RECLOSE 2-ACS: Poor Responders Show Poor Outcomes Despite Higher Clopidogrel Dose

PARIS, France—High residual platelet reactivity after a 600-mg loading dose of clopidogrel strongly predicts long-term cardiac mortality and thrombotic events in patients with acute coronary syndromes (ACS) who undergo percutaneous coronary intervention (PCI), even when they subsequently receive an increased maintenance dose of the drug or switch to ticlopidine. The results, presented Tuesday, May 17 at EuroPCR 2011, suggest that adjusted dosing may not help overcome resistance to first-generation thienopyridines.

Previous research on clopidogrel loading was conducted mainly in stable patients and provided only short-term follow-up, said presenter David Antoniucci, MD, of Careggi Hospital (Florence, Italy).

The Effect of Reactivity

For the RECLOSE 2-ACS trial, Dr. Antoniucci and colleagues enrolled ACS patients undergoing PCI who had been given a clopidogrel loading dose of 600 mg and were prospectively assessed using light transmittance aggregometry (n = 1,789). In all, 248 (13.9%) showed evidence of high residual platelet reactivity (≥ 70% on ADP 10 μM). These patients then were given an increased maintenance dose of clopidogrel (150-300 mg/daily) or shifted to ticlopidine (500-1,000 mg/daily) under ADP test guidance.

Compared to those with low residual platelet reactivity, poor responders were older and more likely to have hypercholesterolemia, diabetes, previous MI, and LVEF of 40% or lower. They were less likely to present with STEMI.

Over a median follow-up period of 2.8 years, data were obtained for 99% of subjects. Patients with high residual platelet reactivity showed higher rates of the primary composite endpoint (cardiac death, MI, any urgent coronary revascularization, and stroke) at 2 years than patients who responded to clopidogrel, a difference driven by cardiac death. Stent thrombosis rates also were increased in poor responders (table 1).

Table 1. Two-Year Outcomes

 

Low Residual Platelet Reactivity
(n = 1,525)

High Residual Platelet Reactivity
(n = 247)

P Value

Primary Composite

8.7%

14.6%

0.003

Cardiac Mortality

4.3%

9.7%

< 0.001

Nonfatal MI

2.2%

3.2%

0.297

Urgent Revascularization

1.0%

0.4%

0.372

Stroke

1.2%

1.2%

0.967

Stent Thrombosis

2.9%

6.0%

0.010


Landmark analyses showed that differences in the primary endpoint and cardiac mortality had emerged by 6 months and survival curves continued to diverge until 3 years.

High residual platelet reactivity independently predicted both the primary endpoint (HR 1.48; 95% CI 1.08-2.05; P = 0.016) and cardiac mortality (HR 1.81; 95% CI 1.18-2.76; P = 0.006), as did patient age, LVEF less than 40%, and Killip class III or IV. Previous MI was another independent predictor of the primary endpoint, and creatinine greater than 150 μM and 3-vessel disease both indicated higher risk of cardiac mortality.

On a matched comparison of patients with similar baseline characteristics, those with high reactivity still had increased risk of the primary endpoint, cardiac death, and stent thrombosis at 2 years compared with low reactivity subjects.

“In conclusion, high residual platelet reactivity is a strong independent marker of increased risk of thrombotic events and cardiac mortality in patients with acute coronary syndromes receiving invasive treatment, and the adjustment of therapy using the first-generation thienopyridine[s] is completely ineffective in terms of improvement in clinical outcome,” Dr. Antoniucci commented.

Platelet Function Testing, Optimal Intervention Still Up in the Air

Gilles Montalescot, MD, PhD, of Hôpital Pitié-Salpêtrière (Paris, France), complimented the trialists for focusing on ACS rather than stable patients and for obtaining long-term follow-up. Weaknesses of the study include a lack of detail on clopidogrel maintenance dose, glycoprotein IIb/IIIa inhibitor use, and secondary platelet testing after dose adjustment, he said.

The 14% prevalence of high residual platelet reactivity deserves attention, Dr. Montalescot stressed. “Frequently patients do not respond well to clopidogrel, but this is very different from the number we got in GRAVITAS in stable patients [41%]. That is a discrepancy that we have to understand. Many factors obviously play a role in the number of patients being poor responders. Of course, the test is different, but I think the main explanation is the timing of testing,” he proposed, with GRAVITAS patients tested too soon after the loading dose. “This was not the case in the RECLOSE-2 ACS study.”

Evidence is mounting in the literature “that if you have a patient [who is] resistant to clopidogrel or responds less to clopidogrel than other patients, [the patient will] not respond well even to higher doses of clopidogrel,” Dr. Montalescot concluded.

However, RECLOSE 2-ACS does not answer 2 important issues, he added. “First, the issue of intervention based on platelet function testing; we will have to wait for dedicated randomized studies like the ARCTIC study to answer this question,” Dr. Montalescot noted. “And second, we don't know the optimal type of intervention we need in these poor responders to clopidogrel.”

 


Source:
Antoniucci D. High residual platelet reactivity after clopidogrel loading and long-term thrombotic events in patients with acute coronary syndrome undergoing invasive treatment: The RECLOSE 2-ACS trial. Presented at: EuroPCR; May 17, 2011; Paris, France.

 

 

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Disclosures
  • Dr. Antoniucci reports serving as a consultant for CID, Cordis, Eli Lilly, Possis-Medrad, and The Medicines Company.
  • Dr. Montalescot reports financial relationships with several drug and device companies.

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