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.

Hylek EM, Singer DE: Risk factors for intracerebral hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120:897–902.
Hart RG, Pearce LA: In vivo antithrombotic effect of aspirin: Dose versus nongastrointestinal bleeding. Stroke 1993;24:138–139.
Thrift AG, McNeil JJ, Forbes A, Donnan GA: Risk factors for cerebral hemorrhage in the era of well-controlled hypertension. Stroke 1996;27:2020–2025.
Antiplatelet Trialists Collaboration: Collaborative overview of randomized trials of antiplatelet therapy (part I). BMJ 1994;308:81–106.
Turpie AGG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, Klimek M, Hirsh J: A comparison of aspirin with placebo in patients treated with warfarin and heart valve replacement. N Engl J Med 1993;329:524–529.
Dalen JE, Hirsh J (eds): Fourth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy. Chest 1995;108(suppl):225S–522S.
Voith L, Pfiegler G, Hegedus I, Medgyesi F, Bodi A, Csapo K, Boda Z: Coumarin plus low-dose acetylsalicylic acid treatment as prevention of thromboembolic complications in patients with mitral and aortic mechanical prosthetic heart valves (Hungarian with English abstract). Orv Hetil 1997;138:925–929.
Stroke Prevention in Atrial Fibrillation Investigators: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation. Lancet 1996;348:633–638.
Meschengieser SS, Fondevila CG, Frontroth J, Santarelli MT, Lazzari MA: Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: A randomized trial in patients with mechanical prosthetic heart valves. J Thorac Cardiovasc Surg 1997;113:910–916.
Medical Research Council’s General Practice Research Framework: Thrombosis Prevention Trial: Randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. Lancet 1998;351:233–241.
Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace RB, Danielson GK, Orszulak TA, Piehler JM, Schaff HV: Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: Danger of aspirin compared with dipyridamole. Am J Cardiol 1983;51:1537–1541.
Altman R, Boulton F, Rouvier J, Raca R, de la Fuente R, Favaloro K: Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. J Thorac Cardiovasc Surg 1976;72:127–129.
Dale J, Myhre E, Loew D: Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. Am Heart J 1980;99:746–751.
Gullov AL, Koefoed BG, Petersen P, Pedersen TS, Anderson ED, Godtfredsen J, Boysen G: Mini-dose warfarin and aspirin in atrial fibrillation: The AFASAK-2 study. Arch Intern Med 1998;158:1513–1521.
Berlin JA, Laird NM, Sacks HS, Chalmers TS: A comparison of statistical methods for combining event rates from clinical trials. Stat Med 1989;8:141–151.
Hurlen M, Erikssen J, Smith D, Arnesen H, Rollag A: Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: A study in 3166 outpatients. J Intern Med 1994;236:299–304.
Stroke Prevention in Atrial Fibrillation Investigators: Bleeding during antithrombotic therapy in atrial fibrillation. Arch Intern Med 1996;156:409–416.
Loewen P, Sunderji R, Gin K: The efficacy and safety of combination warfarin and ASA therapy: A systematic review of the literature and update of guidelines. Can J Cardiol 1998;14:717–726.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.