New Study Calls for Caution in Use of Triple Anticoagulant Therapy

By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SOURCES: Hess CN, et al. Use and outcomes of triple therapy among older patients with acute myocardial infarction and atrial fibrillation. J Am Coll Cardiol 2015;66:616-627.

Valle JA, Messenger JC. Triple therapy…can we replace more with better? J Am Coll Cardiol 2015;66:628-630.

Patients presenting with acute myocardial infarction (MI) who undergo coronary stenting require treatment with dual antiplatelet therapy, typically for 12 months or more following the event. For patients who also have indications for systemic anticoagulation, most commonly those with atrial fibrillation (AF) and elevated CHA₂DS₂-VASc scores, choosing the most beneficial anticoagulant regimen is difficult. Combining oral anticoagulants with dual antiplatelet therapy, often referred to as triple therapy, comes with well-described bleeding hazards but uncertain benefit.

In this study, Hess et al used a national registry database to identify older patients with a history of AF or flutter who presented with acute MI and underwent in-hospital percutaneous coronary intervention (PCI) with stenting. Longitudinal data from such patients presenting between Jan. 1, 2007 and Dec. 31, 2010 were obtained by linking registry information with data from the Centers for Medicare & Medicaid Services. Medicare Part D data were used to identify warfarin and P2Y12 antagonist use. Notably, warfarin was the only oral anticoagulant available for clinical use in the United States during this period.

The study identified 4959 MI patients older than 65 years of age who had a history of AF and were treated with PCI during this time. Of those patients, 27.6% (n = 1370) were discharged on triple therapy, and 72.4% (n = 3589) were discharged on dual antiplatelet therapy (DAPT) without an additional anticoagulant. Those discharged on triple therapy were most often already on warfarin prior to the index hospitalization. Compared with dual antiplatelet therapy patients, those discharged with triple therapy were more often male and more frequently had a history of PCI or coronary artery bypass graft (CABG), prior stroke, and recent AF or atrial flutter. On the other hand, patients discharged on antiplatelet agents alone were more likely to have experienced an in-hospital major bleeding event. As would be expected, patients prescribed triple therapy had higher predicted stroke risk compared with DAPT patients; however, use of triple therapy was not associated with predicted bleeding risk (P for trend = 0.18). Patients given triple therapy were more likely to have presented with non-ST segment elevation myocardial infarction (NSTEMI) rather than ST segment elevation myocardial infarction (STEMI), more often had a left ventricular ejection fraction ≤ 40%, and were more likely to have received bivalirudin during their PCI procedures. Although use of drug-eluting stents (DES) was similar between groups for patients who suffered STEMI, DES use was lower among triple therapy patients as compared to DAPT patients presenting with NSTEMI.

At 2 years post-discharge, rates of major adverse cardiac events (MACE) were similar between the DAPT and triple therapy groups (32.7 vs 32.6%). Of the individual components, only the unadjusted rate of ischemic stroke was lower in the triple therapy group (3.2% vs 4.7%; P = 0.02). All-cause mortality, MI readmission, and stroke readmission were all similar. After adjustment for patient, treatment, and hospital characteristics, the adjusted hazard ratio (HR) for ischemic stroke was no longer statistically significant.

Unsurprisingly, the incidence of serious bleeding requiring hospitalization within 2 years post-discharge was significantly higher for triple therapy patients compared with those on DAPT (17.6% vs 11.0%; P < 0.0001). This hazard was evident from shortly after discharge, and remained significant throughout the follow-up period. Triple therapy was also associated with a higher incidence of intracranial hemorrhage (adjusted HR, 2.04; 95% confidence interval, 1.25-3.34; P < 0.01).

The authors concluded that approximately one in four older patients with AF undergoing PCI for acute MI were discharged on triple therapy, and that this therapy was associated with higher rates of major bleeding without a measurable benefit in terms of major adverse cardiac events, including stroke.

COMMENTARY

Patients with concomitant needs for anticoagulant and antiplatelet therapies are, and are likely to remain, a particularly challenging group to treat. In this large retrospective study, triple therapy was associated with a significant bleeding hazard without a detectable benefit.

As pointed out in the accompanying editorial by Drs. Valle and Messenger, when it comes to anticoagulant regimens in these patients, “‘more’ does not appear to be ‘better’ … Although the question of whether triple therapy is beneficial for MACE remains troublingly uncertain, the data are convincing for bleeding.” Clearly, we should use caution when taking this approach. And yet, there are subsets of patients at higher risk of ischemic stroke or other thrombotic events for whom combination therapy still appears to be worth considering. Few trials have addressed the question of whether a better alternative exists. One exception is the WOEST trial, published in 2013, which reported a bleeding advantage to use of clopidogrel plus warfarin as compared to triple therapy, without an associated ischemic cost. WOEST was relatively small (573 patients), however, and was underpowered for events such as stent thrombosis.

Whether we are likely to have better data in the near future is uncertain. Many of the trials that are currently in the works, such as REDUAL-PCI and PIONEER AF-PCI, focus on the potential of the newer oral anticoagulants as compared to warfarin in this arena. For now, it is clear clinicians should carefully consider the potential benefits and fully assess bleeding risks in each such patient, and should employ triple therapy only after careful consideration.