For patients on an oral anticoagulant and aspirin, the addition of clopidogrel for 6 weeks after stent implantation offers no net clinical benefit over 6 months of triple therapy, according to the ISAR-TRIPLE trial published in the April 28, 2015, issue of the Journal of the American College of Cardiology.

The findings were originally presented at the Transcatheter Cardiovascular Therapeutics meeting in Washington, DC, in September 2014.

“These results suggest that physicians should weigh the trade-off between ischemic and bleeding risk when choosing the shorter or longer duration of triple therapy,” say Nikolaus Sarafoff, MD, of Klinikum der Universität München (Munich, Germany), and colleagues.

For the trial, investigators enrolled 614 patients (average age about 74 years; 76.7% men) who were receiving a vitamin K antagonist (at the lowest recommended target international normalized ratio) plus aspirin (75-200 mg) at 3 European centers between September 2008 and December 2013. Patients were randomized to also receive 75 mg of clopidogrel daily for 6 weeks (n = 307) or 6 months (n = 307) following stent implantation.

Approximately two-thirds had stable angina. The great majority (83.9%) of all patients took oral anticoagulants for A-fib or flutter, and other indications included a mechanical heart valve and venous thromboembolism. Femoral access was used in 98% of patients, and all but 1 received unfractionated heparin during PCI. Use of oral anticoagulants and aspirin remained very high in both groups throughout the study. At discharge, 37.3% of all patients were treated with proton pump inhibitors.

No Difference by Clopidogrel Duration

At 9 months, there was no difference between the treatment arms in the primary endpoint (death, MI, definite stent thrombosis, stroke, or TIMI major bleeding), with thelack of treatment effect consistent across all prespecified subgroups. Rates of the combined ischemic endpoint (cardiac death, MI, definite stent thrombosis, or ischemic stroke) and TIMI major bleeding were also similar between treatment arms (table 1). Although there were 6 MIs in the 6-week group (half periprocedural), only 1 occurred on day 212, when the patient was no longer on clopidogrel.

Furthermore, there were no excess ischemic events in the 3 months following clopidogrel discontinuation in either group.

A post hoc landmark analysis of the period after the treatments diverged—ie, between 6 weeks and 9 months—showed no differences for the primary endpoint (P = .32) or composite ischemic endpoint (P = .13). However, there were fewer BARC bleeding events in the 6-week group than in the 6-month group (20.5% vs 27.9%; P = .04) and a trend toward a lower cumulative incidence of BARC type 2 or higher bleeding (HR 0.60; 95% CI 0.34-1.04).

Another landmark analysis, of the period between 6 weeks and 6 months, also showed no differences between the groups with regard to the primary or composite ischemic endpoints but a pronounced reduction in BARC bleeding favoring 6 weeks.

Abbreviated Therapy ‘Very Reasonable’

In an accompanying editorial, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA),references 2 large ongoing trials that should “help define the optimal cocktail and duration of antithrombotic agent treatment in patients with [A-fib] and recent stents”—PIONEER AF-PCI, which is testing rivaroxaban (Xarelto; Janssen Pharmaceuticals), and REDUAL-PCI, which is evaluating dabigatran (Pradaxa; Boehringer Ingelheim).

“Until such data become available and outside of clinical trials, it is very reasonable to adopt the general strategy supported by the ISAR-TRIPLE trial, and by the WOEST study, which is to abbreviate the duration of triple antithrombotic therapy,” Dr. Bhatt writes.

Furthermore, “6 weeks certainly seems like a reasonable starting point, titrating the duration and intensity of triple antithrombotic therapy upward or downward, depending on patient and lesion characteristics,” he adds.

Triple Therapy Perhaps Riskier With New Oral Anticoagulants

ISAR-TRIPLE can serve as a “lamppost as we move forward,” Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), told TCTMD in a telephone interview. But with so many variables at play in terms of different drugs, dosages, and durations, he stressed, it hardly answers all the relevant questions.

Dr. Kleiman said he favored eliminating aspirin from the regimen, as was tested in the WOEST trial, over shortening clopidogrel therapy. “We have the DAPT Study now telling us that patients who tolerate long-term DAPT are better off staying on it,” he noted. “Here we’re adding a variable [in the form of an anticoagulant] that makes patients less likely to tolerate long-term DAPT. So I would like to see the WOEST [strategy] expanded.”

Furthermore, Dr. Kleiman said he was “very surprised” that major bleeding was not more common in the group receiving 6 months of triple therapy and suggested the reason may be that the investigators “selected patients really well.”

He proposed that the next randomized trial should treat all patients with triple therapy for 6 weeks and then randomize them to continue clopidogrel or not. “That’s probably the best way to get to the answer,” he said.

“Everyone is pretty scared of triple therapy,” especially in the era of the new oral anticoagulants, which are more powerful than warfarin, Dr. Kleiman said. “We’re holding our breaths” awaiting the results of REDUAL-PCI and PIONEER AF-PCI, he commented. Meanwhile, he said he would “strongly consider” switching a patient who was on a novel oral anticoagulant to warfarin if a stent was needed.

“I’m glad they did ISAR-TRIPLE,” Dr. Kleiman concluded. But understanding the best way to manage patients on oral anticoagulant who need stenting “is not going to come anytime soon,” he said.

Sources:
1. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE trial. J Am Coll Cardiol. 2015;65:1619-1629.
2. Bhatt DL. When is a double better than a TRIPLE? Stenting patients with atrial fibrillation [editorial]. J Am Coll Cardiol. 2015;65:1630-1632. 

Disclosures:

• The study was supported in part by an unrestricted research grant from Abbott, Deutsches Herzzentrum München, and PCI Research at Aarhus University Hospital.
• Dr. Sarafoff reports receiving fees for lectures or travel from Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Lilly/Daiichi Sankyo, and Medtronic.
• Dr. Bhatt reports serving on the boards of or receiving honoraria from multiple associations and publications and receiving research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company.
• Dr. Kleiman reports serving as a consultant to AstraZeneca, Eli Lilly, and Medicure.

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