Higher Clopidogrel Dose Reduces Platelet Activity in Diabetes

February 6, 2007

by Josh Murphy

Increasing the maintenance dosage of clopidogrel (Plavix^®, Sanofi-Aventis) to 150 mg daily minimizes platelet reactivity in diabetic patients with coronary disease who exhibit a suboptimal response to the standard 75 mg dosage, according to investigators at the University of Florida, Jacksonville¹.

Dr. Dominick Angiolillo, Principal Investigator of the OPTIMUS (Optimizing AntiPlatelet Therapy In Diabetes MellitUS) study said that there are many mechanisms responsible for increased platelet reactivity in diabetic patients, including increased intracellular levels of calcium, increased platelet turnover, and insulin resistance.

"Platelets are the target of the effects of insulin, which down-regulates platelet reactivity. However, type 2 diabetics lack this effect due to their insulin resistance, which favors an increase in platelet reactivity," Dr. Angiolillo said.

To test the hypothesis that increasing the dosage of clopidogrel would enhance platelet inhibition, Angiolillo and colleagues randomized type 2 diabetic patients who previously underwent percutaneous coronary intervention and had suboptimal response to standard clopidogrel therapy to either clopidogrel 150 or 75 mg daily for 30 days (N=40). Suboptimal clopidogrel response was defined as ADP-induced maximal platelet aggregation (Agg_max) >50%.

After 30 days, patients resumed standard dosage of clopidogrel. Patients also received 81 mg aspirin daily. Patients with contrindications to aspirin or clopidogrel, impaired glucose tolerance, or type 2 diabetes without pharmacological treatment were excluded.

Aggmax was similar at baseline in the standard and increased dosage groups. At 30 days, there was a significant reduction in Agg_max in the 150 mg group compared to both baseline and standard therapy (Figure 1). 20 µmol/L ADP-induced platelet aggregation at 5 minutes (Agg_late) was also significantly reduced in the 150 mg group at 30 days (Figure 2).

Platelet disaggregation and P2Y12 reactivity also declined significantly at 30 days in the 150 mg group. 30 days after patients in the 150 mg group returned to standard maintenance dosage, levels of Agg_max, Agg_late, diaggregation, and P2Y12 returned to levels comparable to baseline.

Despite the efficacy of increased clopidogrel dosage, it should be noted that 60% of patients in the 150 mg group did not exhibit reduced platelet reactivity. Dr. Angiolillo said that such high inter-individual response is likely due to variability in the metabolism of clopidogrel..

"There may be other mechanisms, different from P2Y12 signaling, which remain upregulated in the diabetic platelet," he said.

Dr. Angiolillo also commented that although reducing platelet function below a certain threshold may improve clinical outcomes, clinicians should not yet up-titrate the dosage of clopidogrel in diabetic patients.

"[A]t the current stage we cannot recommend a similar strategy in clinical practice as studies evaluating the safety and efficacy of more potent antiplatelet drug regimens are warranted," he said.

Reference

1. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized Comparison of a High Clopidogrel Maintenance Dose in Patients With Diabetes Mellitus and Coronary Artery Disease. Circulation 2007;doi:10.1161/CIRCULATIONAHA.106.667741.