The correct answer is: D. Switch rivaroxaban to warfarin (target INR 2.0) and continue single antiplatelet therapy with clopidogrel 75 mg only.

It is estimated that nearly 5% of patients undergoing PCI have a pre-existing indication for anticoagulant therapy.¹ Following PCI, dual antiplatelet therapy (DAPT) is indicated for a minimum of one to 12 months in order to prevent stent thrombosis with bare metal stents (BMS) and drug-eluting stents (DES) respectively.² Current consensus gravitates towards triple therapy with aspirin, clopidogrel, and warfarin with an INR target of 2.0–2.5.^3,4 However this therapy has been associated with significant increase in risk of major bleeding.^5,6 Further, the role of new oral anticoagulants (NOACs) as well as newer antiplatelet agents, such as prasugrel and ticagrelor, with regard to triple therapy remains unclear due to lack of clinical trial data.

In the above vignette, the patient has just received a DES and discontinuation of a P2Y12 inhibitor, such as clopidogrel, would be inappropriate. Premature discontinuation of P2Y12 inhibitors, particularly in the first six months following stent placement, is an important predictor of stent thrombosis.⁷ In another study, patients who discontinued their P2Y12 inhibitor within 30 days of receiving a DES for treatment of myocardial infarction (MI), had a significantly higher likelihood of dying in the year after their MI (all-cause mortality at one year was 7.5% vs. 0.7% for those who continued taking their dual antiplatelet therapy).⁸ Therefore, although resumption of rivaroxaban or switching to warfarin as an anticoagulant agent for atrial fibrillation (AFib) with CHA2DS2-VASc score of 5 may be reasonable in options A and C, these antithrombotic options are ultimately suboptimal as they do not contain a P2Y12 inhibitor in a patient who has just received a DES.

Option B consists of triple therapy with DAPT and rivaroxaban (a factor Xa inhibitor). Although this combination of rivaroxaban with DAPT (aspirin and clopidogrel) has not been studied in an AFib population undergoing PCI, data from the ATLAS ACS-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2–Thrombolysis In Myocardial Infarction 51) trial using 2.5 mg or 5 mg rivaroxaban doses twice-daily suggest that the risk of bleeding is significantly increased compared to DAPT without an anticoagulant.⁹ In this study, the rationale for the use of this antithrombotic combination was the theoretical benefit of inhibiting factor Xa, which plays a role in platelet activation-aggregation cascade in acute coronary syndromes (ACS), in addition to platelet inhibition with DAPT. 15,526 patients with ACS were randomly assigned to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo (all in addition to DAPT). Although, rivaroxaban was found to reduce the composite primary endpoint of death, MI, and stroke at either dose, this benefit was achieved at the cost of an increased risk of Thrombolysis in Myocardial Infarction (TIMI) major bleeding and intracranial hemorrhage.9 The rate of bleeding with the dose of rivaroxaban studied in patients with AFib (20 mg daily, dose reduced to 15 mg daily in patients with moderate renal dysfunction)¹⁰ is not clear when combined with DAPT, but in any case would not be lower than that with the lower-dose rivaroxaban twice-daily regimens studied in ATLAS ACS 2-TIMI 51. Therefore, from a safety standpoint, a triple antithrombotic regimen with full-dose rivaroxaban (20 mg) should be avoided until further head-to-head data are available.

Triple therapy regimens with other NOACs have also yielded similar results. A meta-analysis of 31,286 patients receiving DAPT along with direct thrombin inhibitors or factor Xa inhibitors after ACS found a threefold increase in major hemorrhagic complications with addition of NOACs to DAPT as compared with placebo.¹¹ To further understand the risk of various antithrombotic regimens in AFib patients undergoing PCI, the results of the ongoing PIONEER AF-PCI trial will be useful. This trial is investigating the use of rivaroxaban and warfarin with various combinations of antiplatelet drugs (including prasugrel and ticagrelor) in AFib patients undergoing PCI.

Option D offers warfarin as an anticoagulant option, along with DAPT consisting of aspirin and clopidogrel. Given that data regarding resumption of NOACs or choosing one NOAC over the other following PCI are lacking,¹² switching to warfarin is a reasonable option if the patient is agreeable to frequent INR measurements and there are no specific contraindications for warfarin.

With regard to concomitant antiplatelet therapy, there are some data to suggest that double therapy (consisting of warfarin and clopidogrel 75 mg) has a favorable safety profile when compared with triple therapy (aspirin 80 mg, clopidogrel 75 mg, and warfarin with INR target of 2.0). The WOEST trial (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing) in Europe randomized 573 patients receiving oral anticoagulants and undergoing PCI to either double or triple therapy.¹³ There was a significant reduction in the primary endpoint of bleeding episodes within one year of PCI (19.4% vs. 44.4%, HR 0.36, 95% CI 0.26-0.50, p<0.0001), without significant increases in the rate of thrombotic events such as MI, stent thrombosis, target vessel revascularization, or stroke.¹³ The WOEST study has its limitations—mainly due to its small size. Despite these limitations, based on the WOEST trial and some additional registry data, the latest European Heart Rhythm Association recommendations suggest selection of clopidogrel plus warfarin following PCI in AF patients.¹⁴ While additional studies are needed to confirm this finding in an American population, given the current data and clinical presentation, it would be prudent to choose double therapy consisting of clopidogrel 75 mg and warfarin (target INR 2.0). Of note, the alternate antithrombotic regimen of aspirin 81 mg, clopidogrel 75 mg, and warfarin with target INR of 2.0-2.5 (triple therapy) is a Class IIb recommendation (level of evidence: C) of the current American College of Cardiology (ACCF)/American Heart Association (AHA) guidelines for management of AFib in STEMI patients, with a Class I recommendation (level of evidence: C) to minimize the duration of triple therapy based on individual circumstances.¹⁵

References

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