Three's a crowd: WOEST and combination antithrombotic therapy

One of the most challenging scenarios in cardiology is managing the potential risks and benefits of triple therapy, i.e., the combination of dual antiplatelet therapy (DAPT) (aspirin plus a P2Y12 inhibitor) and oral anticoagulation in patients who have indications for both (e.g., percutaneous coronary intervention (PCI) and atrial fibrillation). Although a number of potential management strategies have been proposed (e.g., placing bare metal stents to limit duration of DAPT, targeting a lower INR range, etc.), none are supported by anything beyond retrospective trials or meta-analyses. Ever since preliminary results from the WOEST trial were announced last year -- a trial comparing triple therapy to the combination of clopidogrel and warfarin alone -- many have been awaiting its full publication to understand how applicable the results would be to clinical practice.

In WOEST, 573 patients receiving oral anticoagulation with warfarin set to undergo PCI were randomized to warfarin plus clopidogrel alone (i.e., double therapy), or warfarin plus aspirin and clopidogrel (i.e., triple therapy) [1].  Baseline characteristics were fairly well-balanced between the two groups, and the indication for oral anticoagulation was atrial fibrillation/atrial flutter, mechanical heart valves, or other thromboembolic disorders (e.g., pulmonary embolism) in approximately 70%, 10%, and 20% of patients, respectively.  At a median follow-up of 365 days, the primary endpoint of any bleeding event within one year of PCI was observed in 19.4% of patients receiving double therapy compared to 44.4% of patients receiving triple therapy (p < 0.0001). No differences in TIMI major bleeding were found. Interestingly, a reduction in the composite secondary endpoint of death, myocardial infarction, stroke, target-vessel revascularization, and stent thrombosis was observed in patients randomized to double therapy (11.1% versus 17.6% with triple therapy, p = 0.025), although the study was not powered to detect differences in this endpoint.

Although a lot of buzz had been generated about WOEST prior to its publication, I was reluctant to recommend double therapy without knowing more about the patient population enrolled in the trial. After reading the full results, I am actually surprised at how at-risk the patient population was for recurrent thrombotic events (i.e., where the addition of a third antithrombotic agent would be of theoretical benefit). The number of cardiovascular risk factors present among patients enrolled in the trial was representative of contemporary practice, and about a third of patients presented with acute coronary syndrome (ACS).  Of the stented lesions, many were fairly high risk, with about 40% of stents being placed in the left anterior descending (LAD) artery, about 30% in the right coronary artery (RCA), and about 25% in the left circumflex (LCx) artery.

Beyond some of the limitations noted by the study authors (e.g., relatively small size, open-label design, not being powered to detect differences in thrombotic events), I believe the main challenge posed by the WOEST trial will be how to incorporate its results into a standard of practice that is rapidly changing.  Whether similar results in bleeding events would be observed with the combination of one of the newer P2Y12 inhibitors prasugrel or ticagrelor and warfarin is not known at this time. Additionally, it is not known whether the new oral anticoagulants apixaban, dabigatran, or rivaroxaban provide the same degree of protection as warfarin in the setting of coronary artery disease. In the case of dabigatran, its use may even be associated with an increased risk of myocardial infarction (further detailed in a previous post), a risk that seems at least in part ameliorated in patients also taking aspirin.

Based on the results of WOEST, I think it is reasonable to consider double therapy with clopidogrel and warfarin alone in a significant number of patients who would have otherwise been candidates for triple therapy. I would especially consider this strategy in the setting of elective PCI. For patients receiving PCI as part of the management of an ACS event (especially myocardial infarction), I am not sure the 30% of patients enrolled in WOEST (i.e., < 200 of the 573 total patients) is enough to justify indiscriminate use of double therapy over triple therapy in this setting. Until a larger study (or one specifically evaluating patients with ACS) is conducted, I think the decision as to which regimen is most appropriate in patients with ACS unfortunately remains a risk versus benefit scenario.

Thoughts? Should we be using double therapy in this population irrespective of indication (i.e., ACS versus elective PCI)? Please leave your comments below.

References

1. Dewilde WJ, Oirbans T, ten Berg JM, et al; for the WOEST study investigators. 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 Mar 30;381(9872):1107-15.