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Prototype devices

It is recognized that a manufacturer may wish to submit a small number  of "prototype models" of a device to clinical investigation in order to assess safety and/or performance; and those such prototypes may need to undergo a number of changes prior to large-scale production.

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 Subject :20 000-patient DAPT clinical trial starts enrolling with eight industr.. 2009-10-06 08:42:24 
Sathvika
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Subject :20 000-patient DAPT clinical trial starts enrolling with eight industry sponsors on board

One year after the bold announcement of a 20 000-patient, $100-million, multisponsor randomized clinical trial testing optimal duration of dual antiplatelet therapy poststenting first jolted the interventional community to attention, the Dual Antiplatelet Therapy (DAPT) trial has started enrolling patients [1]. Dr Laura Mauri (Harvard Clinical Research Institute [HCRI], Boston, MA), co-principal investigator for the study with Dr Dean Kereiakes (Christ Hospital Heart & Vascular Center/Lindner Research Center, Cincinnati, OH), unveiled plans for the trial at last year's TCT meeting, amid rumors that not all of the four drug-eluting-stent (DES) manufacturers were happy with the study design. Clinicians and researchers also expressed concerns about questions the trial would not be able to answer.

Now, according to a press release issued by HCRI, the trial has officially launched with the big four DES makers (Abbott, Boston Scientific, Cordis/Johnson & Johnson, and Medtronic) on board, plus the four companies who make clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and prasugrel (Effient, Eli Lilly/Daiichi-Sankyo). The FDA is also involved in the study.

Roughly 200 institutions, mostly in Canada and the US, will enroll patients in DAPT. According to the trial description on clinicaltrials.gov, up to four postmarket approval studies will be permitted to build aspects of the DAPT trial into their design, in order to contribute a subset of subjects for the DAPT study analyses—a sticking point for companies that already have funding earmarked for studies under way or designed to address questions previously asked of them by the FDA.


Nuts and bolts of DAPT

DAPT is comparing 12 vs 30 months of dual antiplatelet therapy among 15 000 patients who have been treated with DES, powered to assess the primary end points of differences in stent-thrombosis rates and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety end point for DAPT is major bleeding. An additional 5000 patients treated with bare-metal stents will also be enrolled.

By design, all patients will receive 12 months of dual antiplatelet therapy with aspirin and a thienopyridine. At the one-year mark, MACCE-free patients will be randomized in a one-to-one fashion to either placebo plus aspirin or dual antiplatelet therapy (aspirin plus a thienopyridine, with the choice of clopidogrel or prasugrel left to operator discretion) for 18 months. Investigators will study event rates for an additional three months to capture any potential rebound effects of stopping clopidogrel/prasugrel.


Answers needed

one of the study sponsors, Medtronic, had—unsuccessfully—petitioned investigators and the FDA to include a six-month dual antiplatelet therapy arm to be part of the study design, rather than just the 12- and 30-month randomization. Medtronic has long tried to position its Endeavor stent as a safer DES, requiring shorter-duration dual antiplatelet therapy.

Now, a Medtronic spokesperson confirmed that the company believes the question at the heart of DAPT is important, but that this is just one of several studies it is undertaking to address the issue of optimal duration of dual antiplatelet therapy. At this year's TCT meeting, Dr Fausto Feres (Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil) described the design and rationale for the OPTIMIZE clinical trial, randomizing 3000 patients treated with the Endeavor stent to either three or 12 months of dual antiplatelet therapy, with a primary end point of net adverse cardiac and cerebrovascular events. Also enrolling patients is the Scripps Evaluation of Antiplatelet Therapies for Intermediate Duration With the Endeavor Stent (SEASIDE), a 900-patient, nonrandomized single-arm study of patients treated with the Endeavor, given just six months of dual antiplatelet therapy. Medtronic is helping fund both studies.

Clinicians not involved in DAPT also expressed concern at TCT 2008 about the fact that DAPT was not going to address any differences in stent-thrombosis rates between different DES. As Dr William Maisel (Beth Israel Deaconess Medical Center, Boston, MA) told heartwire when the DAPT trial was first announced: "I find it ironic that after months and years of hearing about how stents are different and that one company's stent . . . has different rates of stent thrombosis, we're suddenly lumping them all together. . . . 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 ramification that might affect patient safety, those data will be made public."

A spokesperson for HCRI confirmed that since the choice of stent is not randomized in DAPT, it would be "very difficult to make reliable comparisons," and these types of comparisons are not the goal of the study. "If there is any safety concern that arises, however, this would be presented," she told heartwire.

With the recent US approval of prasugrel, physicians have also started to speculate as to whether prasugrel and clopidogrel might have different effects in terms of preventing stent thrombosis or bleeding risk poststenting. The same spokesperson confirmed that DAPT will not examine differences between choice of thienopyridine, since here again, patients are not randomized to either clopidogrel or prasugrel. However, should any kind of safety signal emerge, that would be made public, she said.

DAPT Study protocol and patient eligibility information have been posted on www.clinicaltrials.gov.

Source

  1. Harvard Clinical Research Institute. Harvard Clinical Research Institute enrolls first patients into DAPT study to advance understanding of dual antiplatelet therapy following drug-eluting stent procedures [press release]. October 2, 2009. Available here.
  2. http://www.theheart.org/article/1010661.do

 

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