acute coronary syndrome was the presumed etiology if any major coronary artery had a >50% stenosis without another OHCA cause., Results: SDCT scans occurred within 1.9 ± 1.0 h of hospital arrival and identified 39% (41/104) of all OHCA causes and 95% (39/41) of causes potentially identifiable by SDCT. Critical findings were identified by SDCT in 98% (43/44) of patients that included potentially life-threatening resuscitation complications of liver or spleen laceration (n = 6); pneumothorax or thoracic organ laceration (n = 8); and mediastinal, pericardial, or vascular hemorrhage (n = 3). SDCT exclusively identified 13 (13%) OHCA causes that would otherwise not be identified without SDCT imaging. No inappropriate treatments resulted from SDCT findings. AKI was common (28%) but only one (1%) patient required new dialysis., Conclusions: This observational cohort study suggests that early SDCT scanning is safe, can expedite the diagnosis of potential causes, and can meaningfully change clinical management after idiopathic OHCA., (© 2021 Society for Academic Emergency Medicine.)

Background and Purpose: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities., Methods: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities., Results: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests., Conclusions: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Background: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events., Methods: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding., Results: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P =0.002; and hazard ratio, 0.77, P =0.005, respectively, P interaction =0.77) and all-cause mortality (hazard ratio, 0.81, P =0.05; and hazard ratio, 0.84, P =0.09, respectively; P interaction =0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative P interaction <0.0001; 1.9% versus 0.6% for all-cause mortality, P interaction =0.02; 2.7% versus 1.7% for major vascular events, P interaction <0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative P interaction =0.001)., Conclusions: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Background & Aims: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial., Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up., Results: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant., Conclusions: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk., Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation., Results: There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528)., Conclusions: In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients with recent coronary artery bypass graft (CABG) surgery are at risk for early graft failure, which is associated with a risk of myocardial infarction and death. In the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) trial, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the primary major adverse cardiovascular events (MACE) outcome of cardiovascular death, stroke, or myocardial infarction. Rivaroxaban 5 mg twice daily alone did not significantly reduce MACE., Objectives: This pre-planned substudy sought to determine whether the COMPASS treatments are more effective than aspirin alone for preventing graft failure and MACE after CABG surgery., Methods: The substudy randomized 1,448 COMPASS trial patients 4 to 14 days after CABG surgery to receive the combination of rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone. The primary outcome was graft failure, diagnosed by computed tomography angiogram 1 year after surgery., Results: The combination of rivaroxaban and aspirin and the regimen of rivaroxaban alone did not reduce the graft failure rates compared with aspirin alone (combination vs. aspirin: 113 [9.1%] vs. 91 [8.0%] failed grafts; odds ratio [OR]: 1.13; 95% confidence interval [CI]: 0.82 to 1.57; p = 0.45; rivaroxaban alone vs. aspirin: 92 [7.8%] vs. 92 [8.0%] failed grafts; OR: 0.95; 95% CI: 0.67 to 1.33; p = 0.75). Compared with aspirin, the combination was associated with fewer MACE (12 [2.4%] vs. 16 [3.5%]; hazard ratio [HR]: 0.69; 95% CI: 0.33 to 1.47; p = 0.34), whereas rivaroxaban alone was not (16 [3.3%] vs. 16 [3.5%]; HR: 0.99, CI: 0.50 to 1.99; p = 0.98). There was no fatal bleeding or tamponade within 30 days of randomization., Conclusions: The combination of rivaroxaban 2.5 mg twice daily plus aspirin or rivaroxaban 5 mg twice daily alone compared with aspirin alone did not reduce graft failure in patients with recent CABG surgery, but the combination of rivaroxaban 2.5 mg twice daily plus aspirin was associated with similar reductions in MACE, as observed in the larger COMPASS trial. (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS [COMPASS]; NCT01776424)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There is limited information on the prognosis of patients who experience MALE., Objectives: Among participants with lower extremity PAD, this study investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE; and 2) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE, peripheral vascular interventions, and all peripheral vascular outcomes over a median follow-up of 21 months., Methods: We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. COMPASS was a randomized, double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation., Results: A total of 128 patients experienced an incident of MALE. After MALE, the 1-year cumulative risk of a subsequent hospitalization was 61.5%; for vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7%. The MALE index event significantly increased the risk of experiencing subsequent hospitalizations (hazard ratio [HR]: 7.21; p < 0.0001), subsequent amputations (HR: 197.5; p < 0.0001), and death (HR: 3.23; p < 0.001). Compared with aspirin alone, the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43% (p = 0.01), total vascular amputations by 58% (p = 0.01), peripheral vascular interventions by 24% (p = 0.03), and all peripheral vascular outcomes by 24% (p = 0.02)., Conclusions: Among individuals with lower extremity PAD, the development of MALE is associated with a poor prognosis, making prevention of this condition of utmost importance. The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications, and this combination should be considered as an important therapy for patients with PAD. (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]; NCT01776424)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease., Methods: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants., Findings: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012)., Interpretation: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide., Funding: Bayer AG., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention., Methods: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months., Results: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group., Conclusions: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

Background: Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy., Methods: Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo., Results: Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD., Conclusions: COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)