In heart attack patients, risk of hospital admission for bleeding increases with the number of antithrombotic drugs used. Patients with non-fatal bleeding are also much more likely to suffer repeat heart attacks or die than those without non-fatal bleeding, based on an analysis of more than 40,000 Danish patients published Dec. 10 in the Lancet
Combinations of aspirin, clopidogrel (Plavix; Bristol-Myers Squibb) 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, according to Rikke Sørensen, MD, from the department of cardiology at Copenhagen University Hospital Gentofte in Hellerup, Denmark, and colleagues. In their study, the authors examined the risk of hospital admission for bleeding associated with different antithrombotic regimens.
Using nationwide registries from Denmark, the authors identified 40,812 patients, aged 30 years or older, who had been admitted to hospital with a 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. The researchers then assessed the risk of hospital admission for bleeding, recurrent heart attack and death for each group.
During a mean follow-up of around 16 months, 1,891 patients were admitted to hospital with bleeding or were diagnosed with bleeding as the cause of death.
Sørensen and colleagues found that the yearly incidence of bleeding was 2.6 percent for the aspirin group, 4.6 percent for clopidogrel, 4.3 percent for vitamin K antagonist, 3.7 percent for aspirin plus clopidogrel, 5.1 percent for aspirin plus vitamin K antagonist, 12.3 percent for clopidogrel plus vitamin K antagonist and 12 percent for triple therapy.
With aspirin as the reference, the adjusted hazard ratio for bleeding was 1.3 for clopidogrel, 1.2 for vitamin K antagonist (not statistically significant), 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 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.
Also, the researchers reported that 38 percent of 1,852 patients with non-fatal bleeding had recurrent heart attack or died during the study period compared with 18 percent of 38,960 patients without non-fatal bleeding.
“In patients with a 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,” the authors wrote. “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 commentary, Erik L. Grove, MD, from the department of cardiology at Aarhus University Hospital in Skejby, Denmark, and Robert F. Storey, MD, from the department of cardiovascular science at the University of Sheffield in the U.K., wrote that 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 characteristics.”