Review ArticleCombination warfarin-ASA therapy: Which patients should receive it, which patients should not, and why?
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
References (27)
- et al.
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
Lancet
(2009) - et al.
The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Chest
(2008) - et al.
The primary and secondary prevention of coronary artery disease. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition)
Chest
(2008) - et al.
Warfarin and antiplatelet combination use among commercially insured patients enrolled in a anticoagulation management service
Chest
(2007) - et al.
Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial
Lancet
(2002) - et al.
Outcomes associated with combined antiplatelet and anticoagulant therapy
Chest
(2008) - et al.
Valvular and structural heart disease. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition)
Chest
(2008) - et al.
Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition)
Chest
(2008) - et al.
RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation
N Engl J Med
(2009) Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study
Am Heart J
(2010)
ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation - executive summary
Circulation
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study
JAMA
Morbidity and mortality: 2007 Chart book on ardiovascular, lung, and blood disease
Cited by (25)
Stroke and bleeding risks in patients with atrial fibrillation
2014, Interventional Cardiology ClinicsCitation Excerpt :A study by Hansen and colleagues63 based on a nationwide registry on AF patients concluded that the overall incidence of bleeding events was the highest for dual antiplatelet therapy and warfarin therapy; using warfarin monotherapy as a reference, the HR (95% CI) for the overall bleeding events was 0.93 (0.88–0.98) for aspirin, 1.06 (0.87–1.29) for clopidogrel, 1.66 (1.34–2.04) for aspirin-clopidogrel, 1.83 (1.72–1.96) for warfarin-aspirin, 3.08 (2.32–3.91) for warfarin-clopidogrel, and 3.70 (2.89–4.76) for warfarin-aspirin-clopidogrel. As expected, the risk of bleeding complications has increased in the setting of combination of antiplatelet agents and OACs; this is particularly relevant in the routine clinical practice where it is likely for patients to be on multiple agents, leading to an increased risk of bleeding complications.64 In a subsequent analysis of the RE-LY trial, the use of antiplatelet agents in addition to dabigatran (110 mg), dabigatran (150 mg), and dose-adjusted warfarin was found associated with an increased risk of bleeding (overall HR 2.01; 95% CI, 1.79–2.25); also, the risk of bleeding was greater with the use of dual antiplatelet agents (HR 2.31; 95% CI, 1.79–2.98) compared with a single antiplatelet agent (HR 1.60; 95% CI, 1.42–1.82).
Towards dual antithrombotic compounds-Balancing thrombin inhibitory and fibrinogen GPIIb/IIIa binding inhibitory activities of 2,3-dihydro-1,4- benzodioxine derivatives through regio- and stereoisomerism
2013, European Journal of Medicinal ChemistryCitation Excerpt :In clinical practice, an effective prophylaxis and treatment of thromboembolic diseases, such as deep vein thrombosis, thromboembolic stroke, pulmonary embolism and myocardial infarction, is achieved by using a combination of various antiaggregatory and anticoagulant drugs [19]. Since the combined use of thrombin inhibitors and glycoprotein IIb/IIIa antagonists in the prevention of cardiovascular diseases has shown additional benefits over treatment directed against thrombin or against platelets alone [20], we envisaged merging anticoagulant and platelet antiaggregatory activity in the same molecule as a promising approach towards novel multitarget antithrombotic agents [21–25]. Recently, other groups have reported the preparation of dual anticoagulant/antiplatelet agents featuring high molecular weight, polysulfated conjugates [26], in contrast to our dual acting compounds with strongly overlapping pharmacophores and low molecular weight.
Antidepressants, antiplatelets and bleeding: One more thing to worry about?
2011, CMAJ. Canadian Medical Association Journal