Author + information
- Received April 2, 2019
- Revision received July 2, 2019
- Accepted July 7, 2019
- Published online September 16, 2019.
- John W. Eikelboom, MBBSa,b,c,∗ (, )@johneikelboom,
- Jacqueline J. Bosch, PhDb,c,
- Stuart J. Connolly, MDa,b,c,
- Olga Shestakovska, MScc,
- Gilles R. Dagenais, MDd,
- Robert G. Hart, MDc,
- Darryl P. Leong, MBBSa,b,c,
- Martin O’Donnell, MBChBc,
- Keith A.A. Fox, MBChBe,
- Deepak L. Bhatt, MD, MPHf,
- John A. Cairns, MDg,
- Christoph Tasto, PhDh,
- Scott D. Berkowitz, MDi,
- Nancy Cook Bruns, MDh,
- Eva Muehlhofer, MDh,
- Rafael Diaz, MDj,
- Aldo P. Maggioni, MDk and
- Salim Yusuf, DPhila,b,c
- aHamilton Health Sciences, Hamilton, Ontario, Canada
- bMcMaster University, Hamilton, Ontario, Canada
- cPopulation Health Research Institute, Hamilton, Ontario, Canada
- dInstitut Universitaire de Cardiologie et Pneumologie de Québec, Québec, Québec, Canada
- eCentre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
- fHarvard Medical School, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts
- gDepartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- hBayer AG, Leverkusen, Germany
- iBayer AG, Whippany, New Jersey
- jEstudios Clínicos Latino America and Instituto Cardiovascular de Rosario, Rosario, Argentina
- kAssociazione Nazionale Medici Cardiologi Ospedalieri Research Center, Firenze, Italy
- ↵∗Address for correspondence:
Dr. John Eikelboom, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
Background In patients with coronary or peripheral artery disease, the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced major adverse cardiovascular events and mortality and increased bleeding.
Objectives This study sought to explore the effects of the combination of rivaroxaban and aspirin compared with aspirin on sites, timing, severity, and management of bleeding in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) study.
Methods This study reports, by treatment group, the number and proportion of patients; hazard rate ratios for bleeding according to site and severity; the timing of bleeding using landmark analyses; and the number and proportion of patients who received blood products and other hemostatic treatments.
Results Of 27,395 patients enrolled (mean age 68 years, 22% women), 18,278 were randomized to the combination of rivaroxaban and aspirin or to aspirin alone and followed for a mean of 23 months. Compared with aspirin alone, the combination increased modified International Society on Thrombosis and Hemostasis major bleeding (288 of 9,152 [3.1%] vs. 170 of 9,126 [1.9%]), (HR: 1.70; 95% CI: 1.40 to 2.05; p < 0.001), International Society on Thrombosis and Hemostasis major bleeding (206 of 9,152 [2.3%] vs. 116 of 9,126 [1.3%]), (HR: 1.78; 95% CI: 1.41 to 2.23; p < 0.0001), and minor bleeding (838 of 9,152 [9.2%] vs. 503 of 9,126 [5.5%]), (HR: 1.70; 95% CI 1.52 to 1.90; p < 0.0001); the combination also increased the need for any red cell transfusion (87 of 9,152 [1.0%] vs. 44 of 9,126 [0.5%]), (HR: 1.97; 95% CI 1.37 to 2.83, p = 0.0002). The gastrointestinal (GI) tract was the most common site of increased major bleeding (140 of 9,152 [1.5%] vs. 65 of 9,126 [0.7%]), (HR: 2.15; 95% CI: 1.60 to 2.89; p < 0.001), and the increase in bleeding was predominantly in the first year after randomization. Approximately one-third of major GI bleeding was gastric or duodenal, one-third was colonic or rectal, and one-third was from an unknown GI site. The study investigators reported that approximately three-quarters of major bleeding episodes were of mild or moderate intensity. A similar proportion of patients in each treatment group who experienced major bleeding received platelets, clotting factors, or other hemostatic agents.
Conclusions The combination of rivaroxaban and aspirin compared with aspirin alone increased major bleeding, mainly from the GI tract. Most excess bleeding occurred during the first year after randomization, was of mild or moderate intensity, and was managed with conventional supportive therapy. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424)
The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial demonstrated that in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD), the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the risk of cardiovascular (CV) death, stroke, or myocardial infarction (MI) (the primary efficacy outcome) by 24% (1–3). This benefit was accompanied by an increase in bleeding.
The objective of this paper is to report details of the sites, timing, and investigator-reported severity of bleeding, as well as medical management of bleeding in patients randomized to receive rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily in the COMPASS trial, thereby to facilitate evaluation by clinicians and patients of the balance between benefits and risks of the treatment.
COMPASS was a multicenter international trial that enrolled patients with stable chronic CAD or PAD (4). Following successful completion of a 30-day running-in phase during which patients were treated with aspirin or placebo rivaroxaban, patients were randomized to receive the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily. The primary efficacy outcome was the composite of CV death, stroke, or MI. The intent was to continue the trial until 2,200 patients had experienced a primary outcome event but the trial was stopped after a mean follow-up of 23 months because of clear evidence of benefit of the combination of rivaroxaban and aspirin versus aspirin alone.
The main safety outcome was major bleeding, classified using a modification of the International Society on Thrombosis and Hemostasis (ISTH) definitions for major bleeding in nonsurgical patients (5) or in surgical patients (6). The ISTH definition of major bleeding in nonsurgical patients includes fatal bleeding and/or symptomatic bleeding in a critical area or organ, defined as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin level of 20 g/l (1.24 mmol/l) or more, or leading to transfusion of 2 or more units of whole blood or red cells (5). The ISTH definition of major bleeding in surgical patients includes each of the components included in the definition for nonsurgical patients, as well as surgical site bleeding (6). The modified ISTH definition used in the COMPASS study was adopted in response to advice received from the U.S. Food and Drug Administration and included fatal bleeding, symptomatic bleeding in a critical area or organ, surgical site requiring reoperation, and bleeding leading to hospitalization or presentation to an acute care facility without overnight stay; the modified definition did not include hemoglobin drop or need for transfusion. Hemorrhagic stroke was counted both as a primary efficacy outcome and as a major bleed. Any bleeding event that did not meet the definition for modified ISTH major bleeding was counted as minor bleeding. All bleeding events were centrally adjudicated without knowledge of treatment allocation.
Investigators separately classified bleeding according to intensity, as mild, moderate, or severe, based on their assessment of the impact of the bleed on the patient’s daily activities (mild: usually transient in nature and generally not interfering with normal activities; moderate: sufficiently discomforting to interfere with normal activities; severe: prevents normal activities). Investigator-reported intensity of bleeding was not adjudicated.
Management of bleeding
The protocol provided guidance for the study investigators on the management of bleeding. The protocol indicated that temporary discontinuation of rivaroxaban was likely to be sufficient to control bleeding in most cases considering its relatively short half-life, that local measures should be applied if needed to control bleeding, and that intravenous fluids and blood transfusion support should be provided as indicated. In case of life-threatening bleeding, the investigator was advised to obtain advice from a hematologist, and reference was made to evidence from animal studies suggesting that prothrombin complex concentrates or recombinant factor VIIa could partially restore hemostasis following treatment with factor Xa inhibitors such as rivaroxaban. The protocol also made reference to the results of a randomized trial involving healthy patients treated with rivaroxaban that demonstrated prothrombin complex concentrate reversed prolongation of the prothrombin time (7). A specific antidote for rivaroxaban was not commercially available during the COMPASS trial.
All events that occurred between randomization and the date of stopping the rivaroxaban and aspirin arms of the trial (February 6, 2017) were included and analyzed according to the intention-to-treat principle. Crude incidences were calculated as the number of patients with a first bleeding outcome divided by the total number of patients. Survival analyses were based on the time to a first event. Only the first bleeding event was counted in each category but patients could contribute more than 1 bleeding event in different categories.
The effects of the combination of rivaroxaban and aspirin and those of aspirin alone were compared using a stratified log-rank test. Kaplan-Meier estimates of the cumulative hazard function were used to evaluate the timing of event occurrences in the treatment groups and the consistency of the respective treatment effects at different time points. Stratified Cox proportional hazards models were used to obtain the hazard ratio (HR) and corresponding 95% confidence interval (CI). The assumptions of the Cox models were verified by visually assessing the standard plots of the log of negative log of Kaplan-Meier estimates of the survival function versus the log of time.
For evaluation of timing of events, the follow-up time of patients was divided into the first year after randomization, the second year after randomization, and the time thereafter. Patients at risk of the outcome during each of these time periods were those alive at the beginning of the period who had not previously experienced the event. The HR were estimated by a Cox model assuming piecewise proportionality of the hazards in the time intervals. An on-treatment analysis censoring patients at the time of permanent discontinuation of study treatment was also performed to further evaluate the timing of events.
For evaluation of bleeding management, the proportion of patients with bleeding in each treatment group who received red cells, platelets, clotting factors (including prothrombin complex concentrate), recombinant factor VIIa, or antifibrinolytic therapy, was determined. A 2-sided p value <0.05 was deemed to be statistically significant.
The focus of this paper is on the comparison between the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily and aspirin 100 mg once daily. Rivaroxaban 5 mg twice daily was not superior to aspirin alone and increased bleeding, and this regimen has not been submitted to regulatory authorities for approval.
The mean age of the 27,395 patients enrolled in the COMPASS trial was 68 years, 22% were female, and mean follow-up was 23 months. A total of 18,278 patients were randomized to the combination of rivaroxaban and aspirin or to aspirin alone.
The combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily increased modified ISTH major bleeding (288 of 9,152 [3.1%] vs. 170 of 9,126 [1.9%]; HR: 1.70; 95% CI: 1.40 to 2.05; p < 0.0001) as well as ISTH major bleeding classified according to the original definition (206 of 9,152 [2.3%] vs. 116 of 9,126 [1.3%]; HR: 1.78; 95% CI: 1.41 to 2.23; p < 0.0001) (Figure 1, Online Table 1). Incidence rates were approximately one-third lower when major bleeding was defined according to the original ISTH definition instead of the modified ISTH definition used in the COMPASS study. Corresponding data for the comparison between rivaroxaban 5 mg twice daily and aspirin 100 mg once daily are presented in Online Table 2.
The effects of the combination of rivaroxaban and aspirin compared with aspirin alone on the most common sites of major bleeding and on any bleeding was consistent in the subgroup of patients with CAD and in those with PAD (Online Table 3).
Although the combination of rivaroxaban and aspirin compared with aspirin did not significantly increase fatal bleeding (15 of 9,152 [0.2%] vs. 10 of 9,126 [0.1%]; HR: 1.49; 95% CI: 0.67 to 3.33; p = 0.32), symptomatic critical organ bleeding (73 of 9,152 [0.8%] vs. 53 of 9,126 [0.6%]; HR: 1.37; 95% CI: 0.96 to 1.95; p = 0.08), or bleeding into a surgical site leading to reoperation (15 of 9,152 [0.2%] vs. 12 of 9,126 [0.1%]; HR: 1.24; 95% CI: 0.58 to 2.65; p = 0.58), estimates of hazards for these more severe types of bleeds were consistent with the increase in hazards observed for any major bleeding. The combination compared with aspirin alone increased major bleeding leading to hospitalization or presentation to acute care facility without overnight stay (259 of 9,152 [2.8%] vs. 147 of 9,126 [1.6%]; HR: 1.76; 95% CI: 1.44 to 2.16; p < 0.0001), including both bleeding leading to hospitalization (214 of 9,152 [2.3%] vs. 121 of 9,126 [1.3%]; HR: 1.77; 95% CI: 1.42 to 2.21; p < 0.0001) and bleeding with same day discharge (45 of 9,152 [0.5%] vs. 28 of 9,126 [0.3%]; HR: 1.60; 95% CI: 1.00 to 2.56; p = 0.05).
Sites of major bleeding are presented in the Central Illustration and in Table 1. The most common site of major bleeding in patients randomized to the combination of rivaroxaban and aspirin was the gastrointestinal (GI) tract, followed in order by intracranial, skin or injection site, eye, nasal, urinary, respiratory, and genital tract. The combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily significantly increased major GI bleeding (140 of 9,152 [1.5%] vs. 65 of 9,126 [0.7%]; HR: 2.15; 95% CI: 1.60 to 2.89; p < 0.0001) and skin or injection site bleeding (29 of 9,152 [0.3%] vs. 12 of 9,126 [0.1%]; HR: 2.39; 95% CI: 1.22 to 4.69; p = 0.01). With both combination therapy and aspirin alone, approximately one-third of major GI bleeds were gastric or duodenal, one-third were colonic or rectal, and one-third were from an unknown GI site.
The combination of rivaroxaban and aspirin increased minor bleeding (838 of 9,152 [9.2%] vs. 503 of 9,126 [5.5%]; HR: 1.70; 95% CI: 1.52 to 1.90; p < 0.0001) (Online Table 1). The magnitude of this increase was similar to that for modified ISTH major bleeding (HR: 1.70), but first minor bleeding events were 2× to 3× more common than first major bleeding events (incidence rates in rivaroxaban plus aspirin group: minor 9.2% vs. major 3.1%; incidence rates in aspirin only group: 5.5% vs. 1.9%).
Sites of minor bleeding are presented in Table 1. The most common site of minor bleeding in patients randomized to the combination of rivaroxaban and aspirin was skin or injection site, followed in order by GI, nasal, urinary, respiratory, eye, intracranial, and other. The 7 intracranial bleeding events classified as minor (rivaroxaban plus aspirin = 3, aspirin = 4) were asymptomatic microbleeds, asymptomatic superficial siderosis, minor surgical site bleeding after neurosurgery, or bleeding associated with head trauma. The combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily significantly increased minor skin or injection site, GI, nasal, urinary, genital tract, and other bleeding.
Timing of bleeding, cardiovascular events, and mortality
Most of the excess major bleeding and excess gastrointestinal bleeding with the combination of rivaroxaban and aspirin compared with aspirin alone occurred during the first year after randomization, both by intention-to-treat (Table 2) and by on-treatment analyses (Online Table 4). In contrast, the benefits of the combination of rivaroxaban and aspirin compared with aspirin alone in reducing CV death, stroke, or MI and mortality were consistent in years 1, 2, 3, and beyond. The balance between the absolute increase in fatal or symptomatic critical organ bleeding and absolute reduction in CV death, stroke, or MI was increasingly favorable over time (Figure 2).
Intensity of major bleeding
The investigator-reported intensity of major bleeding, major bleeding leading to hospitalization, and major or minor bleeding is presented in Table 3. The combination of rivaroxaban and aspirin compared with aspirin alone produced a similar increase in HR for severe (70 of 9,152 [0.8%] vs. 39 of 9,126 [0.4%]; HR: 1.79; 95% CI: 1.21 to 2.64; p = 0.003), moderate (124 of 9,152 [1.4%] vs. 81 of 9,126 [0.9%]; HR: 1.53; 95% CI: 1.15 to 2.02; p = 0.003), and mild (106 of 9,152 [1.2%] vs. 63 of 9,126 [0.7%]; HR: 1.68; 95% CI: 1.23 to 2.29; p = 0.001) major bleeding.
Medical management of major bleeding
Medical management of major bleeding is summarized in Table 4. The proportion of patients with a first major bleeding event requiring red cell transfusion was 30.2% (87 of 288) in patients treated with the combination of rivaroxaban and aspirin and 25.9% (44 of 170) in those treated with aspirin alone. The proportion of patients with major bleeding receiving platelets, clotting factors, recombinant factor VIIa, or antifibrinolytic therapy was low and similar irrespective of whether patients were treated with the combination of rivaroxaban and aspirin or aspirin alone (Table 4).
In patients with chronic CAD or PAD enrolled in the COMPASS trial, the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily was associated with a 1.7-fold increase in both major and minor bleeding, most commonly from the GI tract. The most common known sites of major GI bleeding were the stomach, duodenum, colon, and rectum, whereas approximately one-third were from an unknown site. Although we did not collect information on the use of investigations for GI bleeding, it is likely that most unknown bleeding among those who underwent investigation was from pathology in the small bowel, including mass lesions, inflammation, or vascular abnormalities not detected on routine upper or lower GI tract endoscopic examination (8).
The increase in bleeding appeared to be confined to the first year after randomization, with no significant excess bleeding thereafter, whereas benefits in preventing CV death, stroke, or MI, as well as mortality continued to accrue over time. Our findings in relation to the timing of the effect of rivaroxaban plus aspirin compared with aspirin alone on bleeding during the first year are unlikely to be explained by differential discontinuation of study drug, because permanent discontinuation rates were similar in the 3 randomized treatment groups and an on-treatment analysis produced similar results. One possible explanation for the early excess bleeding is that more intensive antithrombotic therapy unmasks underlying pathology. Once this pathology is unmasked, rates of bleeding are similar by treatment group because treatment does not affect the rate of the development of new pathology, which is similar in both groups. A similar phenomenon of early bleeding has been reported in trials of warfarin (9), as well as in trials of antiplatelet therapy with the combination of aspirin and clopidogrel (10) or aspirin alone (11).
The combination of rivaroxaban and aspirin compared with aspirin alone produced a similar increase in major bleeding of severe, moderate, and mild intensity (blinded evaluation of bleeding by the investigator), but the majority of these events were deemed to be of mild or moderate intensity. A similar proportion of patients with major bleeding treated with the combination of rivaroxaban and aspirin or aspirin alone required red cell transfusion and other supportive therapies including platelets, fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates. The lack of a need for aggressive supportive therapies in patients who bled during treatment with the combination of rivaroxaban and aspirin compared with aspirin alone likely reflects the low dose of rivaroxaban that was tested and its short half-life. A 2.5 mg twice daily dose of rivaroxaban is equivalent to only one-half of the daily dose used for prevention of venous thromboembolism in patients undergoing major orthopedic surgery (10 mg once daily), and the elimination half-life of rivaroxaban is 5 to 9 h in healthy young subjects and 11 to 13 h in elderly subjects (12). Thus, in most cases of bleeding, rivaroxaban is rapidly eliminated, without the need to consider additional therapies to enhance hemostasis.
The modified ISTH definition for major bleeding used in the COMPASS trial resulted in major bleeding event rates that were approximately one-third higher than the estimate obtained using the conventional ISTH definition. Although the hazards for major bleeding were similar irrespective of definition, the differences in absolute event rates may affect interpretation by clinicians and patients of the balance between the benefits and risks of treatment using the combination of rivaroxaban and aspirin.
A limitation of these results is that patients deemed to be at high risk of bleeding were excluded from the COMPASS trial. Future studies are needed to explore whether the favorable outcomes seen with the combination of rivaroxaban and aspirin in the COMPASS study can be extended to patients at high risk of bleeding, for example, those with end-stage kidney disease.
Among persons with chronic CAD or PAD, most of the increase in bleeding with the combination of rivaroxaban and aspirin compared with aspirin alone was GI, occurred in the first year after starting treatment, was of mild or moderate intensity, and did not require red cell transfusion or specific corrective therapy. In contrast, the reduction in CV death, stroke, or MI continued to accrue after the first year, suggesting accumulating net clinical benefit over time.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Patients with chronic CAD or PAD treated with the combination of rivaroxaban and aspirin face a greater risk of bleeding compared with patients treated with aspirin therapy alone. Most of the excess bleeding occurs during the first year, arises in the GI tract, and can be managed using conventional supportive therapies.
TRANSLATIONAL OUTLOOK: Future studies should explore whether the combination of rivaroxaban plus aspirin for secondary prevention of CV disease can be extended to patients at high risk of bleeding, such as those with a history of bleeding or with end-stage kidney disease.
The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) study was sponsored by Bayer AG, Germany. Dr. Eikelboom has received consulting fees and grant support from AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, Sanofi, and Servier. Dr. Bosch serves on the Advisory Board of and has received honoraria from Bayer AG. Dr. Connolly has received lecture and consulting fees from Boehringer Ingelheim, Janssen, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Medtronic, Pfizer, Portola, and Servier; and has received grants from Bristol-Myers Squibb, Bayer, Portola, Janssen, and Daiichi-Sankyo. Dr. Hart serves as the Principal Investigator on the NAVIGATE ESUS trial; serves on the COMPASS Steering Committee and Event Adjudication Committee; and has received honoraria and research support from Bayer AG. Dr. Leong has received speaking honoraria from Bayer AG. Dr. Fox has received grants from Bayer/Janssen and AstraZeneca; and has received consultancy fees from Bayer/Janssen, Sanofi/Regeneron, and Verseon. Dr. Bhatt has served on the Advisory Boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; has served on the Boards of Directors of Boston Veterans Affairs Research Institute, Society of Cardiovascular Patient Care, TobeSoft; has served as the chair of American Heart Association Quality Oversight Committee; has served on Data Monitoring Committees of 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 Lifesciences), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), Population Health Research Institute; has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice chair, American College of Cardiology Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI Clinical Trial Steering Committee funded by Boehringer Ingelheim), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer AG), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees), Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and VA CART Research and Publications Committee (chair); has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; has served as a trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Cairns has participated in research that received grants from Abbott, AstraZeneca, Medtronic, and Boston Scientific; and has received personal fees from Abbott, Bayer AG, Bristol-Myers Squibb, and Pfizer. Drs. Tasto, Berkowitz, Cook Burns, and Muehlhofer are employees of Bayer AG. Dr. Diaz has received research grants from Sanofi, Amgen, Public Health Research Institute, and Duke Clinical Research Institute; and has received honoraria from Sanofi and Bayer AG. Dr. Maggioni has received honoraria for participation in study committees sponsored by Bayer AG, Novartis, and Fresenius. Dr. Yusuf has received grants and honoraria from Bayer AG, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Cadila Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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- Abbreviations and Acronyms
- coronary artery disease
- confidence interval
- hazard ratio
- International Society on Thrombosis and Hemostasis
- myocardial infarction
- peripheral artery disease
- Received April 2, 2019.
- Revision received July 2, 2019.
- Accepted July 7, 2019.
- 2019 The Authors
- Connolly S.J.,
- Eikelboom J.W.,
- Bosch J.,
- et al.,
- for the COMPASS Investigators
- Bosch J.,
- Eikelboom J.W.,
- Connolly S.J.,
- et al.
- Schulman S.,
- Angerås U.,
- Bergqvist D.,
- et al.,
- for the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
- Eerenberg E.S.,
- Kamphuisen P.W.,
- Sijpkens M.K.,
- Meijers J.C.,
- Buller H.R.,
- Levi M.
- Bhatt D.L.,
- Flather M.D.,
- Hacke W.,
- et al.,
- for the CHARISMA Investigators