Increased Clopidogrel Fails to Overcome High Platelet Reactivity

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High residual platelet reactivity after clopidogrel loading independently predicts the risk of long-term thrombotic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), researchers conclude in a study published in the September 20, 2011, issue of the Journal of the American Medical Association. However, the findings show that even with higher clopidogrel doses, outcomes fail to improve.

Results from RECLOSE 2-ACS (Responsiveness to Clopidogrel and Stent Thrombosis 2-ACS) were previously presented May 17, 2011, at EuroPCR in Paris, France.

David Antoniucci, MD, and colleagues from Careggi Hospital (Florence, Italy) studied 1,789 ACS patients undergoing PCI from April 2005 to April 2009. After subjects received a clopidogrel loading dose of 600 mg, their platelet reactivity was assessed via light transmittance aggregometry (APACT4, Helena Laboratories, Milan, Italy) using adenosine diphosphate (ADP) as an agonist. Those who had high residual platelet reactivity (≥ 70% platelet aggregation) subsequently received an increased maintenance dose of clopidogrel (150-300 mg/daily) or switched to ticlopidine (500-1000 mg/daily) under ADP test guidance.

Differences Driven by Cardiac Death Rates

High reactivity was documented in 14% of the cohort. At 2 years, patients with high residual platelet reactivity had higher risk of experiencing the primary endpoint (composite of cardiac death, nonfatal MI, any urgent coronary revascularization, and stroke) compared with low-reactivity patients, an increase driven by a difference in cardiac death. There were no differences between the 2 groups for individual components of the primary endpoint, although stent thrombosis rates were raised among high-reactivity patients (table 1).

Table 1. Primary and Secondary Endpoints at 2 Years

Kaplan-Meier survival curves estimated that by 4.5 years, the incidence of the primary endpoint would be nearly doubled in the high- vs. low-reactivity groups at 27.5% vs. 14.5%, respectively (P < 0.001). Cardiac mortality, meanwhile, was estimated to be 12.7% in high-reactivity patients and 6.9% in low-reactivity patients (P < 0.001).

On multivariable analysis, high platelet reactivity was independently associated with increased risk of the primary endpoint and cardiac death (table 2).

Table 2. Multivariable Analysis

This association remained significant after propensity score adjustment both for the primary endpoint (HR 1.47; 95% CI 1.06-2.04; P = 0.02) and for cardiac mortality (HR 1.63; 95% CI 1.06-2.51; P = 0.03). No significant interaction was found between high-reactivity and the other covariates.

Increasing the dose of clopidogrel or switching to ticlopidine can help overcome clopidogrel resistance in approximately 60% of patients but has no effect on clinical outcome, the investigators say. The finding is consistent with the results of the GRAVITAS trial, the first large-scale study assessing the clinical impact of doubling a long-term dosage of clopidogrel in PCI patients with high residual reactivity.

In a telephone interview with TCTMD, Matthew J. Price, MD, of the Scripps Clinic (La Jolla, CA), lead investigator for GRAVITAS, added that RECLOSE 2-ACS provides further confirmation in a purely ACS population—and with the benefit of longer follow-up—that platelet reactivity while on clopidogrel therapy is an independent predictor of cardiovascular events after PCI for ACS. Although ACS patients were included in GRAVITAS, they were a minority.

But according to Dr. Price, RECLOSE 2-ACS is still insufficient to assess whether adjusting clopidogrel offers a way to improve outcomes. “It’s unclear whether the effect was very strong even in those who responded to the higher dose [of clopidogrel], because the numbers were too small to take away anything with regard to assessing clinical response,” he said.

Moving Forward a Challenge

Although RECLOSE 2-ACS confirms the prognostic value of measuring high residual platelet reactivity to predict ischemic outcomes and the limited ability of earlier-generation P2Y12 inhibitors to influence such reactivity, many unmet needs still preclude supporting routine platelet function testing, says Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL).

In an editorial accompanying the study, Dr. Angiolillo writes that the light transmittance aggregometry test with ADP is not user friendly and suggests that “using a more broadly applicable test, such as a point-of-care assay, would have been of greater practical value.” Moreover, RECLOSE 2-ACS defined platelet reactivity based on a single measurement soon after PCI, but other studies have shown that platelet reactivity is vulnerable to changes over time, especially in the early weeks after PCI. He also questions the cutoff value for high reactivity, as it was based on patients with a different risk profile than that of the RECLOSE 2-ACS patients.

Most importantly, though, the fact that even large-scale platelet function studies like RECLOSE 2-ACS and GRAVITAS have been unable to improve outcomes leaves clinicians with questions about what to do with the results of such tests.

Dr. Price agreed that it is hard to know where to go from here. “It’s challenging to move forward because what we need is a large randomized clinical trial, especially with the imminent availability of generic clopidogrel,” he said. Clopidogrel is scheduled to go off-patent in May 2012.

“To run such a trial would require a large number of patients and be expensive, and there currently is no economic incentive for anyone to sponsor such a trial,” Dr. Price said. “For now, what we are left with is the absence of evidence, not the evidence of absence. We need to continue to move forward with such a trial and with smaller studies that support the hypothesis.”

Study Details

Compared with patients with low residual platelet reactivity, those with high reactivity were older and had a higher incidence of diabetes, hypercholesterolemia, and history of MI. In the low reactivity group, patients were more apt to present with STEMI, while congestive heart failure and LVEF less than 40% were more frequent in the high reactivity group. 

All patients received loading doses of 325 mg aspirin and 600 mg clopidogrel followed by maintenance doses of 325 mg/daily aspirin and 75 mg/daily clopidogrel for at least 6 months.

 

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Sources:
1. Parodi G, Marcucci R, Valenti R, et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA. 2011;306:1215-1223.

2. Angiolillo DJ. Applying platelet function testing in clinical practice: What are the unmet needs? JAMA. 2011;306:1260-1261.

 

 

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