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Reducing recurrent ulcer bleedings in cardiology – the role of aspirin, clopidogrel, and proton-pump inhibitors

An article from the e-journal of the ESC Council for Cardiology Practice

Aspirin reduces the risk for vascular disease but increases the rate of ulcer bleeding. Clopidogrel is recommended in patients with aspirin intolerance. However, aspirin + esomeprazole may be superior when compared to clopidogrel in ulcer bleeding prevention.

Cardiovascular Pharmacotherapy

Cardiovascular disease is the leading cause of death in Western countries.
A Meta-analysis of five primary prevention trials showed that aspirin reduces the risk for coronary heart disease (CHD) by 28% (OR 0.72; 95% CI 0.60-0.87).
In patients with established CHD, aspirin significantly reduces the risk of subsequent vascular events.
Associated with the use of aspirin, though, is an increased rate of gastrointestinal bleeding 1. Estimated rates of major bleeding episodes go up to 4-12 per 1000 in elderly patients.
Long-term administration of clopidogrel, an inhibitor of the platelet adenosine diphosphate inhibitor has beneficial effects in patients with acute coronary syndromes and is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death (CAPRIE Study). Aspirin was associated with severe upper gastrointestinal discomfort (p=0.096), intracranial haemorrhage (p=0.23), and gastrointestinal haemorrhage (p=0.05) compared to clopidogrel in the CAPRIE study.
In a gastroscopic study conducted with 36 volunteers, short-term treatment with clopidogrel did not induce macroscopic changes in the gastrointestinal mucosa 2. Current guidelines of the AHA for patients with unstable angina and non-ST-segment elevation myocardial infarction therefore suggest the use of clopidogrel as an alternative therapy for patients who have a history of major gastrointestinal bleeding with aspirin therapy 3.

In a prospective, randomised, double-blind study, Chan et al. 4 compared the incidence of recurrent ulcer bleedings in 320 patients with a history of helicobacter pylori-negative ulcer bleeding receiving either aspirin (80mg daily, n=159) plus esomeprazole (2x20mg daily) or clopidogrel (75mg daily, n=161). The cumulative incidence of recurrent bleeding within 12 months was 8.6% (95% CI 4.1-13.1) among clopidogrel users compared to 0.7% (95% CI 0-2.0) in the aspirin plus esomeprazole group (p for difference 0.001). The authors conclude that in high-risk patients, aspirin plus esomeprazole is superior to clopidogrel for the prevention of recurrent bleeding. The study questions current guidelines which favour clopidogrel in patients with a history of ulcer bleeding and aspirin intolerance.

The results of the study contrast with current guidelines but are highly interesting for patients with a history of ulcer bleeding using aspirin in primary and secondary prevention. These patients may be kept on aspirin with the concomitant use of a proton-pump inhibitor. Furthermore, in view of an increasing and prolonged use of clopidogrel in combination with aspirin after percutanous coronary intervention using bare metal and drug-eluting stents, these results may have further implications.
Until today, the increased overall risk of bleeding in patients on clopidogrel plus aspirin has been mostly attributed to the dose-dependent ulcerogenic effect of aspirin 5. In the study by Chan et al., clopidogrel users had a significantly higher risk of recurrent bleeding which mostly occurred in the previously identified ulcer location (71.4%), indicating that clopidogrel may have detrimental effects in these high-risk patients 4. Unfortunately, the pathophysiological mechanism which may induce the recurrent bleeding in patients receiving clopidogrel remains unknown and was not addressed in the presented study. In addition, although not stated, most patients were of Asian origin and genetic differences may have contributed to the study results.


To conclude, patients with a history of ulcer bleedings should be carefully evaluated for the indication of an anti-platelet therapy. In eligible, high-risk patients, aspirin in combination with a proton-pump inhibitor may be associated with a reduced risk of ulcer bleedings compared to the treatment with clopidogrel alone. Future studies will have to confirm the results and will need to evaluate the underlying molecular mechanisms which may induce the recurrent bleeding in patients receiving clopidogrel.


1.  Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials. Br J Clin Pharmacol. 1993;35:219-226.

2.  Fork FT, Lafolie P, Toth E, Lindgarde F. Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers. A gastroscopic study. Scand J Gastroenterol. 2000;35:464-469.

3.  Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE, III, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC, Jr. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation. 2002;106:1893-1900.

4.  Chan FK, Ching JY, Hung LC, Wong VW, Leung VK, Kung NN, Hui AJ, Wu JC, Leung WK, Lee VW, Lee KK, Lee YT, Lau JY, To KF, Chan HL, Chung SC, Sung JJ. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238-244.

5.  Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, Diaz R, Commerford PJ, Valentin V, Yusuf S. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108:1682-1687.


Vol3 N°27

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.