In heart attack patients, risk of hospital admission for bleeding increases with the number of antithrombotic (clot-busting) drugs used. Patients with non-fatal bleeding are also much more likely to suffer repeat heart attack or die than those without this non-fatal bleeding. This analysis of more than 40,000 Danish patients is reported in an Article in this week's edition of The Lancet, written by Dr Rikke Sørensen, Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark, and colleagues.
Combinations of aspirin, clopidogrel, and vitamin K antagonists (such as warfarin) are widely used in patients after a heart attack. However, data on the safety of combinations are sparse. In this study, the authors examined the risk of hospital admission for bleeding associated with different antithrombotic regimens.
By use of nationwide registers from Denmark, the authors identified 40 812 patients aged 30 years or older who had been admitted to hospital with first-time heart attack 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 heart attack, and death were then assessed for each group.
During a mean follow-up of around 16 months, 1891 (4•6%) patients were admitted to hospital with bleeding or were diagnosed with a bleeding as the cause of death. 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 (1.0), increased risk of bleeding was 1•3 for clopidogrel, 1•2 for vitamin K antagonist*, 1•5 for aspirin plus clopidogrel, 1•8 for aspirin plus vitamin K antagonist, 3•5 for clopidogrel plus vitamin K antagonist, and 4•1 for triple therapy.
The number of patients that needed to be treated in one year in order for one to be harmed, (the number needed to harm) was 81 for aspirin plus clopidogrel, 45 for aspirin plus vitamin K antagonist, 15 for clopidogrel plus vitamin K antagonist, and 13 for triple therapy. 702 (38%) of 1852 patients with non-fatal bleeding had recurrent heart attack or died during the study period compared with 7178 (18%) of 38 960 patients without non-fatal bleeding.
The authors conclude: "In patients with first-time heart attack, all combinations of aspirin, clopidogrel, and vitamin K antagonists are associated with increased risk of nonfatal and fatal bleeding, apart from monotherapy with a vitamin K antagonist, compared with aspirin alone. Increased risk of bleeding was proportional to the number of drugs used. Non-fatal bleeding is an independent predictor associated with increased risk of recurrent heart attack or death. We propose that treatment with triple therapy or dual therapy with clopidogrel plus vitamin K antagonist should be prescribed only after thorough individual risk assessment and careful consideration of the risk–benefit ratio."
In an accompanying Comment, Dr Erik L Grove, Department of Cardiology, Aarhus University Hospital, Skejby, Denmark, and Dr Robert F Storey, Department of Cardiovascular Science, University of Sheffield, UK, say: "The findings by Sørensen and colleagues suggest that a greater awareness of the prognostic importance of bleeding is warranted; they also underline the need for careful selection of antithrombotic drug combinations according to individual patient's characteristics."
Dr Rikke Sørensen, Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.T) +45 23962884 E) rs@heart.dk
Dr Erik L Grove, Department of Cardiology, Aarhus University Hospital, Skejby, Denmark. T) +45 6178 9091 E) erikgrove@dadlnet.dk
For full Article and Comment, see: http://press.thelancet.com/riskbleeding.pdf
Note to editors: *This particular finding (for vitamin K antagonists) was not statistically significant.
Journal
The Lancet