Repositorio
Institucional

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

LANCET

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.

Antecedentes La enfermedad arterial coronaria es una causa importante de morbilidad y mortalidad en todo el mundo, y es una consecuencia de eventos trombóticos agudos que involucran la activación de plaquetas y proteínas de coagulación. Los inhibidores del factor Xa y la aspirina reducen los eventos trombóticos, pero aún no se han probado en combinación o entre sí en pacientes con enfermedad arterial coronaria estable. Métodos En este ensayo ambulatorio multicéntrico, doble ciego, aleatorizado y controlado con placebo, se reclutaron pacientes con enfermedad arterial coronaria estable o enfermedad arterial periférica en 602 hospitales, clínicas o centros comunitarios en 33 países. Este documento informa sobre pacientes con enfermedad arterial coronaria. Los pacientes elegibles con enfermedad arterial coronaria debían haber tenido un infarto de miocardio en los últimos 20 años, enfermedad arterial coronaria multivaso, antecedentes de angina estable o inestable, intervención coronaria percutánea multivaso previa o cirugía previa de injerto de derivación de arteria coronaria multivaso. Después de un período de ejecución de 30 días, los pacientes fueron asignados aleatoriamente (1: 1: 1) para recibir rivaroxabán (2,5 mg por vía oral dos veces al día) más aspirina (100 mg una vez al día), rivaroxabán solo (5 mg por vía oral dos veces al día) o aspirina sola (100 mg por vía oral una vez al día). La aleatorización fue generada por computadora. Cada grupo de tratamiento fue doble simulación, y los pacientes, investigadores y personal del estudio central fueron enmascarados a la asignación del tratamiento. El resultado primario del ensayo COMPASS fue la ocurrencia de infarto de miocardio, accidente cerebrovascular o muerte cardiovascular. Este ensayo está registrado en ClinicalTrials.gov, número NCT01776424, y está cerrado a nuevos participantes. Hallazgos Entre el 12 de marzo de 2013 y el 10 de mayo de 2016, 27 395 pacientes fueron inscritos en el ensayo COMPASS, de los cuales 24 824 pacientes tenían enfermedad arterial coronaria estable de 558 centros. La combinación de rivaroxabán más aspirina redujo el resultado primario más que la aspirina sola (347 [4%] de 8313 frente a 460 [6%] de 8261, cociente de riesgos instantáneos [HR]: 0,74

IC del 95%: 0,65-0,86

p < 0,0001). En comparación, el tratamiento con rivaroxabán solo no mejoró significativamente el resultado primario en comparación con el tratamiento con aspirina sola (411 [5%] de 8250 frente a 460 [6%] de 8261, HR: 0,89

IC del 95%: 0,78-1,02

p = 0,094). El tratamiento combinado de rivaroxabán más aspirina resultó en más hemorragias graves que el tratamiento con aspirina sola (263 [3%] de 8313 frente a 158 [2%] de 8261, HR 1,66, IC del 95% 1,37-2,03, p < 0,0001), y de forma similar, se observaron más hemorragias en el grupo de rivaroxabán solo que en el grupo de aspirina sola (236 [3%] de 8250 frente a 158 [2%] de 8261, HR 1,51, IC del 95% 1,23-1,84, p < 0,0001). El sitio más común de hemorragia grave fue gastrointestinal, ocurriendo en 130 [2%] pacientes que recibieron rivaroxabán combinado más aspirina, en 84 [1%] pacientes que recibieron rivaroxabán solo, y en 61 [1%] pacientes que recibieron aspirina sola. Rivaroxabán más aspirina redujo la mortalidad en comparación con aspirina sola (262 [3%] de 8313 frente a 339 [4%] de 8261, HR 0,77, IC del 95% 0,65-0,90, p = 0,0012). Interpretación En pacientes con enfermedad arterial coronaria estable, la adición de rivaroxabán a aspirina redujo los eventos vasculares mayores, pero aumentó el sangrado mayor. No hubo un aumento significativo en el sangrado intracraneal u otro sangrado de órganos críticos. También hubo un beneficio neto significativo a favor de rivaroxabán más aspirina y las muertes se redujeron en un 23%. Por lo tanto, la adición de rivaroxabán a aspirina tiene el potencial de reducir sustancialmente la morbilidad y la mortalidad por enfermedad arterial coronaria en todo el mundo.

Artículo original

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.

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.

10.1016/S0140-6736(17)32458-3

pdf

Medicine, General & Internal

Sistema Cardiovascular y Cardiaco

Farmacología y Farmacia

Medicina General e Interna

version publicada

hibrida

verde

metadata

metadata

WOS:000423867000023

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

Artículo original

ELSEVIER SCIENCE INC

LANCET

Medicina general e interna

0140-6736

en

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.

pdf

Bayer#Population Health Research Institute/Bayer#Population Health Research Institute#McMaster University#Hamilton Health Sciences, Hamilton#Bayer/Janssen

205

218