determinants of persistence with bisphosphonate A Study in Women with Postmenopausal Osteoporosis

Transcription

1 Clinical Therapeutics/Volume 28, Number 2, 2006 Determinants of Persistence with Bisphosphonates: A Study in Women with Postmenopausal Osteoporosis FernieJ.A. Penning-van Beest, PhD1; Wim G. Goettsch, PhD1;Jo/~lle A. Erkens, PhD1; and Ron M.C. Herings, PhD 1,2 1PHARMO Institute, Utrecht, The Netherlands; and 2Department of Pharmaco-epidemiology and Pharmacotherap.y, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands ABSTRACT Background: Although bisphosphonates are useful in the management of osteoporosis, patients often discontinue treatment. Objectives: The aims of this study were to investigate persistence with bisphosphonates, and to assess whether the dose interval influenced persistence, among women with postmenopausal osteoporosis. Methods: Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, drug-dispensing records from community pharmacies linked to hospital discharge records of >1 million subjects in defined areas in The Netherlands. Women who were new users of alendronate (daily or weekly), etidronate (daily), or risedronate (daily) during the period from January 2000 through September 2003 were eligible for inclusion in the study if they were aged >55 years or had been hospitalized for a menopausal disorder. One-year rates of persistence with treatment (defined as the percentage of patients who used the drug for >365 days without failure to continue renewals) were determined by using episodes of bisphosphonate treatment. The association between persistence and dose intervals, type of bisphosphonate, and other determinants (including age, occurrence of gastrointestinal adverse events as measured by use of concomitant medications [eg, antacids, proton pump inhibitors, histamine 2 (H2)-receptor antagonists, misoprostol, laxatives, antidiarrheals, bowel motility enhancers] and fractures) was assessed. To study whether persistence with bisphosphonates was associated with the former use of other antiosteoporosis medication or the presence of drug-induced osteoporosis, the use of hormone replacement therapy, raloxifene, and systemic corticosteroids in the 6 months before the index date were included as determinants. Results: The study sample included 2124 women who were new users of bisphosphonates. The mean (SD) age of the study population was 71.6 (8.7) years. After 1 year, 51.9 % of weekly alendronate users and 30.1% to 42.2% of daily bisphosphonate users were persistent. In the multivariate analysis (which included age, concomitant medication, and fractures), patients using alendronate weekly were significantly more likely to persist than those using alendronate daily (relative risk [RR], 1.56 [95% CI, ]). The likelihood of persistence was similar among those who used the daily regimens of risedronate, etidronate, and alendronate. The occurrence of gastrointestinal adverse events was associated with decreased persistence with bisphosphonates (H2-receptor antagonists: RR, 0.71 [95% CI, ]; bowel motility enhancers: RR, 0.78 [95% CI, ]). Conclusions: In this study, dose interval and the occurrence of gastrointestinal adverse events were independent determinants of persistence with bisphosphonate therapy. Although the likelihood of persistence with bisphosphonate use was significantly higher among those who used a less frequently administered regimen, persistence rates were still suboptimal. (Clin Ther. 2006;28: ) Copyright Excerpta Medica, Inc. Key words: bisphosphonates, dose regimen, gastrointestinal side effects, osteoporosis, persistence, postmenopausal. This workwas presented in part at the International Society for Pharmacoeconomics and Outcomes Research 7th Annual European Congress, October 24-26, 2004, Hamburg, Germany, and Osteologie 2005, March 3-5, 2005, Basel, Switzerland. Accepted for publication December 21, Express Track online publication January 19, doi:l /].clinthera /06/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright Excerpta Medica, Inc. 236 Volume 28 Number 2

2 F.J.A. Penning-van Beest et al. INTRODUCTION Osteoporosis is a systemic condition characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and, consequently, an increased fracture risk. 1 Bone mass declines and the risk of fractures increases with age, especially after menopause. Osteoporosis has clinical and public health importance because osteoporotic fractures are one of the most common causes of disability and an important contributor to medical costs in many regions of the world. 2 Because low bone mass is a major risk factor for fractures, the treatment of osteoporosis focuses on the prevention of bone loss or even increasing bone mass. 1 Bisphosphonates are potent inhibitors of the osteoclast-mediated resorption of bone and, thus, useful for increasing bone mass. 3 Long-term adherence to bisphosphonates is required to realize the full benefits of treatment. 3,4 Recently, a poor 1-year persistence rate with bisphosphonates (24%) was observed in a study by McCombs et al. 5 Several possible reasons for discontinuation of bisphosphonate treatment exist. First, the regimen required to minimize the risk of esophageal irritation and maximize bioavailability is quite stringent. Second, drug-related gastrointestinal adverse events (AEs) such as dysphagia, esophagitis, gastric ulcer, and duodenal ulcer can be problematic. 6 Third, because osteoporosis is often asymptomatic in early stages, and because treatment benefits such as reduced fracture risk are not experienced by the individual patient, motivation to continue treatment may be low. Persistence with bisphosphonate use may be higher when medication can be administered less frequently. In 2 crossover studies, >80% of postmenopausal women taking bisphosphonates preferred once-weekly administration to once-daily administration. 7,8 The aims of this study were to investigate persistence with bisphosphonates and to assess whether the dose interval influenced persistence, among women with postmenopausal osteoporosis. PATIENTS AND METHODS Setting Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, the drug-dispensing records from community pharmacies (including information on over-the-counter drugs) linked to hospital discharge records of >1 million anonymous community-dwelling inhabitants of 33 medium-sized areas in The Netherlands. The individuals included in the PHARMO database are representative of the whole country in terms of age, sex, and geographic distribution. The computerized drugdispensing histories contain complete data concerning the dispensed drug, type of prescriber, dispensing date, dispensed amount, prescribed dose regimen, and duration of use (prescription length). Drug names are coded according to the anatomical-therapeutic-chemical classification. The hospital records include detailed information concerning the primary and secondary diagnoses, procedures, and dates of hospital admission and discharge. All diagnoses are coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). 9 For a detailed description of the database, we refer to earlier work. 1~ Patient Sample The source population included all new users (incident users) of bisphosphonates in The Netherlands in the period from January 2000 to September These new patients had not been dispensed any bisphosphonates for >6 months before their first prescription (index date). Women who met the following criteria were eligible: new use of alendronate daily 10 mg or weekly 70 mg (the weekly formulation was introduced in 2001), etidronate daily 400 mg, or risedronate daily 5 mg; age >55 years; and registration in the PHARMO database for _>6 months before and 15 months after the index date. (These medications were selected because they were indicated for the prevention or treatment of postmenopausal osteoporosis.) In addition, women were eligible if they were aged <55 years but had been hospitalized for a defined menopausal disorder during the period from 1991 to the index date (ICD-9-CM diagnosis codes , 256.2, , and V49.81 or classification of performances code 565.4). Risedronate weekly was not included because this drug was introduced to the Dutch market in the first month of 2003; therefore, new users of risedronate weekly would not have met the inclusion criteria. Patients were divided into 4 groups based on their initial prescription: alendronate daily, alendronate weekly, risedronate daily, or etidronate daily. For all patients, the prescriber of the first prescription and the presence of a fracture in the 6 months before the index date (ICD-9-CM codes 733.1, , ) were determined. February

3 Clinical Therapeutics Persistence One-year rates of persistence with treatment (defined as the percentage of patients who used the drug for >365 days without failure to continue renewals) were assessed using episodes of bisphosphonate treatment based on the method established by Catalan and LeLorier. 11 In general, a treatment episode is defined as a period of time in which a continuous specific pharmacotherapeutic treatment takes place. To establish bisphosphonate treatment episodes, the duration of use of each dispensed prescription was calculated by dividing the number of units dispensed by the number of units to be used per day, as defined in the pharmacies. If the gap between the end of 1 prescription and the start of the next prescription was <30 days, the treatment was considered to be uninterrupted. The treatment episode was measured as the time span between the start of the first prescription and the end of the final prescription. The latter was set at half the duration of time after the last date that the drug was dispensed, with the assumption that patients stopped their medication sometime after filling the last prescription. Persistence with the initial bisphosphonate was defined as the number of days from the start of the index dispensation (index date) to the time of first failure to continue renewals of the initial bisphosphonate (ie, the duration of the first episode). Persistence with any bisphosphonate was defined as the number of days from the index date to the time of first failure to continue renewals of any bisphosphonate. Determinants of Persistence The dose interval and type of bisphosphonate were the main determinants of persistence in this study. The association between persistence and gastrointestinal AEs due to bisphosphonate intake (measured by the new use of antacids, proton pump inhibitors [PPIs], histamine 2 (H2)-receptor antagonists, misoprostol, laxatives, antidiarrheals, and bowel motility enhancers in the year after the index date) was also investigated. The new use of antacids, PPIs, H2-receptor antagonists, and misoprostol at the index date was studied because these drugs may have been concomitantly prescribed to prevent gastrointestinal AEs due to bisphosphonate intake, which may affect persistence. To study whether persistence with bisphosphonates was associated with the former use of other antiosteoporosis medication or the presence of drug-induced osteoporosis, the use of hormone replacement therapy, raloxi- fene, and systemic corticosteroids in the 6 months before the index date were included as determinants. Similarly, patient age and the occurrence of fractures in the 6 months before and the year after the index date were considered. Finally, the use of NSAIDs, antacids, PPls, H2-receptor antagonists, and misoprostol in the 6 months before the index date was included as determinant, because the potential for gastric damage by bisphosphonates has been found to increase with the use of NSAIDs and with increased ph. 12 Data Analysis The rates of persistence with any bisphosphonate and with the initial bisphosphonate at 365 days were determined. Persistence with the initial bisphosphonate was also presented in Kaplan-Meier curves for 1 year for the different bisphosphonates. Univariate and multivariate Cox proportional hazard analyses were conducted to identify the association of dose interval and other determinants with persistence with the initial bisphosphonate. Statistical significance was defined at an 0~ level of All statistical analyses were performed using SAS software, version 8.2 (SAS Institute Inc., Cary, North Carolina). RES U LTS The inclusion criteria of this study were met by 2124 women who were new users of bisphosphonates. The mean (SD) age of the study population was 71.6 (8.7) years (Table I). The first prescription of bisphosphonates was usually obtained from a general practitioner (65.3% [n = 1386]). The majority of patients (97.8% [n = 2078]) had no fractures in the 6 months before the index date. Of the 2124 patients, 911 (42.9%) had continuously used any bisphosphonate for >365 days and 775 (36.5%) had continuously used the initially prescribed bisphosphonate regimen (alendronate daily, alendronate weekly, etidronate daily, or risedronate daily) for >365 days (P < 0.001). The figure shows 1-year persistence with initial bisphosphonates. Persistence with etidronate declined noticeably at 90 days; etidronate is dispensed in 90-day combination packages, including 14 tablets of etidronate and 76 tablets of calcium carbonate. Persistence with the other bisphosphonates decreased gradually over time. At 365 days, 51.9% (176/339) of the users of alendronate weekly and 30.1% (204/678, etidronate) to 42.2% (68/161, risedronate) of the users of daily bisphosphonates were persistent. 238 Volume 28 Number 2

4 F.J.A. Penning-van Beest et al. Table I. General characteristics of women aged >SS years (or with a hospitalization for a menopausal disorder) who were new users of bisphosphonates in The Netherlands from January 2000 to September 2003 (N = 2124). Characteristic Value Age, mean (SD), y 71.6 (8.7) Age group, no. (%) <55 y 5 (0.2) y 229 (10.8) y 282 (13.3) y 307 (14.5) y 441 (20.8) >74 y 860 (40.5) Initial bisphosphonate, no. (%) Alendronate daily 946 (44.5) Alendronate weekly 339 (16.0) Risedronate daily 161 (7.6) Etidronate daily 678 (31.9) Prescriber of first prescription, no. (%) General practitioner 1386 (65.3) Internist 327 (15.4) Rheumatologist 183 (8.6) Other specialist 178 (8.4) Other physician 50 (2.4) Fracture in the 6 months before index date, no. (%) 46 (2.2) The associations between persistence with the initial bisphosphonate and dose interval, type of bisphosphonate, age, fractures, and concomitant medication are shown in Table II. In the multivariate analysis (which included age and concomitant medication, as well as other variables), patients using alendronate weekly were significantly more likely to persist using the initially prescribed bisphosphonate than patients using alendronate daily (relative risk [RR], 1.56 [95% CI, ]). The likelihood of persistence was similar among those who used the daily regimens of risedronate, etidronate, and alendronate. The occurrence of gastrointestinal AEs (measured by the new use of antacids, PPls, and other agents) during the year after the index date was associated with decreased persistence with bisphosphonates (H2-receptor antagonists: RR, 0.71 [95% CI, ]; bowel motility enhancers: RR, 0.78 [95% CI, ]). Older patients were more likely to persist with therapy (aged years: RR, 1.30 [95% CI, ]; aged years: RR, 1.30 [95% CI, ]). Those who used NSAIDs during the 6 months before beginning bisphosphonate therapy were also more likely to persist (RR, 1.16 [95% CI, ). DISCUSSION In this study, dose interval and the occurrence of gastrointestinal AEs were independent determinants of persistence with bisphosphonates. Although patients whose medication regimens required less frequent administration were more persistent when compared with patients whose regimens required daily administration, persistence rates were still suboptimal. There are several limitations to this study. Persistence with treatment was based on dispensing data and determined by using episodes of bisphosphonate treatment. A limitation of dispensing data is that it is unknown whether a patient actually took the dispensed drug. However, it seems likely that patients who obtain prescription refills do take their medication. As noted in "Patients and Methods," the end of the final prescription was set at half the prescription duration time after the final dispensing date, with the assumption that patients stopped taking their medication sometime after filling the final prescription. Consequently, persistence may have been underestimated. However, we expect that this underestimation was only slight, and that even if a different date had been used for the end of the final prescription, the results still would have reflected suboptimal persistence. Another limitation of the approach used in this study is that the incidence of gastrointestinal AEs was based solely on data regarding the use of antacids, PPls, H2-receptor antagonists, misoprostol, laxatives, antidiarrheals, and bowel motility enhancers. These data may not be an accurate estimate of the use of all therapies for gastrointestinal AEs. Moreover, gastrointestinal symptoms requiring the use of these drugs may have been the result of causes other than bisphosphonate use. At 12 months, persistence with the initial bisphosphonate was 36.5%; persistence with any bisphosphonate was 42.9%. In a study by McCombs et al, 5 1-year persistence with bisphosphonates was only 24%. The stringency of the prescribed regimen and the occurrence of gastrointestinal AEs are possible reasons for February

5 Clinical Therapeutics Alendronate daily --- Alendronate weekly... Etidronate daily... Risedronate daily _,d., v G3 60- G3 el_ I I I I I I I I Time (d) Figure. Kaplan-Meier survival curves of the use of initial bisphosphonate for 1 year among women aged _>55 years (or with a hospitalization for a menopausal disorder) who were new users of bisphosphonates in The Netherlands from January 2000 to September 2003 (N = 2124). discontinuation of bisphosphonate treatment. Furthermore, due to the silent nature of osteoporosis, patients' motivation to continue bisphosphonate treatment may be low. Long-term adherence to bisphosphonates is required to realize the full benefits of this treatment. 3,4 Future research should quantify the relationship between compliance and persistence with bisphosphonates and the risk for osteoporotic fractures. Persistence with alendronate was significantly higher with a longer dose interval (ie, weekly vs daily administration). It seems reasonable to assume that a less frequently administered regimen would be more convenient to patients, and therefore be easier to sustain. Participants in 2 crossover studies on preference for weekly or daily administration also concluded that the once-weekly regimen was more convenient and would be likely to improve long-term compliance. 7,8 However, medication regimens that call for less frequent administration may also be less tolerant of a single missed dose, because each dose constitutes a larger percentage of the total treatment. The occurrence of gastrointestinal AEs (as measured by the new use of antacids, PPIs, H2-receptor antagonists, misoprostol, laxatives, antidiarrheals, and bowel motility enhancers) was also associated with lower persistence with bisphosphonates. This supports reports from the literature of gastrointestinal AEs as a reason for discontinuation of bisphosphonate treatment.]3, u Concomitant prescriptions for drugs for acid-related disorders at the index date to prevent gastrointestinal AEs were not significantly associated with persistence. However, this analysis was based on a small number of patients. The influence of gastrointestinal AEs on persistence could be expected to differ between alendronate, rised- 240 Volume 28 Number 2

6 F.J.A. Penning-van Beest et al. Table II. Determinants of persistence with the initially prescribed bisphosphonate among women aged _>55 years (or with a hospitalization for a menopausal disorder) who were new users of bisphosphonates in The Netherlands from January 2000 to September 2003 (N = 2124). All Subjects, Persistent Subjects, Determinant No. No. (%) Total (36.5) Initial bisphosphonate prescribed Alendronate daily (34.6) Alendronate weekly (51.9) Risedronate daily (42.2) Etidronate daily (30.1) Age group <55 y 5 1 (20.0) y (31.0) y (37.2) y (39.4) y (39.9) >74 y (35.0) Characteristics in the 6 months before index date NSAID use (38.5) Corticosteroid use (34.9) PPI use (34.0) HRT use (37.7) H2-receptor antagonist use (39.0) Antacid use (34.4) Fracture (34.8) Raloxifene use 17 5 (29.4) Misoprostol use 0 Characteristics at the index dater PPI use (31.8) H2-receptor antagonist use 11 4 (36.4) Antacid use 5 3 (60.0) Misoprostol use 0 Characteristics in the year after the index dater Laxative use (31.7) PPI use (28.4) Bowel motility enhancer use (23.7) Antidiarrheal use (32.9) H2-receptor antagonist use (23.5) Antacid use 37 7 (18.9) Misoprostol use 0 Relative Risk (95% CI) U nivariate M ultivariate ~ ( ) 1.56 ( ) 1.16 ( ) 1.15 ( ) 0.99 ( ) 0.99 ( ) 0.76 ( ) 0.71 ( ) ( ) 1.19 ( ) 1.27( ) 1.30( ) 1.28 ( ) 1.30 ( ) 1.10 ( ) 1.16 ( ) 1.14 ( ) 0.93 ( ) 0.91 ( ) 0.99 ( ) 1.04 ( ) 0.97( ) 0.92 ( ) 0.85 ( ) 0.87 ( ) 1.19 ( ) 1.92 ( ) 0.84 ( ) 0.83 ( ) 0.70 ( ) 0.84 ( ) 0.68 ( ) 0.63 ( ) 1.16 ( ) 0.94 ( ) 0.90 ( ) 0.88 ( ) 0.86 ( ) 0.78 ( ) 0.89 ( ) 0.71 ( ) 0.77 ( ) PPI = proton pump inhibitor; HRT = hormone replacement therapy; H 2 = histamine 2. *The following items were included in the model: initial bisphosphonate; age group; use ofnsaids, corticosteroids, or PPIs before the index date; and use of antacids, PPIs, H2-receptor antagonists, laxatives, antidiarrheals, or bowel motility enhancers after the index date. fthe drugs had not been prescribed in the 6 months before the index date. tthe drugs had not been prescribed in the 6 months before or at the index date. February

7 Clinical Therapeutics ronate, and etidronate. Etidronate is only administered for 2 weeks every 3 months, with patients receiving calcium during the intervening periods. However, it was beyond the scope of this study to investigate the determinants of persistence for the individual bisphosphonates. Adjusting for gastrointestinal AEs did not substantially affect the association between dose interval and persistence. Thus, the association found between increased persistence and less frequent administration cannot completely be explained by the occurrence of fewer gastrointestinal AEs. CONCLUSIONS In this study, dose interval and the occurrence of gastrointestinal AEs were independent determinants of persistence with bisphosphonate therapy. Although the likelihood of persistence with bisphosphonate use was significantly higher among those who used a less frequently administered regimen (ie, weekly vs daily), persistence rates were still suboptimal. ACKNOWLEDGM ENTS This study was supported by an unrestricted grant from E Hoffmann-La Roche Ltd., Basel, Switzerland, and GlaxoSmithKline, Philadelphia, Pennsylvania. The authors acknowledge the critical review of the study proposal and/or manuscript by Ansgar Hebborn, Ramzi Mrad, and Annette B. Beiderbeck of E Hoffmann- La Roche, Ltd.; and Niall Lynch and Mayur Amonkar of GlaxoSmithKline. REFERENCES 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy.jama ;285: Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359: McClung MR. Bisphosphonates in osteoporosis: Recent clinical experience. Expert Opin Pharmacother. 2000;1: Bone HG, Hosking D, Devogelaer JP, et al, for the Alendronate Phase III Osteoporosis Treatment Study Group. Ten years' experience with alendronate for osteoporosis in postrnenopausal women. N EnglJ Med. 2004; 350:1189-I McCornbs JS, Thiebaud P, McLaughlin-Miley C, Shi J. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas. 2004;48: Baker DE. Alendronate and risedronate: What you need to know about their upper gastrointestinal tract toxicity. Rev Gastroenterol Disord. 2002;2: Simon JA, Lewiecki EM, Smith ME, et al. Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10 mg: A multicenter, randomized, openlabel, crossover study. Clin Ther. 2002;24: Kendler D, Kung AW, Fuleihan Gel-H, et al. Patients with osteoporosis prefer once weekly to once daily dosing with alendronate. Maturitas. 2004;48: International Classification of Diseases, Ninth Revision, Clinical Modification. 6th ed. Washington, DC: US Dept of Health and Human Services, Centers for Disease Control and Prevention, Centers for Medicare and Medicaid Services; Herings RM. PHARMO: A Record Linkage System for Postmarketing Surveillance of Prescription Drugs in The Netherlands [dissertation]. Utrecht, The Netherlands: Utrecht University, Department of Pharmaco-epidemiology and Pharmacotherapy; I. Catalan VS, LeLorierJ. Predictors of long-term persistence on statins in a subsidized clinical population. Value Health. 2000;3: Graham DY. What the gastroenterologist should know about the gastrointestinal safety profiles of bisphosphonates. Dig Dis Sci. 2002;47:1665-I Turbi C, Herrero-Beaumont G, Acebes JC, et al. Compliance and satisfaction with raloxifene versus alendronate for the treatment ofpostmenopausal osteoporosis in clinical practice: An open-label, prospective, non-randomized, observational study. Clin Tker. 2004;26: Segal E, Tamir A, Ish-Shalom S. Compliance of osteoporotic patients with different treatment regimens. IsrMed AssocJ. 2003;5: Address correspondence to: EJ.A. Penning-van Beest, PhD, PHARMO Institute, PO Box 85222, 3508 AE Utrecht, The Netherlands. E-maih fernie. penning@pharmo.nl 242 Volume 28 Number 2