Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial

doi:10.1053/j.gastro.2019.04.041

Randomized Controlled Trial

. 2019 Aug;157(2):403-412.e5.

doi: 10.1053/j.gastro.2019.04.041. Epub 2019 May 2.

Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial

Paul Moayyedi¹, John W Eikelboom², Jackie Bosch², Stuart J Connolly², Leanne Dyal³, Olga Shestakovska², Darryl Leong², Sonia S Anand², Stefan Störk⁴, Kelly R H Branch⁵, Deepak L Bhatt⁶, Peter B Verhamme⁷, Martin O'Donnell⁸, Aldo P Maggioni⁹, Eva M Lonn¹⁰, Leopoldo S Piegas¹¹, Georg Ertl⁴, Matyas Keltai¹², Nancy Cook Bruns¹³, Eva Muehlhofer¹³, Gilles R Dagenais¹⁴, Jae-Hyung Kim¹⁵, Masatsugu Hori¹⁶, P Gabriel Steg¹⁷, Robert G Hart², Rafael Diaz¹⁸, Marco Alings¹⁹, Petr Widimsky²⁰, Alvaro Avezum²¹, Jeffrey Probstfield²², Jun Zhu²³, Yan Liang²³, Patricio Lopez-Jaramillo²⁴, Ajay Kakkar²⁵, Alexander N Parkhomenko²⁶, Lars Ryden²⁷, Nana Pogosova²⁸, Antonio Dans²⁹, Fernando Lanas³⁰, Patrick J Commerford³¹, Christian Torp-Pedersen³², Tomek Guzik³³, Dragos Vinereanu³⁴, Andrew M Tonkin³⁵, Basil S Lewis³⁶, Camilo Felix³⁷, Khalid Yusoff³⁸, Kaj Metsarinne³⁹, Keith A A Fox⁴⁰, Salim Yusuf²; COMPASS Investigators

Affiliations

¹ The Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. Electronic address: moayyep@mcmaster.ca.
² The Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.
³ University of Philippines, Manila, Philippines.
⁴ University of Würzburg and University Hospital, Würzburg, Germany.
⁵ University of Washington Medical Center, Seattle, Washington.
⁶ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts.
⁷ University of Leuven, Leuven, Belgium.
⁸ National University of Ireland, Galway, Ireland.
⁹ National Association of Hospital Cardiologists Research Center (ANMCO), Florence, Italy.
¹⁰ The Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada; Bayer, Leverkusen, Germany.
¹¹ Hospital do Coracao, Sao Paulo, Brazil.
¹² Semmelweis University, Budapest, Hungary.
¹³ Bayer, Leverkusen, Germany.
¹⁴ Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, Canada.
¹⁵ Catholic University of Korea, Seoul, South Korea.
¹⁶ Osaka International Cancer Institute, Osaka, Japan.
¹⁷ Hopitaux de Paris, Paris, France.
¹⁸ Estudios Clinicos Latino America and Instituto Cardiovascular de Rosario, Rosario, Argentina.
¹⁹ Amphia Ziekenhuis and Werkgroep Cardiologische Centra Nederland (WCN), Utrecht, the Netherlands.
²⁰ Cardiocenter, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.
²¹ Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil.
²² University of Washington, Seattle, Washington.
²³ FuWai Hospital, Beijing, China.
²⁴ Research Institute, Fundaciun Oftalmoligica de Santander (FOSCAL)-Bucaramanga, Bucaramanga, Colombia.
²⁵ Thrombosis Research Institute and University College London, London, UK.
²⁶ Institute of Cardiology, Kiev, Ukraine.
²⁷ Karolinska Institutet, Stockholm, Sweden.
²⁸ National Research Center for Preventative Medicine, Moscow, Russia.
²⁹ College of Medicine, University of the Philippines-Manila, Ermita, Manila, Philippines.
³⁰ Universidad de La Frontera, Temuco, Chile.
³¹ University of Cape Town, Cape Town, South Africa.
³² University of Aalborg, Copenhagen, Denmark.
³³ University of Glasgow, Glasgow, UK; Collegium Medicum Jagiellonian University, Krakow, Poland.
³⁴ University of Medicine and Pharmacology, Carol Davila University and Emergency Hospital, Bucharest, Romania.
³⁵ Monash University, Melbourne, Victoria, Australia.
³⁶ Lady Davis Carmel Medical Center, Haifa, Israel.
³⁷ Facultad de Ciencias de la Salud Eugenio Espejo-Universidad Tecnoligica Equinoccial, Quito, Ecuador.
³⁸ Universiti Teknologi Mara, Selangor, Malaysia.
³⁹ Universit Paris Diderot, Hopital Bichat, Assistance Publique, Paris, France; Turku University Central Hospital and Turku University, Turku, Finland.
⁴⁰ Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

PMID: 31054846
DOI: 10.1053/j.gastro.2019.04.041

Randomized Controlled Trial

Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial

Paul Moayyedi et al. Gastroenterology. 2019 Aug.

. 2019 Aug;157(2):403-412.e5.

doi: 10.1053/j.gastro.2019.04.041. Epub 2019 May 2.

Authors

Affiliations

¹ The Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. Electronic address: moayyep@mcmaster.ca.
² The Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.
³ University of Philippines, Manila, Philippines.
⁴ University of Würzburg and University Hospital, Würzburg, Germany.
⁵ University of Washington Medical Center, Seattle, Washington.
⁶ Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts.
⁷ University of Leuven, Leuven, Belgium.
⁸ National University of Ireland, Galway, Ireland.
⁹ National Association of Hospital Cardiologists Research Center (ANMCO), Florence, Italy.
¹⁰ The Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada; Bayer, Leverkusen, Germany.
¹¹ Hospital do Coracao, Sao Paulo, Brazil.
¹² Semmelweis University, Budapest, Hungary.
¹³ Bayer, Leverkusen, Germany.
¹⁴ Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec, Canada.
¹⁵ Catholic University of Korea, Seoul, South Korea.
¹⁶ Osaka International Cancer Institute, Osaka, Japan.
¹⁷ Hopitaux de Paris, Paris, France.
¹⁸ Estudios Clinicos Latino America and Instituto Cardiovascular de Rosario, Rosario, Argentina.
¹⁹ Amphia Ziekenhuis and Werkgroep Cardiologische Centra Nederland (WCN), Utrecht, the Netherlands.
²⁰ Cardiocenter, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.
²¹ Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil.
²² University of Washington, Seattle, Washington.
²³ FuWai Hospital, Beijing, China.
²⁴ Research Institute, Fundaciun Oftalmoligica de Santander (FOSCAL)-Bucaramanga, Bucaramanga, Colombia.
²⁵ Thrombosis Research Institute and University College London, London, UK.
²⁶ Institute of Cardiology, Kiev, Ukraine.
²⁷ Karolinska Institutet, Stockholm, Sweden.
²⁸ National Research Center for Preventative Medicine, Moscow, Russia.
²⁹ College of Medicine, University of the Philippines-Manila, Ermita, Manila, Philippines.
³⁰ Universidad de La Frontera, Temuco, Chile.
³¹ University of Cape Town, Cape Town, South Africa.
³² University of Aalborg, Copenhagen, Denmark.
³³ University of Glasgow, Glasgow, UK; Collegium Medicum Jagiellonian University, Krakow, Poland.
³⁴ University of Medicine and Pharmacology, Carol Davila University and Emergency Hospital, Bucharest, Romania.
³⁵ Monash University, Melbourne, Victoria, Australia.
³⁶ Lady Davis Carmel Medical Center, Haifa, Israel.
³⁷ Facultad de Ciencias de la Salud Eugenio Espejo-Universidad Tecnoligica Equinoccial, Quito, Ecuador.
³⁸ Universiti Teknologi Mara, Selangor, Malaysia.
³⁹ Universit Paris Diderot, Hopital Bichat, Assistance Publique, Paris, France; Turku University Central Hospital and Turku University, Turku, Finland.
⁴⁰ Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

PMID: 31054846
DOI: 10.1053/j.gastro.2019.04.041

Abstract

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.

Keywords: Drug; Heart Disease Prevention; Stomach; Thrombosis.

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Comment in

Pantoprazole did not reduce risk for a composite of upper gastrointestinal events in stable arterial disease.
Dayanand P, Borzak S. Dayanand P, et al. Ann Intern Med. 2019 Oct 15;171(8):JC45. doi: 10.7326/ACPJ201910150-045. Ann Intern Med. 2019. PMID: 31610558 No abstract available.
Reply.
Moayyedi P, Eikelboom JW, Yusuf S. Moayyedi P, et al. Gastroenterology. 2020 Jan;158(1):285-286. doi: 10.1053/j.gastro.2019.10.032. Epub 2019 Nov 5. Gastroenterology. 2020. PMID: 31704300 No abstract available.
Pantoprazole in Prevention of Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin-A Short Word of Caution.
Bronswijk M. Bronswijk M. Gastroenterology. 2020 Jan;158(1):283-284. doi: 10.1053/j.gastro.2019.08.063. Epub 2019 Nov 5. Gastroenterology. 2020. PMID: 31704304 No abstract available.
Pantoprazole in COMPASS- No Prevention of Gastroduodenal Events or Other Useful Net Results.
Donzelli A, Giudicatti G. Donzelli A, et al. Gastroenterology. 2020 Jan;158(1):284-285. doi: 10.1053/j.gastro.2019.09.050. Epub 2019 Nov 5. Gastroenterology. 2020. PMID: 31704305 No abstract available.

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Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial

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Pantoprazole to Prevent Gastroduodenal Events in Patients Receiving Rivaroxaban and/or Aspirin in a Randomized, Double-Blind, Placebo-Controlled Trial

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