Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study

Hallas et al. deserve praise for highlighting the importance of
gastrointestinal risks with antithrombotic therapy in their population-
based study [1]. Of particular relevance to us was the significantly
increased relative risk of combined aspirin and clopidogrel therapy
(relative risk 7.4, 95% confidence interval 3.5 to 15). However, we feel
this needs to be interpreted cautiously given that only thirteen cases of
1443 (0.009%) were exposed to dual antiplatelet therapy.

There is a paucity of evidence regarding the gastrointestinal
complications associated with dual therapy and we wholeheartedly agree
further studies are required. Nevertheless, randomised trials have
demonstrated an increased risk of bleeding in comparison with aspirin
monotherapy [2,3]. This risk obviously needs to be counterbalanced with
the benefits in both percutaneous coronary intervention and secondary
prevention of cardiovascular disease (20% relative risk reduction in the
CURE study).

The co-prescription of proton pump inhibitors with aspirin has been
shown to reduce gastrointestinal ulcers [4]. In contrast, there is a
shortfall of evidence for the prevention and treatment of ulcers in the
dual antiplatelet setting. Both clopidogrel and aspirin have a
synergistic effect on platelet aggregation and thromboxane A2 production
[5]. This appears to apply equally to gastrointestinal bleeding risk.
Unfortunately, there are presently no plausible underlying mechanisms for
this. As well as further clinical studies in this field, basic
pathophysiological research is needed.

Guidelines for the use of dual antiplatelet therapy in cardiovascular
medicine are now well established. However, the apparent increased risks
of gastrointestinal bleeding should not be ignored. The National Institute
for Clinical Excellence recommends the use of gastroprotective proton pump
inhibitors in combination with long term aspirin monotherapy. We
acknowledge the lack of evidence for their use in dual antiplatelet
therapy, but suggest that the addition of a proton pump inhibitor would
reduce the bleeding risks. We strongly advocate that our cardiology
colleagues consider such a triple therapy approach in high risk patients
when instigating antiplatelet treatment.

1. Jesper Hallas, Michael Dall, Alin Andries, Birthe Søgaard
Andersen, Claus Aalykke, Jane Møller Hansen, Morten Andersen and Annmarie
Touborg Lassen.
Use of single and combined antithrombotic therapy and risk of serious
upper gastrointestinal bleeding: population based case-control study. BMJ

2. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial)
Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients
with acute myocardial infarction: randomised placebo-controlled trial.
Lancet 2005; 366: 1607–21.

3. The CURE investigators. Effect of clopidogrel in addition to
aspirin in patients with acute coronary syndromes without ST segment
elevation. N Engl J Med 2001;345:494-502.

4. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and
esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005;352:
238–44.

5. Mehta SR, Yusuf S. Short- and long-term oral antiplatelet therapy
in acute coronary syndromes and percutaneous coronary intervention. J Am
Coll Cardiol. 2003 Feb 19;41(4 Suppl S):79S-88S.

Competing interests:
None declared