Elsevier

American Heart Journal

Volume 162, Issue 6, December 2011, Pages 1018-1025
American Heart Journal

Clinical Investigation
Coronary Artery Disease
Platelet reactivity in patients with chronic kidney disease receiving adjunctive cilostazol compared with a high-maintenance dose of clopidogrel: Results of the Effect of Platelet Inhibition According to Clopidogrel Dose in Patients with Chronic Kidney Disease (PIANO-2 CKD) randomized study

https://doi.org/10.1016/j.ahj.2011.09.003Get rights and content

Background

Chronic kidney disease (CKD) is a factor of low response to clopidogrel. We sought to assess the functional impact of cilostazol in CKD patients with undergoing hemodialysis.

Methods

Seventy-four patients with CKD undergoing hemodialysis and percutaneous coronary intervention were enrolled. Patients were randomly assigned to receive clopidogrel (75 mg/d [group 1, n = 24]), high-maintenance dose of clopidogrel (150 mg/d [group 2, n = 25]), or clopidogrel (75 mg/d) with cilostazol (200 mg/d [group 3, n = 25]) for 14 days. Another 50 patients with normal renal function undergoing percutaneous coronary intervention were treated with 75 mg of clopidogrel and served as the control group. Platelet function was evaluated before and after antiplatelet therapy with light transmittance aggregometry and with VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). Platelet activation markers (soluble CD40 ligand and soluble P-selectin) were also assessed.

Results

The baseline platelet function measurements were similar in the 3 groups of patients; however, the CKD groups had significantly higher platelet aggregation activity compared with the control groups. The rate of high on-treatment platelet reactivity was significantly lower in group 3 than in groups 1 and 2 (10% vs 43% vs 32%, respectively; P < .05). After 14 days of antiplatelet therapy, the changes in plasma soluble CD40 ligand and soluble P-selectin levels were significantly higher in group 3 compared with groups 1 and 2 (P < .01); however, there were no significant differences in platelet function and activation markers between groups 1 and 2.

Conclusions

Adjunctive cilostazol improves platelet inhibition compared with 75 or 150 mg of clopidogrel in CKD patients undergoing hemodialysis.

Section snippets

Patients and study protocol

The PIANO-2 CKD clinical trial was a prospective, open, randomized platelet function study involving patients with CKD. Between September 2009 and June 2011, 74 consecutive CKD patients undergoing chronic hemodialysis and PCI for stable coronary artery disease were enrolled in this study. To compare the levels of platelet aggregation according to renal function, 50 patients undergoing PCI for stable coronary artery disease were enrolled in the study as the control group. The exclusion criteria

Baseline patient characteristics

Baseline characteristics, cardiovascular risk factors, and concomitant medications of the study population are summarized in Table I. The CKD and control groups were similar with respect to age, gender, and cardiovascular risk factors. No significant differences were observed in the 3 CKD groups. All patients demonstrated full compliance with the study protocol.

Maximal platelet aggregation profiles

The baseline Aggmax values were not significantly different in the 3 CKD groups (Table II); however, the control group had

Responses to different antiplatelet treatments

The rate of HOPR was significantly lower in the adjunctive cilostazol group than in the 75 mg/d or 150 mg/d clopidogrel groups (12% vs 46% vs 32%, respectively; P < .05) (Figure 3). Similar results were obtained when 20 μmol/L ADP-induced Aggmax >50% was used to define suboptimal clopidogrel responders (32% vs 75% vs 68%, respectively; P < .05) (4). The post hoc analysis showed that there were no differences in the rates of HOPR and suboptimal clopidogrel responders between groups 1 and 2. Both

Platelet activation markers assay

Before treatment, there were no significant differences in the plasma sCD40L and sP-selectin levels in the 3 CKD groups. After 14 days of antiplatelet therapy, both platelet activation markers were significantly decreased in each group (Figure 4). However, the plasma sCD40L (271.0 ± 38.3 pg/mL) and sP-selectin (50.0 ± 10.5 ng/mL) levels were significantly lower in group 3 (P < .01) compared with groups 1 and 2. The changes in both platelet activation markers were significantly higher in group 3

Discussion

This is the first randomized, prospective study to assess platelet responsiveness to clopidogrel in patients with CKD undergoing chronic hemodialysis. The 3 major results of this study were as follows: (1) CKD patients had higher platelet reactivity compared with patients with normal renal function, (2) an increase in the clopidogrel maintenance dose from 75 to 150 mg did not result in further suppression of platelet aggregation, and 3) adjunctive cilostazol treatment intensified inhibition of

Disclosure

There are no potential conflicts of interest.

Acknowledgements

This study was supported by the program of Kyung Hee University for the young researcher in medical science (KHU-20100741). The authors thank our nurses for assistance in executing this study.

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