Renal dysfunction is a strong independent predictor of stent thrombosis. The aim of the present study was to evaluate the strength and direction of the association between kidney function and clopidogrel efficacy. The study group consisted of consecutive patients (n = 275) who underwent stent implantation. Drug efficacy was measured using the vasodilator-stimulated phosphoprotein (VASP) index 20 ± 4 hours after clopidogrel 600 mg. Nonresponse was defined as an VASP index ≥50%. Renal function was determined using serum cystatin C. The upper reference levels are 1.12 mg/L for ≤65 years of age and 1.21 mg/L for >65 years of age. Estimated glomerular filtration was calculated using cystatin C. The median value of cystatin C was 1.16 mg/L (twenty-fifth and seventy-fifth percentiles 0.96 and 1.43); 47.63% of the study population had cystatin C above reference levels and 33.1% of patients were nonresponders to clopidogrel. No correlation was found between clopidogrel efficacy assessed with the VASP index and kidney function assessed with cystatin C (Spearman r = −0.070, p = 0.248). Based on cystatin C the proportion of nonresponders to clopidogrel was 34.4% versus 31.9% (p = 0.702) in patients with impaired renal function compared to normal renal function, respectively. The proportion of clopidogrel nonresponders did not differ (p = 0.902) among groups with normal (28.8%), mildly impaired (34.8%), moderately impaired (32.9%), and severely impaired (34.8%) renal function. In conclusion, renal function assessed by cystatin C does not predict clopidogrel efficacy. Renal dysfunction is a complex entity and its significant relation to stent thrombosis cannot be explained simply by a decrease in clopidogrel efficacy.
It has been established that chronic kidney disease accelerates the course of coronary atherosclerosis independent of conventional cardiovascular risk factors. Therefore, it is understandable that in patients undergoing percutaneous coronary intervention (PCI), a considerable proportion (∼19%) has a history of impaired renal function. Chronic renal dysfunction is a strong independent predictor of poor outcome after intracoronary stent implantation. Stent thrombosis, on the one hand, and major bleeding, on the other hand, are independently related to PCI procedures in patients with renal dysfunction. It has been established that thrombotic and bleeding complications after stent placement are significantly related to the degree of platelet suppression by clopidogrel. The aim of present study was to evaluate the strength and direction of the association between kidney function and antiplatelet efficacy of clopidogrel.
Methods
The analysis included patients who underwent PCI with a stent in a tertiary care institution. Patients with contrast-induced nephropathy were excluded. Ethical review board approval was obtained and the study was conducted according to the ethical principles in the Declaration of Helsinki and Good Clinical Practice guidelines and all participants gave written informed consent.
Clopidogrel efficacy was measured 20 ± 4 hours after a clopidogrel 600-mg loading dose. Measurements were performed using flow cytometric analysis of the vasodilator-stimulated phosphoprotein (VASP) phosphorylation state (BioCytex, Marseille, France). Adequate response to clopidogrel was defined as a platelet reactivity index (PRI) <50%. All assessments of renal function were determined using serum cystatin C. Cystatin C was measured using an immunoassay on an Advia 1800 analyzer (Siemens Healthcare Diagnostics, Deerfield, Illinois). Blood samples for VASP index measurements and serum cystatin C were collected at the same time. The upper reference levels for serum cystatin C are (1) 1.12 mg/L for patients ≤65 years old and (2) 1.21 mg/L for patients >65 years old. Estimated glomerular filtration rate (eGFR) using serum cystatin C was calculated using 2 formulas developed from the pooling of several cohorts with GFR measured using iothalamate : (1) cystatin C-based eGFR = 76.7 × cystatin C −1.19 and (2) cystatin C-based eGFR = 127.7 × cystatin C −1.17 × age −1.13 × 0.91 (if a woman) × 1.06 (if African-American).
Stages of renal dysfunction were categorized according to the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation as follows: stage 1—normal GFR >90 ml/min/1.73 m 2 ; stage 2—mild decrease in GFR 60 to 90 ml/min/1.73 m 2 ; stage 3—moderate decrease in GFR 30 to 59 ml/min/1.73 m 2 ; and stage 4—severe decrease in GFR <30 ml/min/1.73 m 2 .
Values of continuous variables are presented as arithmetic means or medians and their variability is characterized by SDs or by quartiles (twenty-fifth and seventy-fifth percentiles). Comparison of means between groups was based on Student’s 2-sample t test and the Mann–Whitney nonparametric test. For categorical data, differences in proportions among groups were analyzed using Fisher’s exact test and its generalization. Degree of association between 2 continuous variables was quantified using the Spearman rank correlation coefficient (r s ). Robust linear regression was used to analyze the relation between values of PRI and their potential predictors. All statistical tests were evaluated at a significance level of 0.05. Statistical analysis was performed using STATA 9.2 (STATA Corp. LP, College Station, Texas).
Results
The study group consisted of 275 patients with PCI/stent. Baseline characteristics of the study population are presented in Table 1 . Median value of cystatin C was 1.16 mg/L (twenty-fifth and seventy-fifth percentiles, 0.96 and 1.43); 47.63% of the study population had serum cystatin C above reference levels. These patients were significantly older, more frequently women, and with previous myocardial infarction compared to patients with normal levels of serum cystatin C. The correlation between cystatin C and creatinine-based eGFR determined using the Modification of Diet in Renal Disease study equation was strong (r s = −0.688, p <0.001; Figure 1 ) .
| Variable | Cystatin C Within Reference Range | Cystatin C Outside Reference Range | p Value | Clopidogrel Responders | Clopidogrel Nonresponders | p Value |
|---|---|---|---|---|---|---|
| (n = 144) | (n = 131) | (n = 184) | (n = 91) | |||
| Men | 95 (66%) | 69 (53%) | 0.027 | 115 (63%) | 49 (54%) | 0.192 |
| Age (years), mean ± SD | 65.0 ± 11.8 | 71.8 ± 10.4 | <0.001 | 67.4 ± 11.9 | 69.8 ± 11.0 | 0.121 |
| Hypertension | 95 (66%) | 100 (76%) | 0.064 | 119 (65%) | 76 (84%) | 0.001 |
| Diabetes mellitus | 45 (31%) | 48 (37%) | 0.373 | 57 (31%) | 36 (40%) | 0.176 |
| Cigarette smoke | 55 (38%) | 37 (28%) | 0.096 | 64 (35%) | 28 (31%) | 0.587 |
| Acute coronary syndrome | 78 (54%) | 81 (62%) | 0.222 | 105 (55%) | 57 (63%) | 0.3 |
| Previous stroke | 9 (6%) | 16 (12%) | 0.096 | 15 (8%) | 10 (11%) | 0.505 |
| Previous myocardial infarction | 35 (24%) | 47 (36%) | 0.047 | 54 (29%) | 28 (31%) | 0.889 |
| Previous coronary artery bypass grafting | 12 (8%) | 20 (15%) | 0.09 | 22 (12%) | 10 (11%) | 0.112 |
| Periphery artery disease | 12 (8%) | 14 (11%) | 0.541 | 16 (9%) | 10 (11%) | 0.521 |
| Statin therapy | 55 (38%) | 57 (44%) | 0.392 | 71 (39%) | 41 (45%) | 0.361 |
| Aspirin therapy | 69 (48%) | 51 (39%) | 0.145 | 80 (44%) | 40 (44%) | 1 |
| Platelet count ×10 9 /L | ||||||
| Mean ± SD | 231.9 ± 58.4 | 241.6 ± 90.8 | 0.31 | 238.8 ± 81.9 | 232.1 ± 61.6 | 0.464 |
| Median (25th–75th percentiles) | 227 (198–264) | 230 (186–278) | 0.844 | 228 (194–270) | 232 (186–274) | 0.828 |
| Platelet reactivity index (%) | ||||||
| Mean ± SD | 37.8 ± 22.1 | 40.5 ± 22.2 | 0.311 | 26.3 ± 13.9 | 64.9 ± 9.5 | <0.001 |
| Median (25th–75th percentiles) | 36.4 (19.9–55.5) | 40.2 (21.9–58.9) | 0.319 | 26.4 (14.3–38.3) | 64.0 (56.2–71.0) | <0.001 |
| Modification of Diet in Renal Disease creatinine (ml/min/1.75 m 2 ) | ||||||
| Mean ± SD | 83.3 ± 18.0 | 60.1 ± 23.0 | <0.001 | 74.2 ± 22.5 | 66.9 ± 25.4 | 0.026 |
| Median (25th–75th percentiles) | 82.4 (71.2–96.8) | 59.0 (45.4–75.1) | <0.001 | 74.0 (58.1–90.7) | 65.0 (50.9–83.6) | 0.041 |
One hundred eighty-four evaluated patients (66.9%) responded well to clopidogrel therapy with a PRI <50%. No correlation was found between clopidogrel efficacy assessed using the VASP index and kidney function assessed with serum cystatin C (r s = −0.070, p = 0.248). A linear regression adjusted for age was performed and did not show any significant relation between VASP index values and serum cystatin C (p = 0.401).
Based on cystatin C, the proportion of nonresponders (PRI ≥50%) to clopidogrel was 34.4% versus 31.9% (p = 0.702) in patients with impaired renal function compared to normal renal function, respectively.
Patients were categorized into 4 groups based on eGFR (calculated from cystatin C) according to the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation staging of kidney function (calculations and staging are detailed in Methods). The proportion of clopidogrel nonresponders did not differ significantly (p = 0.902) among groups with normal (28.8%), mildly impaired (34.8%), moderately impaired (32.9%), and severely impaired (34.8%) renal function ( Table 2 , Figure 2 ) .
| eGFR (ml/min/1.73 m 2 ) | Subjects | Clopidogrel Nonresponders (%) |
|---|---|---|
| ≥90 | 52 | 15 (28.8%) |
| 60–89 | 115 | 40 (34.8%) |
| 30–59 | 85 | 28 (32.9%) |
| <30 | 23 | 8 (34.8%) |
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