Considerable variability in platelet activity among patients with coronary artery disease in response to an increased maintenance dose of clopidogrel

Abstract

Background: Variable platelet response to clopidogrel has been widely observed. Studies have shown that the mean aggregation response to clopidogrel can be changed by a higher maintenance dose. However, these studies have not focused on individual changes.

Objectives: This study examined the platelet function effects of increasing the maintenance clopidogrel dose from 75 to 150 mg/day with a focus on inter-individual response.

Patients/methods: Twenty patients with known coronary artery disease receiving 75 mg/day clopidogrel were recruited and given 150 mg/day clopidogrel for 30 days, then returned to 75 mg/day for an additional 30 days. Platelet function was assessed through light-transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay at baseline, 30 days, and 60 days.

Results: Mean platelet inhibition was significantly improved with the increased maintenance dose when measured by the VerifyNow P2Y12 assay (P2Y12 reaction units: 191+/-15 vs. 158+/-17, P=0.013), but not when measured by LTA (LTA-adenosine diphosphate 5: 40+/-3 vs. 36+/-3, P = 0.11; LTA-adenosine diphosphate 20: 50+/-3 vs. 47+/-3, P = 0.23). However, only 50% of individual patients experienced improved platelet inhibition, as measured by the VerifyNow P2Y12 assay, when treated with the increased maintenance dose. Furthermore, poor baseline platelet response did not predict improved responsiveness at the increased dose.

Conclusion: Despite changing the population's mean antiplatelet response, an increased maintenance dose of clopidogrel did not improve antiplatelet response in a substantial number of patients; nor did baseline platelet function predict response to a higher maintenance dose.

Figures

Figure 1. Clopidogrel 150 mg/day significantly decreased ADP-induced platelet function as assessed by the VerifyNow assay

Subjects with known CAD collectively demonstrated decreased platelet aggregation with 150 mg of clopidogrel at 30 days compared with 75 mg of clopidogrel at baseline and 60 days (p = 0.013). Although extensive variability was present, overall there was no significant difference in platelet response at 60 days compared to baseline. Platelet function was assessed by the VerifyNow point of care device, and values are reported as P2Y12 reaction units (PRU). In the top portion of the figure, individual subject values are plotted across the 3 time points from baseline (75 mg) to 30 days (150 mg) to 60 days (75 mg). Solid lines indicate subjects whose values decreased from baseline to the 30-day time point, and dashed lines denote an increase from baseline to 30 days. In the bottom portion of the figure, aggregate results (mean ± standard deviation) are presented for each time point.

Figure 2. No significant effects of clopidogrel 150 mg/day were observed with ADP-induced platelet aggregation assessed by light transmittance aggregometry

Platelet function did not differ significantly by clopidogrel dose (75 mg versus 150 mg) when analyzed by aggregometry (p = 0.11). Maximal platelet aggregation was assessed for 6 minutes after stimulation with 5 μM ADP. Solid lines indicate a decrease from baseline to the 30-day time point, and dashed lines denote an increase from baseline to 30 days. Aggregate results (mean ± standard deviation) are presented for each time point in the bottom portion of the figure.

Figure 3. Baseline platelet function at 75 mg clopidogrel did not predict response to the increased dose of clopidogrel

The baseline results for subjects taking 75 mg clopidogrel were plotted against the changes in response after switching to 150 mg clopidogrel (values at 30-day time point minus values at baseline). Pearson correlations (r) were calculated for the VerifyNow P2Y12 assay (Figure 4A), light transmittance aggregometry stimulated by 5 μM ADP (Figure 4B), and light transmittance aggregometry with 20 μM ADP (Figure 4C). For all three assays, there were no significant correlations between baseline values and changes in platelet response (p = 0.37, 0.063, and 0.35, respectively, for Figures 4A, 4B, and 4C). PRU = P2Y12 reaction units, LTA = light transmittance aggregometry, and ADP = adenosine diphosphate.