David A. Johnson, MD, FACG, FACP 

Medscape Gastroenterology.  2006;8(2) ?2006 Medscape

Cardioprotective Aspirin Users and Their Excess Risk of Upper Gastrointestinal Complications

Hernandez-Diaz S, Garcia Rodriguez LA

BMC Med. 2006;4:22

Summary

Cardiovascular disease is the leading cause of morbidity and mortality in Europe and North America The overall incidence of myocardial infarction is approximately 1 to 3 cases per 1000 person-years.^[1] Clearly, there are identifiable risk factors that put patients at increased likelihood for coronary artery disease and the attendant consequences. These risks include smoking, family history, diabetes, hypertension, and hyperlipidemia, among others. It appears that the long-term use of low-dose aspirin reduces the risk for myocardial infarction by about 25% to 30%, irrespective of the baseline risk. Accordingly, this relative change has a greater absolute impact on persons with an elevated underlying risk. It has been estimated that treating patients with a moderately high baseline risk with aspirin would prevent up to 4 myocardial infarctions per 1000 persons treated per year, while treating low-risk patients would prevent less than 1 event per 1000 persons treated per year.^[1]

Recognizably, aspirin is a nonsteroidal anti-inflammatory drug (NSAID), and thereby the cardiovascular benefits from low-dose aspirin have to be balanced against the potential gastrointestinal harm. Observational studies have estimated that the incidence of serious upper gastrointestinal tract complications (bleeding, perforation, obstruction) among NSAID users in the general population is on the order of 1 case per 1000 person-years, with a case fatality rate of approximately 5% to 10%.^[2] Aspirin use, even at low doses, has been associated with a significant risk for upper gastrointestinal bleeding. In a study from Europe, the odds ratios for patients who presented with acute upper gastrointestinal bleeding increased with from 2.3 (95% confidence interval [CI] = 1.2-4.4) for 75 mg/day to 3.9 (95% CI = 2.5-6.3) for 300 mg/day.^[3] Additionally, alterations in the dose formulations of aspirin (eg, buffered or enteric coated) do not lower the related gastric/duodenal ulcer bleeding risks.^[4]

On the basis of these data, the average incidence of upper gastrointestinal complications would be close to 2-3 cases per 1000 person-years for aspirin users. Clinical trials, typically conducted in low-risk subjects, have also estimated an overall excess of 1-2 cases of upper gastrointestinal complications per 1000 patients treated with aspirin per year.^[1]

Additionally, there are high-risk groups of patients more likely to suffer NSAID-related upper gastrointestinal complications. These risks include age older than 60 years, prior ulcer history, prior ulcer complications, concomitant steroid or anticoagulant use, and multiple- or high-dose NSAID use.^[5]

The purpose of this current study was to characterize the gastrointestinal risk profile of low-dose aspirin users in real clinical practice, and estimate the excess risk for upper gastrointestinal complications attributable to aspirin among patients with different gastrointestinal risk profiles.

This study used 2 large databases for their analysis: the General Practice Research Database in the United Kingdom and the Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria in Spain. Baseline risk of upper gastrointestinal complications according to major gastrointestinal risk factors and the excess risk attributable to aspirin within levels of these factors was established from the literature using published meta-analyses that identified both absolute and relative risks of upper gastrointestinal complications.

In both of these databases, many of the patients on low-dose aspirin also had risk factors that identified them as at higher risk for NSAID-related complications: namely, 60% were older than 60 years of age, 4% to 6% had a recent history of peptic ulcers, and more than 13% used other NSAIDs. The estimated average excess risk for upper gastrointestinal complications attributable to aspirin was approximately 5 extra cases per 1000 aspirin users per year. However, the excess risk varied in parallel to the underlying gastrointestinal risk and may exceed 10 extra cases per 1000 person-years in over 10% of aspirin users.

Viewpoint

To balance the cardiovascular benefits from low-dose aspirin against the potential gastrointestinal harm, studies must consider the coronary heart disease risk for each individual balanced against his/her gastrointestinal risk profile. In addition to the cardiovascular risk, the underlying gastrointestinal risk factors have to be considered when balancing harms and benefits of aspirin use for an individual patient. The gastrointestinal harms may offset the cardiovascular benefits in certain groups of patients in whom the gastrointestinal risk is high and the cardiovascular risk is low.

The gastrointestinal risk profiles should be even more so considered when the combination of antiplatelet/antithrombotic therapies is used. Recognizably, there are increasing data showing that as antithrombotic therapies become more aggressive, these therapies confer particular increased risk for gastrointestinal bleeding complications. A recent study from Denmark^[6] demonstrated that the odds ratio for upper gastrointestinal bleeding associated with these types of therapies were: low-dose aspirin (1.8; 95% CI = 1.5-2.1), clopidogrel (1.1; 95% CI = 0.6-2.1), dipyridamole (1.9;95% CI = 1.3-2.8), and vitamin K antagonists (1.8; 95% CI = 1.3-2.4). More alarmingly, however, was the risk for combined therapies: low-dose aspirin and clopidogrel (7.4;95% CI = 3.5-15), low-dose aspirin and vitamin K antagonists (5.3; 95% CI = 2.9-9.5), and low-dose aspirin and dipyridamole (2.3; 95% CI = 1.7-3.3). These numbers, put in perspective, would suggest that the number of patient treatment years for harm would be 124 for aspirin and clopidogrel, 184 for aspirin and vitamin K antagonists, and 595 for aspirin and dipyridamole.

Clearly, as healthcare providers aim to do good for the patient, we must be cognizant of the first principal of medicine: Do no harm. The emerging data on low-dose aspirin use, either alone or in combination, emphasize the need for balancing the overall risks -- with specific recognition of the upper gastrointestinal risks -- even for "just a little bit of aspirin."

 

Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:161-172.  Hernandez-Diaz S, Rodriguez LA. Incidence of serious upper gastrointestinal bleeding/perforation in the general population: Review of epidemiologic studies. J Clin Epidemiol. 2002;55:157-163.  Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ. 1995;310:827-830.  Kelly JP, Kaufman DW, Jurgelon JM, et al. Risk of aspirin-associated major upper gastrointestinal bleeding with enteric-coated or buffered product. Lancet. 1996;348:1413-1416.  Silversetin FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:241-249.  Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 333:726-729.