Elsevier

Thrombosis Research

Volume 127, Issue 6, June 2011, Pages 513-517
Thrombosis Research

Review Article
Combination warfarin-ASA therapy: Which patients should receive it, which patients should not, and why?

https://doi.org/10.1016/j.thromres.2011.02.010Get rights and content

Abstract

Combination warfarin-ASA therapy is currently used in approximately 800,000 patients in North America as long-term treatment for the primary and secondary prevention of atherothrombotic and thromboembolic diseases. Despite a potentially complementary action of anticoagulant and antiplatelet drugs, the use of combination warfarin-ASA therapy is not based on compelling evidence of a net therapeutic benefit, with the exception of patients with a mechanical heart valve. On the other hand, there is more compelling and consistent evidence that combination warfarin-ASA therapy confers a 1.5- to 2.0-fold increased risk for serious bleeding compared with use of warfarin alone. In everyday practice, clinicians should combine the best available evidence with clinical judgment, considering that in most clinical scenarios, clinical practice guideline may not provide clear recommendations for patients who should, and should not, receive combination warfarin-ASA therapy. The objectives of this review are to describe which patients are receiving combined warfarin-aspirin therapy, to summarize the evidence for the therapeutic benefit and harm of combined warfarin-ASA therapy, and to suggest practical guidelines as to which patients should, and should not, receive such treatment.

Introduction

Warfarin and acetylsalicylic acid (ASA) are widely used for the primary and secondary prevention of thromboembolic and atherothrombotic diseases in patients with chronic atrial fibrillation, coronary artery disease, valvular heart disease and venous thromboembolism. Combining these two agents is appealing because of potentially complementary antiplatelet and anticoagulant actions, which may be especially relevant for patients who have concomitant cardiovascular diseases, such as atrial fibrillation and coronary artery disease (CAD). Despite the potential therapeutic advantages of combination warfarin-ASA therapy, when multiple drugs that affect hemostasis are co-administered, this typically increases patients’ risk for serious bleeding [1]. Many clinicians accept this risk of bleeding because preventing cardiovascular events is typically considered to be of paramount importance whereas bleeding is often considered a self-limiting and treatable condition [2]. However, there is emerging evidence that combination warfarin-ASA therapy may not confer additional therapeutic benefits, except in selected patient groups, whereas the associated increase in bleeding complications is more compelling and may outweigh any potential advantages.

Addressing the putative benefits and risks of combined warfarin-ASA therapy is important because of the large number of patients who are receiving combined therapy. Among patients with chronic nonvalvular atrial fibrillation, recent large trials have found that approximately 35-40% of such patients were also receiving ASA [3], [4]. This means that approximately 800,000 patients with chronic atrial fibrillation in North America alone are receiving warfarin-ASA therapy. What is, perhaps, more important is that this practice is occurring in the absence of evidence of benefit and stronger evidence for harm. Further clouding appropriate clinical management is the lack of clear guidelines as to the appropriateness of combination warfarin-ASA therapy from the American College of Chest Physicians (ACCP) Antithrombotic Consensus Guidelines and the American Heart Association/American College of Cardiology/European College of Cardiology (AHA/ACC/ESC) guidelines [5], [6].

Against this background, the objectives of this review are: 1) to describe which patients are currently receiving combination warfarin-ASA therapy; 2) to summarize the evidence for the therapeutic benefits and harms of combination warfarin-ASA when compared to warfarin therapy alone; and 3) to provide practical guidelines as to which patients should receive and should not receive warfarin-ASA therapy.

Section snippets

Characteristics of Patients who are Receiving Combination Warfarin-ASA Therapy

The reason for the widespread use of warfarin-ASA therapy appears to be driven by the observation that warfarin-treated patients may have multiple diseases in which there is a perceived indication for both an anticoagulant and an antiplatelet drug. Thus, in a community-based study involving patients who were receiving long-term warfarin, 48% of whom had chronic atrial fibrillation, patients who were receiving warfarin-ASA therapy typically had other co-morbidities: 56% had hypertension; 35% had

Evidence for Therapeutic Benefit with Combination Warfarin-ASA vs. Warfarin Alone

A recent meta-analysis of randomized controlled trials assessed treatment with combination warfarin-ASA compared with warfarin alone, in which patients received the same intensity of warfarin (i.e., same target international normalized ratio [INR]) in both treatment arms [10]. Ten studies were identified by a systematic review of the literature: five studies of patients with mechanical heart valves; two studies of patients with chronic atrial fibrillation; two studies of patients with CAD; and

Evidence for Therapeutic Harm with Combination Warfarin-ASA vs. Warfarin Alone

An assessment of treatment harm with combination warfarin-ASA and warfarin therapy should consider both relative risk increase, expressed as an odds ratio (OR) or hazard ratio (HR) and, perhaps more importantly, absolute risk increase. Thus, in patients who are receiving long-term warfarin, the risk for serious (or major) bleeding is, typically, 1-2% per year [3], [4], which may be up to 5% per year in the elderly or those with multiple comorbidities [17], [18]. For example, if the OR for harm

Summary of Evidence Regarding Benefits and Risks of Warfarin-ASA Therapy

Overall, there does not appear to be compelling evidence that warfarin-ASA therapy is more effective than warfarin alone for the prevention of cardiovascular and thromboembolic outcomes but there is consistent and, perhaps, more compelling evidence that warfarin-ASA therapy increases serious bleeding, irrespective of the patient population studied (Table 1). The exception to this conclusion is patients with mechanical heart valves who, despite an increased risk for serious bleeding with

Recommendations from Current Clinical Practice Guidelines

As shown in Table 2, consensus groups do not provide clear guidelines aimed at the practicing clinician for the use of combination warfarin-ASA therapy outside of the context of patients with mechanical heart valves. Thus, the influential ACCP Consensus Conference on Antithrombotic and Thrombolytic Therapy (2008 Edition) states that “for high risk patients with acute myocardial infarction, including those with atrial fibrillation, we suggest the combined use of oral vitamin K antagonists (INR

Managing Patients in Everyday Clinical Practice

For clinicians managing ‘real-world’ patients in whom there may be an indication for warfarin and, possibly, ASA, a suggested clinical management approaches are provided using illustrative case.

Summary

It is estimated that 800,000 patients in North America are receiving combined warfarin-ASA therapy, primarily for the presence of both chronic atrial fibrillation and CAD. Despite such widespread use of combined warfarin-ASA, there is little evidence, apart from patients with a mechanical heart valve, that combination therapy confers a therapeutic benefit compared with warfarin alone. On the other hand, there is consistent and more compelling evidence that combined warfarin-ASA therapy confers

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