Reassuring Data on Use of DAPT and Anticoagulation

September 15, 2014

WASHINGTON, DC — For patients requiring aspirin, clopidogrel, and a vitamin-K antagonist, stopping clopidogrel after six weeks neither reduces the incidence of major bleeding nor increases the incidence of ischemic events.

In a randomized trial comparing a six-week triple-therapy regimen against one that maintained all three drugs for six months, the researchers conclude that the six-week regimen is not superior to a six-month triple therapy program in regard to the combined end point of death, MI, stent thrombosis, stroke, or TIMI major bleeding.

"The main outcome was neutral; however, our study suggests that physicians may be able to shorten the duration of triple therapy in patients who are at increased risk for bleeding," lead investigator Dr Nikolaus Sarafoff (University of Munich, Germany) told heartwire . "However, if you have another patient where you fear ischemic complications—patients with bifurcation lesions, left main lesions—you may also give the longer duration, because the worse bleeding, the TIMI major bleeding, was not increased with the longer duration of triple therapy. Physicians need to weigh the bleeding and ischemic risks of the individual patients."

Presenting the results of ISAR-TRIPLE today here at TCT 2014 , Sarafoff said the trial and the results differ from the What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST)study. In WOEST, which compared triple therapy with aspirin, clopidogrel, and anticoagulant therapy vs dual therapy with clopidogrel and an anticoagulant, there was a significant reduction in any bleeding complications and a decrease in ischemic complications with dual therapy. The reduction in ischemic complications with clopidogrel and a vitamin-K antagonist is not easily explained, said Sarafoff.

The ISAR-TRIPLE study

In ISAR-TRIPLE, investigators randomized 614 patients undergoing implantation of a drug-eluting stent at three European centers. All patients were treated with aspirin and a vitamin-K antagonist and randomized to six weeks or six months of clopidogrel therapy.

Regarding the primary end point at nine months—a composite of death, MI, stent thrombosis, stroke, or TIMI bleeding—there was no difference in clinical outcomes between the two treatment regimens. Similarly, there was no significant difference in ischemic outcomes or TIMI major bleeding.

Any bleeding defined by the Bleeding Academic Research Consortium (BARC) criteria occurred in 40% of patients at nine months with longer triple therapy, which is line with the WOEST study, and in 38% of patients treated for six weeks. This difference was not statistically significant. A post hoc landmark analysis, one that assessed any BARC bleeding from six weeks to nine months, found there was a reduction in BARC bleeding in the patients who received triple therapy for the shorter duration.

Outcomes, Six Weeks vs Six Months of Triple Therapy

End point 6-mo triple therapy, n=307 (%) 6-wk triple therapy, n=307 (%) Hazard ratio (95% CI)
Death, MI, stent thrombosis, stroke, or TIMI major bleeding 8.8 9.8 1.14 (0.68–1.91)
Cardiac death, MI, stent thrombosis, or ischemic stroke 4.3 4.0 0.93 (0.43–2.04)
TIMI major bleeding 4.0 5.3 1.35 (0.64–2.84)

"Triple therapy really increases bleeding complications in the general population compared with dual antiplatelet therapy or anticoagulation alone," said Sarafoff. "People fear these complications, but some patients really need these therapies, so our data give more insight into the incidence of those complications and into the optimal duration of triple therapy."

Candidates for Triple Therapy

In ISAR-TRIPLE, 83% of patient had atrial fibrillation, which made them candidates for anticoagulant therapy to reduce the risk of stroke or thromboembolic events. Patients with pulmonary embolism, deep vein thrombosis, or those with mechanical valves also have indications for oral anticoagulant therapy.

During a morning press conference, Sarafoff said that the risk of stent thrombosis/ischemic events is highest in the early stages following PCI, while bleeding risks with triple therapy increase with longer duration of therapy.

The European Society of Cardiology consensus document on the use of antithrombotic therapy in atrial-fibrillation patients presenting with acute coronary syndrome (ACS) and undergoing PCI was recently updated in August 2014. In it, the experts recommend triple therapy in stable PCI patients for just one month before switching to a single antiplatelet agent and anticoagulation.

The ISAR-TRIPLE study should reassure physicians that the guidelines are appropriate, especially since the guideline recommendations were based on a single randomized trial [WOEST] and observational data, said Sarafoff. In fact, the recommendations carry a level of evidence rated C and state that physicians should make treatment decisions based on the risk of bleeding and thromboembolic events using the HAS-BLED and CHA2DS2-VASc scores.

"I also want to point out that we have no proven concept to reduce TIMI major complications in this patient subset," said Sarafoff. "Shortening the duration didn't reduce major bleeding, the WOEST trial didn't reduce major bleeding, and giving a new oral anticoagulant agent hasn't reduced major bleeding."

For Dr Stephan Windecker (University Hospital Inselspital, Bern, Switzerland), who was not affiliated with the trial, the investigators should be congratulated because there have been so few data to guide physicians in their treatment of AF patients undergoing PCI. While the findings are reassuring, he is perplexed there is no effect on bleeding outcomes between the six-week and six-month treatment strategies.

"In clinical practice, bleeding under triple therapy, and this is supported by large-scale observational data, is a risk," said Windecker. "My take-home from this is that I'd rather shorten triple therapy in order to reduce the risk of bleeding."

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