Increased Risk of Intracranial Hemorrhage when Aspirin Is Combined with Warfarin: A Meta-Analysis and Hypothesis

Abstract

Background: Oral anticoagulation with vitamin K antagonists increases the risk of intracranial hemorrhage; whether addition of aspirin to oral anticoagulation augments this risk is unclear. Methods: Meta-analysis of randomized clinical trials in which aspirin was added to oral anticoagulants. Results: Six randomized clinical trials were identified, including a total of 3,874 participants. Use of aspirin with oral anticoagulants was associated with more than double the frequency of intracranial hemorrhage (relative risk = 2.4, 95% CI = 1.2–4.8, p = 0.02). Conclusion: We hypothesize that aspirin when added to oral vitamin K antagonists may increase the risk of intracranial hemorrhage, but this observation requires confirmation. The magnitude of this effect is uncertain, and the clinical importance is likely different for different patient populations.

Anticoagulants for atrial fibrillation: Why is the treatment rate so low?

“…12 In addition, combining aspirin with an oral anticoagulant at higher anticoagulation intensities may increase the risk and severity of intracranial hemorrhage, particularly in elderly patients. 13 (Refs. from long format guidelines.)…”

Premorbid Use of Clopidogrel Portends Worse Outcomes in Patients Treated Surgically for Intracranial Hemorrhage

“…Statistical methodology helps to minimize these confounders to some extent, however the age difference between study groups was definitive: non-APAC age group averaged 50.6 years, compared to the APAC group of 71.7 years. In addition, many of the patients on clopidogrel were on more than one agent, which is a known risk factor for ICH [11] [15]- [17]. There were only 9 patients taking clopidogrel as a single agent, making statistical analysis underpowered when looking at clopidogrel alone; thus the results of this study may be best looked at in terms of dual antiplatelet therapy.…”

“…In addition, it is not uncommon for patients to be placed on a dual or even a triple regimen of APAC medications. The combined use of two or more medications appears to carry a greater risk of spontaneous ICH than does the use of single agents [11] [15]- [17]. Given the increasing use of APACs [1]- [5] and the rapid development of newer agents, the neurosurgical implications are significant.…”

Contemporary Management of Atrial Fibrillation: Update on Anticoagulation and Invasive Management Strategies

“…This metaanalysis showed that adjusted-dose warfarin is remarkably effective in reducing the risk of stroke for patients with AF. 92 Compared with placebo, adjusted-dose warfarin decreased the relative risk of stroke by 62% (95% confidence interval [CI], 48%-72%). 82 The absolute reduction of stroke risk by adjusted-dose warfarin vs placebo was 2.7% annually for primary prevention and 8.4% annually for secondary prevention.…”

“…Using aspirin in addition to warfarin has been found to increase elderly patients' absolute risk of serious bleeding by 0.6% during a 90-day observation period and to increase their relative risk of intracranial hemorrhage by a factor of 2.4. 92,103 For patients with chronic stable coronary artery disease and AF, adjusted-dose warfarin without aspirin is probably sufficient. 3,104 Observational data suggest that the combination of aspirin, clopidogrel, and warfarin may be associated with a high risk of bleeding.…”