BMJ  2006;333:712-713 (7 October), doi:10.1136/bmj.38992.480544.80

Editorial

Combining aspirin with antithrombotic agents

Risk of bleeding is increased but can be minimised

The use of aspirin and other antiplatelet agents has sky rocketed in the past decade as the indications have widened to include primary and secondary prevention of myocardial and cerebrovascular ischaemia. In the United States, an estimated 34.8% of men and 26.2% of women over 40 years use aspirin every day or on alternate days.¹ Half of these patients are classified as at high risk of cardiovascular disease. With the development of safer antiplatelet agents such as thienopyridines and the publication of major randomised studies, the combination of aspirin and clopidogrel has become a class I recommendation (that is, it is considered to be beneficial, useful, and effective) after percutaneous coronary interventions with stenting in the US and in Europe.^{2 3} Combined antithrombotic therapy is recommended for up to 12 months "in patients who are not at high risk of bleeding."² The problem for clinicians is to balance the benefits of combined antiplatelet therapy with the potentially increased risk of gastrointestinal bleeding. In this week's BMJ a case control study by Hallas and colleagues goes some way to measuring this risk.⁴

Aspirin is widely known to cause mucosal ulceration that can lead to upper gastrointestinal bleeding. Lower doses and slow release formulations of aspirin have been used in the hope that they carry a reduced risk of bleeding. In a meta-analysis of almost 66 000 people, Derry and colleagues found no relation between gastrointestinal bleeding and aspirin dose or formulation.⁵ They also showed that risk of bleeding was not lower with prolonged use of aspirin, so the notion of mucosal tolerance to aspirin remains a myth. These findings were confirmed in a later study from Spain, which focused on patients taking low dose aspirin to prevent cardiovascular diseases.⁶

Clopidogrel has been recommended as the treatment of choice for patients with coronary heart disease who cannot tolerate aspirin.⁷ This is based primarily on the CAPRIE study, which compared the efficacy of clopidogrel with aspirin in preventing myocardial ischaemia.⁸ Gastrointestinal bleeding was reported in 1.99% of patients taking clopidogrel and 2.66% of those taking aspirin (p = 0.05). It has been shown repeatedly that combining aspirin with clopidogrel increases the risk of gastrointestinal bleeding compared with using aspirin⁹ or clopidogrel alone.¹⁰

Hallas and colleagues found that upper gastrointestinal bleeding was associated with the use of low dose aspirin, dipyridamole, and vitamin K antagonists but not with clopidogrel.⁴ The finding that clopidogrel did not increase bleeding risk contradicts other reports.¹¹ This discrepancy could be related to the relatively small sample size of the current study (only 1443 participants, with 30 cases of bleeding). Importantly, the authors found that combining aspirin with any of the antithrombotic agents (clopidogrel, dipyridamole, or vitamin K antagonist) greatly increased the risk of bleeding. The highest risk of bleeding came from combining aspirin with clopidogrel (odds ratio 7.4, 95% confidence interval 3.5 to 15). Thus, should we or should we not use combined antiplatelet agents in patients with high risk of cardiovascular or cerebrovascular disease?

The risk of gastrointestinal bleeding varies among users of antiplatelet agents. Older people, those with a history of gastrointestinal bleeding or peptic ulcer, and those who use non-steroidal anti-inflammatory drugs or cyclo-oxygenase-2 inhibitors are more likely to develop aspirin induced bleeding.¹² Aspirin users who are infected by Helicobacter pylori are also more prone to bleeding, but the risk is greatly reduced when the infection is cleared.¹³ These variations provide some guidance for assessing and balancing the risk of cardiovascular or cerebrovascular events against the risk of gastrointestinal bleeding.

The table shows the recommended strategy to prevent upper gastrointestinal bleeding in patients who need aspirin alone or aspirin combined with another antiplatelet agent. No randomised trials or observational studies are available to inform recommendations for patients who need combined antithrombotic therapy (such as aspirin and clopidogrel). The recommendations are therefore based on logical deductions and are open for debate.

View this table: [in this window] [in a new window]   Recommended strategy to prevent upper gastrointestinal bleeding in patients who need aspirin alone or aspirin combined with another antiplatelet agent

 

In addition to these strategies, combined antithrombotic therapy should be given for the shortest duration possible to minimise the risk of bleeding. As the number of people needing combined antithrombotic therapy is increasing every day, carefully designed clinical trials are needed to devise the best ways to protect patients at high risk of cardiovascular and gastrointestinal events.

Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, PR China
(joesung{at}cuhk.edu.hk)

---

Competing interests: None declared.

Research p 726

References

1. Kim C, Beckles GL. Cardiovascular disease risk reduction in the behavioral risk factor surveillance system. Am J Prev Med 2004;27: 1-7.[Medline]
2. Smith SC, Feldman TE, Hirshfeld JW, Jacobs AK, Kern MJ, King SB III, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guideline. Circulation 2006;113: 156-75.[Free Full Text]
3. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, et al. ESC guidelines for percutaneous coronary interventions. Eur Heart J 2005;26: 804-47.[Free Full Text]
4. Hallas J, Dall M, Andries A, Søgaard Andersen B, Aalykke C, Møller Hansen J, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006;333: 726-8.[Abstract/Free Full Text]
5. Derry S, Lok YK. Risk of gastrointestinal hemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321: 1183-7.[Abstract/Free Full Text]
6. Serrano P, Lanas A, Arroyo MT, Ferreira. Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases. Aliment Pharmacol Ther 2002;16: 1945-53.[CrossRef][ISI][Medline]
7. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2002;40: 1366-74.[Free Full Text]
8. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996;348: 1329-39.[CrossRef][ISI][Medline]
9. Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST elevation acute coronary syndrome. Circulation 2004;110: 1202-8.[Abstract/Free Full Text]
10. Diener HC, Bogousslovsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischemic stroke or transient ischemic attack in high risk patients (MATCH): randomized, double-blind placebo-controlled trial. Lancet 2004;364: 331-7.[CrossRef][ISI][Medline]
11. Lanas A, Garcia-Rodriguez LA, Arroyo MT, Gomollon F, Feu F, Gonzalez Perez A, et al. Risk of upper gastrointestinal bleeding associated with selective COX-2 inhibitors, traditional non-aspirin NSAIDs, aspirin and combinations. Gut 2006, May 10 [Epub ahead of print].
12. Lanas A, Bajador E, Serrano P, Fuentes J, Carreno S, Guardia J, et al. Nitrovasodilators, low-dose aspirin, other non-steroidal antiinflammatory drugs and the risk of upper gastrointestinal bleeding. N Engl J Med 2000;343: 834.[Abstract/Free Full Text]
13. Chan FKL, Chung SCS, Suen BY, Lee YT, Leung WK, Leung VK, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001;344: 967-73.[Abstract/Free Full Text]

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