Three Months of DAPT Noninferior to 12 With Zotarolimus Stent: OPTIMIZE

ARCTIC-INTERUPTION DAPT Study Also Adds New Information

Shelley Wood

October 31, 2013

SAN FRANCISCO, CA (updated) — Patients who took just three months of aspirin plus clopidogrel following PCI with a zotarolimus-eluting stent (Endeavor, Medtronic) faced risks of adverse events similar to those of patients who took the recommended 12 months of dual antiplatelet therapy (DAPT), say OPTIMIZE investigators [1].

Results from the 3000-patient trial are published today in the Journal of the American Medical Association to coincide with their presentation by Dr Fausto Feres (Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil) here at TCT 2013 .

"Among patients undergoing PCI with implantation of zotarolimus-eluting stents, short-term (three months) dual antiplatelet therapy was noninferior to long-term (12 months) dual antiplatelet therapy for the occurrence of death, MI, stroke, or major bleeding, without significantly increasing the risk of stent thrombosis," Feres and colleagues concluded.

In a morning press conference, Feres addressed the question of whether these results applied only to the Endeavor or whether they would also extend to other newer devices. "If I answer this as a physician, I would say yes, this would apply to the other second-generation stents. If I reply as a scientist, I'd say that needs to be looked at in a randomized fashion. But [as a doctor], I would say yes, this applies to the other second-generation stents, because we have seen with other second-generation stents a very low incidence of stent thrombosis."

Dr Fausto Feres

Proving that, he added, would likely take a 15 000-patient trial. "And that's going to be hard to do."

Dr Dean J Kereiakes (Christ Hospital Heart & Vascular Center/Lindner Research Center, Cincinnati, OH), however, was the scheduled discussion for the trial and is also co-PI on the >26,000 patient DAPT trial addressing the very question of DAPT duration in different approved devices. He had plenty of gripes about the trial.

"My major concern is with a noninferiority comparison using a composite primary end point that combines both safety and efficacy measures," he told heartwire . "This type of end point is selected to enhance power, but the individual components . . . are discordant, they go in opposite directions, they vary in importance, but are all treated as if they are the same."

This is the fourth trial that has been unblinded and underpowered, he noted, although others have at least separated out the bleeding and ischemic end points. "This is the first trial to walk out on thin ice and combine both safety and efficacy measures. The big DAPT trial, he notes, has coprimary end points of differences in stent-thrombosis rates and major adverse cardiovascular and cerebrovascular events (MACCE), plus a primary safety end point for the DAPT trial is major bleeding. This, he said, is the trial that will give a definitive answer on dual antiplatelet duration poststenting.

Rationale for OPTIMIZE

OPTIMIZE investigators, however, say their trial provides important new information on top of mounting evidence that newer-generation drug-eluting stents (DES) that promote healing of the vessel wall—or at least don't delay it—may not lead to the same risk of late stent thrombosis. Reports of stent thrombosis occurring after six and even 12 months with first-generation DES prompted regulators to recommend that any patient receiving a DES receive at least 12 months of aspirin plus a thienopyridine.

Operators and stent manufacturers, however, have in recent years argued that the newest stents have safer polymers, better drug-release kinetics, and better scaffolds that justified shorter-duration DAPT.

Optimizing Drug Treatment Post-PCI

Seeking to prove this, OPTIMIZE investigators randomized 3211 patients equally to either three or 12 months of DAPT, with follow-up at both these time points. Most patients were relatively low risk, with either stable angina or silent ischemia; just 5% in both groups had NSTEMI, and no acute-MI patients were included.

As Feres reported at the TCT meeting today, the primary end point—a composite of all-cause death, MI, stroke, or major bleeding ("net adverse clinical and cerebral events [NACCE])—was seen in 93 patients receiving three months and 90 patients receiving 12 months of DAPT (6.0% vs 5.8%), a nonsignificant difference. Major adverse cardiac events, as well as any of the primary end point components, were also not statistically different between groups.

When the first 90 days were analyzed separately from days 91 through one year, no significant differences in any of the study end points were seen. Of particular concern, definite or probably stent thrombosis occurring between the three- and 12-month marks was documented in four patients taking just three months of DAPT protection vs one in the 12-month DAPT group. Rates of "any bleeding" were more than double in the longer-duration DAPT group (14 events vs six), a number that missed statistical significance (p=0.07).

"Although not specifically studied, it is possible that the results of our trial may be especially relevant for patients at high risk of bleeding complications following PCI, such as the elderly and patients with a history of hemorrhagic events," the authors write.

Importantly, key higher-risk subgroups, including patients with diabetes, multivessel disease, history of ACS, and bifurcation lesions, also showed no difference according to DAPT duration.

Informing Decisions

Commenting on the study during the press conference, Dr Cindy Grines (Detroit Medical Center, MI) said the findings would likely help guide her decision to stop or continue DAPT. "I try to individualize, if it's a high-risk patient with multiple stents, long stents, or one of the risk factors like small [mean luminal diameter] MLD, diabetes, renal failure, or ACS, then I'm definitely going to give [dual antiplatelet therapy] longer. But I think [this trial information is] going to be real helpful in the short, more focal [lesions] that you think are not at high risk of thrombosis and if you feel like you got a good result. "

Keep in mind, Grines added, that the OPTIMIZE trial investigators stuck to a specific protocol, requiring high-pressure inflations with a noncompliant balloon. That's something "that doesn't commonly happen" in clinical practice, she said.

Of note, as Kereiakes pointed out in his discussion of the trial, the Endeavor is scarcely used in clinical practice; the Integrity Resolute having replaced this iteration within Medtronic's DES development program. "I see this platform as obsolete," Kereiakes told heartwire . "For me, OPTIMIZE is a nonevent."

ARCTIC-INTERUPTION Confirms Results

This morning's TCT 2013 late-breaking trials included a second study of DAPT duration, this one comparing 12 months and 18 months of DAPT in the ARCTIC trial (this extension trial dubbed "ARCTIC-INTERUPTION"), also showed no differences in ischemic outcomes (composite of death, MI, stent thrombosis, stroke, or urgent revascularization) between groups (3.8% and 4.3%, respectively). Of note, however, major and minor bleeds were more common in the continued DAPT arm. "So safety is affected by continuation of treatment," said Dr Gilles Montalescot (Pitié-Salpêtrière University Hospital, Paris, France), who presented the trial results to the press.

Importantly, however, only 50% of patients from the original ARCTIC trial were randomized into the extension study, for a range of reasons, including physician and patient preferences. As a result, ARCTIC INTERUPTION included a relatively low-risk group of patients, and that's true for all of the studies that have addressed this question.

"The next step would be to study this in ACS patients," Montalescot told heartwire , but until that happens, he does not think the results of shorter-duration DAPT studies can be extended to ACS patients.

Feres reported receiving speaker's honoraria from Biosensors International, Eli Lilly, Medtronic Vascular, Sanofi, and Terumo. Montalescot reported research grants to his institution or consulting/lecture fees from Abbott Vascular, Accumetrics, AstraZeneca, Bayer, Biotronik, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, Duke Institute, Eli Lilly, Europa, Fédération Française de Cardiologie, Fondation de France, GlaxoSmithKline, INSERM, Institut de France, Iroko, Lead-up, Menarini, Medtronic, Nanospheres, Novartis, Pfizer, ReCor Medical, Roche, Sanofi, Stentys, Société Française de Cardiologie, Springer, the Medicines Company, the TIMI group, WebMD, and Wolters.

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