Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation | Clinical Trial - ISAR-TRIPLE

Apr 29, 2015
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Presenter/Author:
Nikolaus Sarafoff, MD
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Deutsches Herzzentrum Muenchen
Date Presented:
09/15/2014
Date Published:
04/20/2015
Date Updated:
04/29/2015
Original Posted Date:
04/29/2015
References

Description:

The need for triple therapy with aspirin, clopidogrel, and a vitamin K antagonist is a commonly encountered clinical scenario in patients undergoing percutaneous coronary intervention (PCI), with concomitant conditions such as atrial fibrillation (AF) or venous thromboembolism (VTE). However, this appears to significantly increase the bleeding risk. The current trial sought to compare a 6-week versus a 6-month duration of triple therapy in patients undergoing drug-eluting stent (DES) implantation.

Contribution to the Literature: In patients undergoing DES PCI and with an indication for oral anticoagulation, a 6-month duration of triple therapy with aspirin, clopidogrel, and warfarin is not superior to a 6-week duration of triple therapy for ischemic endpoints.

Study Design

  • Randomized
  • Parallel

Patient Populations:

  • DES implantation and indication for oral anticoagulation
  • Number of enrollees: 614
  • Duration of follow-up: 9 months
  • Mean patient age: 74 years
  • Percentage female: 23%

Exclusions:

  • Age ≤18 years
  • Previous stent thrombosis
  • DES in left main

Primary Endpoints:

  • MACE (death, MI, stent thrombosis, stroke, or TIMI major bleeding) at 9 months

Secondary Endpoints:

  • Ischemic complications at 9 months
  • Bleeding complications at 9 months

Drug/Procedures Used:

Patients were randomized in a 1:1 fashion to receive a 6-week duration (aspirin, clopidogrel, and oral anticoagulation [OAC] for 6 weeks; aspirin and OAC indefinitely after that) or a 6-month (aspirin, clopidogrel, and OAC for 6 months; aspirin and OAC indefinitely after that) duration of triple therapy. Aspirin was used in a dose of 75-200 mg daily, clopidogrel at 75 mg daily, and warfarin or phenprocoumon with a target international normalized ratio (INR) of 2.0 (2.5 in patients with mechanical valves).

Principal Findings:

A total of 614 patients were randomized, 307 to 6 weeks of triple therapy and 307 to 6 months. Baseline characteristics were fairly similar between the two arms. More than two thirds of the patients underwent PCI for stable angina. The most common indication for OAC use was AF (84%), mechanical valve (7%), and VTE (6%). The median INR during follow-up was 2.2-2.3, with a 69% time in therapeutic range at 6 months. Nearly one half the patients underwent PCI with second-generation DES, 32% with biodegradable polymer DES, 11% with polymer-free DES, and 5% with first-generation DES.

The primary major adverse cardiac event (MACE) endpoint of death, myocardial infarction (MI), stent thrombosis, stroke, or TIMI major bleeding at 9 months was similar between the 6-week and 6-month triple therapy arms (9.8% vs. 8.8%, hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.68-1.91, p = 0.63). The composite ischemic endpoint (cardiac death, MI, stent thrombosis, ischemic stroke) (4.0% vs. 4.3%, p = 0.87) and TIMI major bleeding (5.3% vs. 4.0%, p = 0.44) were both similar. There were two stent thrombosis events in the 6-week arm, but none in the 6-month arm. On landmark analysis at 6 weeks, any Bleeding Academic Research Consortium (BARC) bleeding was lower in the 6-week therapy arm (20.5% vs. 27.9%, p = 0.04).

Interpretation:

The results of the ISAR-TRIPLE trial indicate that a 6-week duration of triple therapy is not superior to a 6-month duration of triple therapy in patients undergoing DES PCI, who also had an indication for OAC use.

This is an important topic since it is a commonly encountered clinical scenario and major bleeding can be as high as 10% at 1 year in patients on triple therapy. This trial appeared underpowered to study smaller bleeding differences, as were noted on the landmark analysis. Also, this trial really tested two strategies: 1) is a shorter duration of triple therapy safer, and 2) is aspirin + OAC better than aspirin + clopidogrel + OAC. The WOEST trial found that clopidogrel + OAC was in fact superior to aspirin + clopidogrel + OAC in reducing bleeding outcomes. Many clinicians prefer the use of bare-metal stents in patients needing concomitant OAC to overcome the need for long-term triple therapy.

References:

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;65:1619-29.

Presented by Dr. Nikolaus Sarafoff at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2014), Washington, DC, September 15, 2014.

Keywords: Vitamin K, Myocardial Infarction, Stroke, Follow-Up Studies, Angina, Stable, Phenprocoumon, Drug-Eluting Stents, Warfarin, Venous Thromboembolism, Ticlopidine, Percutaneous Coronary Intervention, International Normalized Ratio, Polymers, Atrial Fibrillation, Confidence Intervals, Transcatheter Cardiovascular Therapeutics


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