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  ORIGINAL INVESTIGATION Open Access Comparative effect of clopidogrel and aspirinversus aspirin alone on laboratory parameters:a retrospective, observational, cohort study Yasuo Takahashi 1* , Yayoi Nishida 1 , Tomohiro Nakayama 2 and Satoshi Asai 3 Abstract Background:  Clopidogrel and aspirin are antiplatelet agents that are recommended to reduce the risk of recurrentstroke and other cardiovascular events. Combination therapy of clopidogrel and aspirin has been shown to increasethe risk of hemorrhage, but the effects of the drugs on laboratory parameters have not been well studied inpatients in routine clinical practice. Therefore, we evaluated and compared the effects of combination therapy withclopidogrel plus aspirin and aspirin monotherapy on laboratory parameters using a clinical database. Methods:  We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtainedbetween November 2004 and April 2011, to identify cohorts of new users (n = 159) of clopidogrel (75 mg/day)plus aspirin (100 mg/day) and new users (n = 834) of aspirin alone (100 mg/day). We used a multivariableregression model and regression adjustment with the propensity score to adjust for differences in baselinecovariates between settings, and compare the mean changes in serum levels of creatinine, aspartateaminotransferase, alanine aminotransferase and hematological parameters, including hemoglobin level,hematocrit, and white blood cell (WBC), red blood cell and platelet counts up to two months after the start of study drug administration. Results:  After adjustment, the reduction of WBC count in clopidogrel plus aspirin users was significantly greaterthan that in aspirin alone users. All other tests showed no statistically significant difference in the mean changefrom baseline to during the exposure period between clopidogrel plus aspirin users and aspirin alone users. Thecombination of clopidogrel and aspirin increased the risk of gastrointestinal bleeding compared with aspirinalone, with a relative risk ranging from 2.06 (95% CI, 1.02 to 4.13; p = 0.043) for the multivariate model and 2.61(95% CI, 1.18 to 5.80; p = 0.0184) for propensity adjustment. Conclusion:  Our findings suggested that hematological adverse effects may be greater with combinationtherapy of clopidogrel plus aspirin than with aspirin monotherapy. Keywords:  Clopidogrel, Aspirin, Laboratory parameter, Antiplatelet therapy, Propensity-score adjustment Background Clopidogrel and aspirin are antiplatelet agents that arerecommended to reduce the risk of recurrent stroke andother cardiovascular events [1,2]. Combination therapy,typically with clopidogrel and aspirin, is commonly used for the prevention of cardiovascular events, whengiven for an appropriate indication and duration [3].Aspirin inhibits platelet cyclooxygenase by irreversibleacetylation, thereby preventing the formation of thromb-oxane A2 which is a powerful stimulant of platelet ag-gregation [4]. Clopidogrel, a thienopyridine, acts by inhibiting adenosine receptors, which inhibits the early step of platelet activation [5]. Thus, the effect of combin-ing aspirin and clopidogrel is synergistic in preventingplatelet aggregation, and this combination may offer cer-tain theoretical benefits over either agent alone. Someclinical trials have investigated the efficacy of the com-bination of clopidogrel and aspirin. The combination * Correspondence: takahashi.yasuo@nihon-u.ac.jp 1 Division of Genomic Epidemiology and Clinical Trials, Clinical Trials ResearchCenter, Nihon University School of Medicine, 30-1 Oyaguchi-Kami Machi,Itabashi-ku, Tokyo 173-8610, JapanFull list of author information is available at the end of the article C ARDIO V ASCULAR D IABETOLOGY © 2013 Takahashi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the srcinal work is properly cited.  Takahashi  et al. Cardiovascular Diabetology   2013,  12 :87http://www.cardiab.com/content/12/1/87  has been shown to reduce the risk of ischemic events inpatients with myocardial infarction with or without ST-segment elevation, and after angioplasty or stenting[6-10]. On the other hand, in the MATCH trial, combin-ation therapy with clopidogrel plus aspirin in patientswith a prior stroke or TIA showed no significant benefitin reducing major vascular events compared withclopidogrel alone [11]. The CHARISMA trial has shownthat the combination of clopidogrel and aspirin wasnot significantly more effective than aspirin alone inreducing the rate of myocardial infarction, stroke, ordeath from cardiovascular causes [12]. Based on theseclinical findings, combination therapy with aspirin andclopidogrel is recommended for treatment of acute cor-onary syndromes and the prevention of coronary eventsafter placement of a stent as the most appropriate indi-cations [1]. The nature of antiplatelet therapy involvesan inherent risk of bleeding complications. Althoughthis combination of antiplatelet agents has been demon-strated to offer clinical benefits under certain conditions,it does raise the risk of bleeding complications [13].Thus, there is a consensus that dual antiplatelet therapy involves the issue of bleeding risk. Although previous re-ports have assessed the side effects of antiplatelet agents,they usually focused on the adverse events of antiplateletagents [14,15], and few studies have focused on the ef-fects of the drugs on laboratory parameters. Therefore,we evaluated and compared the effects of combinationtherapy with clopidogrel plus aspirin and aspirin mono-therapy on laboratory parameters including creatinine,aspartate aminotransferase (AST), and alanine amino-transferase (ALT) levels and hematological parametersincluding red blood cell (RBC) count, white blood cell(WBC) count, platelet count, hemoglobin level andhematocrit, which are typically used in clinical practicefor checking side effects of drugs. Methods Data source We obtained the study data from electronic medical re-cords stored in the Nihon University School of Medicine(NUSM) Clinical Data Warehouse (CDW), which is acentralized data repository that integrates separate data-bases, including an order entry database and a laboratory results database, from the hospital information systemsat three hospitals affiliated with NUSM, and is describedelsewhere [16]. The prescription database in the CDW contains information from approximately 0.6 million pa-tients, and prescribing data are linked longitudinally todetailed clinical information such as patient demograph-ics, diagnosis, and laboratory data. Several epidemio-logical studies examining the effects of drugs onlaboratory parameters using NUSM ’ s CDW have beenpublished [17-20]. Study population The cohorts identified for the study included Japanesepatients aged over 20 years who had been newly treatedwith clopidogrel (75 mg per day) plus aspirin (100 mgper day) or aspirin alone (100 mg per day) betweenNovember 2004 and April 2011 (detailed profile in-cluded in Additional file 1). We excluded patients whohad received other antiplatelet drugs, anticoagulants orthrombolytics during the study period. We also excludedpatients who had severe comorbid conditions: increasedrisk of bleeding including diagnosis of severe hepatic in-sufficiency, renal failure or current peptic ulceration, his-tory of systemic bleeding, other history of bleedingdiathesis or coagulopathy, or a contraindication to as-pirin or clopidogrel during the study period. Conse-quently, we identified 159 new users of clopidogrel plusaspirin and 834 new users of aspirin alone. The ethicscommittee of Nihon University School of Medicine ap-proved the study protocol. Exposure and outcome In this study, the index date was defined as the date of first prescription of the study drugs. The baseline meas-urement period (non-exposure period) was defined aswithin six months before the index date in theclopidogrel plus aspirin and aspirin alone cohorts. Theexposure period (outcome measurement period) was de-fined as between two weeks and two months after thestart of treatment with clopidogrel plus aspirin or aspirinalone to evaluate the short-term effect of the study drugs. Blood test data (creatinine, AST, and ALT levels,and hematological parameters including RBC count,WBC count, platelet count, hemoglobin level andhematocrit) were collected for each individual at thedate nearest the index date in the baseline period, and atthe date nearest two months after the start of treatmentin the exposure period. Consequently, the mean (95%confidence interval (CI)) exposure of clopidogrel plus as-pirin and aspirin alone users was 36.0 (33.8-38.2) daysand 36.7 (35.8-37.7) days, respectively. There was no sta-tistically significant difference in mean exposure days be-tween them. Information on bleeding episodes of patients who were newly diagnosed with intracranialhemorrhage or gastrointestinal (GI) bleeding in the ex-posure period was collected. Covariates For each individual, information on patient demograph-ics (age and sex), medical history, current medication,and laboratory results was collected. Medical history in-cluded information on cerebrovascular disease (ICD-10codes, I60-I69), ischemic heart disease (I20-I25), otherheart disease (I30-I52), other peripheral vascular disease(I73), liver disease (K70-K77), kidney disease (N00-N19),  Takahashi  et al. Cardiovascular Diabetology   2013,  12 :87 Page 2 of 7http://www.cardiab.com/content/12/1/87  gout (M10), thyroid gland disorders (E00-E07), hyperlip-idemia (E78.0-E78.5), hypertension (I10), and diabetesmellitus (E10-E14) that had been diagnosed prior to theindex date. We recorded current users of medication in-cluding antihypertensive agents, steroids, lipid-loweringdrugs, insulin, oral antihyperglycemic agents, non-steroidal anti-inflammatory drugs (NSAIDs), protonpump inhibitors (PPIs), histamine2-receptor antagonists(H2 blockers), other anti-peptic ulcer agents, immuno-suppressive drugs, diuretics, and anti-arrhythmic drugs,defined as patients who had received these agents in the60 days preceding the index date. Statistical analysis All analyses were performed with SAS software, version9.2 (SAS Institute, Cary, NC). All reported p-values aretwo sided. A result was considered statistically signifi-cant if the p value was less than 0.05. To compare differ-ences in baseline characteristics, we used  t  -test forcontinuous variables and chi-squared test for categoricaldata. Also, we used  t  -test to compare the mean values of laboratory parameters at baseline between clopidogrelplus aspirin users and aspirin alone users. The generallinear model approach was performed to calculatemultivariate-adjusted values of blood test parametersand to compare the adjusted least-squares means of changes from the baseline value to the exposure valuebetween clopidogrel plus aspirin users and aspirin aloneusers. To reduce bias by controlling for baseline covari-ates between settings, two adjusted models arepresented. The first model had regression (covariance)adjustment with the propensity score. This method is aneffective tool to reduce bias in nonrandomized studies[21,22], and is described elsewhere [23]. In brief, thepropensity score for each subject was obtained by fittinga logistic regression model that includes the predictor variable (i.e., clopidogrel plus aspirin users or aspirinalone users) as an outcome and all baseline covariatesincluding age, sex, comorbid diseases (cerebrovasculardisease, ischemic heart disease, other heart disease, liverdisease, kidney disease, gout, thyroid gland disorders,hyperlipidemia, hypertension, and diabetes mellitus)and previous drugs (including antihypertensive agents,steroids, lipid-lowering drugs, oral antihyperglycemicagents, NSAIDs, PPIs, H2 blockers, other anti-pepticulcer agents, immunosuppressive drugs, anti-arrhythmicdrugs and chemotherapeutic drugs), as listed in Table 1.With the propensity score included in the general linearmodel, we assessed and compared the adjusted least-squares means of changes in laboratory parametersduring the exposure period from baseline betweenclopidogrel plus aspirin users and aspirin alone users.The second model adjusted for age, sex and theremaining covariates, which were selected using abackward stepwise elimination method (p <0.10). To es-timate the relative risk of intracranial hemorrhage or GIbleeding for clopidogrel plus aspirin users and aspirinalone users, we used the odds ratio and 95% CI from lo-gistic regression in which we controlled for covariatesusing the two adjustment models described above. Results The study included 159 patients who had been newly treated with clopidogrel plus aspirin and 834 patientswho had been newly treated with aspirin alone. Table 1shows the baseline characteristics of the patients. Inclopidogrel plus aspirin users, the mean age was 64.6 yearsand 20.1 percent were women. Aspirin alone userswere older and were more likely to be women thanclopidogrel plus aspirin users; the mean age was68.3 years and 39.5 percent were women. More thantwo-thirds of each cohort had ischemic heart disease,hyperlipidemia or diabetes mellitus, suggesting raisedrisk of cardiovascular disease. Clopidogrel plus aspirinusers were more likely to have ischemic heart diseaseand hyperlipidemia, and were less likely to have cere-brovascular disease, liver disease, and kidney diseasethan aspirin alone users. In current medications, clopidogrelplus aspirin users were more likely to utilize lipid-loweringdrugs than aspirin alone users. On the other hand, as-pirin alone users were more likely to utilize calciumchannel blockers, thiazide diuretics, NSAIDs, H2blockers, diuretics and anti-arrhythmic drugs. Table 2shows the mean values in laboratory parameters atbaseline. The mean hemoglobin level in clopidogrelplus aspirin users was higher than that in aspirin aloneusers. None of the other tests showed any statistically significant difference in mean values at baseline be-tween clopidogrel plus aspirin users and aspirin aloneusers. Because differences in baseline covariates, in-cluding age, sex, comorbid diseases and current medi-cation, between clopidogrel plus aspirin users andaspirin alone users may create potential bias, we used amultivariate regression model and regression adjust-ment with propensity score to control for potentialconfounding covariates in our observational study.Table 3 shows the mean changes in WBC count dur-ing the exposure period compared with the baselineperiod. In clopidogrel plus aspirin users, the reductionof WBC count was significantly greater than that in as-pirin alone users before and after adjustment for covari-ates. The mean changes in other laboratory parameterswere not significantly different in clopidogrel plus as-pirin users in comparison to those in aspirin alone users(data are included in Additional file 2). Table 4 showsthe prevalence of patients who had hemorrhagic eventsduring the exposure period. The rate of GI bleeding was3.14 percent in clopidogrel plus aspirin users, as  Takahashi  et al. Cardiovascular Diabetology   2013,  12 :87 Page 3 of 7http://www.cardiab.com/content/12/1/87  compared with 0.67 percent in aspirin alone users, witha relative risk of 2.61 (95% CI, 1.18 to 5.80; p=0.0184)for propensity adjustment and a relative risk of 2.06(95% CI, 1.02 to 4.13; p =0.043) for the multivariatemodel, suggesting that the risk of GI bleeding was increasedin patients treated with the combination of clopidogrel andaspirin. The risk of intracranial hemorrhage was not signifi-cantly different between clopidogrel plus aspirin users andaspirin alone users. Discussion In this study, we evaluated and compared the effects of combination therapy of clopidogrel plus aspirin andaspirin monotherapy on laboratory parameters includ-ing creatinine, AST, ALT, hemoglobin level, hematocrit,WBC, RBC and PLT counts in a short-term administra-tion period up to two months. We found that the re-duction of WBC count in clopidogrel plus aspirin userswas significantly greater than that in aspirin aloneusers. These results suggest that the hematological ad- verse effect on leukocytes is greater with combinationtherapy of clopidogrel plus aspirin than with aspirinmonotherapy.A variety of hematological adverse reactions, includingleukopenia, agranulocytosis, and thrombocytopenia, havebeen reported in patients receiving clopidogrel or aspirin Table 1 Baseline characteristics of study population Characteristics Clopidogrel plus aspirin Aspirin alone p(n=159) (n=834) Age (years, mean± SE) 64.6 ± 1.0 68.3 ± 0.4 0.0005Women 32 (20.13%) 329 (39.45%) <0.0001 Medical history Cerebrovascular disease 40 (25.16%) 375 (44.96%) <0.0001Ischemic heart disease 140 (88.05%) 536 (64.27%) <0.0001Liver disease 38 (23.9%) 369 (44.24%) <0.0001Kidney disease 57 (35.85%) 378 (45.32%) 0.0273Hypertension 107 (67.3%) 495 (59.35%) 0.0603Diabetes mellitus 122 (76.73%) 606 (72.66%) 0.2879Hyperlipidemia 147 (92.45%) 668 (80.10%) 0.0002 Current medication Insulin 3 (1.89%) 60 (7.19%) 0.0119Oral hypoglycemic drug 25 (15.72%) 106 (12.71%) 0.3035Lipid-lowering drug 38 (23.9%) 144 (17.27%) 0.0476Antihypertensive drug 51 (32.08%) 590 (70.74%) <0.0001ARB 27 (16.98%) 199 (23.86%) 0.0579ACEI 4 (2.52%) 49 (5.88%) 0.0841Beta-blocker 7 (4.4%) 53 (6.35%) 0.3437CCB 39 (24.53%) 524 (62.83%) <0.0001 Thiazide diuretic 9 (5.66%) 127 (15.23%) 0.0013Other 14 (8.81%) 80 (9.59%) 0.756NSAID 12 (7.55%) 191 (22.9%) <0.0001Steroid 4 (2.52%) 82 (9.83%) 0.0026H2 blocker 17 (10.69%) 455 (54.56%) <0.0001Proton pump inhibitor 19 (11.95%) 151 (18.11%) 0.059Antiepileptic drug 2 (1.26%) 55 (6.59%) 0.008Immunosuppressive drug 0 (0%) 18 (2.16%) 0.0616Diuretic 8 (5.03%) 129 (15.47%) 0.0005Antiarrhythmic drug 12 (7.55%) 104 (12.47%) 0.0765 Data are numbers of individuals (%) unless otherwise stated. The item of other peripheral vascular disease is not presented because its number was zero.Abbreviations:  ARB  angiotensin II receptor blocker,  ACEI   angiotensin-converting enzyme inhibitor,  CCB  calcium channel blocker,  NSAID  non-steroidal anti-inflammatory drug,  H2 blocker   histamine2-receptor antagonist.  Takahashi  et al. Cardiovascular Diabetology   2013,  12 :87 Page 4 of 7http://www.cardiab.com/content/12/1/87

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