Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data

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.

Treatment with aspirin and clopidogrel is recommended after acute myocardial infarction to reduce recurrent ischaemic events. Some patients have an additional indication for treatment with a vitamin K antagonist. Treatment with multiple antithrombotic drugs after myocardial infarction represents a clinical dilemma because risk of bleeding is exacerbated with combination therapy and longer duration of treatment. Although several studies have reported rates of bleeding, research on antithrombotic drugs has generally focused on improving efficacy rather than safety. Additionally, the safety of several drug combinations has not been investigated in clinical trials. Guidelines for the management of patients with myocardial infarction who also have an indication for vitamin K antagonists are unclear. Combination treatment is widely used and some guidelines recommend an untested combination of clopidogrel plus vitamin K antagonist as the preferred option for patients with myocardial infarction who are treated with an intracoronary stent. Since bleeding episodes in patients with myocardial infarction are associated with increased morbidity and mortality, the use of undocumented treatment combinations raises concerns.

The nationwide study examined 40,812 unselected patients treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists after myocardial infarction to examine the risk of non-fatal and fatal bleeding in a real-life setting and to identify the safest combinations of antithrombotic drugs.

The study examined the association between occurrence of non-fatal and fatal bleeding and treatment with combinations of aspirin, clopidogrel, and vitamin K antagonists in a nationwide cohort of patients with first-time myocardial infarction. All drug combinations were associated with an increased risk of hospital admission for non-fatal and fatal bleeding, apart from monotherapy with a vitamin K antagonist. Increased risk of bleeding was proportional to the number of drugs used. Notably, dual therapy with clopidogrel plus vitamin K antagonist was nearly as hazardous as triple therapy. The risk of the combined endpoint of recurrent myocardial infarction or death was higher in patients with non-fatal bleeding than in patients without non-fatal bleeding.

Several studies have reported frequency of bleeding in patients with acute coronary syndromes who were treated with different antithrombotic drugs. However, these studies have been difficult to compare because of diverse definitions of the bleeding diagnoses.

The main strength of this study was the completeness of data, with a nationwide unselected cohort of patients with myocardial infarction followed in a real-life setting and with complete data for dispensed prescriptions.

Thus, in patients with first-time myocardial infarction, all combinations of aspirin, clopidogrel, and vitamin K antagonists are associated with increased risk of non-fatal 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 myocardial infarction or death. Therefore, this study proposes 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.

Source:  Summarised from the original article in The Lancet, Volume 374, Issue 9706, Pages 1967 - 1974, 12 December 2009