Progress in Pre-PCI Clopidogrel Dosing: Increases Can Be Based on Platelet Reactivity

March 29, 2008

March 29, 2008 (Chicago, IL) - Resistance to the antiplatelet effects of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in the setting of PCI is thought to be an important cause of thrombus-mediated complications and clinical events, so recent research has explored ways to bump up the dosage based on various assays that quantify platelet function without also causing more bleeding complications. Now a small, prospective randomized trial has demonstrated--for the first time, it was said--that titrating the clopidogrel upward based on the results of a platelet-reactivity test can safely reduce the risk of clinical events, at least over the short term [1].

The study suggested, preliminarily, that resistance to a 600-mg clopidogrel loading dose is common in PCI-scheduled patients, at least as such "resistance" was defined in the study; that the resistance is associated with a high rate of postprocedure events; that it can be safely overcome by increasing the clopidogrel dose according to the results of a platelet-reactivity test; and importantly, that the strategy ultimately makes a difference to the patients, according to Dr Laurent Bonello (Hôpital Université Nord and Université de la Méditerranée, Marseilles, France).

"Adjusting the loading dose of clopidogrel according to platelet monitoring with the [vasodilator-stimulated phosphoprotein] VASP assay is feasible, safe, and efficacious in reducing post-PCI major adverse cardiac events [MACE]," Bonello said during his presentation of the study here at the American College of Cardiology 57th Annual Scientific Session/i2 Summit-SCAI Annual Meeting.

The study depended on a laboratory test that measures P2Y12 platelet-surface chemoreceptor reactivity to adenosine diphosphate; the receptor is what clopidogrel binds to in vivo. The clopidogrel uptitration strategy called for stepwise dosage increases until the VASP index yielded by the test dropped below 50%, corresponding to greater clopidogrel platelet responsiveness.

To heartwire , Bonello said the test used in the study isn't available as a point-of-care assay and that it is limited to the laboratory environment and is currently not appropriate for clinical practice. Still, he observed, the study shows that it can potentially improve PCI clinical outcomes.

Dr Paul A Gurbel (Sinai Hospital, Baltimore, MD), the featured discussant for Bonello's presentation, agreed that the study represents a step away from the "one-size-fits-all dosing mentality" now used in the setting of pre-PCI clopidogrel. Indeed, he said, it is progress toward adoption of platelet-reactivity–based clopidogrel dosing targets.

To heartwire , Gurbel said the study, although small, is "provocative and encouraging" and suggests the possibility that a laboratory marker can guide clopidogrel dosing in individual patients in much the same way that anticoagulant doses are individualized. It also showed that, potentially, "the alteration of therapy based on the test is associated with better outcomes."

As reported by Bonello, 162 patients with clopidogrel resistance underwent nonemergent PCI (for stable or unstable angina or non-ST-segment-elevation MI) using a 600-mg clopidogrel loading dose accompanied by 250-mg aspirin. They were randomized to a control group or to receive additional clopidogrel with the VASP-index test to guide dosage elevations to achieve a VASP index <50%.

Clopidogrel resistance was defined as a VASP index >50% after a 600-mg clopidogrel dose.

The two groups were similar in baseline features, including CV risk factors, PCI indication, number of stents used, mean stent length, number of diseased vessels, and adjuvant use of glycoprotein IIb/IIIa inhibitors.

Patients in the assay-guidance group were allowed up to three additional loading doses of 600 mg each, given successively as needed every 24 hours until the VASP index dropped below 50%, prior to PCI. The result: they received a mean dosage of 1620 mg, which was associated with an average VASP-index decline from 69.3 to 37.6 (p<0.001) among the 67 patients whose clopidogrel resistance was overcome. The remaining 11 patients in the assay-guidance group retained their clopidogrel resistance even after receiving the maximum allowed dose of 2400 mg.

Standard vs VASP-index–guided clopidogrel pre-PCI loading dose, 30-day outcomes

End point Control, n=84 (%) VASP-guidance, n=78 (%) p
MACE 10 0 0.007
TIMI-defined major and minor bleeding 5 4 NS

MACE=major adverse cardiac events, the primary end point, a composite of MI, death, or repeat revascularization

The 10% rate for the clinical composite primary end point in the control group consisted of two cases of revascularization, four of acute or subacute in-stent thrombosis, and two CV deaths. There were no such events in the assay-guidance group.

In emphasizing the study's preliminary nature, Gurbel, as the study's discussant, described his take on the study's limitations and weaknesses. The small sample size precluded any exploration of the VASP index's relationship to bleeding risk, something important to know before it's used in clinical practice; similarly, it would have been instructive to know the relationship between VASP index score and periprocedural biomarkers of infarction.

The event rate was lower than expected, he also noted, weakening the study's statistical strength. And, he observed, it would be useful to know how the capacity of the VASP index assay to guide therapy compares with other available platelet-function tests.

The trial was supported by grant from the Federation Française de Cardiologie; the researchers had no disclosures. Based on online research conducted by heartwire, in 2008 Gurbel has reported receiving consulting fees from AstraZeneca Pharmaceuticals, Bayer Healthcare, Eli Lilly, Sanofi-Aventis, and Schering Plough and to have contracted research from AstraZeneca, Eli Lilly, and Sandoz.

  1. Bonello L. Platelet monitoring of clopidogrel response using VASP phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. American College of Cardiology Scientific Sessions/i2 Summit-SCAI Annual Meeting. Chicago, IL; March 29, 2008; Late Breaking Clinical Trials I.

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