The use of non-vitamin K antagonist oral anticoagulants (NVKA) for antithrombotic treatment has freed patients with atrial fibrillation (AF) from the inconvenience and expense of international normalized ratio measurements. However, in the presence of coronary artery disease requiring percutaneous coronary intervention (PCI) the physician is challenged with decisions regarding which antiplatelet regimen to administer. The 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 AF Who Undergo PCI (PIONEER AF-PCI) was the first randomized clinical trial to test safety and efficacy of a NVKA in patients with AF treated with PCI. At 1-year follow-up both dual and triple therapy with rivaroxaban were superior to triple therapy with warfarin in reducing the frequency of bleeding events. Findings from the PIONEER AF-PCI study indicate superiority of dual or triple therapy with rivaroxaban over warfarin.
The use of non-vitamin K antagonist oral anticoagulants (NVKA) has revolutionized the antithrombotic treatment of patients with atrial fibrillation (AF), finally freeing them of the inconvenience and expense of international normalized ratio measurements. However, add to the equation the presence of coronary artery disease requiring percutaneous coronary intervention (PCI) with stent placement and the physician is challenged with decisions regarding what antiplatelet regimen to administer. Although it is estimated that approximately 1–2 million people in the US and Europe have AF and coronary artery disease, there remains a paucity of randomized clinical trials in this population. The What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting (WOEST) trial tested antithrombotic strategies in patients with AF after PCI was.1 This study proved that the use of dual therapy with warfarin and clopidogrel significantly decreased the risk of bleeding complications with no increase in the rate of thrombotic events. Despite the results of WOEST, there is still great heterogeneity in the choice of antithrombotic regimens in clinical practice.
The role of NVKA in this setting is not well defined. Several studies on patients with AF have proved that NVKA reduce the risk of bleeding while maintaining adequate antithrombotic efficacy. These results suggest a wider therapeutic window of NVKA than warfarin that might be particularly beneficial in stented patients with AF. Nevertheless, this hypothesis was not supported by any scientific evidence until the 1-year results of the Study Exploring Two Treatment Strategies of Rivaroxaban and a DoseAdjusted Oral Vitamin K Antagonist Treatment Strategy in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial were finally published.2 The PIONEER AF-PCI study was the first randomized clinical trial to test safety and efficacy of a NVKA in patients with AF treated with PCI. In this study, 2124 patients were randomized to one of the following treatment strategies: 1) dual therapy with low-dose (15 mg daily) rivaroxaban plus a P2Y12 inhibitor for 12 months; 2) triple therapy with very low-dose rivaroxaban (2.5 mg, twice daily) plus dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor for 1, 6 or 12 months; and 3) triple therapy with warfarin plus DAPT (WOEST-like arm) for 1, 6 or 12 months. The primary endpoint was clinically significant bleeding, a composite of major or minor bleeding according to thrombolysis in myocardial infarction (TIMI) criteria or bleeding requiring medical attention. At 1-year follow-up both dual and triple therapy with rivaroxaban were superior to triple therapy with warfarin in reducing bleeding events. Although the PIONEER AF-PCI trial was underpowered to detect differences in ischemic complications, a recent post-hoc analysis showed a significant reduction in the rate of hospitalization for both cardiovascular and bleeding events in the rivaroxaban-based study arms, thus excluding a potential harm of rivaroxaban in combination with one or two antiplatelet drugs.3 Interestingly, the low and very low rivaroxabanbased strategies seemed equivalent in safety and efficacy. While definite conclusions cannot be drawn regarding the thromboembolic protection of these off-label dosages of rivaroxaban in combination with antiplatelet agents, findings from the PIONEER AF-PCI study provides crucial, muchawaited information on NVKA use in patients with AF after PCI that will certainly impact clinical practice.
A potential role of NVKA in combination with antiplatelet drugs had already been investigated for the post-PCI treatment of patients in sinus rhythm. The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE 2) trial tested full-dose apixaban in addition to DAPT in patients presenting with acute coronary syndrome (ACS).4 While conferring protection with regards to ischemic outcomes at 1 year, the full anticoagulating dose of apixaban resulted in an unacceptable increase in the frequency of intracranial hemorrhages and fatal bleeding events that caused the premature interruption of the trial. Conversely, the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial tested non-fully anticoagulating doses of rivaroxaban 5 mg or 2.5 mg, twice daily (PIONEER-AF-PCI-like arm), in combination with DAPT in patients with ACS.5 In this study, the very low-dose (2.5 mg, twice daily) rivaroxaban added to DAPT significantly reduced the rates of mortality and recurrent myocardial infarction compared with placebo. Although a higher rate of major bleeding events was observed, there was no significant increase in the rate of fatal bleeding events with rivaroxaban treatment. The differences between clinical outcomes in this study and the APPRAISE 2 trial might be explained in part by the lower dose of NVKA tested and in part by the fact that unlike the APPRAISE 2 study, the ATLAS ACS 2-TIMI 51 trial excluded patients who had a history of ischemic stroke or transient ischemic attack.
In aggregate, looking back to the trials on NVKA or warfarin performed in the past few years it is apparent that the main objective is the reduction of bleeding events whereas an acceptable thromboembolic protection is usually reached by most treatment regimens. In other words, we can prevent ischemic strokes fairly well with all the drugs at our disposal, but preventing hemorrhagic strokes and other major bleeding events currently represents our main challenge. In this regard, the PIONEER AF-PCI study certainly marks the victory of dual or triple therapy with rivaroxaban over warfarin. Ongoing studies will provide information on the use of dabigatran, apixaban and edoxaban in patients with AF after PCI. Nevertheless, given the low incidence of thromboembolic events in this population it is unlikely that these studies will be powered to demonstrate the non-inferiority to warfarin of NVKA with respect to the prevention of ischemic complications.
Are NVKA the key to finding a ‘one-size-fits-all’ regimen that will simplify treatment decision making after PCI in patients with AF? Possibly, but there is still a long road ahead. High-risk patients are usually excluded from clinical trials and that limits the generalizability of the results. For instance, in the PIONEER-AF-PCI study, the median CHADS2, CHA2DS2- VASc, and HAS-BLED scores were only 2, 4, and 3, respectively. What is the best treatment for patients at high or very high thromboembolic and bleeding risk, or patients with complex coronary artery disease requiring the use of novel P2Y12 inhibitors, which have never been extensively studied in association with NVKA? With these questions in mind, we must admit that the safer risk profile so far shown by rivaroxaban may be the key to solving this conundrum and might entirely change our treatment approach for patients with AF undergoing PCI in the next few years.
- 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.
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- Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34.
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- Gibson CM, Pinto DS, Chi G, et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy. Circulation 2017;135:323–33.
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- Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699–708.
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- Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19.
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