November 16th, 2014

Prolonged Dual Antiplatelet Therapy Affirmed in DAPT

The advent of drug-eluting stents dramatically reduced the restenosis rate associated with bare-metal stents but prompted new concerns about the rare but potentially lethal complication of stent thrombosis (ST). Cardiologists have relied upon dual antiplatelet therapy to prevent ST but there has been considerable uncertainty and controversy about the ideal duration of therapy.

The Dual Antiplatelet Therapy (DAPT) trial was coordinated by the Harvard Clinical Research Institute as part of a large-scale collaboration with the FDA, stent manufacturers, and pharmaceutical companies. The main results of the trial were presented on Sunday at the American Heart Association meeting in Chicago and published simultaneously in the New England Journal of Medicine.

After receiving a drug-eluting stent and one year of treatment with a thienopyridine and aspirin, 9,961 patients were randomized to 18 additional months of treatment with a thienopyridine or placebo. Both groups continued to take aspirin. The trial is the largest randomized controlled trial to examine the key issue of dual antiplatelet therapy duration.

The results provided compelling evidence that long-term dual antiplatelet therapy can reduce the risk of stent thrombosis and major adverse cardiovascular and cerebrovascular events, though at the cost of increased bleeding.

  • Stent thrombosis: 19 (0.4%) in the 30-month group versus 65 (1.4%) in the 12-month group (HR 0.29, p<0.001)
  • Death, MI, and stroke: 211 (4.3%) versus 285 (5.9%) (HR 0.71, p<0.001)
  • MI: 99 (2.1%) versus 198 (4.1%) (HR 0.47, p<0.001)
  • Severe or moderate bleeding: 119 (2.5%) versus 73 (1.6%) (p=0.001)

In an accompanying editorial, Antonio Colombo and Alaide Chieffo take note of “a recent drive within the interventional cardiology community to shorten the duration of dual antiplatelet therapy… from 12 months of therapy to 6 or even 3 months.” They write that dual antiplatelet therapy is still clearly mandatory in the early period, when the risk for stent thrombosis is still unacceptably high. But it is less clear whether the benefits outweigh the risks in the period of extended therapy studied in the DAPT trial. Prolonged therapy is most likely to be indicated in stent patients who are at high risk for stent thrombosis or MI but at low risk for bleeding. “It is possible that the patients who were excluded from randomization because of a previous major adverse cardiovascular or cerebrovascular event are the very patients who would have benefited the most from prolonged treatment,” they write.

Mortality in DAPT

One concern that emerged was that mortality went in the opposite direction of the other components of the major adverse cardiac and cardiovascular events endpoint and favored the control arm. Overall mortality marginally favored the control arm and there was a large difference in noncardiovascular deaths, though there was no difference in cardiac or vascular deaths.

Death: 2% versus 1.5%, p =0.05

  •    Cardiac death: 0.9% versus 1%, p=0.98
  •    Vascular death: 0.1% versus 0.1%, p=0.98
  •    Noncardiovascular: 1% versus 0.5%, p=0.002

The investigators speculated that this unexpected finding was likely explained by the play of chance and perhaps reflected a baseline imbalance in the number of patients with known cancer before enrollment.

To address the “potential public health importance” of the mortality finding, the DAPT investigators performed a separate systemic review and meta-analysis of the mortality findings in trials testing extended duration dual antiplatelet therapy. The results were published in the Lancet. They analyzed 14 trials that randomized nearly 70,000 patients to different durations of dual antiplatelet therapy and  found no significant differences in all-cause, cardiovascular, or noncardiovascular mortality.

At an AHA press conference most experts did not express concern about the mortality finding. Kirk Garratt said it was likely a “red herring.”

Prasugrel Problem?

The DAPT trial was composed of four individual studies sponsored by different stent manufacturers. The TAXUS Liberte Post-Approval Study (TL-PAS) used prasugrel as the thienopyridine and contributed the largest number of  patients who received a paclitaxel-eluting stent. In this arm of the study, withdrawal of prasugrel, either at 12 or 30 months, was associated with an increase in ischemic events, mostly MI, for the first 90 days. The investigators said they were unable to say whether the same effect would occur with other antiplatelet regiments and/or other drug-eluting stents.

 DAPT in the Real World: It’s Complicated.

In an editorial in the Lancet, Gilles Lemesle writes that “one size may not fit all” when it comes to the length of dual antiplatelet therapy. “Physicians should precisely assess each individual (in terms of risk–benefit ratio) when it comes to making a decision about whether to pursue or shorten dual antiplatelet therapy. If extended dual antiplatelet therapy definitely benefits some patients, it might also be deleterious for others.” He further states that the duration of therapy need not be decided immediately after the initial procedure: “Patients should be prescribed dual antiplatelet therapy for 6–12 months and then be re-assessed at each timepoint if they are event-free.” Future ischemic and bleeding events should have a strong influence on the decision, he writes.

At a press conference on DAPT there emerged  a broad consensus among leaders in the field about general principles, but there was little agreement about specific details or recommendations. The general principles, in accord with the Lancet editorial, were that DAPT should be discontinued early in patients at high risk for bleeding complications and should be prolonged in people at high risk for ischemic events. The problem, said Laura Mauri, the principal investigator of DAPT, is that people at high risk for ischemic events also have an elevated bleeding risk. “So it’s complicated,” she said.

Two smaller studies — ISAR-SAFE and ITALIC — that tested shorter durations of dual antiplatelet therapy were also presented at the AHA and discussed at the press conference. These studies both generally supported treatment shorter than one year, but it is impossible to draw firm conclusions from the trials because they were discontinued early for futility due to lower than expected event rates. In general, said experts at the press conference, the tendency is toward shorter duration in Europe and longer duration in the United States.

Commenting on all the trials, Gilles Montalescot said that the accumulated evidence from all the available trials supports both a shorter and a longer dual antiplatelet therapy strategy. He concluded that dual antiplatelet therapy can be safety stopped after six months in patients at high risk for bleeding. If there is no safety concern he said that treatment could be extended out to one year or longer. But he said it is difficult to identify the patients who may benefit from continued therapy and there is “no common rule” for  duration of therapy.

One intriguing finding repeatedly mentioned was the continued long term risk for MI in DAPT that was clearly not related to the stent and that was reduced by prolonged antiplatelet therapy. It is unclear, though, whether the same regimen that prevents stent thrombosis is the best regimen for the long-term prevention of ischemic events, said Richard Chazal, Vice President of the ACC, in an interview.

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