Long-awaited results from the DAPT trial affirm that long-term dual-antiplatelet drug therapy is more effective than aspirin alone at preventing in-stent thrombosis and myocardial infarctions in patients treated with drug-eluting stents but also increases the risk of bleeding.

The impact of the study findings on the drug-eluting stent market is not yet clear. But, by establishing a strategy for further lowering the late-thrombosis risk, the DAPT results could cause drug-eluting stents to take an even bigger share of the total coronary stent market, analysts suggest, while the development of stents with bioabsorbable features may complicate the picture further.

DAPT funded by a consortium of stent and antiplatelet drug makers as well as the government. Since drug-eluting stents became widely available more than eight years ago, registry data has shown that stent-thrombosis is a risk with drug-eluting stents that can be managed with dual-antiplatelet therapy, but the optimal duration of dual-antiplatelet therapy with drug-eluting stents has not been firmly established by clinical evidence. (See Also see "Confusion Over Anti-Clotting Therapy Hinders Drug-Eluting Stent Rebound" - Medtech Insight, 29 October, 2007..)

To resolve the unanswered questions about thrombosis risk and anti-platelet therapy with drug-eluting stents, in 2009 FDA and the Harvard Clinical Research Institute launched an unprecedented international collaboration to run the dual antiplatelet therapy trial (DAPT). (See Also see "FDA Contributes Funds To Industry Post-Stenting Antiplatelet Trial" - Medtech Insight, 20 July, 2009..)

“We know that dual antiplatelet therapy is essential for all patients receiving coronary stents to prevent blood clots within the stents. This study showed that the preventive benefit continues when the medications can be taken for more than one year,” said DAPT principal investigator Laura Mauri, from Harvard Medical School. “Overall the benefits of longer therapy were very consistent throughout the types of patients we studied, and outweighed the risks.”

Mauri presented the long-awaited five-year results from DAPT at the American Heart Association Scientific Sessions in Chicago on Nov. 16 and they were simultaneously published on-line by the New England Journal of Medicine.

“The potential benefits of prolonged dual antiplatelet therapy may depend on the type of stent that is implanted” – New England Journal Of Medicine editorial

About 23,000 patients enrolled in the trial received a drug-eluting stent and, of these, 9,961 were randomized in the primary analysis. All patients took a thienopyridine drug (clopidogrel or prasugrel) plus aspirin for 12 months following the implant of a drug-eluting coronary stent and then these patients were randomized to either continued thienopyridine treatment plus aspirin or to a placebo plus aspirin for the next 18 months.

The American College of Cardiology/American Heart Association currently recommend 12 months of dual antiplatelet therapy after implant of a drug-eluting stent while the European Society of Cardiology recommends six to 12 months of dual antiplatelet therapy with a drug-eluting stent.

Continued treatment with thienopyridine, as compared with placebo, significantly reduced the rates of stent thrombosis (1.4 percent versus 0.4 percent) and major adverse cardiovascular and cerebrovascular events (5.9 percent versus 4.3 percent). Also, the rate of myocardial infarction was lower in the thienopyridine-plus-aspirin-group versus the placebo-plus-aspirin group (2.1 percent vs. 4.1 percent).

However, the combined rate of moderate and severe bleeding incidents was higher with continued thienopyridine treatment than aspirin alone (2.5 percent vs. 1.6 percent). But severe or fatal bleeding events were very uncommon and there was no significant difference between the randomized treatments with respect to severe bleeding or fatal bleeding, Mauri et al explain.

FDA issued a drug safety communication Nov. 16 indicating that the agency is evaluating the results, but notes that it has not yet reviewed trial results or reached any conclusions based on the DAPT findings. FDA plans to issue final conclusions and recommendations once it evaluates DAPT’s results. (See Also see "Antiplatelets In The Wilderness After Mixed Results From DAPT Study" - Pink Sheet, 18 November, 2014..)

The notice says the agency believes that clopidogrel’s and prasugrel’s benefits continue to outweigh their potential risks when used as approved and that healthcare professionals should not change their prescribing practices at this time.

Differentiating Stents?

Stent market watchers are awaiting more detailed analysis from the DAPT study comparing drug-eluting and bare-metal stent outcomes, but the initial data suggested a potential advantage for drug-eluting, which could lead to a market-share increase.

“If the DES penetration rate increased by 500 basis points from our current estimate in 2015 of 82 percent on a worldwide basis to roughly 87 percent, it would boost the $4 billion DES market by about $210 million,” Larry Biegelsen explains in a Nov. 17 research note. “All three major DES manufacturers would benefit from this outcome although Boston Scientific would benefit the most given its higher exposure to DES at about 15 percent of total sales.”

In NEJM, Mauri et al. stress that the reduction in the risk of ischemic events associated with long-term thienopyridine-plus-aspirin therapy appears “consistent across stent type and specific thienopyridine drug used and was evident regardless of the risk of stent thrombosis.”

However “whether the treatment benefits observed will be generalizable to other stent types or non-thienopyridine P2Y12 inhibitors is unknown,” Mauri et al. explain, and “since patients were not randomly assigned to a specific thienopyridine drug or stent type, direct comparisons between different stent types or drugs may be confounded, and within-subgroup estimates of treatment effect may be underpowered.”

In an accompanying editorial in NEJM, Antonio Colombo and Alaide Chieffo of the San Raffaele Scientific Institute in Milan, Italy, point out that DAPT showed a non-statistically-significant trend toward thienopyridine therapy being most effective in patients treated with paclitaxel-eluting stents and the least effective in among recipients of everolimus-eluting stents. “This suggests that the potential benefits of prolonged dual antiplatelet therapy may depend on the type of stent that is implanted,” they argue.

Also, Colombo and Chieffo point out that DAPT excluded patients who had a major adverse cardiovascular or cerebrovascular event, repeat revascularization, or moderate or severe bleeding by the completion of 12 months of dual antiplatelet therapy – 23 patients of the patients who had initially been treated with a drug-eluting stent and enrolled in the study. “It is possible that the patients who were excluded from randomization because of a previous major adverse cardiovascular or cerebrovascular event are the very patients who would have benefited the most from prolonged [dual-antiplatelet] treatment,” the editorialists suggest.

“The key message of the DAPT study is the suggestion that some patients who have been treated with a drug-eluting stent may benefit from extending dual antiplatelet therapy beyond one year, but also that the potential harm with this approach should not be overlooked,” Colombo and Chieffo conclude.

“Moreover, we do not know how long this benefit extends and which patients benefit most. The safest and most effective duration of dual antiplatelet therapy therefore remains uncertain and must be individualized for each patient; presumably in making this judgment, physicians should balance risk factors favoring atherothrombosis against the risk of bleeding,” they advise.

In a Nov. 17 blog post on the American College of Cardiology website, Valentin Fuster, editor of the Journal of the ACC, offers recommendations based on DAPT that are similar to the NEJM editorial: continue patients at high risk for ischemic events on aspirin plus another platelet inhibitor on a long-term basis, Fuster says.

If the patient is at low risk, for example, minor coronary disease and no previous ischemic events, or has a perceived risk of bleeding, Fuster recommends discontinuing dual antiplatelet therapy at six months.

Fuster notes the results of DAPT align closely with a subgroup analysis of the 2006 CHARISMA trial, which showed that clopidogrel added to low-dose aspirin appeared to be beneficial for patients with established cardiovascular disease, whereas patients with multiple risk factors alone for the disease may have been harmed by the treatment combo. (See Also see "CHARISMA Suggests Benefit Of Combo Antiplatelet Therapy In Patients With Established CV Disease" - Pink Sheet, 13 March, 2006.)

In addition to a major grant from the Department of Health and Human Services, the DAPT trial was sponsored by stent-makers Abbott Laboratories Inc., (Xience), Boston Scientific Corp. (Taxus, Promus), Medtronic, Inc. (Endeavor) and Johnson & Johnson/Cordis Corp.(Cypher – discontinued) and the manufacturers of the antiplatelet medications, Bristol-Myers Squibb Co. /Sanofi Pasteur Pharmaceuticals Partnership (Plavix (clopidogrel bisulfate)), Eli Lilly & Co. /Daiichi Sankyo Co. Ltd. (Effient (prasugrel)).

Longer Anti-Platelet Therapy Reduces Thrombosis Risks With Drug-Eluting Stents

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