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Research:
Joseph A. Delaney, MSc, Lucie Opatrny, MD MSc, James M. Brophy, MD PhD, and Samy Suissa, PhD
Drug–drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding
CMAJ 2007; 177: 347-351 [Abstract] [Full text] [PDF]
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Electronic letters published:

[Read eLetter] Untitled
Patricia McGettigan   (4 October 2007)
[Read eLetter] Dual antiplatelet medications and gastrointestinal risk
Damir Fabijanic   (7 September 2007)
[Read eLetter] Combination Antithrombotic Therapy
David E. Good   (24 August 2007)

Untitled 4 October 2007
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Patricia McGettigan
Hull York Medical School

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Re: this article

patricia.mcgettigan{at}hyms.ac.uk Patricia McGettigan

Dear Doctor Suissa, Your study is of great clinical relevance given the frequency of use of certain combinations of antithrombotic drugs or combinations of antithrombotic drugs and anti-inflammatory agents.

Two combinations not reported upon, but often observed in practice, are also of relevance: ASA + NSAID and ASA + selective COX-2 inhibitor. Can you provide risk estimates on GI bleeding for these combinations?

The methods section does not indicate whether you considered the duration of combined co-prescription of the drug combinations or whether you evaluated any co-prescription, irrespective of duration of combined use, that occurred in the 90 days before the index date. This information, if available, is of interest, especially for the combinations involving NSAIDs or selective COX-2 inhibitors, where use, particularly of NSAIDs is often of short duration or intermittent as opposed to continuous.

Thanking You.

Yours Sincerely, Patricia McGettigan.

Conflict of Interest:

None declared
Dual antiplatelet medications and gastrointestinal risk 7 September 2007
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Damir Fabijanic
Split University Hospital, Split, Croatia

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Re: Dual antiplatelet medications and gastrointestinal risk

damir.fabijanic{at}st.t-com.hr Damir Fabijanic

We read with interest the article by Delaney AJ et al (1) and we would like to make some comments according to the increased gastrointestinal risk observed in patients taking antiplatelet medications. Although theirs results are concordant with some previous published data (2,3), it should be emphasized that in the case of dual antiplatelet therapy excess risk seems to be primary attributed to the dose-dependent ulcerogenic effect of acetylsalicylic acid (ASA). When ASA is used as monotherapy, dose reduction result in lower frequency of GD lesion (4). Surprisingly, in their analysis clopidogrel is more harmful for GD mucosa than ASA (1). In CURE study gastrointestinal bleeding increased significantly with increasing aspirin dose both in the placebo and the clopidogrel groups (5). Recently, in our observational study coronary patients treated with ASA ≤100 mg had GD lesions frequently than those treated with equal dose of ASA and 75 mg clopidogrel (6). This “paradox” suggest, that combination of less ulcerogenic dosage of ASA and clopidogrel might be “protective” for GD mucosa. It could be speculated that the less ulcerogenic dosage of ASA, and clopidogrel through increased production of prostaglandins enhance mucosal protective mechanisms. For these reasons, it is important to know which dosage of ASA, either in monotherapy and in combination with clopidogrel, provides maximal cardiovascular protection and minimal GD risk. References: 1. Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007;177:347-51. 2. 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 2006;333:726-30. 3. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery by-pass surgery. Crit Care Med 2001;29:2271-5. 4. Cryer B. Reducing the risk of gastrointestinal bleeding with antiplatelet therapies. N Engl J Med 2005;325:287-9. 5. Peters RJ, Mehta SR, Fox KA, et al. 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;108:1682-7. 6. Fabijanić D, Banić M, Kardum D, et al. Gastroduodenal lesions in coronary artery disease patients: Frequency, endoscopic characteristics and risk factors. Saudi Med J 2007;28:447-9.

Damir Fabijanić, MD, MSc. Vedran Carević, MD Department of Cardiology and Clinical Pharmacology Split University Hospital Spinčićeva 1, Split 21000 Croatia e-mail: damir.fabijanic@st.t-com.hr

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None declared
Combination Antithrombotic Therapy 24 August 2007
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David E. Good
Ochsner Clinic foundation

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Re: Combination Antithrombotic Therapy

Dgood{at}ochsner.org David E. Good

Your epidemiological study regarding the use of antithrombotic medications raises many important questions. In several randomized, controlled trials in patients with CAD, the addition of oral anticoagulation with an INR maintained between 2 and 3 did not significantly increase the risk of major bleeding(1). Oral anticoagulation when added to antiplatelet therapy leads to a marginal but statistically significant effect on reduction of cardiovascular risk. Also, in patients with atrial fibrillation or deep venous thrombosis/ pulmonary embolus as well as CAD, the addition of ASA to oral anticoagulation is important as antiplatelet therapy has very little, if any, effect on the recurrence of DVT/VTE or stroke prevention and warfarin has minimal effect on recurrent coronary events.

With regards to the combination of ASA and clopidogrel there are also data contradictory to your findings. The combination of these two drugs in the CURE trial(3) did not lead to excess major bleeding, although there was some minor confounding with the use of GP IIb/IIIa inhibitors. Supporting your findings, in the charisma trial(2) the long term addition of clopidogrel to ASA was not beneficial in the population as a whole, and did lead to some increase in bleeding. In ACS and post-stent patients, however, dual antiplatelet therapy is crucial and the length of therapy depends upon the clinical setting and stent type. The benefit of clopidogrel must be taken into account in the specific situation and its use limited to those patient groups that should derive benefit. It does not seem prudent to change practice based on these trials due to your findings.

On the other hand, your paper raises the very important question of the combined use of ASA with NSAIDs. There appear to very limited benefit to combining ASA and NSAIDs and this should probably be avoided.

The implication of your article is that warfarin, ASA and clopidogrel should not be used together due to risk of GI bleeding, but this may be a disservice. While your findings are certainly interesting, until further work elucidates the reasons for the excess bleeding risk in your study, these data should be interpreted with caution.

1)Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol. 2003 Feb 19;41(4 Suppl S):62S-69S.

2)Bhatt DL, Fox KAA, Hacke W, et al; for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354

3)CURE Study Investigators. 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.

Conflict of Interest:

None declared