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Aspirin and Gastrointestinal Bleeding
Abstract & commentary
By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman serves on the speakers bureau for Forest Laboratories.
Synopsis: The use of low-dose aspirin is associated with an almost two-fold increase in the risk of upper gastrointestinal bleeding compared with nonuse and this risk is further increased when low-dose aspirin is combined with clopidogrel, oral anticoagulants, nonsteroidal anti-inflammatory drugs, or high-dose oral corticosteroids.
Source: Garcia Rodriguez LA, et al. Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation 2011;123:1108-1115.
Antiplatelet therapy with low-dose (75 to 325 mg per day) acetylsalicylic acid (ASA) and/or clopidogrel is now standard recommended therapy for the secondary prevention of recurrent cardiovascular events,1 and it should be noted that these drugs have been demonstrated to reduce the risk of these cardiovascular events when used either as monotherapy2 or in combination.3 Current guidelines recommend use of antiplatelet therapy for at least 1 year after an acute myocardial infarction or an acute coronary syndrome episode if there are no contraindications to its usage. Unfortunately, multiple clinical trials have demonstrated that the use of both low-dose ASA and/or clopidogrel are not infrequently associated with an increased risk of upper gastrointestinal bleeding (UGIB) and there is even evidence to suggest that this risk is increased when both drugs are administered together.2,3
Garcia Rodriguez and colleagues carefully examined the risk of UGIB among users of low-dose ASA and/or clopidogrel by performing a nested case-control analysis using data extracted from The Health Improvement Network (THIN) UK primary care database, which consisted of data obtained from over 3 million patients aged 40-84 years who were receiving routine medical care by primary care practitioners between January 1, 2000, and December 31, 2007. The manual review of the computerized records determined that 2049 cases of UGIB occurred and these patients were then compared to a matched group of patients without a history of UGIB. Compared with low-dose ASA monotherapy, the risk of UGIB was significantly increased when low-dose ASA was administered with clopidogrel, oral anticoagulants, nonsteroidal anti-inflammatory drugs, or high-dose oral corticosteroids; this association was found not to be present if ASA was administered in combination with statin drugs or low-dose oral corticosteroids.
In this large-scale study of UK primary care patients, there seems to be little question that treatment with low-dose ASA and/or clopidogrel was associated with a small but statistically significant increased risk of UGIB. Since the risk of UGIB was similar with either therapeutic regimen, neither of these drugs appeared to be superior to the other in terms of their UGIB risk profile. The UGIB risk was independent of the duration of therapy, and combination therapy with low-dose ASA and clopidogrel was associated with a greater risk of UGIB than occurred with either monotherapy or nonuse (2.4 to 5.8 fold greater) of either drug. The final data from this extremely large study are similar to the results of several previous observational studies.5-8
The findings of the Garcia Rodriguez study are undoubtedly accurate. But, it should be noted that the multiple previous studies that have assessed the risks and benefits of ASA in various settings have concluded that the significant cardiovascular benefits of ASA which occur when the drug is used in secondary prevention definitely outweigh the relatively infrequent gastrointestinal risks9 of such therapy, but this conclusion may not be accurate when ASA is used for primary prevention, especially in patients who are already receiving statin drug therapy.9,10 For the time being, until the results of ongoing clinical trials become available, physicians should all try to follow the currently published guidelines which recommend low-dose ASA therapy for all men over the age of 55 for the primary prevention of cardiovascular problems and for women over the age of 65 for the primary prevention of strokes assuming that the patients receiving ASA therapy have not had a history of previous GI bleeding or intracranial hemorrhage.
1. Becker RC, et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:776S-814S.
2. Yusaf S, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST segment elevation. N Engl J Med 2001;345:494-502.
3. Diener HC, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischemic stroke or transient ischemic attack in high-risk patients (MATCH): A randomized, double-blind, placebo-controlled trial. Lancet 2004;364:331-337.
4. Anderson JL, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2007; 116:e148-e304 .
5. Gulmez SE, et al. Do statins protect against upper gastrointestinal bleeding? Br J Clin Pharmacol 2009; 67:460-465.
6. Smeeth L, et al. Effects of statins on a wide range of health outcomes: A cohort study validated by comparison with randomized trials. Br J Clin Pharmacol 2009;67:99-109.
7. Garcia Rodriguez LA. Risk of upper gastrointestinal complications among users of traditional NSAIDS and COXIBs in the general population. Gastroenterology 2007;132:498-506.
8. Margulis AV, et al. Positive predictive value of computerized medical records for uncomplicated and complicated upper gastrointestinal ulcers. Pharmacoepidemiol Drug Saf 2009;18:900-909.
9. Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participants data from randomized trials. Lancet 2009; 373:1849-1860.
10. Nelson MR, et al. Epidemiological modeling of routine use of low-dose aspirin for the primary prevention of coronary heart disease and stroke in those aged over 70 years. BMJ 2005;330:1306.