Washington, DC - In what observers are calling a first for device/drug-sponsored trials, eight companies have signed on to fund a $100-million, 20 000-patient drug-eluting stent (DES) trial now dubbed the Dual Antiplatelet Therapy Trial (DAPT). DAPT will look at whether 30 months of dual antiplatelet therapy is better than 12 months for preventing stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE) and also whether the benefit of continued dual antiplatelet therapy relates to reducing stent thrombosis associated with drug-eluting stents or is primarily patient-oriented, relating to disease progression and nontarget lesions.

Dr Laura Mauri

Dr Laura Mauri (Harvard Clinical Research Institute [HCRI], Boston, MA), who is co-principal investigator for the trial with Dr Dean Kereiakes (Christ Hospital Heart & Vascular Center/ Lindner Research Center, Cincinnati, OH), announced the preliminary design for DAPT here at a "Health and Human Services Town Hall Meeting" at TCT 2008. Additional details as to what other researchers or groups might be involved in the steering committee or the executive committee for the trial and the extent to which industry representatives may be involved in the ongoing oversight of the study have not yet been finalized, sources say.

A DES-safety/antiplatelet-duration trial has been in the works since the December 2006 FDA DES safety meeting and indeed first looked to be shaping up as the CODA trial. As previously reported by heartwire, Dr Mitch Krucoff and colleagues at the Duke Clinical Research Institute (DCRI) filed an investigational device exemption (IDE) for their CODA trial earlier this year, designed with a patient-oriented end point of death, MI, and stroke vs bleeding and no bare-metal-stent arm. But device companies, represented by their umbrella trade organization, AdvaMed, reputedly balked at the notion of coughing up support for a trial with a patient-oriented end point that won't specifically establish the safety of a DES or determine the ability of dual antiplatelet therapy to reduce the risk of late stent thrombosis.

Skeletons out of the closet

Dr Mitch Krucoff

In an interview with heartwire, Dr Donald Baim (Boston Scientific, Natick, MA), who was listed in the TCT program as providing the "Advamed Perspective," emphasized that DAPT is unique to the extent that competing companies collaborated on the design of the study. (Advamed has clarified that Baim was not speaking on behalf of Advamed and that Advamed is not involved in the trial.) "This is not a design that was developed in a vacuum that industry was asked to fund. This was a design whose skeleton was designed by the manufacturers, because we were unhappy with a DES-only and MACE-only design."

He explained that the company had put out a bid for the "skeleton" study, won by HCRI, which will now submit the IDE to the FDA. Only one other party, which Baim called a "consortium," put in a bid; heartwire has learned that this was a combined Duke/Cardiovascular Research Foundation (CRF) bid. HCRI, however, was the unanimous choice by the eight companies funding DAPT. These are Cordis/Johnson & Johnson, Boston Scientific, Medtronic, Abbott, Bristol-Myers Squibb, Sanofi-Aventis, Lilly, and Daiichi-Sankyo.

"Although we won't have anything to do with the execution of the study or the analysis of the results—that will be completely independent—the trial as it stands today is very clearly built on the skeleton of the trial that we in industry developed between March and August," Baim said. "If we're putting up, collectively, $100 million to sponsor the trial, we have a lot of say in the trial design. The FDA also has to agree, and they found this acceptable."

DAPT design

In its current form, DAPT is designed to enroll more than 15 000 patients being treated with one of the four DES currently approved in the US, at the operator's discretion, and more than 5000 patients treated with a bare-metal stent. All patients will receive dual antiplatelet therapy during the first year, with the choice of clopidogrel or prasugrel (assuming FDA approval) left up to the physician. After 12 months, after the exclusion of any patients with MACCE or major bleeding during that time, patients will be randomized to either placebo or ongoing dual antiplatelet therapy out to 30 months. Follow-up will then end at 33 months, to include a possible three-month "rebound period."

The co-primary end points for the study will be stent thrombosis and MACCE, and the major safety end point will be major bleeding. Mauri expressed the hope that the first patient could be enrolled before the end of 2008, permitting the study to wrap up in December 2012. The "ambitious" timeline is warranted because of the urgency of the public-health question at stake, she explained.

Mauri, as well as representatives from the FDA, the National Institutes of Health, the Center for Medicare and Medicaid Services, and industry, emphasized in presentations today that the while some elements of DAPT were now finalized, discussions were ongoing among the sponsors, regulators, and other research organizations. Speaking with heartwire after the announcement, representatives from the FDA's Center for Devices and Radiological Health, Ashley Boam and Dr Andrew Farb, said that from the FDA's perspective, the "critical elements" of the trial—primary end points, sample size, and duration of follow-up—were "nailed down at this point."

But some question marks remain. Dr Michael Domanski, who spoke on behalf of the National Heart, Lung, and Blood Institute, raised what he referred to as "questions, not criticisms" about the trial. For one, he noted, new drug-eluting and next-generation stents will be on the market by the time DAPT concludes, "so how applicable will the DAPT results be?" he asked.

He also pointed to the fact that the trial, by leaving stent choice to individual operators, "in effect treats DES as a class . . . and I have real concern as to whether that's really true," he said, particularly since the stents use different base materials, different drugs, and have different elution protocols.

Stent-stent comparisons not a feature of DAPT

Indeed, a unique feature of DAPT is that there will be no analyses conducted according to stent or antiplatelet drug type. According to Boam and Farb, only the FDA and the data safety and monitoring board (DSMB) will have access to all the device- and drug-level data, although they said that individual companies may be permitted to access their own drug or device results. Sequestering this data was reputedly agreed to by the companies and the FDA in advance and indeed was one of the reasons the companies agreed to collaborate, given the lack of any statistical power in a study this size to make comparisons between devices or drugs. Krucoff told heartwire that this is fully appropriate and indeed was a fundamental construct in the original CODA trial as well.

But in a question-and-answer period following today's town hall meeting, several members of the audience pointed out that if one stent emerged as more prone to stent thrombosis than another, physicians and patients should know about it.

Dr William Maisel (Beth Israel Deaconess Medical Center, Boston, MA) was one of the audience members who raised the issue. Reiterating his comments to heartwire, Maisel explained, "I find it ironic that after months and years of hearing about how stents are different and that one company's stent, for biologic or platform or endothelialization reasons, has different rates of stent thrombosis, we're suddenly lumping them all together."

Maisel continued: "I'm willing to accept all that because I think the bigger question is important, and I think it would be impossible to answer it if this concession were not made. But I'd like to have some comfort that someone independent and trustworthy is looking at the data and that if there is an important difference between the stents, with an important clinical ramifications that might affect patient safety, that that data will be made public. I have no concerns about the independence of HCRI and their ability to run a good clinical trial, and I have no concerns about the FDA being well-meaning. But I do harbor some concerns that when the rubber hits the road and there are data to this effect at the end of the trial, I could imagine there might be some difficulty getting that data to see the light of day."

In response, Dr Bram Zuckerman (FDA, Rockville, MD) emphasized that the trial organizers are "well aware that they're going to need an extremely good DSMB."

And Mauri added, "The nature of the trial is that it has to transcend marketing-level competition among manufacturers. . . . There are randomized trials that are designed and powered to [compare stent-thrombosis rates between devices]. This trial was not."

And Mauri emphasized that any important signals coming out of DAPT would be dealt with appropriately. "There will be a need to monitor data to detect whether there is any extreme signal that would require some kind of report to the public if there were a difference in stent-thrombosis rates. I think the chance [of an extreme signal] is unlikely."

CODA's finale?

Speaking with heartwire, Krucoff refused to express any disappointment about CODA's apparent demise, saying carefully that CODA "still has a lot of really good people who are interested in it being done." He also hinted that some of the behind-the-scenes wrangling may have stalled the progress of what he called a "nutty path" for this trial.

"Looking backward, you could say that we all could have been smarter and done this better, but going forward, I think you can say that what industry, through the AdvaMed process, has come up with is a trial that is two to three times more costly than what we were originally asking for with CODA, and by raising the ceiling on what they were willing to fund, this definitely becomes a better clinical trial."

Krucoff would not say what role Duke or CRF might have in DAPT, if any, and said there were "still some enormous questions about how this is going to happen," beyond the selection of the primary investigators, the academic research organization in charge, and the funding commitment. "There are a lot of other political details surrounding this," he said cautiously, "whether this is collaborative and transparent going forward or whether this is going to be an industry-driven, or academically driven, or collaboratively driven initiative."