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Gastroenterology. 2019 Sep;157(3):682-691.e2. doi: 10.1053/j.gastro.2019.05.056. Epub 2019 May 29.

Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin.

Author information

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

Abstract

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.

KEYWORDS:

Bacteria; CVD; Reflux; Thrombosis

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