PARIS, France—Continuing dual antiplatelet therapy beyond 6 months after stenting not only fails to reduce ischemic events but doubles the risk of major bleeding, according to data from a large randomized trial presented August 30, 2011, at the European Society of Cardiology (ESC) Congress. 

Presenter Marco Valgimigli, MD, PhD, of the University of Ferrara (Ferrara, Italy), said that although some advantage of long-term therapy may yet be found, the results suggest that current guidelines, which reflect considerable uncertainty, nonetheless overstate the benefit compared with the risk.

Exposure to a Mix of Stents

For the multicenter PRODIGY (PROlonging Dual-antIplatelet treatment after Grading stent-induced intimal hyperplasia studY) trial, investigators first randomized 2,013 all-comer patients at 3 Italian centers to 1 of 4 stents, which included a mix of device types, generations, and degrees of efficacy:

• A thin-strut BMS (n = 505; no inhibition of intimal hyperplasia)
• A paclitaxel-eluting stent (Taxus; Boston Scientific, Natick, MA; n = 505; moderate inhibition)
• A zotarolimus-eluting stent (Endeavor; Medtronic, Santa Rosa, CA; n = 502; mild inhibition)
• An everolimus-eluting stent (Xience V; Abbott Vascular, Santa Clara, CA; n = 501; high inhibition)

At 30 days, 1,907 eligible patients comprising the 4 stent groups were randomly assigned to receive either 24 months (n = 987) or up to 6 months (n = 983) of dual antiplatelet therapy. (BMS patients with stable disease at the time of PCI, however, were allowed to stop therapy before 6 months.) The patients were well matched for demographic, angiographic, and clinical characteristics.

At 6 months, 83.1% of patients in the 6-month group remained compliant with the regimen, while 94.7% of those in the 24-month group were still on dual antiplatelet therapy at 2 years.

After 24 months, there were no differences between the 2 groups for the primary endpoint (all-cause death, MI, or stroke), all-cause death alone, or all-cause death and MI (table 1).

Table 1. Outcomes at 2 Years

Abbreviation: DAPT, dual antiplatelet therapy.

Likewise, a landmark analysis of events from 6 months onward showed equivalence between 6- and 24-month treatment durations for the primary endpoint (6.4% vs. 7.2%, respectively; HR 0.89; 95% CI 0.64-1.25; P = 0.53).

At 2 years, the cumulative risk of the primary outcome was 10.1% for patients who received 24 months of therapy and 10.0% for patients who received 6 months of therapy (HR 0.98; 95% CI 0.74-1.29; P = 0.91). In addition, the individual risks of death, MI, stroke, or stent thrombosis did not differ between the 2 groups.

In sensitivity analyses, variables such as age, sex, diabetes, renal function, BMS vs. DES, stable vs. unstable CAD, single vs. multiple lesions, and complete vs. incomplete revascularization showed no interaction with treatment duration.

Bleeding a Clear Downside

On the other hand, among patients receiving long-term dual antiplatelet therapy, there was about a twofold greater risk of type 5 bleeding (fatal), type 3 bleeding (overt with hemoglobin drop or intracranial hemorrhage), or type 2 bleeding (overt and ‘actionable’), defined by Bleeding Academic Research Consortium criteria (HR 2.17; 95% CI 1.44-3.22; P = 0.00018). TIMI major bleeding and need for red blood cell transfusion were also notably higher in the 24-month group (1.6% vs. 0.6% and 2.6% vs. 1.3%, respectively; both P = 0.041).

The incidence of net adverse events also was higher with 24-month antiplatelet therapy (P = 0.025).

“This is not the first randomized study going in this direction [against long-term therapy]. It is becoming a consistent trend,” Dr. Valgimigli observed, citing the results of the recent REAL LATE/ZEST LATE and EXCELLENT trials.

He added that although no signal of benefit was seen with longer-term therapy for any patient subgroup, the investigators will continue to mine the dataset looking for that possibility. In addition, a formal economic analysis is planned.

“Meanwhile, the results of this study have important implications for health-care expenditure,” Dr. Valgimigli said. “It shows that prolonging therapy beyond 6 months is not only associated with no clinical benefit but also with a significant increase in actionable bleeding events requiring rehospitalizations and multiple diagnostic and therapeutic resources.”

Defeating an ‘Enemy of DES’

Discussing the presentation, Adnan Kastrati, MD, of the Deutsches Herzentrum (Munich, Germany), identified some weaknesses of the trial, such as its open label design, limited number of patients, and randomization at 30 days (60 would have been better, he suggested). But these issues are outweighed by the trial’s strengths, he noted, such as including all comers with a high proportion of STEMI patients and excellent drug compliance and follow-up. But the most relevant strength, he said, are the clear results: no difference in the primary endpoint and an increase in bleeding between 6 and 24 months.

Dr. Kastrati concluded, “Although we are still waiting for larger randomized trials on the optimal duration of dual antiplatelet therapy, PRODIGY represents one more victory against the greatest enemy of drug-eluting stents: the assumption of the need for endless dual antiplatelet therapy.” 

 

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Source:
Valgimigli M. PRODIGY: Randomized comparison of 6 versus 24 months of clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all comer patients undergoing percutaneous coronary intervention. Presented at: ESC Congress; August 30, 2011; Paris, France.

 

 

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