PRODIGY Published: No Advantage to Long-term Clopidogrel

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Extending dual antiplatelet therapy beyond 6 months after stenting not only fails to reduce thrombotic events but doubles the risk of major bleeding, according to a large all-comers trial published online March 21, 2012, ahead of print in Circulation.

The data were first presented at the European Society of Cardiology Congress in Paris, France, in August 2011.

For PRODIGY (Prolonging Dual-Antiplatelet Treatment after Grading Stent-induced Intimal Hyperplasia Study), investigators led by Marco Valgimigli, MD, PhD, of the University of Ferrara (Ferrara, Italy),  first randomized 2,013 patients with stable CAD or ACS at 3 Italian centers to PCI with 1 of 4 stents, which included a mix of device types, generations, and degrees of efficacy:

  • A third-generation thin-strut BMS (n = 505)
  • A paclitaxel-eluting stent (Taxus; Boston Scientific, Natick, MA; n = 505)
  • A zotarolimus-eluting stent (Endeavor Sprint; Medtronic, Santa Rosa, CA; n = 502)
  • An everolimus-eluting stent (Xience V; Abbott Vascular, Santa Clara, CA; n = 501)

After 30 days of dual antiplatelet therapy (during which time 33 patients died and 10 withdrew from the study), the remaining 1,970 patients were randomized to continue on antiplatelet therapy for 6 months (n = 983) or 24 months (n = 987). In the short-term group, stable patients who had received BMS were allowed to stop clopidogrel any time after 30 days.

The 2 groups were well matched with regard to baseline and angiographic characteristics.

No Upside, Some Downside for Prolonged DAPT

At 24-month follow-up, estimated rates of the primary efficacy endpoint, a composite of all-cause death, MI, or stroke, were similar for the short- and long-term therapy arms. Likewise, there was no difference between the groups in rates of the component endpoints or Academic Research Consortium-defined definite or probable stent thrombosis (table 1).

Table 1. Cumulative Efficacy Outcomes at 24 Months

 

6-Month Dual Therapy
(n = 983)

24-Month Dual Therapy
(n = 987)

P Value

All-Cause Death, MI, or Stroke

10%

10.1%

0.91

All-Cause Death

6.6%

6.6%

0.98

MI

4.2%

4.0%

0.80

Stroke

1.4%

2.1%

0.17

Definite or Probable Stent Thrombosisa

1.5%

1.3%

0.70

a Defined by Academic Research Consortium criteria.

 
By contrast, there was approximately a two-fold higher incidence of several safety endpoints including multiple classes of Bleeding Academic Research Consortium (BARC) bleeding and TIMI major bleeding as well as need for red blood cell transfusion (table 2).

Table 2. Cumulative Safety Outcomes at 24 Months

 

6-Month Dual Therapy
(n = 983)

24-Month Dual Therapy
(n = 987)

P Value

BARC Type 5 (Fatal), 3 (Overt),
or 2 (Other Overt) Bleeding

3.5%

7.4%

0.00018

BARC Type 5
or 3 Bleeding

1.9%

3.4%

0.037

TIMI Major Bleeding

0.6%

1.6%

0.041

Red Blood Cell Transfusion

1.3%

2.6%

0.041

 
In landmark analyses of 6 to 24 months after the index PCI in the 1,924 patients who reached 6-month follow-up, the cumulative incidence of the primary efficacy endpoint was similar between the short-term therapy arm and the long-term therapy arm (6.4% vs. 7.2%; P = 0.53). Likewise, among the 1,443 patients randomized to DES, the rates of the composite endpoint did not differ between the short-term therapy arm and the long-term therapy arm (6.0% vs. 6.8%; P = 0.51). Furthermore, in the DES group, rates of all-cause death, all-cause death or MI, and definite stent thrombosis did not differ from 6 months onward between the short- and long-term therapy groups.

The equivalence in primary ischemic outcome between the 6-month and 24-month therapy arms was consistent across multiple prespecified subgroups, including those characterized by stent type (DES vs. BMS), lesion type (simple vs. complex), and diabetes status.

The authors acknowledge that because the study was powered to detect a threshold 40% reduction in ischemic events with 24-month vs. 6-month dual antiplatelet therapy, a smaller benefit cannot be ruled out. Moreover, inclusion of the quarter of patients who received BMS in the overall analysis may have diluted a potential benefit of prolonged therapy for DES patients.

In an accompanying editorial, Neal S. Kleiman, MD, of the Methodist DeBakey Heart and Vascular Center (Houston, TX), observes that clinicians face a dilemma: On one hand, there is ample mechanistic evidence that DES patients face a prolonged period of stent thrombosis risk. On the other hand, clinical data favoring extended dual antiplatelet therapy are equivocal.

No Tipping Point Yet for Short-term Therapy

ZEST-LATE, BASKET-LATE, and now the PRODIGY trial “indicate that courses of clopidogrel exceeding 12 months do not contribute favorably to patient outcomes, and may in fact be detrimental,” Dr. Kleiman writes, prompting the question: Is it now time to revise the guidelines and recommend that thienopyridine therapy be terminated after 6 or 12 months?

Dr. Kleiman’s answer is no, and he offers multiple reasons:

  • The much larger and methodologically more rigorous randomized DAPT trial testing 12 vs. 30 months of dual antiplatelet therapy is still under way
  • The 2 LATE trials and PRODIGY were not designed to distinguish between outcomes of patients with high-risk vs. low-risk features
  • In BASKET-LATE, the median time to stent thrombosis was about 90 days after cessation of dual therapy, suggesting a need for prolonged follow-up
  • Different DES are associated with different levels of strut endothelialization and thus thrombotic risk; so far, trials have not been powered to determine whether this significantly impacts the optimal duration of dual therapy

Assessing the overall picture, Dr. Kleiman concludes that although current evidence favoring extended dual antiplatelet therapy is slight, “the view is clouded by the high degree of heterogeneity among patient characteristics, among stent designs, and possibly among drug treatments.”

While awaiting the results of the more definitive DAPT study, due in 2014, “the logical approach,” Dr. Kleiman says, is to continue therapy for a minimum of 12 months in most DES patients, with longer durations reserved for those who have complex presentations or difficult stent procedures and earlier termination for those with poor drug tolerance.

Study Details

All patients received aspirin (160-325 mg orally or 500 mg intravenously as a loading dose and 80-160 mg orally indefinitely) and clopidogrel (300 or 600 mg as a loading dose and then 75 mg per day according to the randomization scheme). Unfractionated heparin or bivalirudin was used for anticoagulation during intervention. Use of glycoprotein IIb/IIIa antagonists, pre- or post-dilation, or IVUS was at operators’ discretion.

 


Sources:
1. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual antiplatelet therapy after coronary stenting: A randomized multicenter trial. Circulation. 2012;Epub ahead of print.

2. Kleiman NS. Grabbing the horns of a dilemma: The duration of dual antiplatelet therapy after stent. Circulation. 2012.Epub ahead of print.

 

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PRODIGY Published: No Advantage to Long-term Clopidogrel

Extending dual antiplatelet therapy beyond 6 months after stenting not only fails to reduce thrombotic events but doubles the risk of major bleeding, according to a large all comers trial published online March 21, 2012, ahead of print in Circulation.
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Disclosures
  • The study was funded by the University of Ferrara.
  • Dr. Valgimigli reports receiving research grants and honoraria from and serving on the advisory boards of multiple pharmaceutical and device companies.
  • Dr. Kleiman reports receiving research grants from Bristol-Myers Squibb/Sanofi-Aventis and serving on the advisory board for Eli Lilly.

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