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Renal Function Assessed Using Cystatin C and Antiplatelet Efficacy of Clopidogrel Assessed Using the Vasodilator-Stimulated Phosphoprotein Index in Patients Having Percutaneous Coronary Intervention

2011; Elsevier BV; Volume: 109; Issue: 5 Linguagem: Inglês

10.1016/j.amjcard.2011.10.019

ISSN

1879-1913

Autores

Zuzana Moťovská, Denisa Odvodyová, Michaela Fischerová, Soňa Štěpánková, Marek Malý, Petra Morawska, Petr Widimský,

Tópico(s)

Antiplatelet Therapy and Cardiovascular Diseases

Resumo

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. 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.1McCullough P.A. Cardiorenal risk: an important clinical intersection.Rev Cardiovasc Med. 2002; 3: 71-76Abstract Full Text PDF PubMed Google Scholar, 2Yerkey M.W. Kernis S.J. Franklin B.A. Sandberg K.R. McCullough P.A. Renal dysfunction and acceleration of coronary disease.Heart. 2004; 90: 961-966Crossref PubMed Scopus (56) Google Scholar Therefore, it is understandable that in patients undergoing percutaneous coronary intervention (PCI), a considerable proportion (∼19%) has a history of impaired renal function.3van Werkum J.W. Heestermans A.A. Zomer A.C. Kelder J.C. Suttorp M.J. Rensing B.J. Koolen J.J. Brueren B.R. Dambrink J.H. Hautvast R.W. Verheugt F.W. ten Berg J.M. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry.J Am Coll Cardiol. 2009; 53: 1399-1409Abstract Full Text Full Text PDF PubMed Scopus (600) Google Scholar 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.4Aoki J. Lansky A.J. Mehran R. Moses J. Bertrand M.E. McLaurin B.T. Cox D.A. Lincoff A.M. Ohman E.M. White H.D. Parise H. Leon M.B. Stone G.W. Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial.Circulation. 2009; 119: 687-698Crossref PubMed Scopus (168) Google Scholar, 5Daemen J. Wenaweser P. Tsuchida K. Abrecht L. Vaina S. Morger C. Kukreja N. Jüni P. Sianos G. Hellige G. van Domburg R.T. Hess O.M. Boersma E. Meier B. Windecker S. Serruys P.W. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study.Lancet. 2007; 369: 667-678Abstract Full Text Full Text PDF PubMed Scopus (1602) Google Scholar, 6Iakovou I. Schmidt T. Bonizzoni E. Ge L. Sangiorgi G.M. Stankovic G. Airoldi F. Chieffo A. Montorfano M. Carlino M. Michev I. Corvaja N. Briguori C. Gerckens U. Grube E. Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.JAMA. 2005; 293: 2126-2130Crossref PubMed Scopus (2962) Google Scholar, 7Doyle B.J. Ting H.H. Bell M.R. Lennon R.J. Mathew V. Singh M. Holmes D.R. Rihal C.S. Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005.JACC Cardiovasc Interv. 2008; 1: 202-209Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 8Medi C. Montalescot G. Budaj A. Fox K.A. López-Sendón J. FitzGerald G. Brieger D.B. GRACE InvestigatorsReperfusion in patients with renal dysfunction after presentation with ST-segment elevation or left bundle branch block: GRACE (Global Registry of Acute Coronary Events).JACC Cardiovasc Interv. 2009; 2: 26-33Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 9Goldenberg I. Subirana I. Boyko V. Vila J. Elosua R. Permanyer-Miralda G. Ferreira-González I. Benderly M. Guetta V. Behar S. Marrugat J. Relation between renal function and outcomes in patients with non–ST-segment elevation acute coronary syndrome: real-world data from the European Public Health Outcome Research and Indicators Collection Project.Arch Intern Med. 2010; 170: 888-895Crossref PubMed Scopus (63) Google Scholar It has been established that thrombotic and bleeding complications after stent placement are significantly related to the degree of platelet suppression by clopidogrel.10Motovska Z. Kala P. Benefits and risks of clopidogrel use in patients with coronary artery disease: evidence from randomized studies and registries.Clin Ther. 2008; 30: 2191-2202Abstract Full Text PDF PubMed Scopus (10) Google Scholar, 11Motovska Z. Knot J. Widimsky P. Stent thrombosis—risk assessment and prevention.Cardiovasc Ther. 2010; 28: e92-e100Crossref PubMed Scopus (16) Google Scholar The aim of present study was to evaluate the strength and direction of the association between kidney function and antiplatelet efficacy of clopidogrel. The analysis included patients who underwent PCI with a stent in a tertiary care institution.12European Perspectives in Cardiology Centres of Excellence: the Cardiocentre Prague, Czech Republic.Circulation. 2008; 118: f13-f18Google Scholar 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) 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 iothalamate13Stevens L.A. Coresh J. Schmid C.H. Feldman H.I. Froissart M. Kusek J. Rossert J. Van Lente F. Bruce R.D. Zhang Y.L. Greene T. Levey A.S. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD.Am J Kidney Dis. 2008; 51: 395-406Abstract Full Text Full Text PDF PubMed Scopus (897) Google Scholar: (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 Foundation14National Kidney FoundationK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar as follows: stage 1—normal GFR >90 ml/min/1.73 m2; stage 2—mild decrease in GFR 60 to 90 ml/min/1.73 m2; stage 3—moderate decrease in GFR 30 to 59 ml/min/1.73 m2; and stage 4—severe decrease in GFR <30 ml/min/1.73 m2. 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 (rs). 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). 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 equation15Levey A.S. Bosch J.P. Lewis J.B. Greene T. Rogers N. Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (13364) Google Scholar, 16Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function—measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2404) Google Scholar was strong (rs = −0.688, p <0.001; Figure 1) .Table 1Baseline characteristicsVariableCystatin C Within Reference RangeCystatin C Outside Reference Rangep ValueClopidogrel RespondersClopidogrel Nonrespondersp Value(n = 144)(n = 131)(n = 184)(n = 91)Men95 (66%)69 (53%)0.027115 (63%)49 (54%)0.192Age (years), mean ± SD65.0 ± 11.871.8 ± 10.4<0.00167.4 ± 11.969.8 ± 11.00.121Hypertension95 (66%)100 (76%)0.064119 (65%)76 (84%)0.001Diabetes mellitus45 (31%)48 (37%)0.37357 (31%)36 (40%)0.176Cigarette smoke55 (38%)37 (28%)0.09664 (35%)28 (31%)0.587Acute coronary syndrome78 (54%)81 (62%)0.222105 (55%)57 (63%)0.3Previous stroke9 (6%)16 (12%)0.09615 (8%)10 (11%)0.505Previous myocardial infarction35 (24%)47 (36%)0.04754 (29%)28 (31%)0.889Previous coronary artery bypass grafting12 (8%)20 (15%)0.0922 (12%)10 (11%)0.112Periphery artery disease12 (8%)14 (11%)0.54116 (9%)10 (11%)0.521Statin therapy55 (38%)57 (44%)0.39271 (39%)41 (45%)0.361Aspirin therapy69 (48%)51 (39%)0.14580 (44%)40 (44%)1Platelet count ×109/L Mean ± SD231.9 ± 58.4241.6 ± 90.80.31238.8 ± 81.9232.1 ± 61.60.464 Median (25th–75th percentiles)227 (198–264)230 (186–278)0.844228 (194–270)232 (186–274)0.828Platelet reactivity index (%) Mean ± SD37.8 ± 22.140.5 ± 22.20.31126.3 ± 13.964.9 ± 9.5<0.001 Median (25th–75th percentiles)36.4 (19.9–55.5)40.2 (21.9–58.9)0.31926.4 (14.3–38.3)64.0 (56.2–71.0)<0.001Modification of Diet in Renal Disease creatinine (ml/min/1.75 m2) Mean ± SD83.3 ± 18.060.1 ± 23.0<0.00174.2 ± 22.566.9 ± 25.40.026 Median (25th–75th percentiles)82.4 (71.2–96.8)59.0 (45.4–75.1)<0.00174.0 (58.1–90.7)65.0 (50.9–83.6)0.041Clopidogrel nonresponders were defined by a platelet reactivity index ≥50%; no patients took corticosteroids. Open table in a new tab Clopidogrel nonresponders were defined by a platelet reactivity index ≥50%; no patients took corticosteroids. 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 (rs = −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 Foundation16Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function—measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2404) Google Scholar 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) .Table 2Proportion of clopidogrel nonresponders based on cystatin-based estimated glomerular filtration rate⁎Cystatin C-based eGFR = 76.7 × cystatin C−1.19.eGFR (ml/min/1.73 m2)SubjectsClopidogrel Nonresponders (%)≥905215 (28.8%)60–8911540 (34.8%)30–598528 (32.9%)<30238 (34.8%)There was no significant difference in the proportion of clopidogrel nonresponders among the 4 groups based on cystatin-based estimated glomerular filtration rate (p = 0.902). Clopidogrel nonresponders were defined by a platelet reactivity index ≥50%. Cystatin C-based eGFR = 76.7 × cystatin C−1.19. Open table in a new tab There was no significant difference in the proportion of clopidogrel nonresponders among the 4 groups based on cystatin-based estimated glomerular filtration rate (p = 0.902). Clopidogrel nonresponders were defined by a platelet reactivity index ≥50%. Randomized studies and observational registry data have clearly shown poor outcomes for patients with impaired renal function after stent implantation. Thrombotic and bleeding complications are significantly related to chronic renal dysfunction.3van Werkum J.W. Heestermans A.A. Zomer A.C. Kelder J.C. Suttorp M.J. Rensing B.J. Koolen J.J. Brueren B.R. Dambrink J.H. Hautvast R.W. Verheugt F.W. ten Berg J.M. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry.J Am Coll Cardiol. 2009; 53: 1399-1409Abstract Full Text Full Text PDF PubMed Scopus (600) Google Scholar, 4Aoki J. Lansky A.J. Mehran R. Moses J. Bertrand M.E. McLaurin B.T. Cox D.A. Lincoff A.M. Ohman E.M. White H.D. Parise H. Leon M.B. Stone G.W. Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial.Circulation. 2009; 119: 687-698Crossref PubMed Scopus (168) Google Scholar, 5Daemen J. Wenaweser P. Tsuchida K. Abrecht L. Vaina S. Morger C. Kukreja N. Jüni P. Sianos G. Hellige G. van Domburg R.T. Hess O.M. Boersma E. Meier B. Windecker S. Serruys P.W. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study.Lancet. 2007; 369: 667-678Abstract Full Text Full Text PDF PubMed Scopus (1602) Google Scholar, 6Iakovou I. Schmidt T. Bonizzoni E. Ge L. Sangiorgi G.M. Stankovic G. Airoldi F. Chieffo A. Montorfano M. Carlino M. Michev I. Corvaja N. Briguori C. Gerckens U. Grube E. Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.JAMA. 2005; 293: 2126-2130Crossref PubMed Scopus (2962) Google Scholar, 7Doyle B.J. Ting H.H. Bell M.R. Lennon R.J. Mathew V. Singh M. Holmes D.R. Rihal C.S. Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005.JACC Cardiovasc Interv. 2008; 1: 202-209Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 8Medi C. Montalescot G. Budaj A. Fox K.A. López-Sendón J. FitzGerald G. Brieger D.B. GRACE InvestigatorsReperfusion in patients with renal dysfunction after presentation with ST-segment elevation or left bundle branch block: GRACE (Global Registry of Acute Coronary Events).JACC Cardiovasc Interv. 2009; 2: 26-33Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 9Goldenberg I. Subirana I. Boyko V. Vila J. Elosua R. Permanyer-Miralda G. Ferreira-González I. Benderly M. Guetta V. Behar S. Marrugat J. Relation between renal function and outcomes in patients with non–ST-segment elevation acute coronary syndrome: real-world data from the European Public Health Outcome Research and Indicators Collection Project.Arch Intern Med. 2010; 170: 888-895Crossref PubMed Scopus (63) Google Scholar These disorders are also strongly related to antiplatelet (non)efficacy of clopidogrel.10Motovska Z. Kala P. Benefits and risks of clopidogrel use in patients with coronary artery disease: evidence from randomized studies and registries.Clin Ther. 2008; 30: 2191-2202Abstract Full Text PDF PubMed Scopus (10) Google Scholar, 11Motovska Z. Knot J. Widimsky P. Stent thrombosis—risk assessment and prevention.Cardiovasc Ther. 2010; 28: e92-e100Crossref PubMed Scopus (16) Google Scholar The interaction between chronic kidney disease and low response to clopidogrel was identified as an independent predictor of cardiac death.17Morel O. El Ghannudi S. Jesel L. Radulescu B. Meyer N. Wiesel M.L. Caillard S. Campia U. Moulin B. Gachet C. Ohlmann P. Cardiovascular mortality in chronic kidney disease patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 inhibition by clopidogrel.J Am Coll Cardiol. 2011; 57: 399-408Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar The present study suggests that clopidogrel efficacy is not significantly influenced by decreased glomerular filtration. No association was confirmed between severity of renal insufficiency and degree of clopidogrel-induced platelet inhibition. An important point of the present study was the method. Phosphorylation of VASP was used to measure clopidogrel efficacy. This is currently the only available assay that is specific to P2Y12 receptors and therefore the inhibitory effect of clopidogrel on platelets.18Michelson A.D. Methods for the measurement of platelet function.Am J Cardiol. 2009; 103: 20A-26AAbstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar Timing of the clopidogrel efficacy measurement was also optimal.19Motovska Z. Widimsky P. Petr R. Bilkova D. Marinov I. Simek S. Kala P. Optimal pretreatment timing for high load dosing (600 mg) of clopidogrel before planned percutaneous coronary intervention for maximal antiplatelet effectiveness.Int J Cardiol. 2010; 144: 255-257Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Patients received clopidogrel in the catheter laboratory; therefore noncompliance as a critical confounding factor of clopidogrel nonresponsiveness was avoided. Renal function was assessed with cystatin C. This small protease inhibitor is produced in all nucleated cells at a constant rate and is freely filtered by the glomerulus without secretion or subsequent reabsorption into the blood.20Laterza O.F. Price C.P. Scott M.G. Cystatin C: an improved estimator of glomerular filtration rate?.Clin Chem. 2002; 48: 699-707PubMed Google Scholar Therefore, generation of cystatin C appears to be less variable than creatinine.21Westhuyzen J. Cystatin C: a promising marker and predictor of impaired renal function.Ann Clin Lab Sci. 2006; 36: 387-394PubMed Google Scholar Recent investigations and analyses of correlations and diagnostic accuracy of different GFR markers have indicated that serum cystatin C is a more reliable marker of GFR in patients with chronic kidney disease than serum creatinine.22Bellomo R. Kellum J.A. Ronco C. Defining acute renal failure: physiological principles.Intensive Care Med. 2004; 30: 33-37Crossref PubMed Scopus (302) Google Scholar, 23Hojs R. Bevc S. Ekart R. Gorenjak M. Puklavec L. Serum cystatin C as an endogenous marker of renal function in patients with chronic kidney disease.Ren Fail. 2008; 30: 181-186Crossref PubMed Scopus (23) Google Scholar, 24U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2007Google Scholar After PCI mortality in patients with chronic renal dysfunction is higher than in the general population.25Hage F.G. Venkataraman R. Zoghbi G.J. Perry G.J. DeMattos A.M. Iskandrian A.E. The scope of coronary heart disease in patients with chronic kidney disease.J Am Coll Cardiol. 2009; 53: 2129-2140Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 26Widimsky P. Rychlik I. Renal disease and acute coronary syndrome.Heart. 2010; 96: 86-92Crossref PubMed Scopus (16) Google Scholar Despite similar angiographic success rates, clinical benefits are lower in patients with (vs without) renal dysfunction because of higher rates of ischemia and bleeding complications. Traditional cardiovascular risk factors also show an increased prevalence in patients with chronic kidney disease. However, renal dysfunction is related to risk factors that are unique to this complex entity: inflammation, oxidative stress, decreased nitric oxide availability, hyperhomocysteinemia, hyperphosphatemia, vascular calcification, increased vascular stiffness, left ventricular hypertrophy, anemia, endothelial dysfunction, volume overload, and electrolyte imbalance.27Muntner P. Hamm L.L. Kusek J.W. Chen J. Whelton P.K. He J. The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease.Ann Intern Med. 2004; 140: 9-17Crossref PubMed Scopus (364) Google Scholar The high-risk background of patients with chronic renal disease predisposes them to higher risks of cardiovascular complications. Renal insufficiency appears to be clinically associated with bleeding tendencies. The pathophysiology that underlies this tendency involves platelet dysfunction (affecting all aspects of platelet function) and an imbalance of mediators associated with normal endothelial function.28Sohal A.S. Gangji A.S. Crowther M.A. Treleaven D. Uremic bleeding: Pathophysiology and clinical risk factors.Thromb Res. 2006; 118: 417-422Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Selection and dosage of antithrombotic drugs comprise another important risk factor related to bleeding complications in patients with impaired renal function. Patients with renal impairment have been identified as the group most likely to receive excess doses of antiplatelet and antithrombin agents.29Alexander K.P. Chen A.Y. Roe M.T. Newby L.K. Gibson C.M. Allen-LaPointe N.M. Pollack C. Gibler W.B. Ohman E.M. Peterson E.D. CRUSADE InvestigatorsExcess dosing of antiplatelet and antithrombin agents in the treatment of non–ST-segment elevation acute coronary syndromes.JAMA. 2005; 294: 3108-3116Crossref PubMed Scopus (491) Google Scholar Results of the present study cannot substantiate an independent relation between risks associated with renal dysfunction after PCI and antiplatelet effects of clopidogrel. Evaluation of laboratory data are in agreement with published clinical observations from the large (n = 12,253) Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial.30Keltai M. Tonelli M. Mann J.F. Sitkei E. Lewis B.S. Hawken S. Mehta S.R. Yusuf S. CURE Trial InvestigatorsRenal function and outcomes in acute coronary syndrome: impact of clopidogrel.Eur J Cardiovasc Prev Rehabil. 2007; 14: 312-318Crossref PubMed Scopus (121) Google Scholar The study confirmed an inverse relation between renal function and outcomes. The primary outcome (cardiovascular death, myocardial infarction, and stroke) occurred significantly (p <0.0001) more frequently in patients with a severe decrease in renal function (creatinine-based eGFR 60 ml/min) or moderately impaired (creatinine-based eGFR 30 to 59.9 ml/min) renal function. Nonetheless, adding clopidogrel to the standard treatment of non–ST-segment acute coronary syndrome produced a significant beneficial effect in all 3 tertiles of renal function (p for heterogeneity = 0.11). Clopidogrel treatment significantly increased the risk of minor bleeding in all tertiles of renal function; however, degree of bleeding appeared unrelated to severity of renal dysfunction. Clopidogrel was found to be beneficial and safe in patients with and without chronic kidney disease.

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