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DAPT Study: Extended Treatment After Stenting Lowers Stent Thrombosis and Heart Attacks
Data Also Shows Increased Stent Thrombosis for Bare Metal Stents
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Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents
-- New England Journal
of Medicine

Dual Antiplatelet Therapy after Drug-Eluting Stents How Long to Treat?
-- Editorial, New England Journal
of Medicine

stent with pills
November 16, 2014 -- "Longer is better." That's what Dr. Dean Kereiakes told Angioplasty.Org when characterizing the results of the long-awaited Dual Antiplatelet Therapy (DAPT) study, which were presented today at the annual American Heart Association Scientific Sessions in Chicago. Dr. Kereiakes is the co-principal investigator for this five year study of 10,000 patients, which adds to the knowledge base of whether long-term treatment with aspirin and a thienopyridine, such as Plavix, after stent implantation is beneficial to patients.

The DAPT trial was requested by the U.S. FDA after data in 2006 showed an increased risk of stent thrombosis (blood clotting inside a stent) with drug-eluting stents. For background on this issue, read our Editor's blog post, "Plavix and Aspirin After Stent: 8 Years Later – Is Longer Better?"

The study was presented at AHA today by Laura Mauri MD, MSc, principal investigator of the DAPT Study, interventional cardiologist at the Brigham and Women’s Hospital, Associate Professor of Medicine at Harvard Medical School and Chief Scientific Advisor for HCRI. The study was simultaneously published in the New England Journal of Medicine. The main question was whether 30 months of DAPT after stenting was superior to twelve, and the results favored the longer period. The study looked at the period starting one year after stent implantation in 9,961 patients who had received drug-eluting stents and who had been on DAPT (aspirin plus an antiplatelet drug, most commonly clopidogrel/Plavix) for the previous twelve months. At this point the patients were randomized: half continued on DAPT and the other half were given a placebo plus aspirin.

The results at 30 months showed significantly lower rates of stent thrombosis in the DAPT group (0.4% vs 1.4%, p<.001) and lower rates of heart attack in the DAPT group (2.1% vs 4.1%, p<.001). Severe or moderate bleeding predictably was higher in the DAPT group (2.53% vs 1.57%, p=.001). However, none of these differences translated to a significant change in overall mortality, and surprisingly the non-cardiovascular death rate was higher in the DAPT group. The investigators posited that this may have been due to the fact that more patients with cancer wound up being randomized into the extended DAPT cohort. Dr. Mauri stated:

Laura Mauri MD, MSc
Laura Mauri MD, MSc
"The benefits of continuing dual antiplatelet therapy for 30 months were quite remarkable. The relative risk of a stent-related blood clot was reduced by 71%, compared with taking only aspirin after one year. The DAPT Study was the first and only study that was adequately powered to detect this benefit. Furthermore, the relative risk of heart attack was reduced by 53% by preventing these stent-related events, as well as by preventing events in vessels beyond the stented lesion.... The benefits with extended treatment were present across all stent and drug types included in the study. Additionally, the results were consistent regardless of patient characteristics, such as whether the stent was placed during a heart attack or whether the procedure was technically simple or complex."

Interestingly, 55% of the increased heart attacks in the non-DAPT group were not related to stent thrombosis at all, implying that DAPT has a beneficial effect on overall disease progression exclusive of the stent, something discussed by Dr. Antonio Colombo in an accompanying editorial.

When asked if the results of the DAPT study are going to change practice, Dr. Kereiakes told Angioplasty.Org:

Dean J. Kereiakes, MD
Dean J. Kereiakes, MD
"I think they should, in two instances: "longer is better" with reduction in ischemic events. And these are hard end-points, like heart attack and stent thrombosis.

"The other real conceptual change is that bare metal stents are not a safe haven. We did an analysis of bare metal stents and drug-eluting stents, and at the end of 33 months, the stent thrombosis rate was significantly higher (p=.01) in the bare metal stent-treated patients."

The data on increased stent thrombosis rates in bare metal stents may be one of the surprises of the DAPT trial because, in 2006, when the first concerns over increased stent thrombosis rates in DES surfaced, a large number of clinicians reverted to the earlier bare metal devices. Dr. Kereiakes will be presenting a more detailed analysis of these data in a Tuesday presentation, but this observation mirrors some of the findings in the ZEUS study, reported on previously by Angioplasty.Org.

Although the DAPT trial seems to give a green light to extended duration of DAPT therapy, many clinicians have stated that "one size fits all" medicine cannot be invoked in these situations, that a more individualized approach is required. Some patients are less at risk for stent thrombosis, or they may need surgery requiring cessation of DAPT therapy. Recent studies, with newer second generation stents, have shown no adverse effects from early interruption of DAPT therapy.

In fact, one very important set of data that was not shown in the initial presentation of DAPT was the stent thrombosis rates for first vs. second generation DES. It's been estimated that stent thrombosis has been halved in the more recent devices and, while the investigators have stated the treatment benefits extended across stent types, it would be most interesting to see the absolute numbers (in DAPT 60% of patients were treated with second-generation DES).

The differences between the older and newer stents, how those results might change the balance between greater benefit for extended duration of DAPT vs. increased hazard of bleeding, and many other issues are yet to be parsed from the very large amount of data collected, a fact acknowledged by Dr. Bram Zuckerman, head of the FDA Cardiovascular Devices Division, who stated in a press briefing earlier today, "This is a real step forward in how clinical trials in medical devices can be done. This field and the results are a bit confusing right now. But there's a lot of meat here. The benefit-risk framework will take some more time for clinicians to appreciate. It will take a lot more work...and we look forward to continuing this process from the FDA perspective."

Angioplasty.Org will continue to report on developments in this area as they are presented, including several additional DAPT studies that are being presented at this weeks American Heart Association meeting..

Reported by Burt Cohen, November 16, 2014