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Combination warfarin-asa therapy: which patients should receive it, which patients should not, and why?

Contents lists available at ScienceDirect j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h ro m re s Combination warfarin-ASA therapy: Which patients should receive it, which patients Department of Medicine, McMaster University and St Joseph's Healthcare, Hamilton, ON, Canada 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 Received in revised form 14 February 2011 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 andconsistent 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 2011 Elsevier Ltd. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Characteristics of Patients who are Receiving Combination Warfarin-ASA Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Evidence for Therapeutic Benefit with Combination Warfarin-ASA vs. Warfarin Alone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Evidence for Therapeutic Harm with Combination Warfarin-ASA vs. Warfarin Alone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary of Evidence Regarding Benefits and Risks of Warfarin-ASA Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Recommendations from Current Clinical Practice Guidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Managing Patients in Everyday Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical settings in which there is good evidence for combination warfarin-ASA therapy . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical settings in which there is weak or insufficient evidence for combination warfarin-ASA therapy . . . . . . . . . . . . . . . . . . .
Clinical settings in which, despite insufficient evidence, combination warfarin-ASA therapy may be reasonable . . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
embolism. Combining these two agents is appealing because ofpotentially complementary antiplatelet and anticoagulant actions, Warfarin and acetylsalicylic acid (ASA) are widely used for the which may be especially relevant for patients who have concomitant primary and secondary prevention of thromboembolic and athero- cardiovascular diseases, such as atrial fibrillation and coronary artery thrombotic diseases in patients with chronic atrial fibrillation, disease (CAD). Despite the potential therapeutic advantages of coronary artery disease, valvular heart disease and venous thrombo- combination warfarin-ASA therapy, when multiple drugs that affecthemostasis are co-administered, this typically increases patients’ riskfor serious bleeding [1]. Many clinicians accept this risk of bleeding ⁎ St Joseph's Healthcare Hamilton, Room F-544, 50 Charlton Ave. East, Hamilton, ON, because preventing cardiovascular events is typically considered to be Canada L8N 4A6. Tel.: +1 905 521 6178; fax: +1 905 521 6068.
E-mail address: [email protected]
of paramount importance whereas bleeding is often considered a self- 0049-3848/$ – see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2011.02.010 J.D. Douketis / Thrombosis Research 127 (2011) 513–517 limiting and treatable condition [2]. However, there is emerging patients with CAD; and one study of patients at high risk for evidence that combination warfarin-ASA therapy may not confer cardiovascular disease. The risk for cardiovascular/thromboembolic additional therapeutic benefits, except in selected patient groups, events was significantly reduced by combination warfarin-ASA whereas the associated increase in bleeding complications is more therapy (OR = 0.66; 95% CI: 0.52-0.84). However, this therapeutic compelling and may outweigh any potential advantages.
benefit was driven by five studies involving patients with mechanical Addressing the putative benefits and risks of combined warfarin- heart valves (OR = 0.27; 95% CI: 0.15-0.49). However, there was no ASA therapy is important because of the large number of patients who statistically significant risk reduction for these outcomes in the two are receiving combined therapy. Among patients with chronic studies of patients with atrial fibrillation (OR = 0.99; 95% CI: 0.47- nonvalvular atrial fibrillation, recent large trials have found that 2.07) and in the OR involving patients with either CAD or at high risk approximately 35-40% of such patients were also receiving ASA [3,4].
for cardiovascular disease (OR = 0.69; 95% CI: 0.35-1.36).
This means that approximately 800,000 patients with chronic atrial Two other randomized trials deserve mention but were excluded fibrillation in North America alone are receiving warfarin-ASA from this meta-analysis because different intensities of warfarin were therapy. What is, perhaps, more important is that this practice is administered in the two treatment arms. In the ASPECT-2 [11] and occurring in the absence of evidence of benefit and stronger evidence WARIS II [12] studies, patients with CAD were randomly allocated to for harm. Further clouding appropriate clinical management is the receive warfarin (target INR range: 2.0-2.5) plus ASA or warfarin lack of clear guidelines as to the appropriateness of combination alone (target INR range: 3.0-4.0 in ASPECT-2 and 2.8-4.2 in WARIS-II) warfarin-ASA therapy from the American College of Chest Physicians or ASA alone. In the ASPECT-2 trial, there was no significant (ACCP) Antithrombotic Consensus Guidelines and the American Heart differences in composite endpoint of myocardial infarction, stroke Association/American College of Cardiology/European College of or death in patients who received combination warfarin-ASA or only Cardiology (AHA/ACC/ESC) guidelines [5,6].
warfarin (OR = 0.92; 95% CI: 0.36-1.85). In WARIS II, there was also no Against this background, the objectives of this review are: 1) to significant difference in the composite outcome of non-fatal re- describe which patients are currently receiving combination infarction, stroke or death between warfarin-ASA-treated and warfarin-ASA therapy; 2) to summarize the evidence for the warfarin-treated patients but there was a non-significant trend for a therapeutic benefits and harms of combination warfarin-ASA when lower incidence of non-fatal re-infarction between these two groups compared to warfarin therapy alone; and 3) to provide practical guidelines as to which patients should receive and should not receive Other relevant data to assess the efficacy of combination warfarin- ASA compared with warfarin alone comes from a sub-group analysisof warfarin-treated patients in the SPORTIF trial, which compared Characteristics of Patients who are Receiving Combination Warfarin- warfarin (target INR range: 2.0-3.0) to ximelagatran for stroke prevention in patients with chronic atrial fibrillation [13]. Thus,among warfarin-treated patients there was no significant difference The reason for the widespread use of warfarin-ASA therapy in the risk for coronary events (0.6% vs. 1.0% per year) or stroke (1.7% appears to be driven by the observation that warfarin-treated patients vs. 1.5%) in users of warfarin-ASA and warfarin alone.
may have multiple diseases in which there is a perceived indication A retrospective cohort study of over 4,500 warfarin-treated for both an anticoagulant and an antiplatelet drug. Thus, in a patients managed by an anticoagulation clinic is noteworthy [14].
community-based study involving patients who were receiving When combination warfarin-ASA users and warfarin-only users were long-term warfarin, 48% of whom had chronic atrial fibrillation, compared, there was no significant difference in rates of coronary patients who were receiving warfarin-ASA therapy typically had other events (OR = 0.99; 95% CI: 0.37-2.62) or thromboembolic events co-morbidities: 56% had hypertension; 35% had CAD; 27% had chronic (OR = 1.48; 95% CI: 0.43-5.08) between these two patient groups heart failure; and 23% had diabetes [7]. In this study, CAD was the despite statistical adjustment for potential confounders.
strongest predictor for combination warfarin-ASA therapy (odds ratio Finally, in a linked administrative database done in Denmark [OR], 7.56; 95% confidence interval [CI]: 6.50-8.82), thereby suggest- involving over 70,000 patients with atrial fibrillation who were ing that clinicians may be adding ASA to warfarin therapy with the receiving warfarin or combination warfarin-ASA therapy did not intent of providing a CAD-specific antithrombotic effect.
confer a therapeutic advantage for stroke prevention and, in fact, was From a broader perspective, both atrial fibrillation and CAD are associated with an increased risk for ischemic stroke compared to common diseases, with an estimated prevalence of 2.5 million people warfarin-only users (hazard ratio [HR] = 1.27; 95% CI: 1.14-1.40) [15].
[8] and 16 million people [9], respectively, in North America. With an Additional data as to the efficacy of warfarin alone to prevent acute aging population and increasing prevalence of atrial fibrillation and myocardial ischemia comes from the ACTIVE-W trial which compared CAD, the issue of whether there is a net therapeutic benefit of warfarin therapy to combination ASA-clopidogrel in patients with combination warfarin-ASA therapy over warfarin therapy alone will chronic atrial fibrillation [16]. In this study, the incidence of acute become increasingly relevant. Although new oral anticoagulants such myocardial infarction was higher in patients receiving ASA-clopidogrel as dabigatran and rivaroxaban will supplant warfarin in many than warfarin-treated patients (0.86% vs. 0.55% per year; risk ratio, 1.58; patients who require long-term anticoagulation [3,4], the uncertainty 95% CI: 0.94-2.67). In the RE-LY trial, which compared warfarin to as to added therapeutic benefit and probable increased bleeding risk dabigatran for stroke prevention in patients with chronic atrial with combination warfarin-ASA therapy will remain.
fibrillation, the annual risk for symptomatic acute myocardial ischemiawas, as in the ACTIVE-W trial, similarly low among warfarin-treated Evidence for Therapeutic Benefit with Combination Warfarin-ASA Evidence for Therapeutic Harm with Combination Warfarin-ASA A recent meta-analysis of randomized controlled trials assessed treatment with combination warfarin-ASA compared with warfarinalone, in which patients received the same intensity of warfarin (i.e., An assessment of treatment harm with combination warfarin-ASA same target international normalized ratio [INR]) in both treatment and warfarin therapy should consider both relative risk increase, arms [10]. Ten studies were identified by a systematic review of the expressed as an odds ratio (OR) or hazard ratio (HR) and, perhaps literature: five studies of patients with mechanical heart valves; two more importantly, absolute risk increase. Thus, in patients who are studies of patients with chronic atrial fibrillation; two studies of receiving long-term warfarin, the risk for serious (or major) bleeding is, J.D. Douketis / Thrombosis Research 127 (2011) 513–517 typically, 1-2% per year [3,4], which may be up to 5% per year in the ASA in combination with a new oral anticoagulant and it is likely that the elderly or those with multiple comorbidities [17,18]. For example, if the addition of ASA will confer an increase in bleeding risk [3,4].
OR for harm is 1.5 (50% higher), this means if a patient's baseline risk forbleeding is estimated at 3% per year with warfarin therapy, it will be Summary of Evidence Regarding Benefits and Risks of approximately 4.5% per year with combined warfarin-ASA therapy.
Furthermore, there is increasing recognition as to the clinical impact ofmajor bleeding, which is fatal in 9-10% of cases [19,20] and is associated Overall, there does not appear to be compelling evidence that with an increased risk for adverse cardiovascular outcomes [21,22].
warfarin-ASA therapy is more effective than warfarin alone for the The aforementioned meta-analysis also assessed the risk for major prevention of cardiovascular and thromboembolic outcomes but bleeding associated with combination warfarin-ASA compared with there is consistent and, perhaps, more compelling evidence that warfarin alone [10]. There was an increased risk for major bleeding warfarin-ASA therapy increases serious bleeding, irrespective of the with warfarin-ASA over warfarin, with an annual risk of 2.3% vs. 1.3 %, patient population studied (Table 1). The exception to this conclusion a difference which is clinically significant, although it did not quite is patients with mechanical heart valves who, despite an increased attain statistical significance (OR = 1.43; 95% CI: 1.00-2.02). Similar risk for serious bleeding with combination therapy, derive a net findings were obtained from a large community-based study [14], therapeutic benefit with warfarin-ASA because the reduction in which found a statistically significant 2-fold higher risk for major thromboembolic events outweighs the increase in the risk for serious bleeding among patients on combination warfarin-ASA compared bleeding [24,25]. In other patients such as those with chronic atrial with warfarin alone (OR = 2.06; 95% CI: 1.01-4.36).
fibrillation, which is the dominant clinical indication for long-term The analysis of bleeding risk among warfarin-treated patients in the anticoagulant therapy, and those with chronic CAD, evidence is SPORTIF trial found a significantly increased risk for major bleeding lacking that adding ASA to warfarin is more effective than warfarin compared to the risk in patients who received warfarin alone (annual alone to prevent stroke or other cardiovascular events.
risk: 3.9% vs. 2.3%, P = 0.01) [23]. As in the previous study, ASA therapy In terms of the net therapeutic harm relating to serious bleeding in the SPORTIF trial conferred a 2-fold increased risk for major bleeding associated with combined warfarin-ASA therapy, this can be esti- among warfarin-treated patients (OR, 1.96; 1.49-2.58).
mated based on the following considerations: first, combined therapy In the ASPECT-2 trial, there was a non-statistically significant confers a 1-2% absolute risk increase in major (serious) bleeding per increased risk for major bleeding with combination warfarin-ASA year compared with warfarin alone; and, second, the case-fatality compared to warfarin alone (2% vs. 1 % per patient year, respectively), associated with each major bleed is approximately 9-10% [19,20].
although the intensity of anticoagulation was less in the ASA-treated Thus, for every 1,000 patients (who do not have a mechanical heart group thereby limiting an assessment of the putative additive effect of valve) treated with warfarin-ASA therapy per year, it is estimated that ASA on bleeding risk. Combination warfarin-ASA therapy conferred an there would be an additional 10–20 major bleeds and, based on the approximately 2-fold increase in minor-bleeding compared to warfarin case-fatality rate of 9-10%, an additional 1–2 deaths per year.
alone (15% vs. 8% per patient year, P b0.05) In the WARIS-II trial, there Although these numbers seem small, they should be considered in was no significant difference in bleeding between warfarin-ASA-treated the context of the approximately 800,000 patients in North America and warfarin-treated patients (0.57% vs. 0.68 % per year, respectively) alone who are receiving combined warfarin-ASA therapy in the although the overall incidence of bleeding was low at b1% per year and absence of a compelling evidence for a net therapeutic benefit. Thus, the possibility of more bleeding among warfarin-ASA treated patients on a population level, combined warfarin-ASA therapy may lead to an additional 800 to 1,200 deaths per year in North America alone.
Finally, a linked database of patients with atrial fibrillation who were receiving warfarin found that among those who were receiving Recommendations from Current Clinical Practice Guidelines combination warfarin-ASA, had a 1.8-fold increased risk for majorbleeding (HR = 1.83; 95% CI: 1.72-1.96) [15]. Furthermore, this study As shown in Table 2, consensus groups do not provide clear guidelines found that combination warfarin and clopidogrel (a thienopyridine aimed at the practicing clinician for the use of combination warfarin-ASA derivative with antiplatelet effects mediated by platelet ADP-receptor therapy outside of the context of patients with mechanical heart valves.
inhibition) conferred a substantially higher risk for bleeding com- Thus, the influential ACCP Consensus Conference on Antithrombotic and pared with warfarin alone (HR = 3.08; 95% CI: 2.32-3.91); the risk of Thrombolytic Therapy (2008 Edition) states that “for high risk patients bleeding was highest in patients receiving ‘triple therapy’, consisting with acute myocardial infarction, including those with atrial fibrillation, we of combination warfarin-ASA-clopidogrel (HR = 4.05; 95% CI: 3.08- suggest the combined use of oral vitamin K antagonists (INR 2–3) plus low- dose aspirin (100 mg/d or less) for at least 3 months after the myocardial Additional data as to the risks of combined ASA-dabigatran and ASA- infarction (grade 2A)” [5]. Although this recommendation may apply to rivaroxaban are forthcoming since up to 40% of patients were receiving patients who have had an acute coronary syndrome, they do not advise Table 1Summary of Therapeutic Benefits and Bleeding Harm with Combination Warfarin-ASA vs. Warfarin Alone.
Study Type Comparing Warfarin-ASA vs. Warfarin alone Legend: †studies of patients with atrial fibrillation; ‡studies of patients with coronary artery disease; ¶ischemic stroke risk; n/a, not available; RCT, randomized controlled trial; NNH,number-needed-to-harm (number of patients treated per year with warfarin-ASA to cause 1 additional major bleed compared to warfarin alone).
J.D. Douketis / Thrombosis Research 127 (2011) 513–517 Clinical Practice Guideline Statements for Combination Warfarin-ASA Therapy.
Clinical Settings in which there is Strong, Weak or Insufficient Evidence for TherapeuticBenefit with Combination Warfarin-ASA Therapy.
Strong evidence for therapeutic benefit: - mechanical mitral valve In patients with mechanical heart valves who Grade 1B thromboembolism, such as atrial fibrillation, Weak/insufficient evidence for therapeutic - chronic AF alone hypercoagulable state, low ejection fraction, benefit: warfarin-ASA not recommended or - chronic stable CAD history of atherosclerotic vascular disease, we recommend the addition of low-dose ASA Insufficient evidence for therapeutic benefit - chronic AF (or prior VTE) + recent (50–100 mg once-daily) to long-term VKA The addition of ASA 75–100 mg once daily to Class I therapeutic warfarin is recommended for all patients with mechanical heart valves.
Legend: AF, atrial fibrillation; VKA, vitamin K antagonist; CAD, coronary artery disease; For high risk patients with acute myocardial Grade 2Ainfarction, including those with atrial fibrillation, large anterior myocardialinfarction, significant heart failure, Clinical settings in which there is good evidence for combination thromboembolic event, we suggest thecombined use of oral VKAs (INR range: 2.0- Consider a 67-year old patient on long-term warfarin therapy 3.0) plus low-dose ASA (100 mg once-dailyor less) for at least 3 months after the because of valvular atrial fibrillation who undergoes mitral valve replacement with a bileaflet mechanical prosthesis. After surgery, For most patients with AF who have stable adding ASA to warfarin is recommended because in this setting there is compelling evidence of a net therapeutic benefit with combination range: 2.0-3.0) should provide satisfactoryantithrombotic prophylaxis against both warfarin-ASA compared with warfarin alone. Furthermore, although cerebral and myocardial ischemic events.
the evidence for benefit is less compelling, combined warfarin-ASAtherapy should be considered in patients with a mechanical aortic Legend: AF, atrial fibrillation; ASA, acetylsalicylic acid; VKA, vitamin K antagonists; CAD,coronary artery disease.
valves, especially those with older, caged-ball or tilting-disc, valves orin those patients with newer bileaflet valves who have additional risksfor thromboembolism.
clinicians as to whether combination warfarin-ASA therapy should becontinued beyond the initial 3-month period after the acute coronary Clinical settings in which there is weak or insufficient evidence for event. Furthermore, there are no guidelines about managing patients with chronic stable CAD who are receiving ASA and subsequently arediagnosed with chronic atrial fibrillation.
Consider a 75-year old patient with nonvalvular atrial fibrillation The ACC/AHA/ESC guidelines (2006 Edition), under the section who is not receiving warfarin and develops an acute coronary related to management of atrial fibrillation, are somewhat more explicit, syndrome, which is treated with medical therapy alone based on the indicating that “for most patients with atrial fibrillation who have stable coronary disease that is not amenable to a percutaneous intervention or coronary artery disease, warfarin anticoagulation alone (target INR 2.0 to surgical revascularization. The patient is discharged home to receive 3.0) should provide satisfactory antithrombotic prophylaxis against both ASA therapy, which aims to stabilize any ongoing plaque rupture and cerebral and myocardial ischemic events” [6]. However, as with the ACCP prevent coronary thrombosis, which is most likely to occur within the guidelines, this consensus group recommendation does not directly initial 4–12 weeks after an acute coronary syndrome. Warfarin is also inform clinicians about the potential therapeutic benefits and harms of commenced because of atrial fibrillation to minimize the risk for stroke.
combined warfarin-ASA therapy and in providing guidelines for patients During the subsequent three months the patient has no further coronary with atrial fibrillation who develop an acute coronary syndrome and for events. It is reasonable, therefore, to use combined warfarin-ASA during ASA-treated patients with chronic CAD who develop atrial fibrillation.
the initial 3 months, but after this period ASA can be stopped given the Taken together, consensus guidelines are anchored on evidence- evidence that warfarin alone is effective for chronic stable coronary based recommendations and, therefore, it is not surprising that there artery disease. Now consider a 71-year old patient with stable CAD who are few definitive recommendations about the clinical scenarios is receiving long-term ASA therapy, is found to have atrial fibrillation on described above. Nonetheless, the practicing clinicians who fre- a routine examination and, over time, is classified as having chronic quently assess patients in whom there is an indication for long-term atrial fibrillation. Hypertension and heart failure are also present as warfarin and in whom co-administered ASA is being considered, there comorbidities. In this case, there is a clear indication for long-term is a need to provide guidance to inform clinical practice. An attempt to warfarin therapy alone, based on a CHADS2 score of 2 [26]. In this address this somewhat unmet need using the available evidence on patient, warfarin therepy alone should be sufficient.
the therapeutic benefits and harms, coupled with clinical judgment, isprovided in Table 3.
Clinical settings in which, despite insufficient evidence, combinationwarfarin-ASA therapy may be reasonable Managing Patients in Everyday Clinical Practice There are clinical settings where, despite a lack of evidence to support combined warfarin-ASA therapy, such treatment may be consi- For clinicians managing ‘real-world’ patients in whom there may dered. The first is patients with chronic atrial fibrillation (or venous be an indication for warfarin and, possibly, ASA, a suggested clinical thromboembolism) who are receiving long-term warfarin and require management approaches are provided using illustrative case.
placement of coronary stent. Ideally, in warfarin-treated patients who J.D. Douketis / Thrombosis Research 127 (2011) 513–517 require coronary stent placement, consideration should be given to [4] ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and placement of a bare-metal stent instead of a drug-eluting stent, as the Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study.
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