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Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study

BMJ 2006; 333 doi: (Published 05 October 2006) Cite this as: BMJ 2006;333:726
  1. Jesper Hallas, professor (jhallas{at},
  2. Michael Dall, registrar3,
  3. Alin Andries, registrar4,
  4. Birthe Søgaard Andersen, senior registrar4,
  5. Claus Aalykke, senior registrar3,
  6. Jane Møller Hansen, senior physician3,
  7. Morten Andersen, senior researcher2,
  8. Annmarie Touborg Lassen, senior registrar5
  1. 1 Department of Clinical Pharmacology, IST, Syddansk Universitet, 5000 Odense, Denmark
  2. 2 Research Unit of General Practice, Syddansk Universitet
  3. 3 Department of Medical Gastroenterology, Odense University Hospital, Odense
  4. 4 Department of Cardiology, Odense University Hospital
  5. 5 Department of Infectious Medicine, Odense University Hospital
  1. Correspondence to: J Hallas
  • Accepted 14 August 2006


Objectives To assess the risk of serious upper gastrointestinal bleeding associated with the newer antithrombotic agents used alone or in combination with other antithrombotic drugs; to describe the trends in use of antithrombotic drugs in the background population.

Design Population based case-control study.

Setting Funen County, Denmark (population 470 000).

Subjects 1443 cases of serious upper gastrointestinal bleeding identified during 2000-4; 57 720 age and sex matched controls.

Main outcome measure Exposure to low dose aspirin, clopidogrel, dipyridamole, vitamin K antagonists, and combined antithrombotic treatment.

Results Adjusted odds ratios associating drug use with upper gastrointestinal bleeding were 1.8 (95% confidence interval 1.5 to 2.1) for low dose aspirin, 1.1 (0.6 to 2.1) for clopidogrel, 1.9 (1.3 to 2.8) for dipyridamole, and 1.8 (1.3 to 2.4) for vitamin K antagonists. Corresponding figures for combined use were 7.4 (3.5 to 15) for clopidogrel and aspirin, 5.3 (2.9 to 9.5) for vitamin K antagonists and aspirin, and 2.3 (1.7 to 3.3) for dipyridamole and aspirin. Other combinations were used too infrequently to allow estimation. The number of treatment years needed to produce one excess case varied from 124 for the clopidogrel-aspirin combination to 8800 for clopidogrel alone. During the study period, exposure to combined antithrombotic regimens increased by 425% in the background population.

Conclusion Antithrombotic treatment is becoming increasingly aggressive. Combined antithrombotic treatment confers particular risk and is associated with high incidence of gastrointestinal bleeding.


  • Contributors JH wrote the first protocol draft, validated some cases, did the analyses, and wrote the first article draft. BSA, JMH, ATL, MD, CA, and AA provided input to the protocol and article and validated some cases. MA provided input to the article draft and analyses. All authors have approved the current version. JH is the guarantor.

  • Funding The University of Southern Denmark and Funen County provided data free of charge.

  • Competing interests JH has received fees for teaching from AstraZeneca and the Danish Association of the Pharmaceutical Industry and research grants from Novartis and Nycomed. JMH has received fees for teaching from AstraZeneca. All other authors: none declared.

  • Ethical approval The Danish Data Protection Agency approved the study. Approval from an ethics committee was not needed.

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