Optimal Antithrombotic Therapy in Patients Receiving Long-term Oral Anticoagulation Requiring Percutaneous Coronary Intervention: “Triple Therapy” or “Triple Threat”

Abstract

The number of patients requiring long-term oral anticoagulation (OAC), usually warfarin, for a variety of conditions, predominantly atrial fibrillation (AF), mechanical prosthetic heart valves, or previous systemic or VTE, is rapidly increasing.1Lip GY Anticoagulation therapy and the risk of stroke in patients with atrial fibrillation at ‘moderate risk' [CHADS2 score=1]: simplifying stroke risk assessment and thromboprophylaxis in real-life clinical practice.Thromb Haemost. 2010; 103: 683-685Crossref PubMed Scopus (81) Google Scholar In parallel, the number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation, either electively or for acute coronary syndrome, where dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine (most commonly clopidogrel) is mandatory to prevent stent thrombosis,2Bertrand ME Rupprecht HJ Urban P Gershlick AH CLASSICS Investigators Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS).Circulation. 2000; 102: 624-629Crossref PubMed Scopus (1035) Google Scholar, 3Rubboli A Halperin JL Pro: ‘Antithrombotic therapy with warfarin, aspirin and clopidogrel is the recommended regime in anticoagulated patients who present with an acute coronary syndrome and/or undergo percutaneous coronary interventions'.Thromb Haemost. 2008; 100: 752-753PubMed Google Scholar, 4Roldán V Marín F Contra: ‘Antithrombotic therapy with warfarin, aspirin and clopidogrel is the recommended regimen in anticoagulated patients who present with an acute coronary syndrome and/or undergo percutaneous coronary interventions'. Not for everybody.Thromb Haemost. 2008; 100: 754-755PubMed Google Scholar is also escalating. Consequently, physicians are faced with tough management decisions regarding the optimal antithrombotic strategy for patients with a current indication for long-term OAC who also require PCI and stent implantation.3Rubboli A Halperin JL Pro: ‘Antithrombotic therapy with warfarin, aspirin and clopidogrel is the recommended regime in anticoagulated patients who present with an acute coronary syndrome and/or undergo percutaneous coronary interventions'.Thromb Haemost. 2008; 100: 752-753PubMed Google Scholar, 4Roldán V Marín F Contra: ‘Antithrombotic therapy with warfarin, aspirin and clopidogrel is the recommended regimen in anticoagulated patients who present with an acute coronary syndrome and/or undergo percutaneous coronary interventions'. Not for everybody.Thromb Haemost. 2008; 100: 754-755PubMed Google Scholar Unfortunately, there are no large-scale randomized trials of dual and triple antithrombotic therapy in this setting. Treatment options are controversial3Rubboli A Halperin JL Pro: ‘Antithrombotic therapy with warfarin, aspirin and clopidogrel is the recommended regime in anticoagulated patients who present with an acute coronary syndrome and/or undergo percutaneous coronary interventions'.Thromb Haemost. 2008; 100: 752-753PubMed Google Scholar, 4Roldán V Marín F Contra: ‘Antithrombotic therapy with warfarin, aspirin and clopidogrel is the recommended regimen in anticoagulated patients who present with an acute coronary syndrome and/or undergo percutaneous coronary interventions'. Not for everybody.Thromb Haemost. 2008; 100: 754-755PubMed Google Scholar because current guidelines are an evidence-based medicine-free zone. There is a pathophysiologic rationale for the use of both DAPT and warfarin in this setting; warfarin is more efficacious than DAPT in preventing stroke and other vascular events, with similar rates of major bleeding in AF5Connolly S Pogue J Hart R ACTIVE Writing Group of the ACTIVE Investigators 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: 1903-1912Abstract Full Text Full Text PDF PubMed Scopus (1740) Google Scholar because the thrombus in this condition is fibrin rich. Conversely, warfarin is insufficient to prevent the platelet-dependent stent thrombosis achieved by DAPT.6Rubboli 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: 101-106Crossref PubMed Scopus (86) Google Scholar However, a challenge exists to avoid thrombotic complications while minimizing the risk of harm from bleeding, the most common nonischemic complication of acute coronary syndrome. Even minor bleeding is associated with worse prognosis and may lead to reduced compliance with DAPT or OAC, precipitating stent thrombosis or thromboembolism.7Rao SV O'Grady K Pieper KS et al.A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes.J Am Coll Cardiol. 2006; 47: 809-816Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar This is a complex clinical dilemma because stroke risk and bleeding risk share several common risk factors, including advancing age, hypertension, and diabetes. This is further complicated because many patients with ST-elevation myocardial infarction (STEMI) are now treated with primary PCI and may only develop an indication for OAC after PCI. The key question therefore is should such patients receive triple therapy with warfarin, aspirin, and clopidogrel, or is DAPT alone sufficient? In this issue of CHEST (see page 260), Zhao and colleagues8Zhao H-J Zheng Z-T Wang Z-H et al.“Triple therapy” rather than “triple threat”: a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment.Chest. 2011; 139: 260-270Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar present the findings of a meta-analysis evaluating two antithrombotic regimens after stent implantation. Triple therapy (aspirin, clopidogrel, and warfarin) is compared with DAPT (aspirin and clopidogrel) among patients receiving long-term OAC, mostly for AF, but also for severe left ventricular dysfunction, mechanical prosthetic heart valves, and VTE. Nine clinical trials involving a heterogeneous group of 1,996 subjects were included, although none were randomized controlled trials (RCTs). The major adverse cardiovascular event rate was significantly lower with triple therapy compared with DAPT (OR, 0.60; 95% CI, 0.47-0.93; P = .02), including a significant reduction in all-cause mortality (OR, 0.63; 95% CI, 0.42-0.86; P = .005). However, this was at the expense of a significant increase in major bleeding (OR, 2.12; 95% CI, 1.05-4.29; P = .04), but the increase in minor bleeding was not statistically significant (OR, 1.74; 95% CI, 0.90-3.35; P = .10) with triple therapy compared with DAPT. The authors concluded that triple therapy is the best option for the majority of patients requiring receiving OAC who have undergone stent implantation, especially those with high thromboembolic risk but low bleeding risk.8Zhao H-J Zheng Z-T Wang Z-H et al.“Triple therapy” rather than “triple threat”: a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment.Chest. 2011; 139: 260-270Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar In addition to the usual limitations of retrospective, nonrandomized data, several caveats regarding the results of this meta-analysis8Zhao H-J Zheng Z-T Wang Z-H et al.“Triple therapy” rather than “triple threat”: a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment.Chest. 2011; 139: 260-270Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar should be considered. Only major bleeding occurring in the first 6 months was recorded, whereas many guidelines recommend DAPT for 12 months following PCI with drug-eluting stents (DESs). The prevalence of major bleeding with triple therapy increases with treatment duration, from 2.6% to 4.6% at 30 days to 13.9% at 6 months, and 7.4% to 10.3% at 1 year.3Rubboli A Halperin JL Pro: ‘Antithrombotic therapy with warfarin, aspirin and clopidogrel is the recommended regime in anticoagulated patients who present with an acute coronary syndrome and/or undergo percutaneous coronary interventions'.Thromb Haemost. 2008; 100: 752-753PubMed Google Scholar In addition, time in therapeutic international normalized ratio range, which is a key determinant of both thromboembolic and adverse bleeding events, was not reported in this meta-analysis.9Connolly SJ Pogue J Eikelboom J ACTIVE W Investigators et al.Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range.Circulation. 2008; 118: 2029-2037Crossref PubMed Scopus (742) Google Scholar The proportion of PCIs undertaken via the radial route is also not discussed. This is important because radial access may significantly reduce access-related bleeding complications compared with the femoral approach and is advocated in recent guidelines.10Lip GY Huber K Andreotti F European Society of Cardiology Working Group on Thrombosis et al.Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.Thromb Haemost. 2010; 103: 13-28Crossref PubMed Scopus (267) Google Scholar Furthermore, the number of elective vs emergency PCIs is not mentioned, nor is the proportion of emergency PCIs that were for STEMI and non-STEMI. All these factors may influence the type of stent used and, moreover, whether PCI is considered at all because reluctance to use triple therapy may have reduced access to PCI for patients receiving long-term OAC. In most of the trials included, the use of triple therapy or DAPT was at the discretion of the physician, according to the presumed potential for benefit vs risk, which inherently introduces selection bias. The recently published European Society of Cardiology Working Group on Thrombosis consensus document guidelines (endorsed by the European Heart Rhythm Association and the European Association of Percutaneous Cardiovascular Interventions for the management of AF patients requiring PCI)10Lip GY Huber K Andreotti F European Society of Cardiology Working Group on Thrombosis et al.Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.Thromb Haemost. 2010; 103: 13-28Crossref PubMed Scopus (267) Google Scholar is based on a systematic review of 18 studies incorporating approximately 3.500 patients. The recommended international normalized ratio range for patients receiving triple therapy is 2.0 to 2.5. In elective PCI, a DES is recommended only in circumstances with a strong evidence base for benefit, such as in patients with diabetes. For a bare-metal stent, 4 weeks of triple therapy is suggested, followed by 12 months of combination OAC and clopidogrel. Triple therapy is recommended for at least 3 months with a “-limus” DES, and for at least 6 months with a paclitaxel DES. In patients with AF who have a low-thromboembolic risk without STEMI, DAPT alone is recommended. For those with moderate to high thromboembolic risk, triple therapy for 3 to 6 months (or longer if bleeding risk is low) is suggested. If thrombotic risk is severe (such as a high thrombolysis in myocardial infarction risk score), OAC plus clopidogrel for 12 months is recommended. Following primary PCI, triple therapy for 3 to 6 months is suggested (or longer if bleeding risk is low), followed by OAC plus clopidogrel for 12 months. Radial access is strongly endorsed in all scenarios.10Lip GY Huber K Andreotti F European Society of Cardiology Working Group on Thrombosis et al.Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.Thromb Haemost. 2010; 103: 13-28Crossref PubMed Scopus (267) Google Scholar A definitive evidence-based approach to antithrombotic therapy for patients receiving OAC requiring PCI and/or stent implantation would require large-scale RCTs and registries comparing DAPT with triple therapy. Currently, the available evidence is confined to small, single-center, retrospective cohort analyses.10Lip GY Huber K Andreotti F European Society of Cardiology Working Group on Thrombosis et al.Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.Thromb Haemost. 2010; 103: 13-28Crossref PubMed Scopus (267) Google Scholar Ongoing clinical trials that may enhance our understanding include the Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation (ISAR-TRIPLE) trial, which hypothesizes that reducing the duration of clopidogrel from 6 months to 6 weeks following DES implantation in patients receiving aspirin and OAC is associated with improved outcomes.11DeEugenio D Kolman L DeCaro M et al.Risk of major bleeding with concomitant dual antiplatelet therapy after percutaneous coronary intervention in patients receiving long-term warfarin therapy.Pharmacotherapy. 2007; 27: 691-696Crossref PubMed Scopus (88) Google Scholar Additionally, the What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting (WOEST) study is evaluating whether warfarin plus clopidogrel is equally efficacious, yet safer than triple therapy, in patients requiring OAC and DAPT.12What is the optimal antiplatElet and anticoagulant in patients with oral anticoagulation and StenTing (WOEST) study.http://www.clinicaltrials.gov/ct2/results?term=ISAR-TRIPLEGoogle Scholar However, the pace of change in the development of antithrombotic drugs and stent technology may preclude a truly contemporaneous RCT. Therapies are emerging with the potential to reduce both stroke risk and bleeding risk simultaneously. For example, warfarin for patients with AF may be superseded by oral factor Xa inhibitors or direct thrombin inhibitors with equal or greater efficacy yet reduced bleeding risk.13Connolly SJ Ezekowitz MD Yusuf S RE-LY Steering Committee and Investigators et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8898) Google Scholar Ticagrelor is a novel antiplatelet agent associated with significantly reduced major adverse cardiovascular events rates compared with clopidogrel, with similar bleeding risk.14Wallentin L Becker RC Budaj A PLATO Investigators et al.Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-1057Crossref PubMed Scopus (5558) Google Scholar Endothelial progenitor cell capture stents may require only 1 month of DAPT.15Co M Tay E Lee CH et al.Use of endothelial progenitor cell capture stent (Genous Bio-Engineered R Stent) during primary percutaneous coronary intervention in acute myocardial infarction: intermediate- to long-term clinical follow-up.Am Heart J. 2008; 155: 128-132Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar However, data are lacking regarding how the newer antiplatelet drugs (prasugrel and ticagrelor) interact with either warfarin or novel OACs, and long-term data on stent safety and long-term patency with these drugs are vital. The balance between “triple therapy” and “triple threat” can be influenced beneficially by a combination of sound clinical judgment in the context of consensus guidelines, validated risk stratification schema for stroke risk16Hughes M Lip GY Guideline Development Group, National Clinical Guideline for Management of Atrial Fibrillation in Primary and Secondary Care, National Institute for Health and Clinical Excellence Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data.Thromb Haemost. 2008; 99: 295-304Crossref PubMed Scopus (336) Google Scholar and bleeding risk,17Pisters R Lane DA Nieuwlaat R de Vos CB Crijns HJGM Lip GY 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: 1093-1100Abstract Full Text Full Text PDF PubMed Scopus (3333) Google Scholar and the judicious use of bare-metal stent if practical. An individualized approach to treatment, possibly enhanced in the future by novel drugs and stent technology, may tip the balance yet further toward triple therapy for more patients.