Clinical Therapeutics/Volume 36, Number 9, 2014
Managing Antithrombotic Therapy in Patients With Both Atrial Fibrillation and Coronary Heart Disease Peter L. Thompson, MD1; and Freek W.A. Verheugt, MD2 1
Heart Research Institute, Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia; and 2Heart-Lung Centre, University Medical Centre of Nijmegen, Department of Cardiology, Ozne Lieve Vrouve Gasthuis, Amsterdam, the Netherlands
ABSTRACT Purpose: Atrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y12 antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy. Methods: We conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents. Findings: Oral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dualantiplatelet therapy with aspirin and clopidogrel or a new P2Y12 inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events. Implications: Available clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer
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P2Y12 inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care. (Clin Ther. 2014;36:1176–1181) & 2014 Published by Elsevier HS Journals, Inc. Key Words: aspirin, atrial fibrillation, coronary heart disease, P2Y12 antiplatelet agents novel oral anticoagulants, warfarin.
BACKGROUND Previous European1 and US2 consensus statements for managing patients with combined coronary heart disease (CHD) and atrial fibrillation (AF) were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y12 antiplatelet inhibitors. In this commentary, we highlight the lack of sound evidence to guide clinical decision making and the need for the rapid development of clinical trials to close the large gaps in evidence.
THE NEED FOR COMBINED ANTICOAGULATION AND ANTIPLATELET THERAPY IN AF AND CHD In patients with AF, the significant risk of stroke and the need for anticoagulation in patients is now widely recognized.3 Randomized trials of antiplatelet agents have shown only marginal benefit over placebo,4 whereas trials of oral anticoagulation with vitamin K antagonists (VKAs) have been convincing.5 Oral anticoagulation is now recommended in all guidelines for AF patients with a risk of stroke, as estimated from their CHA2DS2VASc score.6,7 Accepted for publication August 18, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.08.010 0149-2918/$ - see front matter & 2014 Published by Elsevier HS Journals, Inc.
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P.L. Thompson and F.W.A. Verheugt CHD is also widely recognized as an atherothrombotic disease, but the mechanisms of coronary thrombosis in CHD differ so markedly from those that cause left atrial thrombus in AF that different antithrombotic agents are necessary. Antiplatelet therapy with aspirin has been shown to reduce the 2-year risk of cardiovascular events in stable CHD8 and is now recommended in all guidelines for patients with stable CHD9,10 and after an acute coronary syndrome (ACS).11–14 In most medical systems, aspirin is now used in nearly 100% of patients recovering from an ACS.15,16 Clopidogrel as monotherapy in stable CHD has only marginal benefits over aspirin,17 but the addition of clopidogrel to aspirin has been shown to be superior to aspirin alone in patients after percutaneous coronary intervention (PCI)18 and after an acute coronary syndrome,19 whether they received conservative therapy20 or PCI.21 As a result of these convincing trials, the use of dual-antiplatelet therapy (DAPT) is now recommended in all patients who have experienced an ACS11–17 and after PCI.22 The ideal duration of DAPT is yet to be clarified but longer use is being examined in the ongoing DAPT (Dual-Antiplatelet Therapy) study23 and shorter use in the ISAR-SAFE (Safety and Efficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting) study.24 The need to combine anticoagulation and antiplatelet therapy in patients with AF and CHD increases the risk of bleeding, which adversely influences prognosis.25 Although bleeding risk scores such as HAS-BLED26 (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (465 years), Drugs/alcohol concomitantly) can predict bleeding risk in AF,27 their use has not been demonstrated in practice to reduce the risk of bleeding. Clinical decision making in patients with concomitant CHD and AF has become more complex with the introduction to practice of NOACs including dabigatran,28 rivaroxaban,29 and apixaban,30 which are more effective and easier to use than warfarin or other VKAs. Similar results were recently reported with edoxaban.31 A recent meta-analysis showed the superiority of NOACs over warfarin with lower rates of stroke or systemic embolic events and half the rate of hemorrhagic stroke, significantly reduced all-cause mortality with a marginally significant increase in gastrointestinal bleeding.32 The use of NOACs is recommended for nonvalvular AF in recent US
September 2014
and European guidelines.6,7 The availability of new antiplatelet P2Y12 inhibitors such as prasugel33 and ticagrelor,34 which have been shown to be more effective than clopidogrel but with higher bleeding risks, are also now recommended in recent guideline updates for ACSs11–17 and add further complexity. An overview of the evidence to guide the management of patients with stable CHD, nonstented patients with recent ACS, and patients with a coronary stent requiring dual-antiplatelet therapy shows significant deficits.
PATIENTS WITH STABLE CHD AND AF All recent guidelines recommend that patients with AF and a risk of stroke with a CHA2DS2VASc score of Z1 should be treated with oral anticoagulants (OACs),6,7 and that patients with stable CHD should be treated with aspirin.9,10 It is not possible to substitute aspirin and clopidogrel for warfarin in to prevent stroke.31 Although patients with stable CHD and AF and a with low risk of stroke based on their CHA2DS2VASc score can be managed with aspirin alone, guidelines-directed therapy will result in almost all patients with CHD and AF being considered for triple antithrombotic therapy with 2 antiplatelet agents and an OAC. The anticipated increase in risk of bleeding when aspirin or clopidogrel are added to VKAs has been confirmed in large registry studies.35 Although there is evidence of a benefit of warfarin in CHD,36 the finding of a marginally significant increase in myocardial infarction with the higher dose level of dabigatran (150 mg twice daily) in the RELY (Randomized Evaluation of Long-term Anticoagulation Therapy), the first NOAC trial, caused some initial concern.32 It is reassuring that the most recent metaanalysis has shown no increase in myocardial infarction (relative risk ¼ 0.97; 95% CI, 0.78–1.2) when all trials of NOACs versus warfarin are considered.35 Current data to estimate the antithrombotic benefits and bleeding risks of the combinations of NOACs in combination with aspirin are limited to nonrandomized post hoc observations from within the randomized trials; they confirm a moderate increase in the risk of bleeding with the combination.37,38 The lack of reliable randomized trial evidence to guide therapy in this group of patients is concerning.
NONSTENTED POST-ACS PATIENTS WITH AF Although coronary intervention is regarded as the most effective treatment in ACSs, many patients experiencing an ACS will be managed conservatively
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Clinical Therapeutics (ie, without insertion of a coronary stent). All ACS guidelines now recommend DAPT in conservatively managed post-ACS patients. The development of AF during this period can present a dilemma as the DAPT may need to be combined with an OAC. The Danish registry data cited previously39 showed that the bleeding risk of triple antithrombotic therapy (aspirin, clopidogrel, and warfarin) was nearly quadrupled compared with monotherapy with warfarin. Shortening the duration of DAPT may be an option. In both the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) and the Chinese COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) study,22,23 most of the benefit was achieved in the first 3 months, with less benefit in the rest of the year, suggesting that withdrawal after 3 to 4 months of clopidogrel may be an option. Increasingly, patients are being discharged from the hospital after an ACS on one of the newer P2Y12 inhibitors such as prasugrel and ticagrelor, and the lack of an evidence base to guide therapy when these patients have AF is concerning.
POST-PCI PATIENTS WITH AF As PCI is now the dominant of therapy for CHD, it is very common for the clinician to be confronted with decisions on how to manage stroke risk in a patient with AF and a coronary stent requiring DAPT. There is the additional concern that undertreatment with antiplatelet therapy may lead to stent thrombosis. The marked variation in how clinicians deal with this challenge reflects the lack of clear evidence and guidelines.39 Incomplete but nevertheless valuable guidance has come from recently reported registry and clinical trial data. A report from a large Danish registry study examined dual and triple antithrombotic therapies in 12,165 AF patients hospitalized with myocardial infarction and/or undergoing PCI between 2001 and 2009.40 Compared with triple antithrombotic therapy (oral anticoagulation plus aspirin plus clopidogrel), there was no increased risk of recurrent coronary events when double therapy was compared with triple therapy. However, when an OAC was missing from the antithrombotic regimen (aspirin plus clopidogrel), there was double the risk of ischemic stroke This registry also confirmed that bleeding risk was nonsignificantly lower for double therapy (OAC plus clopidogrel) and significantly lower for OAC plus aspirin when compared with triple therapy. This observational study suggests that OAC with clopidogrel may be the preferred dual-therapy combination.
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The WOEST (What is the Optimal antiplatelEt & Anticoagulant Therapy in Patients With Oral Anticoagulation and StenTing) study is the only randomized, controlled trial to date that has studied this issue.41 The investigators examined the effect of double versus triple antithrombotic therapy. For patients with coronary stents, the triple-therapy group (warfarin, clopidogrel, and aspirin) was associated with a significantly higher risk of bleeding than the double-therapy group (warfarin and clopidogrel). There was no higher risk of coronary events or stent thrombosis with triple therapy. In this trial, double therapy did not carry a high risk of coronary events and was associated with a significantly lower bleeding risk than triple therapy. Although the results from the WOEST study were clear, there are limitations to applying these results to the care of all patients with AF and CHD. The indication for anticoagulation in patients in the WOEST study was not only for AF but also included 30% of patients with other anticoagulant indications, and there were no differences in more severe grades of bleeding. As a result, caution has been expressed in the uncritical application of the WOEST study results to the management of patients with AF and CHD.42 There is even less justification to translate the WOEST study results to patients taking NOACs and newer P2Y12 antiplatelet agents. An alternative approach may be to shorten the period of exposure to DAPT after PCI to reduce the time of exposure to triple therapy. Some randomized trials have suggested that the duration of DAPT can be o12 months with newer generation stents,43,44 but these trials have lacked the power to recommend widespread adoption of a shorter duration of DAPT. Observational studies have suggested a low risk of major events after the first month of DAPT with a newer drug-eluting stent,45 and a low risk with physician-supervised cessation.46 The results of the ISAR-SAFE trial examining shorter duration of DAPT of o12 months is awaited with interest.27 None of the cited trials examine the effect of interactions between warfarin or NOACS with the newer P2Y12 inhibitor antiplatelet agents, which are being increasingly prescribed for post-PCI patients. The PIONEER AF-PCI (An Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous
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P.L. Thompson and F.W.A. Verheugt Coronary Intervention) trial is specifically exploring the use of rivaroxaban versus warfarin in AF with various combinations of DAPT. The RE-DUAL (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting) study is comparing dual therapy with dabigatran plus clopidogrel or ticagrelor with a triple antithrombotic therapy combination of warfarin plus clopidogrel or ticagrelor plus aspirin in patients undergoing PCI.
CONCLUSIONS Our conclusion from this overview is that rational decision making in patients with both AF and CHD remains challenging and based on very incomplete evidence. Careful randomized trials and registry analyses are urgently needed, particularly evaluating combinations of the NOACs and the new P2Y12 inhibitors.
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ACKNOWLEDGMENTS All authors contributed equally to the literature search, data interpretation, and writing of the manuscript.
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CONFLICTS OF INTEREST Dr. Thompson has received research support and honoraria from Boehringer Ingelheim, Astra Zeneca, Pfizer, Bristol Myers Squibb. Dr Verheugt received honoraria for speaker fees and consultancy from AstraZenenca, Medtronic, Bayer Healthcare, Boehringer-Ingelheim, BMS/Pfizer and Daiichi-Sankyo.
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REFERENCES 1. Lip GY, Huber K, Andreotti F, et al. Consensus Document of European Society of Cardiology Working Group on Thrombosis. Antithrombotic management of atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing coronary stenting: executive summary– a Consensus Document of the European Society of Cardiology Working Group on Thrombosis, endorsed by the European Heart Rhythm Association (EHRA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2010;31:1311–1318. 2. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A NorthAmerican perspective. Thromb Haemost. 2011;106:572–584. 3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983–988. 4. Hart RG, Pearce LA, Aguilar MI, et al. Meta-analysis: antithrombotic therapy to prevent stroke in patients who
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11.
12.
13.
have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–867. Aguilar MI, Hart RG. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2005;Oct 19:CD001925. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719–2747. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014 Apr 10. [Epub ahead of print]. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86. Fihn SD, Gardin JM, Abrams J, et al. Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126:e354–e471. Task Force Members, Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/ AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e663–e828. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569–2619. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST- Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update). Circulation. 2009;120:2271–2306.
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Clinical Therapeutics 14. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999–3054. 15. Chew DP, French J, Briffa TG, et al. Acute coronary syndrome care across Australia and New Zealand: the SNAPSHOT ACS study. Med J Aust. 2013;199:185–191. 16. Eagle KA, Montoye CK, Riba AL, et al. Guideline-based standardized care is associated with substantially lower mortality in Medicare patients with acute myocardial infarction: the American College of Cardiology’s Guidelines Applied in Practice (GAP) Projects in Michigan. J Am Coll Cardiol. 2005;46:1242–1248. 17. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329–1339. 18. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420. 19. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebocontrolled trial. Lancet. 2005;366: 1607–1621. 20. Yusuf S, Zhao F, Mehta SR, et al. 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. 21. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by longterm therapy in patients undergoing percutaneous coronary intervention:
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22.
23.
24.
25.
26.
27.
the PCI-CURE study. Lancet. 2001; 358:527–533. Levine GN, Bates ER, Blankenship JC, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. J Am Coll Cardiol. 2011;58:e44–e122. Mauri L, Kereiakes DJ, Normand SL, et al. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am Heart J. 2010;160:1035–1041. Byrne RA, Schulz S, Mehilli J, et al. ISAR-SAFE Investigators. Rationale and design of a randomized, double-blind, placebo-controlled trial of 6 versus 12 months clopidogrel therapy after implantation of a drugeluting stent: the Intracoronary Stenting and Antithrombotic Regimen: Safety And Efficacy of 6 Months Dual Antiplatelet Therapy After DrugEluting Stenting (ISAR-SAFE) study. Am Heart J. 2009;157:620–624. e2. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774–782. Lip G, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2011;57:173–180. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093–1100.
28. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151. 29. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891. 30. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992. 31. ACTIVE Writing Group of the ACTIVE Investigators. 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;367:1903–1912. 32. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–962. 33. Wiviott SD, Braunwald E, McCabe CH, et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015. 34. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361: 1045–1057. 35. Lamberts M, Gislason GH, Lip GY, et al. Antiplatelet Therapy for Stable Coronary Artery Disease in Atrial Fibrillation Patients on Oral Anticoagulant: A Nationwide Cohort Study. Circulation. 2014;129:1577–1585. 36. Rothberg MB, Celestin C, Fiore LD, et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143:241–250. 37. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation
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38.
39.
40.
41.
42.
43.
44.
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of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation. 2013; 127:634–640. Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2014;35:224–232. Rubboli A, Dewilde W, Huber K, et al. The management of patients on oral anticoagulation undergoing coronary stent implantation: a survey among interventional cardiologists from eight European countries. J Interv Cardiol. 2012 Apr;25:163–169. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol. 2013 Sep 10;62:981–989. Dewilde WJ, Oirbans T, Verheugt FW, et al. WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381:1107–1115. Fox KA. Dual or single antiplatelet therapy with anticoagulation? Lancet. 2013;381:1080–1081. Valgimigli M, Campo G, Monti M, et al. Prolonging Dual Antiplatelet Treatment After Grading Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicentre trial. Circulation. 2012;125: 2015–2026. Kim BK, Hong MK, Shin DH, et al. RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012; 60:1340–1348. Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent
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thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation. Eur Heart J. 2014; 35:1949–1956. 46. Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet. 2013;382:1714–1722.
Address correspondence to: Peter L. Thompson, MD. E-mail: [email protected]
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Managing Antithrombotic Therapy in Patients With Both Atrial Fibrillation and Coronary Heart Disease Peter L. Thompson, MD1; and Freek W.A. Verheugt, MD2 1
Heart Research Institute, Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia; and 2Heart-Lung Centre, University Medical Centre of Nijmegen, Department of Cardiology, Ozne Lieve Vrouve Gasthuis, Amsterdam, the Netherlands
ABSTRACT Purpose: Atrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y12 antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy. Methods: We conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents. Findings: Oral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dualantiplatelet therapy with aspirin and clopidogrel or a new P2Y12 inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events. Implications: Available clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer
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P2Y12 inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care. (Clin Ther. 2014;36:1176–1181) & 2014 Published by Elsevier HS Journals, Inc. Key Words: aspirin, atrial fibrillation, coronary heart disease, P2Y12 antiplatelet agents novel oral anticoagulants, warfarin.
BACKGROUND Previous European1 and US2 consensus statements for managing patients with combined coronary heart disease (CHD) and atrial fibrillation (AF) were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y12 antiplatelet inhibitors. In this commentary, we highlight the lack of sound evidence to guide clinical decision making and the need for the rapid development of clinical trials to close the large gaps in evidence.
THE NEED FOR COMBINED ANTICOAGULATION AND ANTIPLATELET THERAPY IN AF AND CHD In patients with AF, the significant risk of stroke and the need for anticoagulation in patients is now widely recognized.3 Randomized trials of antiplatelet agents have shown only marginal benefit over placebo,4 whereas trials of oral anticoagulation with vitamin K antagonists (VKAs) have been convincing.5 Oral anticoagulation is now recommended in all guidelines for AF patients with a risk of stroke, as estimated from their CHA2DS2VASc score.6,7 Accepted for publication August 18, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.08.010 0149-2918/$ - see front matter & 2014 Published by Elsevier HS Journals, Inc.
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P.L. Thompson and F.W.A. Verheugt CHD is also widely recognized as an atherothrombotic disease, but the mechanisms of coronary thrombosis in CHD differ so markedly from those that cause left atrial thrombus in AF that different antithrombotic agents are necessary. Antiplatelet therapy with aspirin has been shown to reduce the 2-year risk of cardiovascular events in stable CHD8 and is now recommended in all guidelines for patients with stable CHD9,10 and after an acute coronary syndrome (ACS).11–14 In most medical systems, aspirin is now used in nearly 100% of patients recovering from an ACS.15,16 Clopidogrel as monotherapy in stable CHD has only marginal benefits over aspirin,17 but the addition of clopidogrel to aspirin has been shown to be superior to aspirin alone in patients after percutaneous coronary intervention (PCI)18 and after an acute coronary syndrome,19 whether they received conservative therapy20 or PCI.21 As a result of these convincing trials, the use of dual-antiplatelet therapy (DAPT) is now recommended in all patients who have experienced an ACS11–17 and after PCI.22 The ideal duration of DAPT is yet to be clarified but longer use is being examined in the ongoing DAPT (Dual-Antiplatelet Therapy) study23 and shorter use in the ISAR-SAFE (Safety and Efficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting) study.24 The need to combine anticoagulation and antiplatelet therapy in patients with AF and CHD increases the risk of bleeding, which adversely influences prognosis.25 Although bleeding risk scores such as HAS-BLED26 (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (465 years), Drugs/alcohol concomitantly) can predict bleeding risk in AF,27 their use has not been demonstrated in practice to reduce the risk of bleeding. Clinical decision making in patients with concomitant CHD and AF has become more complex with the introduction to practice of NOACs including dabigatran,28 rivaroxaban,29 and apixaban,30 which are more effective and easier to use than warfarin or other VKAs. Similar results were recently reported with edoxaban.31 A recent meta-analysis showed the superiority of NOACs over warfarin with lower rates of stroke or systemic embolic events and half the rate of hemorrhagic stroke, significantly reduced all-cause mortality with a marginally significant increase in gastrointestinal bleeding.32 The use of NOACs is recommended for nonvalvular AF in recent US
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and European guidelines.6,7 The availability of new antiplatelet P2Y12 inhibitors such as prasugel33 and ticagrelor,34 which have been shown to be more effective than clopidogrel but with higher bleeding risks, are also now recommended in recent guideline updates for ACSs11–17 and add further complexity. An overview of the evidence to guide the management of patients with stable CHD, nonstented patients with recent ACS, and patients with a coronary stent requiring dual-antiplatelet therapy shows significant deficits.
PATIENTS WITH STABLE CHD AND AF All recent guidelines recommend that patients with AF and a risk of stroke with a CHA2DS2VASc score of Z1 should be treated with oral anticoagulants (OACs),6,7 and that patients with stable CHD should be treated with aspirin.9,10 It is not possible to substitute aspirin and clopidogrel for warfarin in to prevent stroke.31 Although patients with stable CHD and AF and a with low risk of stroke based on their CHA2DS2VASc score can be managed with aspirin alone, guidelines-directed therapy will result in almost all patients with CHD and AF being considered for triple antithrombotic therapy with 2 antiplatelet agents and an OAC. The anticipated increase in risk of bleeding when aspirin or clopidogrel are added to VKAs has been confirmed in large registry studies.35 Although there is evidence of a benefit of warfarin in CHD,36 the finding of a marginally significant increase in myocardial infarction with the higher dose level of dabigatran (150 mg twice daily) in the RELY (Randomized Evaluation of Long-term Anticoagulation Therapy), the first NOAC trial, caused some initial concern.32 It is reassuring that the most recent metaanalysis has shown no increase in myocardial infarction (relative risk ¼ 0.97; 95% CI, 0.78–1.2) when all trials of NOACs versus warfarin are considered.35 Current data to estimate the antithrombotic benefits and bleeding risks of the combinations of NOACs in combination with aspirin are limited to nonrandomized post hoc observations from within the randomized trials; they confirm a moderate increase in the risk of bleeding with the combination.37,38 The lack of reliable randomized trial evidence to guide therapy in this group of patients is concerning.
NONSTENTED POST-ACS PATIENTS WITH AF Although coronary intervention is regarded as the most effective treatment in ACSs, many patients experiencing an ACS will be managed conservatively
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Clinical Therapeutics (ie, without insertion of a coronary stent). All ACS guidelines now recommend DAPT in conservatively managed post-ACS patients. The development of AF during this period can present a dilemma as the DAPT may need to be combined with an OAC. The Danish registry data cited previously39 showed that the bleeding risk of triple antithrombotic therapy (aspirin, clopidogrel, and warfarin) was nearly quadrupled compared with monotherapy with warfarin. Shortening the duration of DAPT may be an option. In both the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) and the Chinese COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) study,22,23 most of the benefit was achieved in the first 3 months, with less benefit in the rest of the year, suggesting that withdrawal after 3 to 4 months of clopidogrel may be an option. Increasingly, patients are being discharged from the hospital after an ACS on one of the newer P2Y12 inhibitors such as prasugrel and ticagrelor, and the lack of an evidence base to guide therapy when these patients have AF is concerning.
POST-PCI PATIENTS WITH AF As PCI is now the dominant of therapy for CHD, it is very common for the clinician to be confronted with decisions on how to manage stroke risk in a patient with AF and a coronary stent requiring DAPT. There is the additional concern that undertreatment with antiplatelet therapy may lead to stent thrombosis. The marked variation in how clinicians deal with this challenge reflects the lack of clear evidence and guidelines.39 Incomplete but nevertheless valuable guidance has come from recently reported registry and clinical trial data. A report from a large Danish registry study examined dual and triple antithrombotic therapies in 12,165 AF patients hospitalized with myocardial infarction and/or undergoing PCI between 2001 and 2009.40 Compared with triple antithrombotic therapy (oral anticoagulation plus aspirin plus clopidogrel), there was no increased risk of recurrent coronary events when double therapy was compared with triple therapy. However, when an OAC was missing from the antithrombotic regimen (aspirin plus clopidogrel), there was double the risk of ischemic stroke This registry also confirmed that bleeding risk was nonsignificantly lower for double therapy (OAC plus clopidogrel) and significantly lower for OAC plus aspirin when compared with triple therapy. This observational study suggests that OAC with clopidogrel may be the preferred dual-therapy combination.
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The WOEST (What is the Optimal antiplatelEt & Anticoagulant Therapy in Patients With Oral Anticoagulation and StenTing) study is the only randomized, controlled trial to date that has studied this issue.41 The investigators examined the effect of double versus triple antithrombotic therapy. For patients with coronary stents, the triple-therapy group (warfarin, clopidogrel, and aspirin) was associated with a significantly higher risk of bleeding than the double-therapy group (warfarin and clopidogrel). There was no higher risk of coronary events or stent thrombosis with triple therapy. In this trial, double therapy did not carry a high risk of coronary events and was associated with a significantly lower bleeding risk than triple therapy. Although the results from the WOEST study were clear, there are limitations to applying these results to the care of all patients with AF and CHD. The indication for anticoagulation in patients in the WOEST study was not only for AF but also included 30% of patients with other anticoagulant indications, and there were no differences in more severe grades of bleeding. As a result, caution has been expressed in the uncritical application of the WOEST study results to the management of patients with AF and CHD.42 There is even less justification to translate the WOEST study results to patients taking NOACs and newer P2Y12 antiplatelet agents. An alternative approach may be to shorten the period of exposure to DAPT after PCI to reduce the time of exposure to triple therapy. Some randomized trials have suggested that the duration of DAPT can be o12 months with newer generation stents,43,44 but these trials have lacked the power to recommend widespread adoption of a shorter duration of DAPT. Observational studies have suggested a low risk of major events after the first month of DAPT with a newer drug-eluting stent,45 and a low risk with physician-supervised cessation.46 The results of the ISAR-SAFE trial examining shorter duration of DAPT of o12 months is awaited with interest.27 None of the cited trials examine the effect of interactions between warfarin or NOACS with the newer P2Y12 inhibitor antiplatelet agents, which are being increasingly prescribed for post-PCI patients. The PIONEER AF-PCI (An Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous
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P.L. Thompson and F.W.A. Verheugt Coronary Intervention) trial is specifically exploring the use of rivaroxaban versus warfarin in AF with various combinations of DAPT. The RE-DUAL (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting) study is comparing dual therapy with dabigatran plus clopidogrel or ticagrelor with a triple antithrombotic therapy combination of warfarin plus clopidogrel or ticagrelor plus aspirin in patients undergoing PCI.
CONCLUSIONS Our conclusion from this overview is that rational decision making in patients with both AF and CHD remains challenging and based on very incomplete evidence. Careful randomized trials and registry analyses are urgently needed, particularly evaluating combinations of the NOACs and the new P2Y12 inhibitors.
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ACKNOWLEDGMENTS All authors contributed equally to the literature search, data interpretation, and writing of the manuscript.
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CONFLICTS OF INTEREST Dr. Thompson has received research support and honoraria from Boehringer Ingelheim, Astra Zeneca, Pfizer, Bristol Myers Squibb. Dr Verheugt received honoraria for speaker fees and consultancy from AstraZenenca, Medtronic, Bayer Healthcare, Boehringer-Ingelheim, BMS/Pfizer and Daiichi-Sankyo.
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REFERENCES 1. Lip GY, Huber K, Andreotti F, et al. Consensus Document of European Society of Cardiology Working Group on Thrombosis. Antithrombotic management of atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing coronary stenting: executive summary– a Consensus Document of the European Society of Cardiology Working Group on Thrombosis, endorsed by the European Heart Rhythm Association (EHRA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2010;31:1311–1318. 2. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A NorthAmerican perspective. Thromb Haemost. 2011;106:572–584. 3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983–988. 4. Hart RG, Pearce LA, Aguilar MI, et al. Meta-analysis: antithrombotic therapy to prevent stroke in patients who
September 2014
11.
12.
13.
have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–867. Aguilar MI, Hart RG. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2005;Oct 19:CD001925. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719–2747. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014 Apr 10. [Epub ahead of print]. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86. Fihn SD, Gardin JM, Abrams J, et al. Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126:e354–e471. Task Force Members, Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/ AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e663–e828. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569–2619. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST- Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update). Circulation. 2009;120:2271–2306.
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Clinical Therapeutics 14. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999–3054. 15. Chew DP, French J, Briffa TG, et al. Acute coronary syndrome care across Australia and New Zealand: the SNAPSHOT ACS study. Med J Aust. 2013;199:185–191. 16. Eagle KA, Montoye CK, Riba AL, et al. Guideline-based standardized care is associated with substantially lower mortality in Medicare patients with acute myocardial infarction: the American College of Cardiology’s Guidelines Applied in Practice (GAP) Projects in Michigan. J Am Coll Cardiol. 2005;46:1242–1248. 17. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329–1339. 18. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420. 19. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebocontrolled trial. Lancet. 2005;366: 1607–1621. 20. Yusuf S, Zhao F, Mehta SR, et al. 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. 21. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by longterm therapy in patients undergoing percutaneous coronary intervention:
1180
22.
23.
24.
25.
26.
27.
the PCI-CURE study. Lancet. 2001; 358:527–533. Levine GN, Bates ER, Blankenship JC, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. J Am Coll Cardiol. 2011;58:e44–e122. Mauri L, Kereiakes DJ, Normand SL, et al. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am Heart J. 2010;160:1035–1041. Byrne RA, Schulz S, Mehilli J, et al. ISAR-SAFE Investigators. Rationale and design of a randomized, double-blind, placebo-controlled trial of 6 versus 12 months clopidogrel therapy after implantation of a drugeluting stent: the Intracoronary Stenting and Antithrombotic Regimen: Safety And Efficacy of 6 Months Dual Antiplatelet Therapy After DrugEluting Stenting (ISAR-SAFE) study. Am Heart J. 2009;157:620–624. e2. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774–782. Lip G, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2011;57:173–180. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093–1100.
28. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151. 29. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891. 30. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992. 31. ACTIVE Writing Group of the ACTIVE Investigators. 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;367:1903–1912. 32. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–962. 33. Wiviott SD, Braunwald E, McCabe CH, et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015. 34. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361: 1045–1057. 35. Lamberts M, Gislason GH, Lip GY, et al. Antiplatelet Therapy for Stable Coronary Artery Disease in Atrial Fibrillation Patients on Oral Anticoagulant: A Nationwide Cohort Study. Circulation. 2014;129:1577–1585. 36. Rothberg MB, Celestin C, Fiore LD, et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143:241–250. 37. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation
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38.
39.
40.
41.
42.
43.
44.
45.
of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation. 2013; 127:634–640. Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2014;35:224–232. Rubboli A, Dewilde W, Huber K, et al. The management of patients on oral anticoagulation undergoing coronary stent implantation: a survey among interventional cardiologists from eight European countries. J Interv Cardiol. 2012 Apr;25:163–169. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol. 2013 Sep 10;62:981–989. Dewilde WJ, Oirbans T, Verheugt FW, et al. WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381:1107–1115. Fox KA. Dual or single antiplatelet therapy with anticoagulation? Lancet. 2013;381:1080–1081. Valgimigli M, Campo G, Monti M, et al. Prolonging Dual Antiplatelet Treatment After Grading Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicentre trial. Circulation. 2012;125: 2015–2026. Kim BK, Hong MK, Shin DH, et al. RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012; 60:1340–1348. Silber S, Kirtane AJ, Belardi JA, et al. Lack of association between dual antiplatelet therapy use and stent
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thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation. Eur Heart J. 2014; 35:1949–1956. 46. Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet. 2013;382:1714–1722.
Address correspondence to: Peter L. Thompson, MD. E-mail: [email protected]
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