Dr Rikke Sørensen MD a , Morten L Hansen MD a, Steen Z Abildstrom MD b c, Anders Hvelplund MD c, Charlotte Andersson MB a, Casper Jørgensen MD a, Jan K Madsen MD a, Peter R Hansen MD a, Prof Lars Køber MD d, Prof Christian Torp-Pedersen MD a, Gunnar H Gislason MD a. The Lancet, Volume 374, Issue 9706, Pages 1967 - 1974, 12 December 2009

Background
Combinations of aspirin, clopidogrel, and vitamin K antagonists are widely used in patients after myocardial infarction. However, data for the safety of combinations are sparse. We examined the risk of hospital admission for bleeding associated with different antithrombotic regimens.

Methods
By use of nationwide registers from Denmark, we identified 40 812 patients aged 30 years or older who had been admitted to hospital with first-time myocardial infarction between 2000 and 2005. Claimed prescriptions starting at hospital discharge were used to determine the regimen prescribed according to the following groups: monotherapy with aspirin, clopidogrel, or vitamin K antagonist; dual therapy with aspirin plus clopidogrel, aspirin plus vitamin K antagonist, or clopidogrel plus vitamin K antagonist; or triple therapy including all three drugs. Risk of hospital admission for bleeding, recurrent myocardial infarction, and death were assessed by Cox proportional hazards models with the drug exposure groups as time-varying covariates.
Findings
During a mean follow-up of 476·5 days (SD 142·0), 1891 (4·6%) patients were admitted to hospital with bleeding. The yearly incidence of bleeding was 2·6% for the aspirin group, 4·6% for clopidogrel, 4·3% for vitamin K antagonist, 3·7% for aspirin plus clopidogrel, 5·1% for aspirin plus vitamin K antagonist, 12·3% for clopidogrel plus vitamin K antagonist, and 12·0% for triple therapy. With aspirin as reference, adjusted hazard ratios for bleeding were 1·33 (95% CI 1·11—1·59) for clopidogrel, 1·23 (0·94—1·61) for vitamin K antagonist, 1·47 (1·28—1·69) for aspirin plus clopidogrel, 1·84 (1·51—2·23) for aspirin plus vitamin K antagonist, 3·52 (2·42—5·11) for clopidogrel plus vitamin K antagonist, and 4·05 (3·08—5·33) for triple therapy. Numbers needed to harm were 81·2 for aspirin plus clopidogrel, 45·4 for aspirin plus vitamin K antagonist, 15·2 for clopidogrel plus vitamin K antagonist, and 12·5 for triple therapy. 702 (37·9%) of 1852 patients with non-fatal bleeding had recurrent myocardial infarction or died during the study period compared with 7178 (18·4%) of 38 960 patients without non-fatal bleeding (HR 3·00, 2·75—3·27, p<0·0001).
Interpretation
In patients with myocardial infarction, risk of hospital admission for bleeding increased with the number of antithrombotic drugs used. Treatment with triple therapy or dual therapy with clopidogrel plus vitamin K antagonist should be prescribed only after thorough individual risk assessment.
Funding
Danish Heart Foundation and the Danish Medical Research Council.

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