Challenges of Antiplatelet Therapy in Patients Who Require Anticoagulation

From the Mayo Clinic College of Medicine, Rochester, Minnesota. The authors report no financial relationships or conflicts of interest regarding the content herein. Address for correspondence: David Holmes, MD, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905. E-mail: holmes.david@mayo.edu _______________________________ Therapeutic guidelines have come to occupy a central role in recommending and implementing strategies of care for patients with a wide range of cardiovascular diseases. The presence of coexisting diseases requiring different therapies can result in management challenges and ensuing clinical problems. Recently, in the context of a growing elderly population with multiple comorbid cardiovascular conditions, the concomitant use of dual antiplatelet therapy involving aspirin and a thienopyridine in addition to warfarin anticoagulation has increased. Common clinical scenarios include patients receiving a drug-eluting stent who will be on dual antiplatelet therapy for at least 1 year and sometimes indefinitely, and who also need anticoagulation for stroke prevention. As combination dual antiplatelet and anticoagulant therapy (triple therapy) is more often seen in clinical practice, so are the complications of triple therapy, the foremost being significant bleeding. It is important for the clinician to review the indications, complications and recommendations regarding the use of antiplatelet and anticoagulant therapy. Cardiovascular Indications for Antiplatelet and Anticoagulant Therapy Antiplatelet therapy, via inhibition of platelet activation, has been found to play an integral role in the prevention of platelet-mediated thrombosis and in reducing ischemic events in coronary artery disease.1,2 Several studies have shown that the concomitant use of two antiplatelet agents with different mechanisms of platelet inhibition enhances the prevention of ischemic events in both acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) scenarios.3–9 Most commonly, dual antiplatelet therapy has taken the form of aspirin plus a thienopyridine. Current American Heart Association/American College of Cardiology (AHA/ACC) practice guidelines for unstable angina, non-ST-elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI), and PCI recommend the use of dual antiplatelet therapy for up to 1 year.10–12 Combination warfarin plus aspirin therapy has also been studied as part of medical therapy in patients with ACS and has been shown to be effective in preventing recurrent ischemic events compared to aspirin alone.13–16 However, in contrast to dual antiplatelet therapy, warfarin added to aspirin therapy is less effective in preventing stent thrombosis following PCI.17 Anticoagulation therapy or inhibition of the clotting cascade with the use of warfarin as monotherapy is indicated in multiple patient populations including those with atrial fibrillation (AF), prosthetic heart valves, left ventricular thrombus, markedly impaired left ventricular function and for patients with deep venous thrombosis.18–20 In these settings, warfarin anticoagulation has been studied intensively and has been established as a cornerstone of therapy. Notably, although dual antiplatelet therapy has been studied in patients with atrial fibrillation for stroke prevention, this combination has been found less effective than warfarin and is not recommended as a first-line treatment.18,21 Optimal therapy for the prevention of platelet-mediated thrombosis in ACS and PCI requires the use of dual antiplatelet therapy, while optimal treatment of comorbid AF, cardiac valvular prostheses, or recurrent deep venous thrombosis requires ongoing warfarin use. Thus, it is true that for many patients, triple therapy is indicated by guidelines. Antiplatelet and Anticoagulant Therapy: Bleeding Complications The major concern with combining antiplatelet and anticoagulant therapy is bleeding. Taken individually, aspirin, thienopyridines or warfarin alone can increase the risk of bleeding. Aspirin use has been shown to substantially increase the risk of intracranial bleeding, major bleeding and gastrointestinal (GI) bleeding relative to controls.1,2,22–26 Interestingly, there seems to be a dose-dependent bleeding risk. Aspirin doses 75 mg/day. Moreover, higher aspirin doses are not consistently associated with survival benefit compared to low-dose aspirin in ACS patients.1 The risk of a major hemorrhagic event associated with use of a thienopyridine (clopidogrel 75 mg) alone is virtually equivalent to that of full-dose aspirin (325 mg) with fewer GI bleeding events occurring in patients using a thienopyridine versus aspirin.27 Studies examining complications with combination aspirin and thienopyridine antiplatelet therapy demonstrate a variable but overall increase in frequency of bleeding events with dual therapy, possibly influenced by duration of therapy and by aspirin dosage.1,3,24,28 As a single agent, warfarin causes significant bleeding. In a series of elderly patients with AF, warfarin use was associated with a 7% risk of major hemorrhage after 1 year.29 Warfarin in combination with single antiplatelet therapy has been studied in patients with peripheral arterial disease as well as in patients with ACS.13–15,30,31 In the Warfarin Antiplatelet Vascular Evaluation Trial of patients with peripheral arterial disease who were randomly assigned to either a single antiplatelet agent in combination with warfarin or to antiplatelet therapy alone, bleeding events including fatal, life-threatening, intracranial or moderately severe events were increased in the combined therapy group.32 Testa et al performed an analysis of 13 randomized clinical trials of patients treated for ACS.33 In that analysis, the endpoints of interest were: 1) the combined rate of all-cause death, non-fatal infarction or non-fatal thromboembolic stroke; and 2) the combined rate of major bleeding. The 13 studies included 69,741 patients. These authors found that there was no significant difference between aspirin and warfarin versus aspirin and clopidogrel in terms of the risk of death or acute infarction. The combination of aspirin and warfarin was associated with a lower risk of thromboembolic stroke (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.31–0.88) compared to aspirin and clopidogrel. However, the use of aspirin and warfarin was associated with increased major bleeding (OR 1.9, 95% CI 1.2–2.8). Thus, single antiplatelet therapy in combination with warfarin, while effective in reducing some specific adverse events, is associated with increased bleeding. Triple Therapy Information on triple therapy with dual antiplatelet therapy and warfarin is limited. Furthermore, balancing the bleeding risk with the potential ischemic risk of stopping one of the three therapies is even more complex. Depending upon the clinical setting, discontinuing warfarin may result in an increased risk of stroke, while discontinuing one or both antiplatelet agents may result in an increased potential for stent thrombosis. Most of the data on triple therapy come from relatively small series. These are difficult to compare because of the variability in treatment strategies such as different doses and duration of therapy, as well as varying definitions for bleeding.28,32,34–43 In review of the aforementioned studies, the reported major bleeding complications of triple therapy vary widely in the current literature, with bleeding events occurring in 2–21% of trial patients.32,35–43 The relative risk of a major bleeding event in patients on triple therapy appears to be 3- to 5-fold higher than for patients receiving dual antiplatelet therapy alone.32,38,39,42 Importantly, limited duration of triple therapy (in-hospital use) was associated with a 2-fold lower risk of major bleeding than was prolonged use (> 6 months).40 When assessing ACS patients who received a coronary stent, Nguyen et al found no significant difference in combined endpoints of all-cause death, stroke, unscheduled PCI, or MI between patients receiving triple versus dual antithrombotic therapy (aspirin or a thienopyridine plus warfarin) therapy at 6 months.40 This study also reports that in patients undergoing PCI for whom triple therapy was indicated, but who received only dual antiplatelet therapy, a 3-fold increase risk of stroke or thromboembolic event was seen relative to patients receiving triple therapy or warfarin plus a single antiplatelet agent. It should be recognized that less than 25% of these patients continued on triple therapy after 6 months, thus limiting the generalizability of these observations. One of the largest studies included 239 patients on warfarin who underwent PCI between 2003 and 2004.39 Some patients were treated with warfarin plus aspirin alone, while others received triple therapy. In patients treated with warfarin and aspirin, stent thrombosis was seen more frequently (15.2%) compared to patients on triple therapy (1.2%). Warfarin was, however, an independent predictor of major bleeding (OR 3.4, 95% CI 1.2–9.3; p = 0.02). In aggregate, these series document the issue of balancing stroke risk, which is best prevented with warfarin versus stent thrombosis, which is best prevented with dual antiplatelet therapy versus the risk of bleeding on triple therapy. Prevention of Bleeding and Thrombosis Prevention of bleeding or thrombosis in patients receiving triple therapy can be addressed by considering the intrinsic patient characteristics, as well as the dose and duration of antiplatelet and anticoagulant therapy. First, consider the clinical risk of thrombosis versus the risk of bleeding in the individual patient. High-risk thrombogenic states include recent MI, recent stroke, recent PCI, comorbid congestive heart failure, peripheral vascular disease with grafting, cardiac valvular prostheses, history of thromboembolic events, or AF. Bleeding risk can be considered in the context of a patient’s age, prior bleeding history and the ability to closely monitor and control anticoagulation therapy. The bleeding risk conferred by triple therapy depends on the dose and duration of use of each antiplatelet and anticoagulant agent. Thus, placing a bare-metal stent instead of drug-eluting stent in the event of PCI in patients who require indefinite anticoagulation therapy should be considered.12 In patients who are on maintenance triple therapy, several factors should be kept in mind that may decrease the potential for bleeding. The dose of aspirin should be kept low, at 75–81 mg, if possible. Clopidogrel should be administered at its standard dose of 75 mg. Assessment of clopidogrel polymorphism may be helpful in identifying optimal dosing for clopidogrel.44 Careful attention should be paid to the dosing of warfarin. In general, a lower target international normalized ratio (INR) should be the goal (1.5–2.0). The use of proton pump inhibitors makes intuitive sense and should be considered. A caveat to this is the recent finding of a potential interaction with clopidogrel, which can result in decreased platelet inhibition.45 Treatment of Bleeding in Patients on Triple Therapy Patients who are on triple therapy and who experience bleeding pose a particularly important problem. Bleeding that is severe or life-threatening usually mandates the reversal of warfarin therapy. If bleeding is less severe, considerations may be focused on the site and severity of bleeding. Dual antiplatelet therapy can be discontinued, but during that time the patient should be closely monitored, particularly for the risk of stent thrombosis. In those patients who have mild-to-moderate bleeding, efforts should be made to maintain the INR as close to 2.0 as possible, and the aspirin dose should be Future Considerations Clearly, while comorbid cardiac conditions may warrant the use of triple therapy, there are significant risks with the simultaneous use of antiplatelet and anticoagulant agents. This difficulty has been increasingly recognized, prompting investigation into alternative means of managing patients with indications for triple therapy. Alternative anticoagulation therapies, such as different direct thrombin inhibitors and factor Xa antagonists, are on the horizon. Additionally, the Watchman left atrial appendage device has been developed in the hopes of markedly reducing the need for indefinite warfarin therapy in patients with AF.46 Finally, intracoronary stent technology is evolving, prompting more rapid coronary reendothelialization via thinner struts and polymer coating or by employing a bioabsorbable polymer to limit the duration of antiplatelet therapy. With the conscientious use of triple therapy and ongoing innovation, therapy for patients with multiple comorbid cardiovascular conditions, while complex, is manageable.

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