Elsevier

The Lancet

Volume 374, Issue 9706, 12–18 December 2009, Pages 1967-1974
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(09)61751-7Get rights and content

Summary

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.

Introduction

Treatment with aspirin and clopidogrel is recommended after acute myocardial infarction to reduce recurrent ischaemic events.1, 2, 3 Some patients have an additional indication for treatment with a vitamin K antagonist.4 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,5, 6, 7, 8, 9 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.1, 2, 4, 10 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.4, 10 Since bleeding episodes in patients with myocardial infarction are associated with increased morbidity and mortality,11, 12 the use of undocumented treatment combinations raises concerns.

We undertook a nationwide study of 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.

Section snippets

Study population

Four nationwide administrative registers were linked on an individual level and used in this study: (1) the Danish National Patient Register, which holds information about all admissions to Danish hospitals since 1978 with diagnoses coded according to the International Classification of Diseases (ICD)-8 and ICD-10; (2) the Danish Register of Medicinal Product Statistics (the national prescription register), which contains information about all prescriptions dispensed in Danish pharmacies since

Results

We identified 40 812 patients who were admitted to hospital with first-time myocardial infarction in Denmark during 2000–05, and who claimed a prescription of aspirin, clopidogrel, or a vitamin K antagonist within 90 days of hospital discharge. Table 1 shows the baseline characteristics of patients by first drug exposure group. See webappendix p 1 for baseline characteristics of patients according to PCI status. Several patients changed treatment regimen, and therefore drug exposure group,

Discussion

We 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

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