681148 research-article2016 INQXXX10.1177/0046958016681148INQUIRY: The Journal of Health Care Organization, Provision, and FinancingWu et al Healthcare in the National Health Insurance System in Taiwan Long-Term Therapy With Wu-Ling-San, a Popular Antilithic Chinese Herbal Formula, Did Not Prevent Subsequent Stone Surgery: A Nationwide Population-Based Cohort Study INQUIRY: The Journal of Health Care Organization, Provision, and Financing Volume 53: 1–7 © The Author(s) 2016 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0046958016681148 inq.sagepub.com San-Yuan Wu, MD, PhD1, Huey-Yi Chen, MD, PhD1, Kao-Sung Tsai, MD, PhD1,2, Jen-Huai Chiang, MS1, Chih-Hsin Muo, MS1, Fung-Chang Sung, PhD1, Yung-Hsiang Chen, PhD1,3, and Wen-Chi Chen, MD, PhD1 Abstract Traditional Chinese herbal medicine (CHM), which is widely used to treat pain and urolithiasis, is a promising therapy for urinary stone prevention This study investigated the clinical efficacy of a popular CHM, Wu-Ling-San (WLS), in Taiwan for the prophylaxis of recurrent nephrolithiasis as assessed by surgical stone treatment via a nationwide population-based cohort study The National Health Insurance Research Database, 2000–2010, which included one million patient records All patients diagnosed with stone disease at the beginning of the study The matched controls (4-fold the number of WLS patients) were stone patients who did not take WLS Data analysis included the stone surgeries following the first treatment We enrolled 11 900 patients with stone disease, and the incidence of stone patients in this database was 1.19% The prevalence of comorbidities such as benign prostate hyperplasia, chronic kidney disease, diabetes mellitus, and urinary tract infection, but not hypertension, was significantly higher in WLS users Several patients in both groups were prescribed potassium citrate The stone treatment rate was significantly higher in WLS users (17.85%) than in the non-WLS users (14.47%) WLS users with an associated comorbidity had a higher treatment rate than the non-WLS users: 21.05% versus 16.70%, respectively The surgery rate for upper urinary tract stones was higher in WLS users than in the non-WLS users (adjusted hazard ratio, 1.28; 95% confidence interval, 1.08-1.52; P < 05) The stone treatment rate (52.79%) was significantly higher in patients who used a very high amount of WLS (adjusted hazard ratio, 3.02; 95% confidence interval, 2.30-3.98) Stone patients using a high amount of WLS use had a high stone surgical rate Long-term therapy with WLS did not have a preventive effect on stone surgical treatment Long-term potassium citrate therapy as a preventive measure appeared to be underutilized in this study Keywords complementary and alternative medicine, urolithiasis, Chinese herbal formula, population-based study, National Health Insurance Research Database Introduction Many complementary and alternative medicine (CAM) practices have emphasized health promotion; however, this has not been the focus of the bulk of CAM research.1,2 CAM practitioners could be seen as a public health resource to increase the population’s access to certain clinical preventive services.3-6 Urolithiasis is a common condition for which the prevalence varies according to sex and age.7-9 In the US population, the reported prevalence of a history of kidney stones is 10.6% in men and 7.1% in women.10,11 The overall prevalence has increased from 3.8% to 8.8% (in past three decades).10-12 Epidemiologically, urinary stone disease accounted for 9.6% of the total population of Taiwan in 2001.13 Furthermore, this condition accounted for a high proportion of medical visits, with an overall age-adjusted prevalence of 7.35% (5.77% in women and 8.97% in men) in 2010 Huang et al14 reported the China Medical University, Taichung, Taiwan Hungkuang University, Taichung, Taiwan Asia University, Taichung, Taiwan Received 30 August 2016; revised 16 October 2016; revised manuscript accepted 22 October 2016 Corresponding Author: Wen-Chi Chen, China Medical University, No 91, Hsueh-Shih Road, Taichung 40402, Taiwan Emails: wgchen@mail.cmu.edu.tw Creative Commons Non Commercial CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage) 2 INQUIRY Table 1. ICD-9 Codes for Stone Surgeries Codes 55.0 Nephrotomy and nephrostomy 56.0 57.0 58.0 98.51 Surgery 55.01 Nephrotomy 55.02 Nephrostomy 55.03 Percutaneous nephrostomy without fragmentation 55.04 Percutaneous nephrostomy with fragmentation 55.21 Nephroscopy Transurethral removal of obstruction from ureter and renal pelvis 56.3 Ureteroscopy Transurethral clearance of bladder Urethrotomy Extracorporeal shockwave lithotripsy of the kidney, ureter, and/or bladder Source 2014 ICD-9-CM Note ICD-9 = International Classification of Diseases, Ninth Revision overall recurrence rate (a new episode within a 180-day interval) at and years as 6.12% and 34.71%, respectively Uribarri et al15 reported a similar recurrence rate of 35% within years Therefore, medical treatments such as potassium citrate are provided to prevent the recurrence of urinary stones.16 Traditional Chinese herbal medicine (CHM) is widely accepted by Taiwanese and Chinese societies and elsewhere.17 In a previous laboratory and clinical study, we reported the effects of the Wu-Ling-San (WLS) formula on the prevention of recurrent calcium oxalate nephrolithiasis The WLS formula effectively inhibited the process of calcium oxalate nucleation, crystallization, and aggregation in vitro and in vivo In a small short-term randomized control trial, WLS increased urine output without serious adverse effects in comparison with a control group.18-20 However, long-term clinical experience with WLS use as a preventive formula is lacking.21 The effectiveness of WLS should be further confirmed in a large population in a long-term clinical study Recently, a nationwide population-based study that enrolled a large population of patients was conducted in Taiwan for stone disease, and this study enabled us to perform a survey to investigate the clinical usage of the WLS formula to prevent recurrent stone as assessed by stone surgery in Taiwan.14 By utilizing these nationwide data, we were able to elucidate the clinical effect of the WLS formula in the prevention of stone recurrence Methods Database Claimed data from the National Health Insurance Research Database (NHIRD) were used in this study The data were obtained from the health care information of > 96% of all medical claims in Taiwan since 1996 The medical services provided by the NHI program included both Western and traditional medicine as well as outpatient care, inpatient care, physical therapy, dental services, prescription drugs, medical institution services, and registration files with scrambled identifications Representative data between 2000 and 2010 were randomly obtained from the claims dataset of a sample of million enrolled from the entire insured population in the NHI program base (Database, LHID2000) The diagnosis codes from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) were used in the database The NHIRD was previously described in detail.22 This study was approved by the Institutional Review Board of China Medical University (CMUH104-REC2-115), Taiwan Study Sample For the study cohort, we selected patients newly diagnosed with a urinary tract stone (ICD-9-CM codes 592 and 59 993) between January 1, 2000, and December 31, 2010 Patients who were aged ≤ 20 years (n = 1391), received WLS before the renal stone (n = 3046), had a history of malignancy (986, ICD-9-CM 140-208), or had undergone surgery (n = 15 158) were excluded In this case-control study, the case group patients received WLS and the treatment date was defined as the index date In the control group, controls each are frequency matched with each individual case patient according to age (every years), gender, study-year, and index-year Finally, we identified a total of 11 900 patients with stone disease Patients who took WLS were further divided into low (