Despite New Findings, Optimal DAPT Duration Still Up in the Air

Despite years of research and experience, the best approach to dual antiplatelet therapy (DAPT) is far from settled, as much-awaited findings from several trials presented last month at the 2014 American Heart Association (AHA) Scientific Sessions continue to fuel that discussion.

The DAPT Study provided insight into the safety and efficacy of prolonged therapy after DES implantation but may not have caused a major shift in clinicians’ attitudes. Other studies also presented at AHA added to the evidence base in favor of shorter durations. For the time being, it seems how long to keep patients on DAPT will remain an individualized decision based on risk factors.

Individualizing is “already what physicians do,” Gilles Montalescot, MD, PhD, of Pitié-Salpêtrière Hospital (Paris, France), told TCTMD in a telephone interview, noting that patients who need oral anticoagulation or surgery for another problem or who have had nuisance bleeding or other bleeding complications within 3 to 6 months after stenting will have DAPT stopped early.

“Otherwise [patients] would be continued to 1 year and maybe longer, especially if they have a high ischemic risk—multiple stenting, small arteries, prior history of stent thrombosis, and so on,” he said. “The recommendations say to do 1 thing, but you have to adjust according to the patient that you have in front of you.”

Long History of Uncertainty

The clinical trials that evaluated the first DES called for 2 to 6 months of DAPT. In 2006, however, analyses presented at the World Congress of Cardiology in Barcelona, Spain, raised concern about the risk of stent thrombosis with the first-generation devices compared with BMS, spurring recommendations to extend DAPT to at least a year.

Since then, several smaller trials have suggested that shorter DAPT durations may be noninferior to longer treatment, prompting some clinicians to advocate for earlier cessation. The European Society of Cardiology recently revised its revascularization guidelines to recommend 6 months of DAPT, whereas the US guidelines continue to call for at least a year of treatment.

That discrepancy reflects the long-standing uncertainty that prompted the FDA in 2006 to recommend initiating the DAPT Study, which randomized nearly 10,000 DES patients to stop DAPT at 1 year or continue taking aspirin and either prasugrel (Effient; Eli Lilly/ Daiichi Sankyo) or clopidogrel for 30 months.

New Information From AHA

Results from DAPT and 3 smaller trials—ITALIC/ITALIC+, ISAR-SAFE, and TL-PAS—all were presented at the AHA meeting.

ITALIC/ITALIC+ included about 1,900 patients randomized to 6 or 24 months of DAPT, and ISAR-SAFE included about 4,000 patients randomized to 6 or 12 months of DAPT. Both used a combined safety and efficacy primary endpoint, and both concluded that shorter DAPT was noninferior to longer therapy. However, TL-PAS compared 30 and 12 months of DAPT with prasugrel in patients who received a second generation PES and found longer-term therapy to be more effective at preventing ischemic events.

The DAPT Study, with nearly 10,000 patients, had 2 coprimary efficacy endpoints measured from 12 to 30 months poststenting: definite or probable stent thrombosis and MACCE (death, MI, or stroke). It showed that prolonging DAPT reduced stent thrombosis by a relative 71%, MACCE by 29%, and MI by 53%. The rate of moderate or severe bleeding, however, was 61% higher with prolonged therapy, and there was a trend toward a 36% increase in all-cause mortality (P = .052). The mortality difference was driven by a higher rate of noncardiovascular deaths, including those related to bleeding, trauma, and cancer.

DAPT is “an extremely important trial because what it tells you is that we probably have been thinking about dual antiplatelet therapy in a very stent-focused and interventional cardiology-focused way, when the benefits of DAPT are much more similar to the benefits one would see with statins and atherosclerosis,” said Daniel I. Simon, MD, of University Hospitals Case Medical Center (Cleveland, OH), who was co–national principal investigator of the Cordis/Johnson & Johnson contribution to the DAPT Study cohort and a co-author on the New England Journal of Medicine paper. He noted that 55% of the MIs were unrelated to stent thrombosis.

“I think it throws a cold shower on people who have said 3 months is enough,” he told TCTMD in a telephone interview. “It’s very clear that you reduce stent thrombosis, MI, and MACCE with prolonged therapy. So you have to at least discuss that with your patient. You may decide that the patient’s risk of bleeding takes away that benefit, but it doesn’t mean that you can say on the basis of underpowered, prematurely terminated, statistically flawed trials that 3 or 6 months are good enough.”

Dr. Montalescot pointed out, however, that the DAPT Study included a highly selected group of patients because only those free from adverse events during the first year after DES implantation were randomized. Thus, the enrolled patients were inherently low risk.

“In these patients without bleeding risk, it makes sense if they are at risk of further ischemic events to keep them on dual antiplatelet therapy. If they are at high bleeding risk, the treatment would be stopped at 6 months as recommended now in the [European] guidelines,” he said, estimating that about one-third of DES patients might require longer-term DAPT.

DAPT: Individualize It

Dr. Montalescot and other clinicians stressed the need for customizing the decision about how long DAPT should be continued.

Eric R. Bates, MD, of the University of Michigan (Ann Arbor, MI), who was on the data and safety monitoring committee for the DAPT Study, told TCTMD in a telephone interview that clinicians have been doing that all along—using shorter therapy for patients at low risk for stent thrombosis and ischemic events and longer therapy for those with higher risks for ischemic events.

“I don’t know how we’re going to solve it, other than to say ‘individualize it’ and do it by a risk assessment of stent thrombosis and risk for spontaneous MI,” he said. Other factors to be considered include coronary anatomy; the use of multiple, overlapping, or bifurcation stents; bleeding risk; diabetes status; smoking status; and stent type, he said, pointing to an analysis of the DAPT Study showing that the benefits of prolonged therapy might differ among DES types.

Dr. Bates said that before the AHA meeting he had been stopping DAPT relatively consistently at 12 months after discussion with his patients. That approach, he said, will likely continue for the foreseeable future until more analyses come out, including the PEGASUS trial. The findings of PEGASUS, which compared 2 doses of ticagrelor (Brilinta; AstraZeneca) plus aspirin with aspirin alone in patients with a prior MI, are expected to be presented at the American College of Cardiology (ACC)/i2 Scientific Session next year.

“I think there’s going to be no ‘one size fits all,’” Dr. Bates said. “This controversy is going to go on for a while.”

After the DAPT Study results were released, the Society for Cardiovascular Angiography and Interventions (SCAI) also advocated for an individualized approach: “Given the currently available scientific evidence on antiplatelet therapy, SCAI recommends the interventional cardiology community should continue to follow the practice guidelines of 1 year of dual antiplatelet therapy,” a statement read. “However, the DAPT findings suggest that, in specific patient cohorts, a longer duration of the therapy may be considered.… Thus, each physician should use his or her judgment in tailoring therapy to the individual patient.” 

Will Practice Change?

Dr. Bates said he does not expect the findings coming out of the AHA meeting to sway many clinicians from their beliefs about the optimal duration of DAPT.

“The people who believe in longer therapy will look at the DAPT [Study] and say, ‘This supports my clinical belief, and I’m going to treat longer and indefinitely in some of these patients,’” he said. “And I assume the people who believe in shorter therapy will look at 10 other trials that suggest lower therapy is just as good and say, ‘Maybe I have a couple of extra MIs in the shorter therapy group, but I have fewer bleeding complications and I save money by not buying more [of the] drug.’”

According to Dr. Simon, the DAPT Study results will spur US guidelines to include a recommendation reflecting the benefits of prolonged therapy in patients at low risk for bleeding, but he agreed that there probably would not be a major shift in how DAPT is used in practice.

“I don’t think it’s going to settle things because you have camps of people who are biased going either way,” he said. Even so, he noted, the DAPT Study “adds perhaps the most important [piece] to the long story, because it’s the first trial that’s adequately powered.”

In a post-meeting webcast on TCTMD, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), said that he was not convinced about the benefits of prolonged DAPT therapy before the trial results were reported and now is probably more likely to consider longer therapy in certain patients, including those with multiple complex stents, diffuse atherosclerosis, and recent ACS.

“This trial has clearly shown efficacy of that practice, and so that makes me want to find the patients that I think will benefit from that therapy,” he said, acknowledging that there was also a signal of harm. “For me there’s certainly no imperative to put people on prolonged DAPT. I think I’ve really got to find the right patients who I think are going [to benefit].”

 

 


Disclosures:

 

  • Dr. Simon reports serving on the advisory boards for Cordis/Johnson & Johnson and Medtronic.
  • Dr. Bates reports receiving honoraria from multiple companies making antiplatelet agents and serving on the ACC/AHA PCI guidelines committee.
  • Dr. Montalescot reports relationships with multiple pharmaceutical and device companies.
  • Dr. Stone reports no relevant conflicts of interest. 

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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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