ACCEL | Until the data from the landmark Dual Anti-Platelet Therapy (DAPT) study1 were presented near the end of 2014, there was a growing body of evidence suggesting that shorter periods of dual antiplatelet therapy were a reasonable option for low-risk patients. For example, FAST MI found that use of DAPT at one year was not a predictor of 5-year mortality, and PRODIGY suggested that 24 months of dual antiplatelet therapy was no better than six months. In patients with stable CAD or low-risk ACS treated with zotarolimus-eluting stents, the OPTIMIZE study showed that three months of DAPT was noninferior to 12 months of therapy for a composite of all-cause death, MI, stroke, or major bleeding without significantly increasing the risk of stent thrombosis.

When OPTIMIZE was presented at TCT.13, Gilles Montalescot, MD, PhD, Pitié-Salpétrière Hospital, Paris, France—who was not involved in the study—said, “It is difficult to follow the guidelines that say we should give one year of dual antiplatelet treatment and only one year. (In OPTIMIZE) there was clearly no benefit from the prolongation of dual antiplatelet therapy whereas safety in terms of major and minor bleeding was significantly impacted.” William O’Neill, MD, Henry Ford Hospital, Detroit, MI, told Fausto Feres, MD, first author of OPTIMIZE, “I’m a very strong proponent of less as far as dual antiplatelets are concerned as I think we often harm people with this approach. So I congratulate you on starting this process—it took a lot of courage as it’s very tough to convince people to go against prevailing wisdom.”

Since randomized controlled trials comparing short- (≤6 months) versus long-term (≥1 year) DAPT have been insufficiently powered to detect significant differences in the risk of MACE, investigators reported in the March 24, 2015, issue of JACC the results of an individual patient data pairwise and network meta-analysis of four trials (N=8,180).2 Compared with prolonged DAPT (1 year), short-term DAPT (< 6 months) was associated with similar rates of MACE but lower rates of bleeding after DES placement. 

DAPT STUDY

With conflicting results, there was a lot of interest in the DAPT Study.1 The overall trial included about 10,000 patients from a total of 11 countries. After PCI and stenting, followed by 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) plus aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin.

Those receiving longer-term treatment were half as likely to develop in-stent thrombosis (a co-primary endpoint) compared to those patients who received DAPT for only 12 months then aspirin plus placebo for an additional 18 months (placebo group). The benefit was largely driven by the fact that longer-duration therapy was associated with about half the incidence of new MI compared to the placebo group.

Kirk Garratt, MD, Lenox Hill Heart and Vascular Institute, New York City, NY, said in a press conference, “Thirty months of treatment with prasugrel plus aspirin was associated with important reductions in major adverse cardiovascular and cerebrovascular events and stent thrombosis compared to 12 months of treatment, with no signal of truly dangerous bleeds being increased with longer therapy.”

He added, “Withdrawal of prasugrel at 12 months was associated with an important increase in the risk of ischemic events early after drug discontinuation, the principal risk being myocardial infarction, and the impact of drug withdrawal was evident within 90 days of drug cessation.” However, an elevated risk of stent thrombosis also was observed during the three months after discontinuation of thienopyridine treatment in those in the long-term therapy group.

The study’s principal investigator and lead author, Laura Mauri, MD, said DAPT “was the first and only study comparing durations of treatment with antiplatelet therapy that was adequately powered to detect a benefit on stent-related heart attacks.” The study enrolled “a broadly inclusive population treated with coronary stents.” Dr. Mauri, who is an interventional cardiologist at Brigham and Women’s Hospital and chief scientific adviser at the Harvard Clinical Research Institute in Boston, MA, added, “Overall the benefits of longer therapy were very consistent throughout the types of patients we studied, and outweighed the risks.” 

YES, BUT…

So that’s a wrap on the debate, right? Not quite. Dr. Mauri and colleagues recently published a systematic review and meta-analysis of 14 eligible trials—including the DAPT Study—that randomly assigned 69,644 participants to different durations of dual antiplatelet therapy.3 Compared with aspirin alone or short-duration dual antiplatelet therapy (≤6 months), continued treatment was not associated with a difference in all-cause mortality (HR: 1.05; p=0.33). Similarly, cardiovascular (p=0.1) and non-cardiovascular mortality (p=0.66) were no different with extended-duration versus short-duration DAPT or aspirin alone.

In the discussion section of their meta-analysis, the authors noted that the results of DAPT did indeed show significant reductions in stent thrombosis and the combination of death, MI, and stroke at 30 months in patients treated with extended thienopyridines. However, unexpectedly, all-cause mortality was higher in patients given a DES randomly assigned to continued thienopyridine (HR: 1.36; 95 percent CI: 1.00–1.85 at 30 months, and 1.36, 1.02–1.82 (p = 0.05) at 33 months). These differences were driven by differences in non-CV mortality. A blinded independent review of causes of death in the DAPT Study found that bleeding events did not arise in most non-CV deaths and did not entirely account for the difference in deaths between groups.

The authors wrote: “In view of the millions of patients treated with thienopyridines, including the more than 1 million undergoing PCI with stents every year worldwide, a true increase in mortality associated with extended thienopyridine use among the diverse population of cardiovascular patients could have profound consequences on public health. Conversely, widespread fear over the risks of continued thienopyridine use could result in inappropriate discontinuation, leading to an increased risk of ischemic events.”

Dr. Mauri and associates published a subsequent paper suggesting that more trials are needed, but with important changes.4 They created a decision analytic model incorporating the best data currently available and found that absolute risk differences in MACCE or stent thrombosis (ST) of 0.2 percent to 0.4 percent would be sufficient to outweigh the increased risk of bleeding and make longer-duration DAPT after DES implantation a preferred approach.

These findings suggest that, in order to compare treatment strategies where there are discordant risks of ischemia and bleeding, trials must be designed to have adequate power to identify differences in ischemic endpoints that might outweigh bleeding risks. This contrasts with many trials that have been powered to compare rates of bleeding between treatment arms that are relatively underpowered for the endpoint of ST. Furthermore, no trials have directly addressed the balance between ischemic benefit and bleeding, and many trials used combined endpoints such as net adverse clinical events in which bleeding and ischemic complications of various severities have been assigned uniform weights.

In fact, even large trials that are adequately powered typically compare individual endpoints across treatment arms rather than reconciling the relative impacts of multiple potential events, ischemic and bleeding, per patient. Clearly, this issue is far from resolved.

References

1. Mauri L, Kereiakes DJ, Yeh RW, et al. N Engl J Med. 2014;371:2155-66.
2. Palmerini T, Sangiorgi D, Valgimigli M, et al. J Am Coll Cardiol 2015;65:1092-102.
3. Elmariah S, Mauri L, Doros G, et al. Lancet. 2015;385:792-8.
4. Garg P, Galper BZ, Cohen DJ, et al. Am Heart J. 2015;169:222-233.e5.

Take-aways

• The DAPT Study demonstrated that 30 months of treatment with prasugrel plus aspirin was associated with important reductions in MACCE and stent thrombosis compared to 12 months of DAPT, with no signal of truly dangerous bleeds being increased with longer therapy.
• However, unexpectedly, all-cause mortality was higher in patients given a drug-eluting stent randomly assigned to continued thienopyridine
• Faults with recent studies suggest a need to alter studies going forward that permit reconciling the relative impacts of multiple potential events, ischemic and bleeding, per patient, in order to better determine the optimal duration of DAPT across the varied population comprising treatment candidates.

Keywords: ACC Publications, CardioSource WorldNews Interventions, Academies and Institutes, Aspirin, Blood Platelets, Boston, Cause of Death, Composite Resins, Drug-Eluting Stents, Myocardial Infarction, Piperazines, Pyridines, Research Personnel, Sirolimus, Stroke, Thienopyridines, Thiophenes, Thrombosis, Ticlopidine

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