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CHICAGO -- Continuing a thienopyridine plus aspirin well beyond 1 year cut major adverse cardiovascular risks after drug-eluting stent (DES) implantation in the landmark Dual Antiplatelet Therapy (DAPT) trial.

Dual therapy for 30 months cut stent thrombosis rates by a relative 71% compared with aspirin alone after 12 months (rate 0.4% versus 1.4% from months 12 to 30, P<0.001), of Brigham and Women's Hospital in Boston, and colleagues found.

Prolonged clopidogrel (Plavix) or prasugrel (Effient) cut major adverse cardiovascular and cerebrovascular events by a relative 29% (rate 4.3% versus 5.9% over the same time frame, P<0.001), the researchers reported here at the American Heart Association meeting and simultaneously online in the New England Journal of Medicine.

While counterbalanced by the expected higher bleeding risk of extending the thienopyridine, "we saw benefits that were even larger than we expected," Mauri told 乌鸦传媒.

Notably, analysis of the data from one of several postmarketing studies that contributed to the FDA-mandated DAPT trial indicated a rebound in events when stopping prasugrel at either 12 or 30 months.

That Taxus Liberte-Post Approval Study showed an inflection point in myocardial infarction (MI) within 90 days of prasugrel discontinuation in both groups.

That makes sense, Mauri said, "because we know the atherosclerosis doesn't go away after we place a coronary stent and much of the reduction of MI was outside of the stented area."

Her analysis suggested 55% of the MI reduction in the overall DAPT trial from longer therapy wasn't related to stent thrombosis.

If the rebound effect is validated in ongoing MI studies, longer -- potentially lifelong -- dual antiplatelet therapy may be warranted, , of the University of Paris, who spoke at a press conference and served as discussant at the session.

Meanwhile, the decision on duration should be an individualized one, he recommended.

Physicians should continue prescribing as they have been doing, the FDA recommended in a .

The agency received summary DAPT trial data on Aug. 22 and has been analyzing it "expeditiously" since then, according to Bram Zuckerman, MD, director of the FDA Division of Cardiovascular Devices.

Additional comment from the agency can be expected in the coming months, he told 乌鸦传媒. An advisory panel meeting or other public hearing is on the table, he said.

"We only studied people up to almost 3 years so we don't know for sure that ischemic benefit will continue indefinitely and on the flip side whether the bleeding risk is reasonable to continue," Mauri cautioned in an interview. "So it's an individualized decision we need to make with our patients."

That conclusion found many assenting voices.

Clinical Implications

These findings run counter to the trend toward shorter and shorter dual antiplatelet therapy duration within interventional cardiology, , and Alaide Chieffo, MD, both of the San Raffaele Scientific Institute in Milan, noted in an editorial accompanying the DAPT study paper.

The apparent contradiction between findings that 3 to 6 months appears safe, at least in selected patients, and DAPT's benefit from prolonged treatment can be explained as the shorter period of being "mandatory" and the longer period being "possibly beneficial," they said.

There's no single answer to the best duration of dual antiplatelet therapy, they concluded.

The decision should be individualized, Montalescot concluded.

"We like to come up with magic numbers but that's just not possible," he said.

Conference chair , of California's Stanford University, was also convinced.

"Everybody needs dual antiplatelet therapy immediately after coronary stenting. I think we know that," he said. As to how long, "that is going to be individualized decision based on that patient, based on their characteristics and risk for an ischemic event, based on their risk for a bleeding event, based on their individual values and preferences."

"In my practice...I will look to short-term therapy as being sufficient to prevent things like stent thrombosis in a group of patients I'm worried about keeping on dual antiplatelet therapy over time," he told 乌鸦传媒. "In patients who have either ongoing ischemic risk or low bleeding risk or tolerable bleeding risk, I think the data also come together in a compelling way that suggest that there is benefit beyond that 12 month period of dual antiplatelet therapy."

However,, of the Icahn School of Medicine at Mount Sinai in New York City, was unconvinced that the study really added much to the clinical perspective.

The trial's answers dealt more with infarct in native vessels -- a question already answered by CHARISMA -- than with stenosis in stented vessels, he said.

The bigger problem, Fuster said, was that if the researchers had included bleeding in with the cardiovascular and cerebrovascular outcomes in a net clinical benefit analysis, the trial would have had the same neutral results as seen in a multitude of smaller studies that looked for net benefit.

"I am not going to change my practice with the data that came today," he told 乌鸦传媒.

"If I have a patient that has a significant degree of risk with previous ischemic events, I would continue two drugs forever," he explained. "On the other hand, if I have a patient with a stent and there's a significant degree of bleeding or has disease that may cause a significant degree of bleeding, like ulcers or liver disease, I would stop the two drugs at 6 months."

Risks of Longer DAPT

As expected, the rate of moderate or severe bleeding was elevated with continued thienopyridine treatment (2.5% versus 1.6%, P=0.001) in Mauri's analysis of 9,961 DES recipients randomized to an additional 18 months of clopidogrel or prasugrel versus placebo along with aspirin after completing 12 months of dual antiplatelet therapy without a major event.

An unexpected finding, though was the borderline significantly elevated overall mortality in the 30-month treatment arm.

The rate of death from any cause was 2.0% for them compared with 1.5% in the 12-month dual antiplatelet therapy group (hazard ratio 1.36, P=0.05).

One potential explanation was a chance imbalance in the proportion of patients enrolled with cancer, leading to higher cancer-related mortality in the continued thienopyridine group, Mauri said.

Vascular and cardiac causes of death were similar between groups, and excluding the patients who died from cancer eliminated the overall mortality association, she noted.

A systematic review by the group, simultaneously reported in The Lancet, showed no interaction between greater than 12 months versus 6 months or less of dual antiplatelet therapy and all-cause mortality (HR 1.05, P=0.33).

"I am comfortable with the additional analyses of the DAPT study that this was likely a red herring," Kirk N. Garratt, MD, of Lennox Hill Hospital in New York City, told reporters at a press conference where he reported the Taxus Liberte-Post Approval Study results.

The FDA was more concerned about the lack of a cardiovascular or all-cause mortality benefit, Mary Ross Southworth, PharmD, deputy director for safety in the agency's Division of Cardiovascular and Renal Drugs, suggested at the press conference.

Subanalyses

DAPT also included 1,687 bare-metal stent recipients, for whom a subanalysis showed randomization to continued thienopyridine also reduced stent thrombosis (relative risk reduction 51% versus 12 months) and was consistent with DES results on bleeding.

Mortality came out similar between the two treatment arms in the BMS group.

In propensity-matched results, DES was noninferior to bare-metal stents for major adverse cardiovascular and cerebrovascular risk and was superior for stent thrombosis.

Subanalyses by patient characteristics, though, turned up similar benefit in patients at low versus higher risk of stent thrombosis.

"I need to chew on that a little more because that's counterintuitive," Harrington said. "I would have guessed that most of the benefit was in the high risk group of patients."