Shelley Wood

October 30, 2013

SAN FRANCISCO, CA — An update from the massive, global Dual Antiplatelet Therapy (DAPT) study is offering some early hints as to how differences in enrollment, randomization, and patient characteristics, based on geographic region, may influence study results and their interpretation.

As previously reported by heartwire , DAPT is the huge, multisponsor trial trying to settle once and for all whether drug-eluting-stent–treated patients should remain on DAPT (clopidogrel or prasugrel [Effient, Daiichi Sankyo/Lilly], plus aspirin) for more than one year after PCI (the trial was designed to compare 12 vs 30 months of DAPT). According to co-PI Dr Laura Mauri (Harvard Clinical Research Institute [HCRI], Boston, MA), the study enrolled more than 26 000 patients and, after one year of DAPT, has now completed randomization of 11 648 patients; full trial results are due out in the fall of 2014. The study primary end points are differences in stent-thrombosis rates and major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety end point for DAPT is major bleeding.

Presenting the update here at TCT 2013 , Mauri said she was confident that events were accruing in the trial at a rate that would ultimately show a difference between treatment groups. But she also urged investigators designing and conducting trials to be very aware of regional differences from the outset.

"The DAPT study has enrolled a very a representative patient population, but there were differences in the regional patterns, both in the patient characteristics and the stents and drugs used, but also in the clinical study execution according to the different sites," she said.

Location, Location, Location

Dr Laura Mauri

The US was far and away the biggest enroller in DAPT, enrolling 23 495 patients. Next largest was the UK, with 629 patients; the remaining 10 countries (in Europe or the Pacific Rim) enrolled between 94 and 388 patients. A total of 455 hospitals are participating in the study.

As Mauri showed here, there are some differences in clinical characteristics by region: North American patients, for example, had more diabetes and hypertension and were more likely to have undergone previous revascularizations, both PCI and CABG.

On the other hand, Europe and Pacific Rim countries (Australia and New Zealand are participating) were significantly more likely to enroll patients presenting with acute STEMI.

When the researchers looked at risk factors for stent thrombosis, clinical, anatomic, and "any" risk factors were all significantly higher in the EU and Pacific Rim countries than in North America. Both North America and Australia/New Zealand have a much higher use of drug-eluting stents than bare-metal stents, while the divide between stent type was much less marked in Europe.

What Mauri highlighted as one of the most striking findings of her early peek at DAPT was the rates of randomization of eligible patients by region. As per the study design, patients are only randomized after 12 months of DAPT, to continuation either on dual therapy or on aspirin alone.

Whereas Europe and Australia/New Zealand enrolled 82% and 83%, respectively, of eligible patients at the one-year mark, US sites enrolled only 55% of eligible patients.

While there were some differences in clinical events during the first 12 months that could explain part of this difference, the main driver was patient or physician decision to not proceed with the randomization phase, Mauri explained.

Addressed in multiple regression analysis, "the most important predictor of nonrandomization in DAPT was to be enrolled in North America," Mauri said, with an odds ratio of 4.32.

Following the presentation, session moderator Dr Daniel J Blackman (Leeds General Infirmary, UK) commented, "It's great we are starting to look at this," adding that he was unaware of any other analyses like this being done while a trial was still ongoing. Regional differences, he said, "are something we've seen quite a bit in recent randomized trials. . . . PLATO was a pretty notable example of this, where the overall result of the trial seemed to be confined to certain geographical locations."

Debate about geographical differences has dogged the PLATO results for years.

Mauri made it clear she did not think her findings would have an impact on the ability of the trial to answer the burning questions of safe/effective DAPT duration, but she did say that this kind of geographical analysis is something "we need to dive into" with large global randomized trials.

"Ultimately, we want to makes sure the results are valid across the spectrum of practices that are included in the trial. It's great to have diversity, right? It's great to be able to generalize, but we also have to know how [differences] impact the primary study findings."

In DAPT so far, Mauri noted that for the study, antiplatelet drugs were provided free of charge to all non-US sites, "so that probably did increase compliance in the overall study. So you can see how nonscientific procedures in the study may have influence on how things work out in the study."

She and her fellow investigators, including co-PI Dr Dean Kereiakes (Christ Hospital Heart & Vascular Center/Lindner Research Center, Cincinnati, OH), are also trying to tease out what she called "site-related characteristics" in addition to patient-related characteristics that might lead to regional variations.

Asked if she was concerned that the plummeting event rates seen with the newer-generation stents might foil the ability of DAPT to actually demonstrate a difference between treatment arms, Lauri said no, at least from looking at the aggregate, unblinded events to date.

"I think we had pretty good estimates of those rates when we designed this study, and we designed the study fairly conservatively. . . . The event rates seem to be tracking along with what we projected, so we are pretty hopeful we'll have the power we need to make a conclusion."

Mauri disclosed research support for HCRI from Abbott, Boston Scientific, Cordis, Medtronic, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Eli Lilly, and Daiichi and consulting for Biotronik, St Jude Medical, and Medtronic.

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