Triple Therapy, Especially With Prasugrel, Increases Bleeding Risk in Acute MI

Regardless of which antiplatelet agent is used, triple therapy results in excess bleeding compared with dual antiplatelet therapy (DAPT) in patients discharged after treatment for acute MI, an observational analysis shows. Investigators also report greater real-world use of clopidogrel than prasugrel in this population, with the latter associated with higher patient-reported bleeding events.

The findings, from a substudy of TRANSLATE-ACS, add more information to the ongoing debate over the use of triple therapy and, in particular, offer insight into the use of prasugrel on top of aspirin and an anticoagulant. “To date, most studies evaluating bleeding and cardiovascular outcomes associated with triple therapy have been nonrandomized in design, predominantly retrospective, and mostly in the setting of clopidogrel use,” write Larry R. Jackson II, MD, of the Duke Clinical Research Institute (Durham, NC), and colleagues.

Jackson et al included 11,756 acute MI patients treated at 233 US hospitals between April 2010 and October 2012 who were discharged on aspirin plus clopidogrel (n = 7,715) or prasugrel (n = 3,424) or triple therapy with either clopidogrel (n = 536) or prasugrel (n = 91). Warfarin was the predominant oral anticoagulant used (93%), with dabigatran and rivaroxaban used in the remainder. Only 3% of patients were taking oral anticoagulants before hospital admission, for reasons including prosthetic valves, venous thromboembolism, and A-fib.

Those given triple therapy after discharge had a greater comorbidity burden and were more likely to present with cardiogenic shock or heart failure than the patients prescribed DAPT.

Findings were reported in the December 21, 2015, issue of JACC: Cardiovascular Interventions.

More Bleeding With Triple Therapy

Overall, prasugrel was used in just 15% of triple therapy patients and in 31% of patients discharged on DAPT, the authors write. Those figures suggest that “physicians are less likely to add prasugrel to an oral anticoagulant and more likely to choose clopidogrel when prescribing DAPT with an oral anticoagulant.”

At 6 months, those on triple therapy with clopidogrel or prasugrel had higher risks of BARC-defined bleeding than those on DAPT with the same antiplatelet agent. Also, those on triple therapy with prasugrel had a greater bleeding risk than those assigned triple therapy with clopidogrel.

When bleeding events were qualified by whether the patient required rehospitalization, there was no difference between the triple therapy patient groups. However, for events that were only patient-reported, those on triple therapy with prasugrel had a much higher risk of bleeding than those on clopidogrel (35.6% vs 19.2%; adjusted OR 3.19; 95% CI1.52-6.66).

There were no differences in adjusted MACE rates at 6 months between any of the therapy groups.

Is Aspirin Even Needed?

In an editorial accompanying the study, Freek W.A. Verheugt, MD, PhD, of Onze Lieve Vrouwe Gasthuis (Amsterdam, the Netherlands), calls the use of DAPT after stenting in patients on oral anticoagulation “vexing and complex.” Even based on the “far from conclusive” results of the TRANSLATE-ACS substudy, he recommends not using novel antiplatelet agents in this population. Additionally, “liberal use of proton pump inhibitors and radial access is advisable,” he writes.

While agreeing with most of what Verheugt proffers, Sorin J. Brener, MD, of New York Methodist Hospital (New York, NY), told TCTMD in an interview that “the editorial is probably a little too bold to say never use [triple therapy with novel antiplatelets].” However, the study “confirms what we know, which is that triple therapy has more bleeding than double therapy,” he said.

Also, Brener noted, it does not matter whether or not the bleeding events require hospitalization, because the fact that patients report them “means that they are upset about it.”

To increase success, Verheugt suggests the possibility of dropping an antithrombotic drug, shortening DAPT duration, or using “safer” oral anticoagulants. Both WOEST and ISAR-TRIPLE have investigated different triple therapy approaches, he says, and those in combination with the ongoing MUSICA-2 study “will guide the management of this difficult group of patients.”

For his part, Brener advises not using triple therapy for long periods of time although “it’s very reasonable to use triple for 1 week or 2 weeks until the coumadin kicks in just to be sure.”

The next question is what therapy should be dropped. Brener cited the ongoing TWILIGHT study as one that will give more information on whether or not aspirin still has a place in the combination and PIONEER AF-PCI as a study that will examine different combinations of both new antiplatelet agents and novel oral anticoagulants. “In 2 years, we’ll know for sure,” Brener said.

Sources: 
1. Jackson LR, Ju C, Zettler M, et al. Outcomes of patients with acute myocardial infarction undergoing percutaneous coronary intervention receiving an oral anticoagulant and dual antiplatelet therapy: a comparison of clopidogrel versus prasugrel from the TRANSLATE-ACS study. J Am Coll Cardiol Intv. 2015;8:1880-1889.
2. Verheugt FWA. Do not use novel antiplatelet agents in patients on oral anticoagulants after stenting [editorial]. J Am Coll Cardiol Intv. 2015;8:1890-1892.

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• Case Study Highlights Risks for A-fib Patients Undergoing PCI in Absence of Evidence-Based Guidelines
• TRANSLATE-ACS Provides Real-World Data on Prasugrel, Clopidogrel Use in Acute MI
• Triple Therapy Yields No Thrombotic Benefit, More Bleeding in Older PCI Patients With A-fib