Triple Antithrombotic Therapy: Recent Data and Future Investigation

Roughly 25,000 Americans with a preexisting indication for oral anticoagulation (OAC) undergo percutaneous coronary intervention (PCI) every year.1, 2 In an effort to minimize the risks of stroke and stent thrombosis, most clinicians prescribe both oral anticoagulation (OAC) and dual antiplatelet therapy (DAPT), commonly referred to as triple antithrombotic therapy (TOAT), for at least some period of time after PCI.3 The few published recommendations for antithrombotic strategies in these patients agree with that practice to varying extents, all recommending at least some duration of TOAT after PCI for the majority of these patients.2,4,5 Thus far, these recommendations have been based mostly on retrospective data and older randomized trials that studied the addition of warfarin to aspirin in acute coronary syndrome (ACS). Recently published studies have challenged these recommendations, suggesting that TOAT may not be the preferred strategy in these patients, and setting the stage for future research. Meanwhile, the promising role of newer anticoagulant agents in ACS and AF has prompted investigation into the role of these agents for patients with AF after PCI.

Published in February 2013, the What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial was a randomized controlled trial (RCT) that investigated the ideal antithrombotic strategy in patients on OAC undergoing PCI.6 Patients scheduled to undergo PCI with a prior indication to continue OAC for at least one year were randomized to two antithrombotic strategies: double therapy, consisting of warfarin and clopidogrel 75 mg, or triple therapy, consisting of warfarin, clopidogrel 75 mg, and aspirin 80 mg.

At one year, patients enrolled in the triple therapy group had a significantly higher cumulative incidence of the primary endpoint of all Thrombolysis in Myocardial Infarction (TIMI) bleeding when compared to double therapy (44.4% vs. 19.4%; HR 0.36; 95% CI 0.26–0.50; P<0.0001). This was accounted for by differences in TIMI minimal and minor bleeding; there were no significant differences in TIMI major bleeding or in intracranial bleeding. The most common sites of bleeding were gastrointestinal and skin. Importantly, strategies to reduce bleeding were not encouraged; only 25-27% of patients were taking proton pump inhibitors and only 34-39% of patients underwent radial access during PCI.

The secondary efficacy endpoints also favored double therapy, which saw a significant reduction in the composite of death, myocardial infarction (MI), stroke, systemic embolism, target vessel revascularization, and stent thrombosis when compared to triple therapy (11.1% vs. 17.6%; HR 0.56; 95% CI 0.35–0.91; P=0.025), a difference that was driven by a reduction in mortality (2.5% vs. 6.3%; HR 0.39; 95% CI 0.16–0.93; P=0.027). Interestingly, double therapy also saw non-significant reductions in MI, stroke, and stent thrombosis.

The reduction in bleeding seen with double therapy, while not surprising, is an important finding. Although there was no difference in major bleeding, the authors appropriately note the impact of minor bleeding events, such as the thrombotic consequences of temporary cessation of antithrombotic therapy. The efficacy results are more surprising, though not unprecedented. Earlier studies of the use of warfarin in ACS included arms that compared warfarin alone to warfarin plus aspirin and found no statistically significant difference in efficacy, suggesting that the addition of aspirin to therapeutic anticoagulation does not add significantly to the prevention of death, non-fatal MI, or stroke after ACS, albeit in a population with much lower rates of PCI.7, 8 More recently in September 2012, a large Denmark registry analysis also found triple and double therapy to provide statistically similar efficacy benefits in patients with AF after PCI.9 The WOEST efficacy results were unexpected, with double therapy providing a mortality benefit along with non-significant reductions in stent thrombosis and MI when compared to triple therapy. These results should be interpreted with caution since the trial was not powered for these individual endpoints, and the concept of reduced antiplatelet therapy leading to fewer ischemic and thrombotic events is counterintuitive and conflicts with prior data.

The latest ESC recommendations on the use of new anticoagulants in AF include a section on the management of patients with AF after ACS. Based on registry data and the WOEST trial, these recommendations note that "clopidogrel plus [a vitamin K antagonist] appears to be the most sensible combination early after PCI in AF patients."10 For now, it is prudent to avoid changing practice until these results are confirmed by larger trials, especially in patients at high risk for stent thrombosis, in whom it is unknown if the risk of stent thrombosis would be unacceptably high on single antiplatelet therapy. Nevertheless, the WOEST trial is arguably the most informative published RCT on this topic and the results will undoubtedly influence future investigation.

While the WOEST trial has provided new insight into the utility of TOAT regimens involving warfarin, the momentum of investigation into newer oral anticoagulants for AF and ACS has stimulated desire to evaluate the role of these agents in TOAT for patients with AF after PCI. The oral factor Xa inhibitor rivaroxaban has gained particular interest due to its encouraging results in both AF and ACS. ROCKET-AF found rivaroxaban 20 mg once daily to be non-inferior to warfarin at preventing stroke or systemic embolism in patients with atrial fibrillation (HR, 0.79; 95% CI, 0.66 to 0.96; P<0.001) while leading to significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003).11 ATLAS ACS 2-TIMI 51 found that when rivaroxaban 2.5 mg twice daily was added to post-ACS medical regimens, 93% of which included DAPT, there was a significant reduction in cardiovascular death, MI, or stroke (9.1% vs. 10.7%, P=0.02) and all-cause mortality (2.9% vs. 4.5%, P=0.002).12 Rivaroxaban 5 mg twice daily also saw significant reductions in cardiovascular death, MI, or stroke, but led to more non-fatal bleeding when compared to the 2.5 mg dose group and did not have a mortality benefit when compared to placebo. Based on this data, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has included secondary prevention in patients with ACS as an indication for rivaroxaban 2.5 mg twice daily.13

ATLAS ACS 2-TIMI 51 excluded patients with AF and it is difficult to apply the results to patients with AF undergoing PCI. The rivaroxaban dose of 2.5 mg twice daily used in ATLAS ACS 2-TIMI 51 was lower than the 20 mg once daily dose used in ROCKET-AF that was non-inferior to warfarin at stroke reduction. While this low-dose TOAT regimen yielded a significant overall survival benefit in ACS patients by improving efficacy without increasing fatal bleeding, it is unclear if it would provide adequate stroke reduction in patients with coexisting AF.

Responding to a need for further investigation, the PIONEER AF-PCI investigators are conducting an open-label, randomized, controlled, multicenter trial that is planning to enroll 2100 patients with AF undergoing PCI. Patients will be randomized to three arms: rivaroxaban 15 mg once daily and a P2Y12 inhibitor; rivaroxaban 2.5 mg twice daily, a P2Y12 inhibitor, and aspirin 75-100 mg daily; or a vitamin K antagonist, a P2Y12 inhibitor, and aspirin 75-100 mg daily. The primary endpoint will be clinically significant bleeding. This intriguing trial hopes to provide data for the use of rivaroxaban in patients with AF after PCI, while comparing the low-dose TOAT regimen used in ATLAS ACS 2-TIMI 51 versus traditional TOAT with warfarin versus rivaroxaban and a P2Y12 inhibitor without aspirin. Furthermore, it will allow the use of newer antiplatelet agents, prasugrel and ticagrelor, which have also yet to be studied in this patient population.

Patients on OAC who undergo PCI challenge clinicians to find antithrombotic strategies that optimally balance their risks of stroke, stent thrombosis, and bleeding. The future climate of research will likely be filled with both excitement and uncertainty. The most helpful studies will likely be those designed to expand on the concepts learned from WOEST and other studies of TOAT with traditional agents while including evaluations and comparisons of the newer antithrombotic agents so that the results will clinically applicable as the use of the newer agents in patients with cardiovascular disease continues to expand. PIONEER AF-PCI promises to be one such trial. As similar future investigative efforts produce more informative data, clinicians will be better equipped to manage the competing risks of these complicated patients.


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Keywords: Acute Coronary Syndrome, Anticoagulants, Aspirin, Fibrinolytic Agents, Percutaneous Coronary Intervention, Retrospective Studies, Stents, Stroke, Thrombosis, Warfarin

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