Standard-dose vs High-dose Clopidogrel After PCI for Clopidogrel 'Non-Responders'
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco.
Source: Price MJ, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. The GRAVITAS randomized trial. JAMA 2011;305:1097-1105.
Current guidelines recommend dual anti-platelet therapy (DAPT) with aspirin and a thienopyridine, such as clopidogrel, following percutaneous coronary intervention (PCI). However, there is significant variation between individuals in the effect of clopidogrel on platelet function. High platelet reactivity while taking clopidogrel (these patients are sometimes referred to as "clopidogrel non-responders") has been associated with higher rates of ischemic events, but the most appropriate management strategy for high on-treatment platelet reactivity remains unknown. Small pharmacodynamic studies have suggested a benefit of higher doses of clopidogrel in reducing platelet reactivity. Whether this translates into reduced events in patients undergoing PCI with drug-eluting stents (DES) remains unknown.
Using a point-of-care assay to assess the degree of platelet reactivity, Price and colleagues screened patients who had undergone PCI with DES, including loading with clopidogrel, within 12-24 hours after the procedure. They screened 5429 patients following PCI with DES and found a large number (n = 2214, 40%) had high on-treatment platelet reactivity. There were significant baseline differences between those with and without high on-treatment platelet reactivity. Those with high on-treatment platelet reactivity were older, more often male, more likely to have diabetes, hypertension, and renal failure but had a lower proportion of smokers. However, they had similar proportions of acute coronary syndromes, similar baseline medications, and similar clopidogrel exposure.
The patients with high on-treatment platelet reactivity (i.e., clopidogrel non-responders) were randomized to a standard dose of clopidogrel (75 mg daily, n = 1105) vs high-dose clopidogrel (150 mg daily, n = 1109) for 6 months post PCI. The high-dose group had better platelet inhibition, shown by lower rates of high on-treatment platelet reactivity at 6 months (36% vs 62%, P < 0.001). There was no difference between standard-dose and high-dose groups in the primary endpoint of cardiovascular death, non-fatal MI, or stent thrombosis (2.3% vs 2.3%, P = NS). There was no difference in the incidence of any of the components of the composite primary endpoint between groups. In addition, there was no difference in total mortality (0.9% vs 0.6%, P = 0.48) and no difference in moderate or severe bleeding (2.3% vs 1.4%, P = 0.1).
In a secondary analysis, those with high on-treatment platelet reactivity who were assigned standard-dose clopidogrel were compared with a random selection of patients (n = 586) who did not have high on-treatment platelet reactivity (i.e., clopidogrel non-responders vs responders). Both these groups were taking the same dose of clopidogrel, yet those with high on-treatment platelet reactivity (non-responders) had numerically higher rates of the primary composite endpoint (2.3% vs 1.4%, P = 0.2), but this failed to reach statistical significance. The authors conclude that among patients with high on-treatment reactivity after PCI with DES, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of cardiovascular death, non-fatal MI, or stent thrombosis.
Commentary
This is a very interesting and important study. The authors are to be congratulated for attempting to individualize anti-platelet therapy for patients following PCI. The first important point to note is that no test of platelet function is perfect. The authors tested one of the more convenient tests, a point-of-care assay, to study platelet function. High on-treatment platelet reactivity with this test has been associated with higher event rates in prior observational studies. The staggeringly high 62% rate of high platelet reactivity in patients taking standard-dose clopidogrel 75 mg daily is discordant with the low clinical event rate of 2.3%. Thus, this test appears to identify a higher risk group, but its specificity is poor. There was improved platelet inhibition with this test using higher dose clopidogrel, but no difference in bleeding or ischemic endpoints. How can we reconcile these discrepancies?
Firstly, the test may not tell the whole story for platelet function. Perhaps other tests, like platelet aggregometry, may be able to better assess platelet function and predict ischemic events. Secondly, the clinical trial strategy of a single-dose escalation may not have been an adequate increase in dose to overcome the high on-treatment platelet reactivity. After a high dose, 32% of patients still demonstrated high platelet reactivity. Perhaps a strategy to incrementally increase the dose and retest until a threshold of platelet inhibition is achieved may have been a more successful strategy, but this remains to be tested in future studies. There may even be a ceiling on the effect that clopidogrel can achieve in any individual patient, and therefore increasing the dose was ineffective. A more potent antiplatelet agent may therefore be necessary. Thirdly, polymorphisms in the cytochrome P450 enzyme system, which metabolizes clopidogrel to it active metabolite, have been shown to decrease the effectiveness of clopidogrel. We are not presented with data regarding the prevalence of these polymorphisms in this study, and thus their effects on the outcome of the study remain unknown. Future clinical trials are needed to assess both the ability of platelet function studies to predict an individual patient's risk and to determine the most appropriate management strategy based on the results of those tests.
Current guidelines recommend dual anti-platelet therapy (DAPT) with aspirin and a thienopyridine, such as clopidogrel, following percutaneous coronary intervention (PCI).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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