Triple Therapy Yields No Thrombotic Benefit, More Bleeding in Older PCI Patients With A-fib

For older patients with A-fib who undergo stenting for acute MI, triple therapy increases bleeding and fails to reduce MACE compared with dual antiplatelet therapy (DAPT), according to an observational study published in the August 11, 2015, issue of the Journal of the American College of Cardiology.

Take Home: Triple Therapy Yields No Thrombotic Benefit, More Bleeding in Older PCI Patients With A-fib

Investigators led by Connie N. Hess, MD, MHS, of the Duke Clinical Research Institute (Durham, NC), analyzed data from 4,959 older patients (mean age approximately 78 years) with A-fib who underwent PCI for acute MI between 2007 and 2010 at 405 US hospitals in the ACTION Registry-Get With The Guidelines database.

At discharge, 72.4% of patients were prescribed DAPT (generally clopidogrel and aspirin), while 27.6% received triple therapy (DAPT plus warfarin).

Compared with DAPT patients, those on triple therapy were more often men and more frequently had a history of PCI or CABG, prior stroke, and recent A-fib or atrial flutter. In addition, they were often already on warfarin before admission. On the other hand, patients discharged on DAPT alone were more likely to have had in-hospital major bleeding.

Use of triple therapy increased with higher predicted stroke risk (P for trend < .0001) but was not linked with predicted bleeding risk (P for trend = .18). The triple therapy group more often presented with NSTEMI (vs STEMI) and were more likely to have an LVEF of 40% or lower. Patients discharged on DAPT were more likely to receive glycoprotein IIb/IIIa inhibitors during PCI, whereas those on triple therapy more often received bivalirudin. Among those undergoing primary PCI, DES use was similar between the triple therapy and DAPT groups.

Similar MACE but More Bleeding

At 2 years, cumulative rates of MACE (primary endpoint; death or readmission for MI or stroke) were similar between the triple therapy and DAPT groups, as were rates of the component endpoints. The only exception was ischemic stroke, which tended to be less common in the triple therapy arm. However, rates of bleeding requiring hospitalization and intracranial hemorrhage were higher for patients on triple vs dual therapy—the risk of bleeding readmission beginning shortly after discharge and persisting over follow-up. Similar patterns were seen after adjustment for patient, treatment, and hospital characteristics (table 1).

Table 1. Two-Year Outcomes in PCI Patients With A-fib

Adjusted results were consistent across subgroups based on age, sex, CHADS2 score, A-fib duration, stent type, and acute MI presentation.

Landmark analysis of 1,591 patients with Medicare Part D coverage showed that patients discharged and maintained on warfarin through 90 days had a 2-year risk of MACE similar to that of DAPT-only patients who had not crossed over to warfarin during that time (adjusted HR 0.96; 95% CI 0.67-1.36). They also had a trend toward more bleeding (adjusted HR 1.50; 95% CI 0.92-2.46).

Upfront vs Delayed Anticoagulation an Open Question  

According to the authors, US guidelines for A-fib management advocate careful consideration of stroke, thrombosis, and bleeding risk in patients with concurrent indications for anticoagulation and antiplatelet therapy and recommend limiting a triple regimen to as short a time as possible. The fact that in the current study the proportion of patients discharged on triple therapy rose with the estimated stroke risk but did not vary with the predicted bleeding risk provides insight into how US providers decide between dual and triple therapy, they add.

Interestingly, Dr. Hess and colleagues observe, about 1 in 9 patients not discharged on warfarin were started on the drug over the next 3 months, perhaps due to completion of P2Y12-inhibitor treatment, resolution of in-hospital bleeding, recurrence of A-fib events, or deferral of treatment decisions to an outpatient care provider. “Further investigation may help clarify the benefits and risk of upfront versus delayed anticoagulation in these PCI-treated patients with [A-fib],” they say.

More Not Always Better

Given inconsistent study findings reported in recent years, “the question of whether triple therapy is beneficial for MACE remains troublingly uncertain, [but] the data are consistent for bleeding,” write Javier A. Valle, MD, and John C. Messenger, MD, both of the University of Colorado School of Medicine (Aurora, CO), in an accompanying editorial.

One study—the randomized WOEST trial—showed both an efficacy and a safety advantage for the combination of warfarin and clopidogrel vs triple therapy, they note. But the sample size was small and only one-quarter of patients received PCI for ACS. “Clearly, ‘less’ is appealing, but further study is needed to declare a definite front-runner,” they say.

Ongoing studies, such as REDUAL-PCI and PIONEER AF-PCI, are focusing on redefining the agents in triple therapy, in part by exploring the potential of new oral anticoagulants, Drs. Valle and Messenger say. “At best, these trials will offer further evidence to support the use of dual therapy without aspirin but with no knowledge of [its] efficacy or safety compared with clopidogrel and warfarin. At worst, they may have negative results and continue the uncertainty surrounding the optimal treatment strategy for patients with indications for [oral anticoagulation] and DAPT.

“When it comes to antithrombotic therapy, ‘more’ does not appear to be ‘better,’” but to date the nature of the “better” alternative remains unclear, they conclude.


1. Hess CN, Peterson ED, Peng SA, 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.
2. Valle JA, Messenger JC. Triple therapy… can we replace more with better [editorial]? J Am Coll Cardiol. 2015;66:628-630.

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Triple Therapy Yields No Thrombotic Benefit, More Bleeding in Older PCI Patients With A-fib

  • The study was supported by grants from the Agency for Healthcare Research and Quality and the American College of Cardiology Foundation’s National Cardiovascular Data Registry.
  • Dr. Ness reports receiving research grant support from Gilead Sciences.
  • Drs. Valle and Messenger report no relevant conflicts of interest.