- Email: [email protected]
Concomitant antiplatelet and anticoagulation therapy: Indications, controversies and practical advice
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15 [4] Larson RJ, Fisher ES. Should aspirin be continued in patients started on warfarin: a systematic review and meta-analysis. J Gen Intern Med 2004;19:879–86. [5] Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey Jr DE, et al. ACC/AHA 2007 Guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. Circulation 2007;50:e90–2. [6] Harrington RA, Becker RC, Ezekowitz M, Meade TW, O'Connor CM, Vorchheimer DA, et al. Antithrombotic therapy for coronary artery disease. Chest 2004;126:513S–48S. [7] Aspirin therapy in diabetes. Diabetes Care 2004;27(supp 1): S72–3. [8] Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J 2006;27(5):519–26. [9] Salem DN, Stein PD, Al-Ahmad A, Bussey HI, Horstkotte D, Miller N, et al. Antithrombotic therapy in valvular heart disease: native and prosthetic. Chest 2004;126:457S–82S. [10] Eikelboom JW, Hirsh J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J Thromb Haemost 2007 Jul;5(Suppl 1):255–63. [11] SPAF Investigators. Adjusted-dose warfarin versus lowintensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation. Lancet 1996;348:633–8. [12] Lechat P, Lardoux H, Mallet A, Sanchez P, Derumeaux G, Lecompte T, et al. Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation: a randomized trial. Cerebrovasc Dis 2001;12:245–52. [13] Dimarco JP, Flaker G, Waldo AL, Corley SD, Greene HL, Safford RE, et al. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: observations from
[14]
[15]
[16]
[17]
[18]
[19]
[20]
S11 the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005;149(4):645–9. Flaker JC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006;152(5):967–73. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689–96. Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007 19;357(3):217–27. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest 2005;127:1515–22. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004;35:2362–7. Buresly K, Eisenberg MJ, Zhang X, Pilote L. Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction. Arch Intern Med 2005;165:784–9. Johnson SG, Rogers KR, Delate T, Witt DM. Outcomes associated with combined antiplatelet and anticoagulant therapy. Chest 2008;133:948–54.
doi:10.1016/j.thromres.2008.08.011
Concomitant antiplatelet and anticoagulation therapy: Indications, controversies and practical advice M. Dowd Clinical Pharmacy Anticoagulation Service, Kaiser Permanente, Denver, Colorado
Available online 25 September 2008
Abstract The use of combination antiplatelet and anticoagulant therapy is commonly encountered in clinical practice and is often a source of clinical controversy in regards to the efficacy versus the safety of this regimen. The benefit of combination therapy relates to the probable additive effect of suppressing both platelet and coagulation factor activities.
E-mail address: [email protected].
S12
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15 The risk of dual therapy is the potential for increased hemorrhagic events which may outweigh the clinical benefit. This review will focus on the clinical evidence that has demonstrated greater efficacy with combination therapy over either antiplatelet or anticoagulant therapy alone. Clinicians should consider the importance of documentation of combination therapy use in their patients in an effort to target those patients with the greatest benefit, and to avoid unnecessary complications. © 2008 Elsevier Ltd. All rights reserved.
Prevalence of combination therapy Statistics from the Centers for Disease Control and Prevention (CDC) estimate that almost 23 million Americans take a daily aspirin [1]. More frequent use of aspirin, especially self-prescribing, has resulted from the lower risk of myocardial infarction (MI) and stroke. Likewise, warfarin prescribing is on the rise due to its proven efficacy in multiple disease states. A recent descriptive study of 4500 patients conducted at our clinical pharmacy anticoagulation service at Kaiser Permanente of Colorado found that 40% of patients taking warfarin were also on concomitant antiplatelet therapy [2]. Six months prior to this study, our service initiated a formal surveillance and documentation of aspirin use and non-use in our patients via our electronic database (Dawn-AC; 4S Systems; Cumbria, UK). The two cohorts which were included in this trial involved a monotherapy cohort of 2800 patients on warfarin alone, and a combination cohort with 1700 patients receiving some type of antiplatelet (primarily aspirin 81 mg daily) with warfarin. The primary outcome for the study was to measure prevalence of combination therapy, with a secondary outcome to identify patient characteristics associated with combination therapy. Results of this study revealed that patients receiving combination therapy were more likely to be male, older and on warfarin for a shorter duration than patients on warfarin monotherapy. Patients on combination therapy were also more likely to have co-morbid conditions such as hypertension, coronary artery disease (CAD), diabetes, heart failure and stroke (p b 0.001 for all results). Likewise, compared to a primary indication of venous thromboembolism, patients with a diagnosis of atrial fibrillation, heart valve disorder, stroke or CAD were more commonly prescribed combination therapy versus monotherapy (p b 0.001). The strongest predictors of combination therapy identified by multivariate logistic regression modeling were a primary indication of CAD compared to venous thromboembolism and a comorbidity of CAD. The findings from this study reinforced our impression that combination therapy was a widespread practice in our organization. Similarly, these results mirror utilization statistics reported from two recent
multinational trials in which 25% of patients with chronic atrial fibrillation were also found to be on combination therapy [3]. With approximately 2.5 million people estimated to have atrial fibrillation as documented by the National Registry of Atrial Fibrillation, dual therapy is a likely occurrence since 30-40% of these patients have a concomitant diagnosis of CAD and 10-15% also have a high risk for stroke [4].
Consensus Guidelines Guidelines are available to help determine which patients are most appropriate for combination therapy. The American College of Chest Physicians (ACCP) recommends combination therapy for certain patients with valvular heart disease [5]. Mechanical valve patients with additional risk factors for stroke such as atrial fibrillation, MI, atrial enlargement, endocardial damage, or a low ejection fraction are considered candidates for combination therapy (low dose aspirin, 75-100 mg daily). Likewise, patients with caged-ball or cageddisk valves, or those who have a mechanical valve and suffer a systemic embolism despite a therapeutic international normalized ratio (INR), are candidates for combination therapy. Patients with rheumatic mitral valve disease with atrial fibrillation, or a history of systemic embolism, who then suffer a systemic event despite a therapeutic INR, should have aspirin added to their regimen. In the setting of atrial fibrillation, the American College of Cardiology, the American Heart Association, and the European Society of Cardiology released guidelines for management in 2006 that suggest most patients who have atrial fibrillation and stable CAD should have satisfactory protection with oral anticoagulation alone [6]. The committees recommend raising the intensity of anticoagulation to a higher INR goal for patients who experience an ischemic stroke or a systemic embolism during treatment with a therapeutic INR, rather than adding an antiplatelet agent. However, the level of evidence for this recommendation was low, as it was based on consensus opinion of experts, case studies, or standard of care.
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15 In the setting of unstable angina or non-ST segment elevation MI, the American College of Cardiology and the American Heart Association recommend that the use of warfarin with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely [7]. Warfarin monotherapy at a higher intensity, or with low dose aspirin at the usual intensity, may be reasonable for patients who are at high risk for CAD and a low bleeding risk who do not require, or are intolerant of, clopidogrel. In regards to the diabetic population who are at an increased risk for CAD, a position statement from the American Diabetes Association in 2004 noted that patients are not candidates for aspirin therapy if they are currently on anticoagulation or have any of the following: aspirin allergy, bleeding tendency, anticoagulant therapy, recent gastrointestinal bleeding or clinically active hepatic disease [8].
Clinical Evidence A recent meta-analysis of ten randomized trials assessed the efficacy and safety of adding aspirin to oral anticoagulation [9]. Studies selected for this analysis were randomized controlled trials in patients requiring oral anticoagulation and evaluated combination therapy versus oral anticoagulation alone. Patients were followed for at least three months and had to be anticoagulated to either the same INR goal or fixed dose of warfarin. At least one prespecified outcome, such as arterial thromboembolic events or major bleeding, had to be objectively documented for inclusion in the metaanalysis. This meta-analysis differed from prior analyses of combination therapy which included patients with a single diagnosis (e.g. mechanical heart valve) or included trials with different INR intensities across the treatment groups. This analysis included over 4000 patients with indications for anticoagulation of mechanical heart valves, atrial fibrillation, unstable angina and primary or secondary prevention of CAD. The doses of aspirin used in these trials ranged from a low dose at less than 100 mg per day to a moderate or high dose range of 200 - 1000 mg per day. Results from this analysis revealed a significant decrease in the risk for arterial events with patients receiving combination therapy (6.3% versus 8.8%). However, this benefit was obtained at an increased risk of major bleeding for patients who received combination therapy (3.8% versus 2.8%). There was no difference in fatal arterial events or all cause mortality between the groups. Data from the secondary analyses that
S13
evaluated individual indications for anticoagulation found identical results in the five trials of over 1000 patients with mechanical heart valves. Conversely, in patients with atrial fibrillation or coronary artery disease, no statistically significant difference was found for the risk of arterial events. In regards to major bleeding, there was no difference between the two treatment groups in patients with atrial fibrillation. The data for this outcome were not evaluated for the two coronary artery disease trials because one of those trials did not document bleeding events. Finally, there was no difference in mortality between the groups in patients with atrial fibrillation or CAD. These investigators concluded that combination therapy appears questionable except in select patients with mechanical heart valves, and they also highlight that combination therapy does increase the risk for bleeding. The majority of the findings in this meta-analysis seem to be supported by the data in three of the mechanical heart valve trials, and the one trial of primary prevention in high risk patients. Potential weaknesses of this analysis include differences in the definition of arterial events, and the criteria of major bleeding amongst the studies. The results of this study question routine prescribing of combination therapy in patients with atrial fibrillation and concurrent CAD or in those at high risk for stroke.
Atrial Fibrillation There are three randomized trials that have evaluated low dose oral anticoagulation (e.g. INR 1.21.5 or fixed dose 1.25 mg daily) with aspirin versus oral anticoagulation alone at the usual intensity (INR 2-3) in patients with atrial fibrillation [10–12]. The rationale for combination therapy in this situation is to reduce the risk of bleeding in elderly patients with lower intensity warfarin and concomitant aspirin and to enhance antithrombotic efficacy in patients at very high risk of thrombotic complications (e.g. prior stroke). These trials were not included in the prior meta-analysis because of the lower intensity of anticoagulation. Aspirin doses ranged from 300-325 mg daily in two of the trials (SPAF III and AFASAK II) and the antiplatelet agent, triflusal, was prescribed at 600 mg daily (equivalent to 300 mg aspirin) in the third trial (NASPEAF = Spanish National Study for Primary Prevention of Embolism in Nonrheumatic Atrial Fibrillation). Outcomes from SPAF III and AFASAK II demonstrated no benefit for combination therapy and no difference in major bleeding between the groups. In the third trial of 1200 patients, combination therapy significantly reduced the risk for the primary outcome of
S14
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15
thromboembolic events plus cardiovascular death in both the low and high risk groups, with no statistical difference in bleeding rate [12]. The findings from this study were considered less definitive as a large proportion of the primary outcomes were in nonthromboembolic events such as sudden death and heart failure. Likewise, the median INR's achieved in the anticoagulation and combination arms were quite similar.
Acute Coronary Syndrome (ACS) Initial management of ACS has consistently shown that combination therapy with a parenteral anticoagulant plus aspirin is more effective than aspirin alone. Likewise, in the long-term management of acute coronary syndrome, a meta-analysis of ten trials including nearly 6,000 patients demonstrated a 25% reduced risk of death, myocardial infarction or thromboembolic stroke when warfarin (titrated to an INR of 2-3) was added to aspirin [13]. This benefit was achieved at the cost of a 2-fold increased risk of major bleeding for those on combination therapy and a nonsignificant increase in intracranial bleeding. There was no difference in mortality between the groups. Several trials have also shown that moderate intensity oral anticoagulation (INR 2-3) with aspirin, or high intensity oral anticoagulation alone (INR 2.8-4.2), is superior to aspirin monotherapy [14,15]. Warfarin monotherapy may be an effective alternative in this patient population; however, this has not been adequately compared to combination therapy with the same level of anticoagulation intensity between groups. Most patients in the ACS trials did not have concomitant atrial fibrillation and on average, were approximately ten years younger than patients with atrial fibrillation. Therefore, results from these trials, especially hemorrhagic rates, may not be fully applicable to the typical patient with atrial fibrillation. The American College of Chest Physicians recommends several treatment options for management of this patient population based on patient risk, intensity of anticoagulation and availability of close monitoring of anticoagulation [16]. Moderate and low risk patients with MI should receive aspirin alone per these guidelines. If meticulous INR monitoring is available, both high and low risk patients should receive either anticoagulation alone at an INR of 3-4, or moderate intensity anticoagulation (INR 2-3) with aspirin. Finally, in high risk patients with MI, defined as a large anterior wall MI, significant heart failure, intra-cardiac thrombus, or history of thromboembolism, moderate intensity anticoagulation with low dose aspirin for three months is recommended.
Conclusions Despite the common practice of using combination therapy in a variety of disease states, there is a lack of convincing evidence to support this approach for most patients due to either inappropriate comparisons or lack of superiority in studies. The most compelling evidence for the use of combination therapy has been shown with mechanical cardiac valves in randomized controlled trials. An area in need of further investigation is the use of triple therapy with aspirin, warfarin and clopidogrel in the setting of percutaneous coronary intervention with coronary stent insertion. The American College of Chest Physicians and the American Heart Association support the use of triple therapy with caution, and recommend it for the minimum duration necessary and at the lowest effective dose (e.g. goal INR 2-2.5) [7]. Many questions remain about the safety and efficacy of combination therapy and it is clear that combination therapy increases the risk of bleeding. A subsequent paper from these proceedings will provide a more in-depth discussion of the bleeding risks. Decisions about aspirin use in most patients receiving warfarin will need to be made on an individual basis.
Conflict of Interest I have no conflict of interest to report.
References [1] Larson RJ, Fisher ES. Should aspirin be continued in patients started on warfarin? A systematic review and meta-analysis. J Gen Intern Med 2004;19:879–86. [2] Johnson SG, Witt DM, Eddy TR, Delate T. Warfarin and antiplatelet combination use among commercially insured patients enrolled in an anticoagulation management service. Chest 2007;131:1500–7. [3] Douketis JD, Arneklev K, Goldhaber SZ, Spandorfer J, Halperin F, Horrow J. Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, case fatality rate, time course, anatomic sites and risk factors for bleeding. Arch Intern Med 2006;166:853–9. [4] Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70. [5] Salem DN, Stein PD, Al-Ahmad A, Bussey HI, Horstkotte D, Miller N, et al. Antithrombotic therapy in valvular heart disease: native and prosthetic. Chest 2004;126:457S–82S. [6] Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 Guidelines for the management of atrial fibrillation. Circulation 2006;114:700–52. [7] Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, et al. ACC/AHA 2007 Guidelines for the management of patients with unstable angina/non-ST-elevation
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15
[8] [9]
[10]
[11]
[12]
myocardial infarction. J Am Coll Cardiol 2007;50 (7):652–726. Position statement- American Diabetes Association: Aspirin therapy in diabetes. Diabetes Care 2004;27:S72–S73. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med 2007;167:117–24. Stroke Prevention Atrial Fibrillation Investigators. Adjusteddose warfarin vs. low intensity, fixed dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996;348:633–8. Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: The AFASAK 2 Study. Arch Intern Med 1999;159:1322–8. Perez-Gomez F, Alegria E, Berjon J, Iriate JA, Zumalde J, Salvador A, et al. Comparative effects of antiplatelet, anticoagulant or combined therapy in patients with valvular
doi:10.1016/j.thromres.2008.08.012
[13]
[14]
[15]
[16]
S15 and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 2004;44:1557–66. Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J 2006;27:519–26. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin or both after myocardial infarction (WARIS II). N Engl J Med 2002;347:969–74. van Es RF, Jonker JJC, Verheught FWA, Deckers JW, Grobbee DE. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 Study): a randomized controlled trial. Lancet 2002;360:109–13. Harrington RA, Becker RC, Ezekowitz M, Meade TW, O'Connor CM, Vorchheimer DA, et al. Antithrombotic therapy for coronary artery disease. Chest 2004;126:513S–48S.
[14]
[15]
[16]
[17]
[18]
[19]
[20]
S11 the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005;149(4):645–9. Flaker JC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006;152(5):967–73. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689–96. Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007 19;357(3):217–27. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest 2005;127:1515–22. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004;35:2362–7. Buresly K, Eisenberg MJ, Zhang X, Pilote L. Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction. Arch Intern Med 2005;165:784–9. Johnson SG, Rogers KR, Delate T, Witt DM. Outcomes associated with combined antiplatelet and anticoagulant therapy. Chest 2008;133:948–54.
doi:10.1016/j.thromres.2008.08.011
Concomitant antiplatelet and anticoagulation therapy: Indications, controversies and practical advice M. Dowd Clinical Pharmacy Anticoagulation Service, Kaiser Permanente, Denver, Colorado
Available online 25 September 2008
Abstract The use of combination antiplatelet and anticoagulant therapy is commonly encountered in clinical practice and is often a source of clinical controversy in regards to the efficacy versus the safety of this regimen. The benefit of combination therapy relates to the probable additive effect of suppressing both platelet and coagulation factor activities.
E-mail address: [email protected].
S12
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15 The risk of dual therapy is the potential for increased hemorrhagic events which may outweigh the clinical benefit. This review will focus on the clinical evidence that has demonstrated greater efficacy with combination therapy over either antiplatelet or anticoagulant therapy alone. Clinicians should consider the importance of documentation of combination therapy use in their patients in an effort to target those patients with the greatest benefit, and to avoid unnecessary complications. © 2008 Elsevier Ltd. All rights reserved.
Prevalence of combination therapy Statistics from the Centers for Disease Control and Prevention (CDC) estimate that almost 23 million Americans take a daily aspirin [1]. More frequent use of aspirin, especially self-prescribing, has resulted from the lower risk of myocardial infarction (MI) and stroke. Likewise, warfarin prescribing is on the rise due to its proven efficacy in multiple disease states. A recent descriptive study of 4500 patients conducted at our clinical pharmacy anticoagulation service at Kaiser Permanente of Colorado found that 40% of patients taking warfarin were also on concomitant antiplatelet therapy [2]. Six months prior to this study, our service initiated a formal surveillance and documentation of aspirin use and non-use in our patients via our electronic database (Dawn-AC; 4S Systems; Cumbria, UK). The two cohorts which were included in this trial involved a monotherapy cohort of 2800 patients on warfarin alone, and a combination cohort with 1700 patients receiving some type of antiplatelet (primarily aspirin 81 mg daily) with warfarin. The primary outcome for the study was to measure prevalence of combination therapy, with a secondary outcome to identify patient characteristics associated with combination therapy. Results of this study revealed that patients receiving combination therapy were more likely to be male, older and on warfarin for a shorter duration than patients on warfarin monotherapy. Patients on combination therapy were also more likely to have co-morbid conditions such as hypertension, coronary artery disease (CAD), diabetes, heart failure and stroke (p b 0.001 for all results). Likewise, compared to a primary indication of venous thromboembolism, patients with a diagnosis of atrial fibrillation, heart valve disorder, stroke or CAD were more commonly prescribed combination therapy versus monotherapy (p b 0.001). The strongest predictors of combination therapy identified by multivariate logistic regression modeling were a primary indication of CAD compared to venous thromboembolism and a comorbidity of CAD. The findings from this study reinforced our impression that combination therapy was a widespread practice in our organization. Similarly, these results mirror utilization statistics reported from two recent
multinational trials in which 25% of patients with chronic atrial fibrillation were also found to be on combination therapy [3]. With approximately 2.5 million people estimated to have atrial fibrillation as documented by the National Registry of Atrial Fibrillation, dual therapy is a likely occurrence since 30-40% of these patients have a concomitant diagnosis of CAD and 10-15% also have a high risk for stroke [4].
Consensus Guidelines Guidelines are available to help determine which patients are most appropriate for combination therapy. The American College of Chest Physicians (ACCP) recommends combination therapy for certain patients with valvular heart disease [5]. Mechanical valve patients with additional risk factors for stroke such as atrial fibrillation, MI, atrial enlargement, endocardial damage, or a low ejection fraction are considered candidates for combination therapy (low dose aspirin, 75-100 mg daily). Likewise, patients with caged-ball or cageddisk valves, or those who have a mechanical valve and suffer a systemic embolism despite a therapeutic international normalized ratio (INR), are candidates for combination therapy. Patients with rheumatic mitral valve disease with atrial fibrillation, or a history of systemic embolism, who then suffer a systemic event despite a therapeutic INR, should have aspirin added to their regimen. In the setting of atrial fibrillation, the American College of Cardiology, the American Heart Association, and the European Society of Cardiology released guidelines for management in 2006 that suggest most patients who have atrial fibrillation and stable CAD should have satisfactory protection with oral anticoagulation alone [6]. The committees recommend raising the intensity of anticoagulation to a higher INR goal for patients who experience an ischemic stroke or a systemic embolism during treatment with a therapeutic INR, rather than adding an antiplatelet agent. However, the level of evidence for this recommendation was low, as it was based on consensus opinion of experts, case studies, or standard of care.
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15 In the setting of unstable angina or non-ST segment elevation MI, the American College of Cardiology and the American Heart Association recommend that the use of warfarin with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely [7]. Warfarin monotherapy at a higher intensity, or with low dose aspirin at the usual intensity, may be reasonable for patients who are at high risk for CAD and a low bleeding risk who do not require, or are intolerant of, clopidogrel. In regards to the diabetic population who are at an increased risk for CAD, a position statement from the American Diabetes Association in 2004 noted that patients are not candidates for aspirin therapy if they are currently on anticoagulation or have any of the following: aspirin allergy, bleeding tendency, anticoagulant therapy, recent gastrointestinal bleeding or clinically active hepatic disease [8].
Clinical Evidence A recent meta-analysis of ten randomized trials assessed the efficacy and safety of adding aspirin to oral anticoagulation [9]. Studies selected for this analysis were randomized controlled trials in patients requiring oral anticoagulation and evaluated combination therapy versus oral anticoagulation alone. Patients were followed for at least three months and had to be anticoagulated to either the same INR goal or fixed dose of warfarin. At least one prespecified outcome, such as arterial thromboembolic events or major bleeding, had to be objectively documented for inclusion in the metaanalysis. This meta-analysis differed from prior analyses of combination therapy which included patients with a single diagnosis (e.g. mechanical heart valve) or included trials with different INR intensities across the treatment groups. This analysis included over 4000 patients with indications for anticoagulation of mechanical heart valves, atrial fibrillation, unstable angina and primary or secondary prevention of CAD. The doses of aspirin used in these trials ranged from a low dose at less than 100 mg per day to a moderate or high dose range of 200 - 1000 mg per day. Results from this analysis revealed a significant decrease in the risk for arterial events with patients receiving combination therapy (6.3% versus 8.8%). However, this benefit was obtained at an increased risk of major bleeding for patients who received combination therapy (3.8% versus 2.8%). There was no difference in fatal arterial events or all cause mortality between the groups. Data from the secondary analyses that
S13
evaluated individual indications for anticoagulation found identical results in the five trials of over 1000 patients with mechanical heart valves. Conversely, in patients with atrial fibrillation or coronary artery disease, no statistically significant difference was found for the risk of arterial events. In regards to major bleeding, there was no difference between the two treatment groups in patients with atrial fibrillation. The data for this outcome were not evaluated for the two coronary artery disease trials because one of those trials did not document bleeding events. Finally, there was no difference in mortality between the groups in patients with atrial fibrillation or CAD. These investigators concluded that combination therapy appears questionable except in select patients with mechanical heart valves, and they also highlight that combination therapy does increase the risk for bleeding. The majority of the findings in this meta-analysis seem to be supported by the data in three of the mechanical heart valve trials, and the one trial of primary prevention in high risk patients. Potential weaknesses of this analysis include differences in the definition of arterial events, and the criteria of major bleeding amongst the studies. The results of this study question routine prescribing of combination therapy in patients with atrial fibrillation and concurrent CAD or in those at high risk for stroke.
Atrial Fibrillation There are three randomized trials that have evaluated low dose oral anticoagulation (e.g. INR 1.21.5 or fixed dose 1.25 mg daily) with aspirin versus oral anticoagulation alone at the usual intensity (INR 2-3) in patients with atrial fibrillation [10–12]. The rationale for combination therapy in this situation is to reduce the risk of bleeding in elderly patients with lower intensity warfarin and concomitant aspirin and to enhance antithrombotic efficacy in patients at very high risk of thrombotic complications (e.g. prior stroke). These trials were not included in the prior meta-analysis because of the lower intensity of anticoagulation. Aspirin doses ranged from 300-325 mg daily in two of the trials (SPAF III and AFASAK II) and the antiplatelet agent, triflusal, was prescribed at 600 mg daily (equivalent to 300 mg aspirin) in the third trial (NASPEAF = Spanish National Study for Primary Prevention of Embolism in Nonrheumatic Atrial Fibrillation). Outcomes from SPAF III and AFASAK II demonstrated no benefit for combination therapy and no difference in major bleeding between the groups. In the third trial of 1200 patients, combination therapy significantly reduced the risk for the primary outcome of
S14
Plenary Sessions/Thrombosis Research 123 (2008) S7–S15
thromboembolic events plus cardiovascular death in both the low and high risk groups, with no statistical difference in bleeding rate [12]. The findings from this study were considered less definitive as a large proportion of the primary outcomes were in nonthromboembolic events such as sudden death and heart failure. Likewise, the median INR's achieved in the anticoagulation and combination arms were quite similar.
Acute Coronary Syndrome (ACS) Initial management of ACS has consistently shown that combination therapy with a parenteral anticoagulant plus aspirin is more effective than aspirin alone. Likewise, in the long-term management of acute coronary syndrome, a meta-analysis of ten trials including nearly 6,000 patients demonstrated a 25% reduced risk of death, myocardial infarction or thromboembolic stroke when warfarin (titrated to an INR of 2-3) was added to aspirin [13]. This benefit was achieved at the cost of a 2-fold increased risk of major bleeding for those on combination therapy and a nonsignificant increase in intracranial bleeding. There was no difference in mortality between the groups. Several trials have also shown that moderate intensity oral anticoagulation (INR 2-3) with aspirin, or high intensity oral anticoagulation alone (INR 2.8-4.2), is superior to aspirin monotherapy [14,15]. Warfarin monotherapy may be an effective alternative in this patient population; however, this has not been adequately compared to combination therapy with the same level of anticoagulation intensity between groups. Most patients in the ACS trials did not have concomitant atrial fibrillation and on average, were approximately ten years younger than patients with atrial fibrillation. Therefore, results from these trials, especially hemorrhagic rates, may not be fully applicable to the typical patient with atrial fibrillation. The American College of Chest Physicians recommends several treatment options for management of this patient population based on patient risk, intensity of anticoagulation and availability of close monitoring of anticoagulation [16]. Moderate and low risk patients with MI should receive aspirin alone per these guidelines. If meticulous INR monitoring is available, both high and low risk patients should receive either anticoagulation alone at an INR of 3-4, or moderate intensity anticoagulation (INR 2-3) with aspirin. Finally, in high risk patients with MI, defined as a large anterior wall MI, significant heart failure, intra-cardiac thrombus, or history of thromboembolism, moderate intensity anticoagulation with low dose aspirin for three months is recommended.
Conclusions Despite the common practice of using combination therapy in a variety of disease states, there is a lack of convincing evidence to support this approach for most patients due to either inappropriate comparisons or lack of superiority in studies. The most compelling evidence for the use of combination therapy has been shown with mechanical cardiac valves in randomized controlled trials. An area in need of further investigation is the use of triple therapy with aspirin, warfarin and clopidogrel in the setting of percutaneous coronary intervention with coronary stent insertion. The American College of Chest Physicians and the American Heart Association support the use of triple therapy with caution, and recommend it for the minimum duration necessary and at the lowest effective dose (e.g. goal INR 2-2.5) [7]. Many questions remain about the safety and efficacy of combination therapy and it is clear that combination therapy increases the risk of bleeding. A subsequent paper from these proceedings will provide a more in-depth discussion of the bleeding risks. Decisions about aspirin use in most patients receiving warfarin will need to be made on an individual basis.
Conflict of Interest I have no conflict of interest to report.
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