RECLOSE-3: Shifting Clopidogrel Nonresponders to Prasugrel Lowers Mortality After PCI

Among patients scheduled for PCI who do not respond to clopidogrel, switching to prasugrel reduces the likelihood of having high residual platelet reactivity, according to the RECLOSE-3 study published online September 16, 2015, ahead of print in JACC: Cardiovascular Interventions. Moreover, prasugrel seems to offer better outcomes to nonresponders than do a higher clopidogrel maintenance dose or ticlopidine.

Between April 2010 and December 2012, David Antoniucci, MD, of Careggi Hospital (Florence, Italy), and colleagues evaluated platelet reactivity in 1,550 patients undergoing PCI with DES after a 600-mg loading dose of clopidogrel. Nonresponders (n = 302), who had platelet aggregation by adenosine diphosphate (ADP) ≥ 70%, were switched to prasugrel 10 mg (Effient; Eli Lilly/Daiichi Sankyo) the day of PCI.

After a repeat test 6 days later, those who had switched had lower ADP values than before (47.1% vs 77.6% (P < .001), and only 26 patients (8.6%) retained high residual platelet reactivity. Dual antiplatelet therapy consisting of aspirin and prasugrel was prescribed for 6 months.

The researchers compared the results of this cohort with those of the 248 clopidogrel nonresponders in the RECLOSE 2-ACS trial, who were switched to a higher maintenance dose of clopidogrel (150-300 mg daily) or to ticlopidine (500-1,000 mg daily) after testing revealed high platelet reactivity. Compared with the RECLOSE 2-ACS group, nonresponders in RECLOSE-3 (42% with ACS) were more likely to have hypertension, prior MI or PCI, and better LV function. RECLOSE-3 patients also were more apt to be undergoing 3-vessel PCI and unprotected left main PCI than the RECLOSE 2-ACS cohort, with a higher number of stents implanted and total stent length per patient.

Switching to Prasugrel Improved Outcomes

Two-year cardiac mortality (primary endpoint) was lower in the RECLOSE-3 patients who began taking prasugrel than in the RECLOSE 2-ACS nonresponders. This superiority held true even when looking only at ACS patients. Additionally, those in RECLOSE-3 had lower rates of the composite of cardiac death and MI and of definite/probable stent thrombosis (table 1).

On multivariate analysis, prasugrel treatment predicted reduced risk of 2-year cardiac death (HR 0.32; 95% CI 0.11-0.92), while age ≥ 75 years (HR 2.89; 95% CI 1.34-6.23) and renal insufficiency (HR 2.35; 95% CI 1.12-4.95) predicted increased risk.

There were no differences in major bleeding between the 2 cohorts, though minor bleeding was higher in RECLOSE-3 than in RECLOSE 2-ACS nonresponders (5.3% vs 1.2%; P = .009).

‘A Modifiable Risk Factor’

“The main finding of the RECLOSE-3 study is that nonresponsiveness to clopidogrel is a modifiable risk factor for cardiac death after PCI,” write Dr. Antoniucci and colleagues. In fact, switching clopidogrel nonresponders to prasugrel resulted in a 2-year cardiac mortality rate nearly identical to that of clopidogrel responders in RECLOSE 2-ACS, they note. Much like the latter study, GRAVITAS also tried to overcome resistance with an increased dose of clopidogrel but found that the strategy had no impact on clinical outcome, they observe.

Its nonrandomized design notwithstanding, this analysis has certain strengths, the investigators assert. For example, the RECLOSE-3 study population is “representative of the broad spectrum of patients with [CAD] who are treated with PCI,” the study authors say. Moreover, they add, all patients received the same clopidogrel loading dose and “platelet reactivity assessment was made using light transmittance aggregometry and a cutoff of the ADP test that have been validated in thousands of patients.”

Performing a randomized study with a control arm of clopidogrel nonresponders maintained on clopidogrel would be unethical, they write, so a study like RECLOSE-3 is likely the only option in this field.

“The results of this study should be considered for further studies of tailored therapy using new antithrombotic agents,” the authors conclude.

Source: 
Valenti R, Marcucci R, Comito V, et al. Prasugrel in clopidogrel nonresponders undergoing percutaneous coronary intervention: the REsponsiveness to CLOpidogrel and StEnt Thrombosis (RECLOSE)-3 study. J Am Coll Cardiol Intv. 2015;Epub ahead of print.

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