Sonoda et al. Journal of Pharmaceutical Health Care and Sciences (2017) 3:6 DOI 10.1186/s40780-017-0075-x RESEARCH ARTICLE Open Access Predictive factors for effectiveness and safety of enoxaparin for total knee arthroplasty in aged Japanese patients: a retrospective review Akihiro Sonoda1,2†, Yuki Kondo1*† , Yasuhiro Tsuneyoshi3, Yoshitaka Iwashita2, Shoji Nakao2, Kazuhisa Ishida2, Kentaro Oniki4, Junji Saruwatari4, Tetsumi Irie1,5 and Yoichi Ishitsuka1 Abstract Background: The aims of this study were to investigate predictive factors involved in effectiveness and safety of enoxaparin for prevention of postoperative venous thromboembolism in aged Japanese total knee arthroplasty (TKA) patients. Methods: Japanese patients over 65 years old who were administered enoxaparin for TKA were enrolled in this study. Their medical records were retrospectively reviewed. Data were corrected at the Izumi Regional Medical Center, from September 2009 to March 2014. Patients were stratified into groups according to whether enoxaparin was effective (no deep vein thrombosis event up to postoperative day 7) or not, and whether they had an adverse drug event (ADE) or not. Results: A total of 128 patients were included in this study. One hundred five (82.0%) patients were in the effective group and 20 (15.6%) in the adverse drug event (ADE) group. Anemia (13 patients), abnormalities in liver function tests (4 patients), clinically relevant non-major bleeding (4 patients) and urticaria (1 patient) were observed as ADEs. Multivariate logistic regression analysis showed that the serum total protein level at postoperative day 1 (POD1, before enoxaparin administration), was associated with effectiveness of enoxaparin, while the serum total protein and hemoglobin level at POD1 were involved in ADE caused by enoxaparin. Conclusions: Although further large scale studies will be warranted, our results suggest that serum total protein level just before enoxaparin treatment for TKA relates to the effectiveness and safety of enoxaparin in a Japanese aged population. In addition, the results indicate that the development of anemia should be carefully monitored during enoxaparin treatment for TKA, particularly in patients with lower levels of serum hemoglobin before treatment. Keywords: Enoxaparin, Total knee arthroplasty, Adverse drug event, Serum total protein, Anemia, Venous thromboembolism * Correspondence: [email protected] †Equal contributors 1Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, Chuo-ku 862-0973, Japan Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sonoda et al. Journal of Pharmaceutical Health Care and Sciences (2017) 3:6 Page 2 of 8 Background To evaluate effectiveness, the patients were classified Venous thromboembolism (VTE) is common after total into two groups, the “effective” group and “ineffective” knee arthroplasty (TKA), and its incidence is particularly group. In this study, “effective” was defined as no DVT high after orthopedic surgery. For example, the inci- event up to postoperative day 7. The safety of enoxa- dence of deep vein thrombosis (DVT) and pulmonary parin was evaluated according to presence (ADE (+) embolism after knee arthroplasty are 41–85% and 1.5– group) or absence (ADE (−)group)ofADE.Thela- 10%, respectively, without anticoagulant therapy [1]. boratory values at POD7 were used for the assessment Enoxaparin sodium (enoxaparin), a low-molecular- of laboratory abnormalities. The ADE in this study weight heparin, has been used to prevent VTE after were defined as > grade 3 according to the National TKA, and has been shown to be effective in clinical tri- Cancer Institute Common Terminology Criteria for als [2, 3]. Generally, enoxaparin has a predictable phar- Adverse Events (version 4.0) [13] and/or clinically macokinetic profile and dose response curve, allowing relevant non-major (CRNM) bleeding [14]. This study simplified dosing without the need for careful monitor- was approved by the Ethics Committee of Kumamoto ing through laboratory tests [4]. However, the standard University (no. 915) and Izumi Regional Medical dose of enoxaparin is sometimes ineffective in DVT Center (no. 20140908–1). All analyses were conducted high risk groups, such as intensive care patients [5]. In using anonymized data. addition, enoxaparin has been associated with severe adverse drug events (ADE), such as bleeding, skin re- Statistical analysis action, liver failure, and anemia [6–8]. ncreasing age is The statistical power of the association analyses of the acommonriskfactorforADEwithmanytypesof effectiveness and ADE of enoxaparin were calculated at medication [9–11], and enoxaparin is no exception. a significance (alpha) level of 0.05 (two-tailed) and an ef- Macieetal.suggestedthatincreasingagewasarisk fect size (zeta) of 0.2–1.0 according to the sample size of factor for bleeding during treatment with enoxaparin the present study using the G*Power software program [12]. Additionally, patient age was related to the effi- (version 3.1.9.2). cacy of enoxaparin in Phase III clinical trials (Trial Continuous variables are expressed as mean ± stand- number: EFC10094, PK568, and PK567). However, it is ard deviation or median (range). The normality of data unclear which factors are associated with the effective- were assessed using Shapiro-Wilk test. Univariate ana- ness and/or ADE of enoxaparin in aged patients. lyses to compare two groups were performed using Finding the predictive factors involved in the effective- Welch’s t test, Mann–Whitney U test or Fisher's exact ness and/or ADE of anticoagulant therapy in aged pa- test. Multivariate logistic regression analysis was used tients is critical to avoid severe DVT and/or ADE. We to test the outcomes from univariate analysis. Parame- conducted this study to investigate the predictive factors ters that showed a correlation (P <0.2)intheunivariate involved in the effectiveness and/or safety of enoxaparin analysis were included in the multivariate analysis. Lo- for TKA in aged Japanese patients. gistic regression was performed using stepwise model selection according to Bayesian information criterion [15]. A receiver operating characteristic (ROC) curve Methods for the significantly affecting factor of effectiveness and Study design safety of enoxaparin was plotted. Additionally, the cut- We retrospectively analyzed the medical records of all off values were decided by Youden index. Significance patients aged 65 years or older who were administered values were set at P < 0.05 for interpretation of the final enoxaparin for TKA. Data were corrected at the Izumi multivariate logistic regression model. The statistical Regional Medical Center, from September 2009 to analyses were performed with JMP® Pro 12 (SAS Insti- March 2014. No exclusion criteria were set. tute Inc., Cary, NC, USA). The following data were collected: age, sex, height, body weight, enoxaparin dose, previous history of DVT, Results use of tourniquet, operative time, volume of bleeding Effectiveness of enoxaparin during surgery, laboratory values at postoperative day 1 A total of 128 patients were included in this study. One (POD1) as the laboratory values before enoxaparin ad- hundred five (82.0%) patients were classified as the ef- ministration, complications (hypertension, diabetes, fective group. The characteristics of the effective and dyslipidemia, chronic heart failure, cerebral vascular ineffective groups are shown in Table 1. In univariate disease), concomitant medications that may interact analysis, serum total protein level at POD1, and the with enoxaparin (non-steroidal anti-inflammatory number of patients who used a tourniquet were signifi- drugs, low dose aspirin, clopidogrel, ticlopidine, cilosta- cantly different between two groups. We evaluated the zol, limaprost alfadex, warfarin, raloxifene). incidence rate of ADE in the efficacy and ineffective Sonoda et al. Journal of Pharmaceutical Health Care and Sciences (2017) 3:6 Page 3 of 8 Table 1 Characteristics of patients classified according to Table 1 Characteristics of patients classified according to effectiveness of enoxaparin effectiveness of enoxaparin (Continued) Effective Ineffective P value Ticlopidine 1 (0.95) 1 (4.35) 0.33 Case, no. (%) 105 (82.0) 23 (18.0) - Cilostazol 1 (0.95) 1 (4.35) 0.33 a Age (years) 77.2 ± 5.11 79.0 ± 4.51 0.10 Limaprost alfadex 5 (4.76) 3 (13.0) 0.15 Sex, no. (%) Warfarin 6 (5.71) 1 (4.35) 1.00 male 25 (23.8) 3 (13.0) 0.40 Raloxifene 4 (3.81) 2 (8.70) 0.29 female 80 (76.2) 20 (87.0) aData are expressed as mean ± SD, bData are expressed as median (range) SE indicates standard error, POD1 post-operative day 1, BUN blood urea nitrogen, Height (cm)b 150 (135–176) 145 (140–165) 0.08 AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate Body weight (kg)b 57 (38–91) 51 (39–69) 0.11 dehydrogenase,