Aspirin Resistance in Patients with Chronic Renal Failure (P 5325) Beste Ozben Sadic 1, Azra Tanrikulu 1, Mehmet Koc 2, Tomris Ozben 3, Oguz Caymaz 1 1 Marmara University, Faculty of Medicine, Department of Cardiology, Istanbul, Turkey 2 Marmara University, Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Istanbul, Turkey 3 Akdeniz University Faculty of Medicine, Department of Biochemistry, Antalya, Turkey
ASPIRIN an effective antiplatelet agent irreversibly inhibites platelet cyclooxygenase-1 enzyme prevents the production of thromboxane A2 (TXA2) It has been used in the primary and secondary prevention of thromboembolic vascular events 2
ASPIRIN RESISTANCE Some patients have recurrent vascular events despite long-term aspirin therapy. Aspirin resistance: the inability of aspirin to produce a measurable response on ex vivo tests of platelet function, to inhibit TXA2 biosynthesis in vivo or to protect individual patients from recurrent thrombotic complications Estimates of the prevalence of aspirin resistance: 5.5% to 60% 3
ASPIRIN RESISTANCE Possible causes of aspirin resistance: poor compliance or inadequate dose, reduced bioavailability, increased platelet turnover, upregulation of non-platelet pathways of thromboxane production, drug interactions, and genetic variability There is currently no standardized approach to the diagnosis and no proven effective treatment for aspirin resistance. 4
ASPIRIN AND CHRONIC RENAL FAILURE Chronic renal failure (CRF) is associated with increased risk of cardiovascular morbidity and mortality. In patients with CRF and undergoing hemodialysis, coronary artery disease incidence is nearly 40% and half of the mortality in these patients is associated with cardiovascular diseases. Thus aspirin use is important in these patients. 5
ASPIRIN AND CHRONIC RENAL FAILURE Although aspirin resistance has been well demonstrated in cardiovascular disorders including coronary artery disease, heart failure, cerebrovascular disease, metabolic syndrome, and diabetes, little is known about aspirin response and its prognostic value in patients with CRF. 6
THE AIM OF THIS STUDY to explore the prevalence of aspirin resistance in patients with chronic renal failure 7
PATIENTS AND METHODS Two-hundred and fortyfive CRF patients (115 patients undergoing chronic hemodialysis and 130 predialytic uremic patients) All predialytic uremic patients had stage 3 or 4 CRF and had estimated glomerular filtration rate (GFR) between 15 and 60 ml/min/1.73m2 for at least 6 months. The patients undergoing chronic hemodialysis had creatinine clearance below 10 ml/min/1.73m2 and had been on chronic hemodialysis treatment 3 times a week for more than 6 months. 8
PATIENTS AND METHODS Control group: 130 consecutive patients with normal renal functions, estimated GFR 90ml/min/1.73m2 and no underlying morphological renal disease. Exclusion criteria: ingestion of ticlopidine, clopidogrel, silostazol, dipyridamole, abciximab, tirofiban or anti-inflammatory drugs for the last 10 days. Patients with stage 2 CRF (patients with underlying morphological renal disease and GFR between 60-89ml/min/1.73m2) or a history of major cardiovascular event within the past 3 months were also excluded. 9
PATIENTS AND METHODS All subjects were taking aspirin regularly. Aspirin responsiveness was determined by Ultegra Rapid Platelet Function Assay-ASA (VerifyNow Aspirin, Accumetrics Inc., SanDiego, California). Aspirin resistance was defined as aspirin reaction unit (ARU) 550. 10
RESULTS Aspirin resistance was detected in 53 hemodialysis patients, 32 uremic patients and 22 controls. The frequency of aspirin resistance was significantly higher in CRF patients compared to controls (34.7% vs 16.9%, p<0.001) and in hemodialysis patients (46.1%) compared to predialytic uremic patients (24.6%, p<0.001) and controls (16.9%, p<0.001). The median aspirin dose was 100 mg/day in all groups. 11
Table 1: Aspirin doses and aspirin resistance in CRF patients and controls Aspirin resistance (n - %) Chronic Renal Failure Group (n=245) Hemodialysis Patients (n=115) Predialytic Uremic Patients 85 (34.7%) (n= 130) Control Group 22 (16.9%) 53 (46.1%) 32 (24.6%) <0.001 P* <0.001 Aspirin reaction unit (ARU) Aspirin dose median (mg/day) Aspirin duration (months) 511 76 <0.001 549 60 478 74 479 72 <0.001 100 100 100 NS 27 42 NS 36 67 18 29 35 50 0.009 12
RESULTS Female frequency was significantly higher in the aspirinresistant patients (53.3% vs 40.7%, p=0.027). There was not any significant difference in age between aspirin-resistant and aspirin-sensitive patients. The frequencies of CRF and hemodialysis were significantly higher in the aspirin-resistant patients (79.4% vs 59.7%, p<0.001 and 49.5% vs 23.1%, p<0.001; respectively). The daily aspirin dose and duration of aspirin therapy were similar between the aspirin-resistant and aspirinsensitive patients. Blood urea nitrogen and creatinine levels were significantly higher while hematocrit levels and platelet counts were significantly lower in the aspirin-resistant patients compared to aspirin-sensitive patients. 13
Table 2: The characteristics and laboratory parameters of aspirin resistant and sensitive patients Aspirin resistant patients (n= 107) Aspirin sensitive patients (n= 268) Age (years) 63.9 13.2 64.7 13.6 0.609 Gender (female/male) (n) Chronic renal failure (%) 57 / 50 109 / 159 0.027 79.4 59.7 <0.001 Hemodialysis (%) 49.5 23.1 <0.001 Hypertension (%) 74.8 76.1 0.783 Diabetes (%) 38.3 31.3 0.196 Coronary artery disease (%) 33.6 34.7 0.939 Smoking (%) 33.6 35.1 0.793 Body mass index (kg/m 2 ) 26.5 ± 5.0 26.8 5.2 0.569 p 14
Table 2: The characteristics and laboratory parameters of aspirin resistant and sensitive patients Aspirin dose (mg/day) Aspirin duration (months) Aspirin resistant patients (n= 107) Aspirin sensitive patients (n= 268) 151.9 ± 86.9 160.6 91.5 0.400 27 ± 47 31 54 0.365 Glucose (mg/dl) 121±56 120 49 0.802 BUN (mg/dl) 79±63 50 48 <0.001 Creatinine (mg/dl) 5.1±4.2 3.3 4.5 <0.001 HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) 38±12 42 14 0.054 103±42 107 38 0.458 Hematocrit (%) 35.8±6.5 38.1 8.4 0.012 Platelet (10 3 /mm 3 ) 214±75 245 99 0.004 p 15
RESULTS There was a significant relation between renal functions and aspirin resistance. Aspirin resistance was detected in 85 CRF patients and only in 22 control patients (34.7% vs 16.9%, p<0.001, Odds Ratio (OR):2.608, 95% Confidence Interval (CI): 1.537 4.424). The frequency of aspirin resistance was significantly higher in patients undergoing hemodialysis compared to both predialytic uremic patients (46.1% vs 24.6%, p<0.001, OR:2.618, 95% CI: 1.523 4.501) and controls (46.1% vs 16.9%, p<0.001, OR:4.196, 95% CI: 2.333 7.548). 16
RESULTS There was a significant positive relation between aspirin resistance and serum creatinine levels. An increase of 1mg/dl in creatinine levels had a 10% increase in odds of having aspirin resistance (p=0.001, 95% CI: 4.1 16.3%). There was also a significant negative relation between aspirin resistance and estimated GFR. An increase of 1ml/min/1.73m 2 in GFR had a 1.1% decrease in odds of having aspirin resistance (p=0.001, 95% CI: 0.5-1.7%). 17
RESULTS There was a significant relation between aspirin resistance and gender. Among the aspirin-resistant patients, the female ratio was 53.3% while only 40.7% of aspirinsensitive patients were female (p= 0.027, OR: 1.663, 95% CI:1.059 2.611). Aspirin reaction units were significantly correlating with HDL cholesterol (p<0.001, r= -0.212), hematocrit (p<0.001, r= -0.271) platelet levels (p<0.001, r= -0.237). 18
RESULTS Multivariate analysis revealed female gender (OR:2.201; 95%CI 1.173 4.129; p=0.014) hemodialysis (OR:3.636; 95%CI 1.313 10.066; p=0.013) HDL cholesterol (OR:0.974; 95%CI 0.950 0.999; p=0.043) as independent predictors of aspirin resistance in this cohort of patients. 19
CONCLUSIONS We found increased aspirin resistance in patients with CRF, especially in patients undergoing chronic hemodialysis. Aspirin resistance might increase the cardiovascular morbidity and mortality in CRF patients, who are already at increased risk for cardiovascular complications. Since aspirin resistance is multifactorial in nature, further studies are necessary to elucidate the exact mechanisms underlying aspirin resistance. 20