Approximately 5% of patients undergoing PCI have atrial fibrillation and require long-term oral anticoagulant therapy.¹ Clinicians are thus frequently confronted with choosing the optimal treatment strategy in patients with both atrial fibrillation and recent coronary stent implantation. Choosing the best treatment strategy is analogous to navigating the Strait of Messina between Scylla and Charybdis. If one navigates the patient towards long-term triple therapy (aspirin plus P2Y12 inhibitor plus oral anticoagulant) the bleeding risk may be excessive; conversely, navigating him or her towards less intense therapy raises the risk the ischemic complications (primarily stroke or stent thrombosis).

Compared with oral anticoagulation therapy alone, the addition of dual antiplatelet therapy (DAPT) to oral anticoagulation therapy leads to a 2-3 fold increase in bleeding risk.^1-5 Other factors that increase bleeding risk include advanced age, female gender, chronic kidney disease and history of bleeding.^{1, 2} DAPT alone is inferior to warfarin for prevention of thromboembolic events in patients with atrial fibrillation.^{1, 6} The ACC/AHA Guideline Focused Update on Duration of DAPT in Patients with CAD⁷ provides some guidance in the management of patients with atrial fibrillation undergoing PCI; additional guidance comes from other guidelines,^{6, 8-10} expert consensus documents,^{1, 5, 11} expert reviews,^{3, 4, 12} and trial data.^13-15 This brief “expert analysis” summarizes recommendations and guidance in the management of patients treated with triple therapy.

What aspirin dose is recommended?
Lower dose (75-100 mg) aspirin provides ischemic protection comparable to higher dose aspirin and is associated with a lower risk of bleeding². The Focused Update on Duration of DAPT therefore recommends an aspirin dose of 81 mg (range 75-100 mg) be used in all patients with CAD treated with DAPT.² This same recommendation should be extrapolated to patients treated with triple therapy.

When should a proton-pump inhibitor be prescribed?
Proton pump inhibitor (PPI) use has been shown to decrease the risk of GI bleeding in patients treated with DAPT, and most bleeding events in patients on triple therapy occur in the GI tract.^{3, 11} In patients treated with triple therapy, particularly those with a history of prior GI bleeding, PPI treatment is recommended.^{2, 5, 9-11}

Is there a preferred P2Y12 inhibitor and at what dose?
Compared to clopidogrel, the third-generation P2Y12 platelet inhibitors prasugrel and ticagrelor result in a greater degree of platelet inhibition and are associated with increased non-CABG related bleeding.^{16, 17} In patients who require triple therapy, clopidogrel is therefore currently recommended for platelet P2Y12 receptor inhibition.^{1, 2, 5}

Is a DOAC or warfarin preferred as part of the combination therapy?
In trials of patients with acute coronary syndromes, triple therapy with full dose direct oral anticoagulants (DOACs), when compared to DAPT alone, leads to notably increased rates of major bleeding, including intracranial bleeding.¹⁵ At present, in patients requiring triple therapy, warfarin is the preferred oral anticoagulant.^{1-3, 5, 6} Several ongoing clinical trials of patients with atrial fibrillation undergoing PCI are evaluating novel treatment regimens of DOACs plus antiplatelet therapy.

Should the target INR be adjusted?
One small prospective study suggested that in patients treated with triple therapy, a lower INR (2.0-2.5) results in lower bleeding rates than a higher INR,¹⁸ although no randomized study has compared triple therapy with a target INR of 2.0-2.5 to a target INR of 2.0-3.0. Some^{1, 5} but not all⁶ guidelines and expert consensus documents recommend a target INR of 2.0-2.5 in patients treated with triple therapy when warfarin is used as the anticoagulant.

How long should one continue triple therapy?
Past guidelines have preferentially recommended the use of bare metal stents in patients requiring triple therapy. However, newer generation drug-eluting stents (DES) are less thrombogenic than first generation DES, recent analyses have found that newer generation DES have similar (or even lower) risk of stent thrombosis than bare metal stents, and several recent trials suggest that in some low risk patients 3-6 months of DAPT may be adequate.^{1-3, 19} Thus, shorter duration triple therapy (such as 3 months for those with stable ischemic heart disease and 6 months for those with ACS) in those treated with newer generation DES may be reasonable,² and this treatment strategy has been recommended.^{1, 2} Based on the results of the WOEST trial,¹³ in those at high risk of bleeding, dual therapy with warfarin and clopidogrel can be considered.^{8, 12} Dual therapy with warfarin and single antiplatelet therapy has been recommended in those with atrial fibrillation and acute coronary syndrome who do not undergo coronary stent implantation.⁶

Ultimately, treatment strategies should be individualized, with consideration of the risk of stroke, the risk and consequences of stent thrombosis, and bleeding risk.

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References

1. Lip GY, Windecker S, Huber K, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014; 35:3155-79.
2. Levine GN, O'Gara PT, Bates ER, et al. 2015 ACC/AHA/SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. J Am Coll Cardiol 2016; doi=10.1016/j.jacc.2016.03.513.
3. Capodanno D, Angiolillo DJ. Management of antiplatelet and anticoagulant therapy in patients with atrial fibrillation in the setting of acute coronary syndromes or percutaneous coronary interventions. Circ Cardiovasc Interv 2014; 7:113-24.
4. Moser M, Olivier CB, Bode C. Triple antithrombotic therapy in cardiac patients: more questions than answers. Eur Heart J 2014; 35:216-23.
5. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost 2011; 106:572-84.
6. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S-e575S.
7. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LAeal. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; doi=10.1016/j.jacc.2016.03.513.
8. 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; 130:e199-e267.
9. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011; 58:e44-122.
10. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 64:e139-e228.
11. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA Clinical Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol XX, XXX. 2008.
12. Dewilde WJ, Janssen PW, Verheugt FW, et al. Triple therapy for atrial fibrillation and percutaneous coronary intervention: a contemporary review. J Am Coll Cardiol 2014; 64:1270-80.
13. Dewilde WJ, Oirbans T, Verheugt FW, et al. 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; 381:1107-15.
14. Rossini R, Musumeci G, Lettieri C, et al. Long-term outcomes in patients undergoing coronary stenting on dual oral antiplatelet treatment requiring oral anticoagulant therapy. Am J Cardiol 2008; 102:1618-23.
15. Oldgren J, Wallentin L, Alexander JH, et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J 2013; 34:1670-80.
16. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045-57.
17. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001-15.
18. Rossini R, Musumeci G, Lettieri C, et al. Long-term outcomes in patients undergoing coronary stenting on dual oral antiplatelet treatment requiring oral anticoagulant therapy. Am J Cardiol 2008; 102:1618-23.
19. Palmerini T, Biondi-Zoccai G, Della RD, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012; 379:1393-402.

Keywords: Acute Coronary Syndrome, Adenosine, Anticoagulants, Aspirin, Atrial Fibrillation, Blood Platelets, Consensus, Drug-Eluting Stents, Gastrointestinal Tract, Female, Hemorrhage, International Normalized Ratio, Male, Platelet Aggregation Inhibitors, Prospective Studies, Proton Pump Inhibitors, Protons, Renal Insufficiency, Chronic, Stroke, Thrombosis, Ticlopidine, Warfarin, Platelet Aggregation Inhibitors

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