August 30, 2011 (Paris, France) — Two years of dual antiplatelet therapy after coronary stenting was no more effective than six months of treatment at reducing ischemic events but doubled the rate of major bleeding in the Prolonging Dual Antiplatelet Treatment after Grading Stent-induced Intimal Hyperplasia Study(PRODIGY).
The results were presented today here at the European Society of Cardiology (ESC) 2011 Congress by Dr Marco Valgimigli (University Hospital of Ferrara, Italy). Valgimigli said the findings "questioned the validity of current guidelines," which, based on registry data, recommend at least 12 months of dual antiplatelet therapy after implantation of a drug-eluting stent. "While we cannot exclude the possibility that a smaller than previously anticipated benefit may still exist in prolonging therapy with clopidogrel for several months after coronary stenting, our study clearly shows that the benefit-to-risk ratio of prolonged therapy has been overemphasized," he concluded.
In total, 2013 patients (74% with acute coronary syndromes and 26% with stable angina) who underwent stenting were randomized to six or 24 months of dual antiplatelet treatment (clopidogrel plus aspirin). The primary end point was all-cause mortality, nonfatal MI, or stroke at two years.
Results showed that the overall risk of the primary end point was almost identical between the two groups. The individual risks of death, MI, stroke, or stent thrombosis also did not differ between the two groups.
PRODIGY: Efficacy Results
| End point | 6-mo dual antiplatelet therapy (%) | 24-mo dual antiplatelet therapy (%) | HR (95% CI) |
| Death/MI/stroke | 10.0 | 10.1 | 0.98 (0.74–1.29) |
| Death | 6.6 | 6.6 | 1.00 (0.72–1.40) |
| Death/MI | 9.6 | 8.9 | 1.07 (0.80–1.43) |
In the trial, patients were also randomized to one of three different drug-eluting stents or a bare-metal stent. It was found that the results did not change based on which stent was used. "There was no difference in ischemic events between the groups when analyzed by type of stent used. If anything, the point estimate slightly favored the short-duration group in patients receiving drug-eluting stents, but there are large confidence intervals, so this should be interpreted with caution," Valgimigli said. He added that they could not identify any particular subset of patients who benefited from prolonged treatment.
Bleeding Results Showed Large Differences Between the Two Groups.
PRODIGY: Bleeding Results
| End point | 6-mo dual antiplatelet therapy (%) | 24-mo dual antiplatelet therapy (%) | p |
| Type 2, 3, or 5 BARC bleeding | 3.5 | 7.4 | 0.00018 |
| TIMI major bleeding | 0.6 | 1.6 | 0.041 |
| Red blood cell transfusion | 1.3 | 2.6 | 0.041 |
BARC=Bleeding Academic Research Consortium
Valgimigli noted that two other trials, REAL-LATE and EXCELLENT, had similar results as PRODIGY, also showing no benefit of longer durations of dual antiplatelet therapy. However, the REAL-LATE trial was heavily criticized for various design flaws when it was presented at American College of Cardiology (ACC) 2010 Scientific Sessions.
Valgimigli commented: "I'm aware of three studies showing similar findings. I think we can now say there is not a large benefit (more than a 29% reduction in ischemic events) of prolonged dual antiplatelet therapy. Our trial cannot rule out the possibility of a smaller benefit. But the risks of bleeding are for sure higher with prolonged therapy, and I think it is likely that this outweighs any possible benefit for ischemia."
Commenting on the PRODIGY results to heartwire, Dr Magnus Ohman (Duke Clinical Research Institute, Durham, NC) said: "We now have three small studies with tantalizingly similar findings. Longer dual antiplatelet therapy (up to two years) does not appear to be adding much clinical benefit, and there is a clear signal of increased bleeding. PRODIGY is probably a better-quality trial than the other two, but we still need to wait for the larger studies for a definitive answer to this question."
Several larger studies are now under way, including the Dual Antiplatelet Therapy Study (DAPT) trial in 20 000 patients, but results will not be available for two to three years.
Ohman said he follows the ACC/American Heart Association guidelines that recommend a minimum of one year of dual antiplatelet therapy after stenting. "I think there are reasonable data to show benefits of one year. But I think there is now a strong question about continuing for longer than a year," he added.
Discussant: "A Clear Result"
Designated discussant for the PRODIGY trial, Dr Adnan Kastrati (Deutsches Herzzentrum, Technische Universität, Munich, Germany), noted that previous trials (PCI-CURE and CREDO) had already established that up to one year of clopidogrel was better than one month after bare-metal stenting, but the PRODIGY trial was now comparing six months of treatment with up to two years in both bare-metal- and drug-eluting-stent patients.
PRODIGY represents one more victory against the greatest enemy of drug-eluting stents--the wrongly assumed need for endless dual antiplatelet therapy.
He said limitations of the PRODIGY trial included an open-label design, randomization at 30 days (it would have been better at six months), and its relatively small size. But it also had strengths--no industry sponsorship, inclusion of all-comer stent patients (including STEMI), inclusion of bare-metal stents, and excellent compliance and follow-up.
He said the trial had shown a clear result, with no benefits but increased bleeding.
Kastrati also presented an analysis of the PRODIGY results combined with those from the REAL-LATE/ZEST-LATE and EXCELLENT studies.
Dual Antiplatelet Therapy Duration of More Than One Year vs Less Than One Year
| Trial | Patients, n | Hazard ratio (95% CI) for major ischemic events | Hazard ratio (95% CI) for bleeding |
| REAL LATE/ZEST LATE | 2701 | 1.73 | 2.96 |
| PRODIGY | 1970 | 1.02 | 2.17 |
| Overall | 4671 | 1.25 (0.76–2.07) | 2.19 (1.46–3.28) |
Dual Antiplatelet Therapy Duration of More Than Six Months vs Less Than Six Months
| Trial | Patients, n | Hazard ratio (95% CI) for major ischemic events | Hazard ratio (95% CI) for bleeding |
| EXCELLENT | 1443 | 1.12 | 2.56 |
| PRODIGY | 1970 | 1.02 | 2.17 |
| Overall | 3413 | 1.05 (0.85–1.31) | 2.21 (1.50–3.25) |
Kastrati concluded: "Although we are still waiting for the results of larger trials, PRODIGY represents one more victory against the greatest enemy of drug-eluting stents--the wrongly assumed need for endless dual antiplatelet therapy."
Heartwire from Medscape © 2011 Medscape, LLC
Cite this: Questions Raised About Clopidogrel Duration Poststenting - Medscape - Aug 30, 2011.
