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Connolly, Stuart J.

Eikelboom, John W.#Bosch, Jackie#Dagenais, Gilles#Dyal, Leanne#Lanas, Fernando#Metsarinne, Kaj#O'Donnell, Martin#Dans, Anthony L.#Ha, Jong-Won#Parkhomenko, Alexandr N.#Avezum, Alvaro A.#Lonn, Eva#Liu Lisheng#Torp-Pedersen, Christian#Widimsky, Petr#Maggioni, Aldo P.#Felix, Camilo#Keltai, Katalin#Hori, Masatsugu#Yusoff, Khalid#Guzik, Tomasz J.#Bhatt, Deepak L.#Branch, Kelley R. H.#Bruns, Nancy Cook#Berkowitz, Scott D.#Anand, Sonia S.#Varigos, John D.#Fox, Keith A. A.#Yusuf, Salim

Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial

ELSEVIER SCIENCE INC

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en

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.

Artículo original

SJC reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, during the conduct of the study, and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Portola, and Sanofi Aventis outside the submitted work. JWE reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo during the conduct of the study, and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi Aventis outside the submitted work. FL reports grants and personal fees from Bayer during the conduct of the study, personal fees from Pfizer, and grants and personal fees from Merck, Sharp & Dohme, Sanofi-Aventis, and Boehringer Ingelheim outside the submitted work. MO'D reports that his institution received grants from Population Health Research Institute/Bayer, during the conduct of the study. ALD reports grants, personal fees, and non-financial support from the Population Health Research Institute during the conduct of the study, and personal fees from Pfizer and Boehringer Ingelheim outside the submitted work. J-WH reports grants from the Population Health Research Institute during the conduct of the study. ANP reports grants and personal fees from Pfizer, Bayer, Janssen, AstraZeneca, Sanofi-Aventis, and Merck, Sharp & Dohme outside the submitted work. AAA reports consultancy fees from Boehringer Ingelheim outside the submitted work. EL reports personal fees from Bayer outside the submitted work. LL reports grants from the Population Health Research Institute during the conduct of the study. CT-P reports grants and personal fees from Bayer during the conduct of the study, and grants from Biotronic outside the submitted work. APM reports personal fees from Novartis, Bayer, Cardiorentis, and Fresenius outside the submitted work. CF reports personal fees from the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada during the conduct of the study. TJG reports personal fees from the Public Health Reasearch Institute during the conduct of the study, and personal fees from Sanofi Aventis outside the submitted work. DLB reports personal fees from the Population Health Research Institute during the conduct of the study, grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, Ironwood, and The Medicines Company, personal fees from the Mayo Clinic, the Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Communications, Harvard Clinical Research Institute, Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, Duke Clinical Research Institute, personal fees and non-financial support from the American College of Cardiology and the Society of Cardiovascular Patient Care, non-financial support from the American Heart Association, and non-financial relationships with Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Veterans Administration, Merck, Clinical Cardiology, St Jude Medical, Biotronik, Cardax, American College of Cardiology, Boston Scientific, FlowCo, PLx Pharma, and Takeda, outside the submitted work., KRHB reports grants from Bayer during the conduct of the study, and advisory board fees from Janssen outside the submitted work. NCB reports employment by Bayer during the conduct of the study. SDB reports employment by Bayer during the conduct of the study. SSA reports personal fees from Bayer and Novartis outside the submitted work. JDV reports personal fees from Novartis outside the submitted work. KAAF reports grants and personal fees from Bayer/Janssen during the conduct of the study, and grants and personal fees from AstraZeneca, personal fees from Sanofi/Regeneron and Eli Lilly outside the submitted work. SY reports grants and personal fees from Bayer during the conduct of the study. All other authors declare no competing interests.

SJC informa subvenciones y honorarios personales de Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer y Daiichi Sankyo durante la realización del estudio, y subvenciones y honorarios personales de Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Portola y Sanofi Aventis fuera del trabajo presentado. JWE informa subvenciones y honorarios personales de Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer y Daiichi Sankyo durante la realización del estudio, y subvenciones y honorarios personales de Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline y Sanofi Aventis fuera del trabajo presentado. FL informa subvenciones y honorarios personales de Bayer durante la realización del estudio, honorarios personales de Pfizer y subvenciones y honorarios personales de Merck, Sharp & Dohme, Sanofi-Aventis y Boehringer Ingelheim fuera del trabajo presentado. MO'D informa que su institución recibió subvenciones de Population Health Research Institute/Bayer durante la realización del estudio. ALD informa subvenciones, honorarios personales y apoyo no financiero de Population Health Research Institute durante la realización del estudio, y honorarios personales de Pfizer y Boehringer Ingelheim fuera del trabajo presentado. J-WH informa subvenciones de Population Health Research Institute durante la realización del estudio. ANP informa subvenciones y honorarios personales de Pfizer, Bayer, Janssen, AstraZeneca, Sanofi-Aventis y Merck, Sharp & Dohme fuera del trabajo presentado. AAA informa honorarios de consultoría de Boehringer Ingelheim fuera del trabajo presentado. EL informa honorarios personales de Bayer fuera del trabajo presentado. LL informa subvenciones de Population Health Research Institute durante la realización del estudio. CT-P declara haber recibido subvenciones y honorarios personales de Bayer durante la realización del estudio, así como subvenciones de Biotronic no relacionadas con el trabajo presentado. APM declara haber recibido honorarios personales de Novartis, Bayer, Cardiorentis y Fresenius no relacionados con el trabajo presentado. CF declara haber recibido honorarios personales del Instituto de Investigación en Salud Poblacional de la Universidad McMaster y de Hamilton Health Sciences, Hamilton, Ontario, Canadá, durante la realización del estudio. TJG declara haber recibido honorarios personales del Instituto de Investigación en Salud Pública durante la realización del estudio, así como honorarios personales de Sanofi Aventis no relacionados con el trabajo presentado. DLB informa honorarios personales del Population Health Research Institute durante la realización del estudio, subvenciones de Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, Ironwood y The Medicines Company, honorarios personales de Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Communications, Harvard Clinical Research Institute, Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, Duke Clinical Research Institute, honorarios personales y apoyo no financiero del American College of Cardiology y la Society of Cardiovascular Patient Care, apoyo no financiero de la American Heart Association y relaciones no financieras con Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Veterans Administration, Merck, Clinical Cardiology, St Jude Medical, Biotronik, Cardax, American College of Cardiología, Boston Scientific, FlowCo, PLx Pharma y Takeda, fuera del trabajo presentado., KRHB informa subvenciones de Bayer durante la realización del estudio y honorarios del consejo asesor de Janssen fuera del trabajo presentado. NCB informa empleo por Bayer durante la realización del estudio. SDB informa empleo por Bayer durante la realización del estudio. SSA informa honorarios personales de Bayer y Novartis fuera del trabajo presentado. JDV informa honorarios personales de Novartis fuera del trabajo presentado. KAAF informa subvenciones y honorarios personales de Bayer/Janssen durante la realización del estudio, y subvenciones y honorarios personales de AstraZeneca, honorarios personales de Sanofi/Regeneron y Eli Lilly fuera del trabajo presentado. SY informa subvenciones y honorarios personales de Bayer durante la realización del estudio. Todos los demás autores declaran no tener conflictos de intereses.

10.1016/S0140-6736(17)32458-3

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http://dx.doi.org/10.1016/S0140-6736(17)32458-3

Medicine, General & Internal

Sistema Cardiovascular y Cardiaco

Farmacología y Farmacia

Medicina General e Interna

WOS:000423867000023

Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial

Artículo original

version publicada

ELSEVIER SCIENCE INC

LANCET

Medicina general e interna

0140-6736

en

Bayer#Boehringer Ingelheim#Bristol-Myers Squibb/Pfizer#Daiichi Sankyo#Janssen#AstraZeneca#Portola#Sanofi Aventis##Eli Lilly#GlaxoSmithKline#Sanofi Aventis#Pfizer#Merck, Sharp & Dohme#Population Health Research Institute/Bayer#Population Health Research Institute#Biotronic#Cardiorentis#Fresenius#McMaster University and Hamilton Health Sciences#Hamilton, ONtario, Canada#Public Health Reasearch Institute#Amarin#Eisai#Ethicon#Medtronic#Roche#Forest Laboratories/AstraZeneca#Ischemix#Amgen#Chiesi#Ironwood#The Medicines Company#Mayo Clinic#Population Health Research Institute#Belvoir Publications#Slack Publications#WebMD#Elsevier# HMP Communications#Harvard Clinical Research Institute#Journal of the American College of Cardiology#Cleveland Clinic#Mount Sinai School of Medicine#Duke Clinical Research Institute#American College of Cardiology and the Society of Cardiovascular Patient Care#American Heart Association#Medscape Cardiology#Regado Biosciences#Boston VA Research Institute#Veterans Administration#Merck#Clinical Cardiology#St Jude Medical#Biotronik#Cardax#American College of Cardiology#Boston Scientific#FlowCo#PLx Pharma#Takeda

Bayer

Population Health Research Institute/Bayer

Population Health Research Institute

McMaster University

Hamilton Health Sciences, Hamilton

Bayer/Janssen

SJC reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, during the conduct of the study, and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Portola, and Sanofi Aventis outside the submitted work. JWE reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo during the conduct of the study, and grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi Aventis outside the submitted work. FL reports grants and personal fees from Bayer during the conduct of the study, personal fees from Pfizer, and grants and personal fees from Merck, Sharp & Dohme, Sanofi-Aventis, and Boehringer Ingelheim outside the submitted work. MO'D reports that his institution received grants from Population Health Research Institute/Bayer, during the conduct of the study. ALD reports grants, personal fees, and non-financial support from the Population Health Research Institute during the conduct of the study, and personal fees from Pfizer and Boehringer Ingelheim outside the submitted work. J-WH reports grants from the Population Health Research Institute during the conduct of the study. ANP reports grants and personal fees from Pfizer, Bayer, Janssen, AstraZeneca, Sanofi-Aventis, and Merck, Sharp & Dohme outside the submitted work. AAA reports consultancy fees from Boehringer Ingelheim outside the submitted work. EL reports personal fees from Bayer outside the submitted work. LL reports grants from the Population Health Research Institute during the conduct of the study. CT-P reports grants and personal fees from Bayer during the conduct of the study, and grants from Biotronic outside the submitted work. APM reports personal fees from Novartis, Bayer, Cardiorentis, and Fresenius outside the submitted work. CF reports personal fees from the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada during the conduct of the study. TJG reports personal fees from the Public Health Reasearch Institute during the conduct of the study, and personal fees from Sanofi Aventis outside the submitted work. DLB reports personal fees from the Population Health Research Institute during the conduct of the study, grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, Ironwood, and The Medicines Company, personal fees from the Mayo Clinic, the Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Communications, Harvard Clinical Research Institute, Journal of the American College of Cardiology, Cleveland Clinic, Mount Sinai School of Medicine, Duke Clinical Research Institute, personal fees and non-financial support from the American College of Cardiology and the Society of Cardiovascular Patient Care, non-financial support from the American Heart Association, and non-financial relationships with Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Veterans Administration, Merck, Clinical Cardiology, St Jude Medical, Biotronik, Cardax, American College of Cardiology, Boston Scientific, FlowCo, PLx Pharma, and Takeda, outside the submitted work., KRHB reports grants from Bayer during the conduct of the study, and advisory board fees from Janssen outside the submitted work. NCB reports employment by Bayer during the conduct of the study. SDB reports employment by Bayer during the conduct of the study. SSA reports personal fees from Bayer and Novartis outside the submitted work. JDV reports personal fees from Novartis outside the submitted work. KAAF reports grants and personal fees from Bayer/Janssen during the conduct of the study, and grants and personal fees from AstraZeneca, personal fees from Sanofi/Regeneron and Eli Lilly outside the submitted work. SY reports grants and personal fees from Bayer during the conduct of the study. All other authors declare no competing interests.

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