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“Triple Therapy” or Triple Threat?
Journal of the American College of Cardiology © 2008 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 51, No. 8, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2007.11.034
FOCUS ISSUE: ATRIAL FIBRILLATION Editorial Comment
“Triple Therapy” or Triple Threat? Balancing the Risks of Antithrombotic Therapy for Patients With Atrial Fibrillation and Coronary Stents* Steven Francescone, MD, Jonathan L. Halperin, MD, FACC New York, New York Patients with atrial fibrillation (AF) who have additional risk factors for thromboembolism benefit from chronic anticoagulant therapy (1). When these patients undergo percutaneous coronary intervention (PCI), the need for platelet inhibitor medication poses a particular clinical challenge because the risk of bleeding is significantly increased, especially when “triple therapy” with a combination of warfarin, aspirin, and a thienopyridine is used. Scant data are available to guide management of such patients. See page 818
First, consider the imperative of preventing ischemic stroke in patients with AF. Warfarin reduces thromboembolism by about one-half while increasing major bleeding to 1% to 2% per year and doubling the risk of intracranial hemorrhage (2). For the highest-risk AF patients (those with prior stroke, transient ischemic attack, or mechanical heart valves), the benefit of anticoagulation generally outweighs the bleeding risk. On the other hand, low-risk patients can be adequately treated with aspirin alone (1). Analysis of data from 12 randomized trials directly comparing the treatments in 12,721 patients, predominantly for primary prevention, favors anticoagulation with a vitamin K antagonist over antiplatelet therapy (relative risk reduction [RR] about 40%, absolute RR about 1% per year) (2). Anticoagulation was also superior to the combination of
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Mount Sinai Medical Center, New York, New York. During the past 2 years, Dr. Halperin has received consulting fees from the following pharmaceutical manufacturers for advisory activities involving the development of new anticoagulant drugs, none of which are currently approved for clinical use in any indication: Astellas Pharma, Bayer AG HealthCare, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi-Sankyo Pharma, GlaxoSmithKline, Johnson & Johnson, and Sanofi-Aventis. In addition, he receives consulting fees from Biotronik, Inc. as Co-Chairman of the Steering Committee for the IMPACT clinical trial evaluating the use of ambulatory monitoring technology in approved implanted cardiac arrhythmia devices to guide anticoagulation therapy for stroke prevention, and an honorarium from Genzyme, Inc. for participation on the Data Safety Monitoring Board of its WALK trial involving gene therapy for patients with severe peripheral arterial disease.
aspirin plus clopidogrel in a large trial (6,706 patients; RR reduction 40% [95% confidence interval 18% to 56%]) (3). The problem stems from differences in the predominant pathophysiological processes involved in myocardial infarction (MI) and ischemic stroke: atherothrombosis versus cardiogenic embolism and the choice of antithrombotic therapy that results. In patients with coronary artery disease, platelet inhibitor therapy is generally prescribed. Although aspirin is the prophylactic antiplatelet drug of choice, it reduces the risk of recurrent stroke, MI, and vascular death by only 13% (4). Clopidogrel was 8% better than aspirin in one large trial and associated with fewer gastrointestinal bleeding complications (5). After PCI, dual antiplatelet therapy with aspirin plus a thienopyridine is superior to aspirin alone (6,7), warfarin alone, or warfarin plus aspirin (6,8,9). Addition of clopidogrel to aspirin in patients with acute coronary syndromes undergoing PCI significantly reduced rates of myocardial infarction and cardiovascular death (6.0% vs. 8.0%) at an average follow-up of 8 months (7). The trial was underpowered, however, to assess the efficacy of dual antiplatelet therapy compared with aspirin alone for stroke prevention (10). This and other trials support administering the combination of clopidogrel plus aspirin for 4 weeks after elective PCI and for up to 8 months in the acute setting when bare-metal stents (BMS) are used. The cumulative incidence of target lesion revascularization is lower with drug-eluting stents (DES) (1.9%/year) than with BMS (5%/year), with the majority of events occurring in the first year with either type of device (11). An apparently greater incidence of late stent thrombosis in patients treated with DES, is attributed to delayed re-endothelialization and higher complexity of coronary lesions (12,13). Stent thrombosis with DES can occur beyond the first year and has been associated with interruption of clopidogrel (14). The inherent risk of prolonged antiplatelet therapy is bleeding (10), which is compounded by adding an anticoagulant. In a secondary analysis of a randomized trial database, addition of aspirin (up to 100 mg daily) in patients with AF who were on warfarin (international normalized ratio 2.0 to 3.0) increased major bleeding (3.9%/year) compared with warfarin alone (2.3%/year, p ⫽ 0.01) with-
Francescone and Halperin Editorial Comment
JACC Vol. 51, No. 8, 2008 February 26, 2008:826–7
out reducing stroke and systemic embolism or MI (15). “Triple therapy” has been associated with major bleeding rates as high as 7%/year (16). In the series of patients with AF undergoing PCI described by Ruiz-Nodar et al. (17), omission of anticoagulation at discharge was associated with increased mortality and major adverse cardiovascular events at a median follow-up interval of 595 days, the longest observation period yet reported. The reduction in adverse events with regimens that included an anticoagulant was mainly attributable to lower rates of mortality and ischemic stroke. Patients with renal failure or acute ST-segment elevation MI were more likely to receive dual antiplatelet therapy without anticoagulation, and this may have contributed to the difference in mortality. There was no significant difference in rates of stent thrombosis between the groups. The data were derived from retrospective analysis and entailed the considerable variability in the type and duration of antithrombotic therapy that typically characterizes practice in the absence of clear and consistent evidence-based guidelines. These limitations preclude reasonable recommendations regarding the safety and efficacy of triple therapy. Even so, the study highlights the importance of maintaining anticoagulation in patients with AF undergoing PCI. In the absence of randomized trials, physicians must individualize antithrombotic therapy, taking into account the risks of hemorrhage, thromboembolism, and stent thrombosis. Patients with AF who have more than 1 moderate risk factor for thromboembolism (clinical heart failure or impaired left ventricular systolic function [ejection fraction less than or equal to 35%], history of hypertension, age ⬎75 years, diabetes mellitus, prior stroke or transient ischemic attack score ⫽ 2 or more) (18) should resume anticoagulation as soon as feasible after PCI. For those at low risk of serious bleeding, treatment with triple therapy may be the best option. Perhaps more to the point, BMS may be preferable to DES in patients with AF who have risk factors for thromboembolism requiring chronic anticoagulation to reduce the need for prolonged combination therapy. A pressing question is whether beyond the first few weeks after stent deployment a maintenance regimen consisting of warfarin plus clopidogrel alone would preserve efficacy while reducing the risk of gastrointestinal bleeding (19). The answer will require additional studies not only in patients with AF but also in the broader population of patients with coronary artery disease who have an ongoing need for anticoagulation. Reprint requests and correspondence: Dr. Jonathan L. Halperin, The Cardiovascular Institute, Mount Sinai Medical Center, Fifth Avenue at 100th Street, New York, New York 10029. E-mail: [email protected]. REFERENCES
1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation— executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and
2. 3.
4.
5. 6.
7.
8.
9.
10.
11. 12. 13. 14.
15.
16.
17.
18. 19.
827
the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854 –906. Hart RG, Pearce LA, Aguilar MI. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann Intern Med 2007;147:590 –2. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903–12. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:483S–512S. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329 –39. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation 1998;98:1597– 603. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339:1665–71. Rubboli A, Milandri M, Castelvetri C, Cosmi B. Meta-analysis of trials comparing oral anticoagulation and aspirin versus dual antiplatelet therapy after coronary stenting. Clues for the management of patients with an indication for long-term anticoagulation undergoing coronary stenting. Cardiology 2005;104:101– 6. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network metaanalysis. Lancet 2007;370:937– 48. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and longterm outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113:1108 –13. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967–71. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584 –91. Flaker GC, Gruber M, Connolly SJ, 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;152:967–73. Khurram Z, Chou E, Minutello R, et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 2006;18: 162– 4. Ruiz-Nodar JM, Marı´n F, Hurtado JA, et al. Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation: implications for bleeding risk and prognosis. J Am Coll Cardiol 2008;51:818 –25. van Walraven C, Hart RG, Wells GA, et al. A clinical prediction rule to identify patients with atrial fibrillation and a low risk for stroke while taking aspirin. Arch Intern Med 2003;163:936 – 43. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745–54.
Vol. 51, No. 8, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2007.11.034
FOCUS ISSUE: ATRIAL FIBRILLATION Editorial Comment
“Triple Therapy” or Triple Threat? Balancing the Risks of Antithrombotic Therapy for Patients With Atrial Fibrillation and Coronary Stents* Steven Francescone, MD, Jonathan L. Halperin, MD, FACC New York, New York Patients with atrial fibrillation (AF) who have additional risk factors for thromboembolism benefit from chronic anticoagulant therapy (1). When these patients undergo percutaneous coronary intervention (PCI), the need for platelet inhibitor medication poses a particular clinical challenge because the risk of bleeding is significantly increased, especially when “triple therapy” with a combination of warfarin, aspirin, and a thienopyridine is used. Scant data are available to guide management of such patients. See page 818
First, consider the imperative of preventing ischemic stroke in patients with AF. Warfarin reduces thromboembolism by about one-half while increasing major bleeding to 1% to 2% per year and doubling the risk of intracranial hemorrhage (2). For the highest-risk AF patients (those with prior stroke, transient ischemic attack, or mechanical heart valves), the benefit of anticoagulation generally outweighs the bleeding risk. On the other hand, low-risk patients can be adequately treated with aspirin alone (1). Analysis of data from 12 randomized trials directly comparing the treatments in 12,721 patients, predominantly for primary prevention, favors anticoagulation with a vitamin K antagonist over antiplatelet therapy (relative risk reduction [RR] about 40%, absolute RR about 1% per year) (2). Anticoagulation was also superior to the combination of
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Mount Sinai Medical Center, New York, New York. During the past 2 years, Dr. Halperin has received consulting fees from the following pharmaceutical manufacturers for advisory activities involving the development of new anticoagulant drugs, none of which are currently approved for clinical use in any indication: Astellas Pharma, Bayer AG HealthCare, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi-Sankyo Pharma, GlaxoSmithKline, Johnson & Johnson, and Sanofi-Aventis. In addition, he receives consulting fees from Biotronik, Inc. as Co-Chairman of the Steering Committee for the IMPACT clinical trial evaluating the use of ambulatory monitoring technology in approved implanted cardiac arrhythmia devices to guide anticoagulation therapy for stroke prevention, and an honorarium from Genzyme, Inc. for participation on the Data Safety Monitoring Board of its WALK trial involving gene therapy for patients with severe peripheral arterial disease.
aspirin plus clopidogrel in a large trial (6,706 patients; RR reduction 40% [95% confidence interval 18% to 56%]) (3). The problem stems from differences in the predominant pathophysiological processes involved in myocardial infarction (MI) and ischemic stroke: atherothrombosis versus cardiogenic embolism and the choice of antithrombotic therapy that results. In patients with coronary artery disease, platelet inhibitor therapy is generally prescribed. Although aspirin is the prophylactic antiplatelet drug of choice, it reduces the risk of recurrent stroke, MI, and vascular death by only 13% (4). Clopidogrel was 8% better than aspirin in one large trial and associated with fewer gastrointestinal bleeding complications (5). After PCI, dual antiplatelet therapy with aspirin plus a thienopyridine is superior to aspirin alone (6,7), warfarin alone, or warfarin plus aspirin (6,8,9). Addition of clopidogrel to aspirin in patients with acute coronary syndromes undergoing PCI significantly reduced rates of myocardial infarction and cardiovascular death (6.0% vs. 8.0%) at an average follow-up of 8 months (7). The trial was underpowered, however, to assess the efficacy of dual antiplatelet therapy compared with aspirin alone for stroke prevention (10). This and other trials support administering the combination of clopidogrel plus aspirin for 4 weeks after elective PCI and for up to 8 months in the acute setting when bare-metal stents (BMS) are used. The cumulative incidence of target lesion revascularization is lower with drug-eluting stents (DES) (1.9%/year) than with BMS (5%/year), with the majority of events occurring in the first year with either type of device (11). An apparently greater incidence of late stent thrombosis in patients treated with DES, is attributed to delayed re-endothelialization and higher complexity of coronary lesions (12,13). Stent thrombosis with DES can occur beyond the first year and has been associated with interruption of clopidogrel (14). The inherent risk of prolonged antiplatelet therapy is bleeding (10), which is compounded by adding an anticoagulant. In a secondary analysis of a randomized trial database, addition of aspirin (up to 100 mg daily) in patients with AF who were on warfarin (international normalized ratio 2.0 to 3.0) increased major bleeding (3.9%/year) compared with warfarin alone (2.3%/year, p ⫽ 0.01) with-
Francescone and Halperin Editorial Comment
JACC Vol. 51, No. 8, 2008 February 26, 2008:826–7
out reducing stroke and systemic embolism or MI (15). “Triple therapy” has been associated with major bleeding rates as high as 7%/year (16). In the series of patients with AF undergoing PCI described by Ruiz-Nodar et al. (17), omission of anticoagulation at discharge was associated with increased mortality and major adverse cardiovascular events at a median follow-up interval of 595 days, the longest observation period yet reported. The reduction in adverse events with regimens that included an anticoagulant was mainly attributable to lower rates of mortality and ischemic stroke. Patients with renal failure or acute ST-segment elevation MI were more likely to receive dual antiplatelet therapy without anticoagulation, and this may have contributed to the difference in mortality. There was no significant difference in rates of stent thrombosis between the groups. The data were derived from retrospective analysis and entailed the considerable variability in the type and duration of antithrombotic therapy that typically characterizes practice in the absence of clear and consistent evidence-based guidelines. These limitations preclude reasonable recommendations regarding the safety and efficacy of triple therapy. Even so, the study highlights the importance of maintaining anticoagulation in patients with AF undergoing PCI. In the absence of randomized trials, physicians must individualize antithrombotic therapy, taking into account the risks of hemorrhage, thromboembolism, and stent thrombosis. Patients with AF who have more than 1 moderate risk factor for thromboembolism (clinical heart failure or impaired left ventricular systolic function [ejection fraction less than or equal to 35%], history of hypertension, age ⬎75 years, diabetes mellitus, prior stroke or transient ischemic attack score ⫽ 2 or more) (18) should resume anticoagulation as soon as feasible after PCI. For those at low risk of serious bleeding, treatment with triple therapy may be the best option. Perhaps more to the point, BMS may be preferable to DES in patients with AF who have risk factors for thromboembolism requiring chronic anticoagulation to reduce the need for prolonged combination therapy. A pressing question is whether beyond the first few weeks after stent deployment a maintenance regimen consisting of warfarin plus clopidogrel alone would preserve efficacy while reducing the risk of gastrointestinal bleeding (19). The answer will require additional studies not only in patients with AF but also in the broader population of patients with coronary artery disease who have an ongoing need for anticoagulation. Reprint requests and correspondence: Dr. Jonathan L. Halperin, The Cardiovascular Institute, Mount Sinai Medical Center, Fifth Avenue at 100th Street, New York, New York 10029. E-mail: [email protected]. REFERENCES
1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation— executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and
2. 3.
4.
5. 6.
7.
8.
9.
10.
11. 12. 13. 14.
15.
16.
17.
18. 19.
827
the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:854 –906. Hart RG, Pearce LA, Aguilar MI. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann Intern Med 2007;147:590 –2. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903–12. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:483S–512S. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329 –39. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation 1998;98:1597– 603. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339:1665–71. Rubboli A, Milandri M, Castelvetri C, Cosmi B. Meta-analysis of trials comparing oral anticoagulation and aspirin versus dual antiplatelet therapy after coronary stenting. Clues for the management of patients with an indication for long-term anticoagulation undergoing coronary stenting. Cardiology 2005;104:101– 6. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network metaanalysis. Lancet 2007;370:937– 48. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and longterm outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113:1108 –13. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967–71. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584 –91. Flaker GC, Gruber M, Connolly SJ, 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;152:967–73. Khurram Z, Chou E, Minutello R, et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 2006;18: 162– 4. Ruiz-Nodar JM, Marı´n F, Hurtado JA, et al. Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation: implications for bleeding risk and prognosis. J Am Coll Cardiol 2008;51:818 –25. van Walraven C, Hart RG, Wells GA, et al. A clinical prediction rule to identify patients with atrial fibrillation and a low risk for stroke while taking aspirin. Arch Intern Med 2003;163:936 – 43. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation 2007;116:745–54.