A PHARMACOECONOMIC EVALUATION OF BISPHOSPHONATES IN THE MANAGEMENT OF POSTMENOPAUSAL OSTEOPOROSIS IN SINGAPORE HING WEE CHUAN BSc(Pharm), NUS A THESIS SUBMITTED FOR THE DEGREE OF MASTERS OF SCIENCE (PHARMACY) DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2003 ACKNOWLEDGEMENTS First and foremost, I would like to express my deepest thanks to Asst Prof Li Shu Chuen, my supervisor, who has offered his unreserved guidance, support, insight and encouragement. Many thanks to all others who have in one way or another contributed their invaluable time and assistance in the course of my work: Dr Chan Yiong Huak, Head of Biostatistics, Clinical Trials & Epidemiology Unit A/Prof Tay Boon Lin, Head of Menopause Unit, KK Hospital Dr Ong Chiou Li, Head of Diagnostic Imaging, KK Hospital Ms Tan Ai Lee, Chief Pharmacist, KK Hospital Ms Lim Peng Hoon, Dept of Diagnostic Imaging, KK Hospital Ms Peggy Fong, Medical Librarian, KK Hospital Mr Chung Hing Ip, Head of Research Administration Unit, KK Hospital Ms Lim Siew Mei, Drug Information Pharmacist, National University Hospital Ms Christine Teng, Drug Information Pharmacist, Tan Tock Seng Hospital Ms Lee Yean Hoon, Medical Affairs Executive, KK Hospital Ms Shirley Farquhar, Customer Service, OVID Technologies, Inc. Sydney Last but not least, my deepest gratitude to my family and all my colleagues for their understanding, encouragement and support. i TABLE OF CONTENTS CHAPTHER ONE : INTRODUCTION - IMPACT OF OSTEOPOROSIS 1.1 Introduction to Osteoporosis 1.2 Incidence of osteoporosis in Singapore 1.3 Clinical impact of osteoporotic fractures 1.4 Financial impact of postmenopausal osteoporotic fractures in Singapore CHAPTHER TWO : MANAGEMENT OF OSTEOPOROSIS - ROLE OF BISPHOSPHONATES 2.1 Overview of agents for osteoporosis 2.2 Pharmacological agents for osteoporosis in KK Hospital 10 2.3 Pre-study review of alendronate usage in KK Hospital 12 2.4 Clinical guidelines on osteoporosis 16 2.5 Economic considerations of bisphosphonates 18 CHAPTHER THREE : OBJECTIVES 20 3.1 Primary objective 20 3.2 Secondary objective 20 CHAPTHER FOUR : METHODOLOGY 21 4.1 Summary 21 4.2 Literature search and retrieval 23 4.3 Criteria 4.3.1 Inclusion criteria 4.3.2 Exclusion criteria 26 26 27 4.4 Initial evaluation of literature 29 4.5 Assessing quality of studies 30 4.6 Efficacy and safety variables 32 4.7 Pooling of efficacy data 34 4.8 Pooling of safety data 37 4.9 Prevention of data error 38 4.10 Pharmacoeconomic analysis 39 CHAPTHER FIVE : RESULTS 40 5.1 40 40 45 49 Efficacy - Results from Meta-analysis 5.1.1 Literature retrieved for efficacy data 5.1.2 Characteristics of efficacy studies 5.1.3 Quality of efficacy studies ii 5.1.4 5.1.5 5.1.6 Efficacy tables Pooled efficacy results from meta-analyses Analyses of heterogeniety of results of meta-analyses 53 71 74 5.2 Correlation between relative risk of fracture and BMD 83 5.3 Gastrointestinal Side Effects - Results from Meta-analysis 5.3.1 Literature retrieved on gastrointestinal side effects 5.3.2 Tables of gastrointestinal side effects 5.3.3 Pooled results of gastrointestinal side effects data 91 91 94 96 5.4 Pharmacoeconomic analyses 5.4.1 Preliminary calculations on costs 5.4.2 Cost effectiveness of bisphosphonates 5.4.3 Monte Carlo simulation of cost-effectiveness model 5.4.4 Building a decision analytic model 5.4.5 Derivation of costs for a decision analytic model 5.4.6 Results from the decision analytic model 98 98 100 104 108 111 114 CHAPTHER SIX : DISCUSSION 121 6.1 121 Discussion CHAPTHER SEVEN : CONCLUSION 128 7.1 128 Conclusion APPENDICES 130 APPENDIX ONE 130 APPENDIX TWO 133 APPENDIX THREE 141 APPENDIX FOUR 143 APPENDIX FIVE 144 APPENDIX SIX 148 APPENDIX SEVEN 159 APPENDIX EIGHT 162 APPENDIX NINE 164 REFERENCES 168 iii LIST OF TABLES Table Description Table 1.1 : Direct costs of hip fractures based on total costs before government subsidy Table 1.2 : Direct costs of vertebral fractures based on total costs before government subsidy Table 1.3 : Breakdown of number of Singapore women by age range Table 1.4 : Costs of Fractures in the population in different age range Table 2.1 : Expenditure of drugs for osteoporosis from KK Hospital 10 Table 2.2 : Number (percentage) of patients with T-scores and Z-scores classified as normal, osteopenic or osteoporotic 13 Number (percentage) of patients on alendronate with T-scores and Z-scores classified as normal, osteopenic, or osteoporotic 14 Table 4.1 : Definition of group size, mean response and standard deviation in formulae 35 Table 5.1 : List of studies retrieved but excluded from efficacy analysis and reasons for exclusion. 42 Table 5.2 : Number of possibly relevant articles retrieved from Micromedex for each bisphosphonate 42 List of relevant articles from National Library of Medicine current bibliographies and Micromedex Drugdex with full-text retrieved 43 Table 5.4 : Sensitivity and specificity of different search strategies for MEDLINE 44 Table 5.5 : Characteristics of Included Studies on Alendronate 45 Table 5.6 : Characteristics of Included Studies on Clodronate 46 Table 5.7 : Characteristics of Included Studies on Etidronate 46 Table 5.8 : Characteristics of Included Studies on Ibandronate 47 Table 5.9 : Characteristics of Included Studies on Pamidronate 47 Table 5.10 : Characteristics of Included Studies on Risedronate 47 Table 5.11 : Characteristics of Included Studies on Tiludronate 48 Table 5.12 : Quality Score of Included Studies on Alendronate 49 Table 5.13 : Quality Score of Included Studies on Clodronate 50 Table 5.14 : Quality Score of Included Studies on Etidronate 50 Table 5.15 : Quality Score of Included Studies on Ibandronate 51 Table 2.3 : Table 5.3 : Page iv Table 5.16 : Quality Score of Included Studies on Pamidronate 51 Table 5.17 : Quality Score of Included Studies on Risedronate 51 Table 5.18 : Quality Score of Included Studies on Tiludronate 52 Table 5.19 : Number of studies available for data pooling for each bisphosphonate (All studies) 53 Table 5.20 : Number of studies available for data pooling for each bisphosphonate (all studies) 71 Table 5.21 : Percentage Change in Lumbar Vertebral BMD at Year (studies with appropriate dosing regimen) 72 Table 5.22 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen) 72 Table 5.23 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen) 72 Table 5.24 : Percentage Change in Femoral Neck BMD at Year (studies with appropriate dosing regimen) 72 Table 5.25 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen) 73 Table 5.26 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen) 73 Table 5.27 : Number of studies available for data pooling for each bisphosphonate (quality score ≥ 2) 75 Table 5.28 : Number of studies available for data pooling for each bisphosphonate (double blinded studies) 75 Table 5.29 : Number of studies available for data pooling for each bisphosphonate (Baseline femoral neck BMD < 0.7 g/cm2 or lumbar vertebral BMD < 0.8 g/cm2) 75 Table 5.30 : Percentage Change in Lumbar Vertebral BMD at Year (studies with appropriate dosing regimen and Quality Score > 2) 76 Table 5.31 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen and Quality Score > 2) 76 Table 5.32 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen and Quality Score > 2) 76 Table 5.33 : Percentage Change in Femoral Neck BMD at Year (studies with appropriate dosing regimen and Quality Score > 2) 77 Table 5.34 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen and Quality Score > 2) 77 Table 5.35 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen and Quality Score > 2) 77 v Table 5.36 : Percentage Change in Lumbar Vertebral BMD at Year (studies with appropriate dosing regimen and double blinded) 78 Table 5.37 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen and double blinded) 78 Table 5.38 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen and double blinded) 78 Table 5.39 : Percentage Change in Femoral Neck BMD at Year (studies with appropriate dosing regimen and double blinded) 79 Table 5.40 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen and double blinded) 79 Table 5.41 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen and double blinded) 79 Table 5.42 : Percentage Change in Lumbar Vertebral BMD at Year (studies with appropriate dosing regimen and Baseline Lumbar BMD < 0.8g/cm2) 80 Table 5.43 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen and Baseline Lumbar BMD < 0.8g/cm2) 80 Table 5.44 : Percentage Change in Lumbar Vertebral BMD at Years (studies with appropriate dosing regimen and Baseline Lumbar BMD < 0.8g/cm2) 80 Table 5.45 : Percentage Change in Femoral Neck BMD at Year (studies with appropriate dosing regimen and Baseline Femoral Neck BMD < 0.70g/cm2) 81 Table 5.46 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen and Baseline Femoral Neck BMD < 0.70g/cm2) 81 Table 5.47 : Percentage Change in Femoral Neck BMD at Years (studies with appropriate dosing regimen and Baseline Femoral Neck BMD < 0.70g/cm2) 81 Table 5.48 : Incidence density of Vertebral, Hip, Any Non-vertebral and Any Fractures in studies 83 Table 5.49 : Correlation coefficient of relative risk of fracture versus mean difference in percentage change in bone mineral density using an exponential model 85 Table 5.50 : Sensitivity analysis of relative risk of fracture versus mean difference in percentage change in bone mineral density using an exponential model 87 Table 5.51 : List of studies retrieved but excluded from safety analysis and reasons for exclusion 93 Table 5.52 : Incidence of Gastrointestinal Side effects in patients with Alendronate 94 Table 5.53 : Incidence of Gastrointestinal Side effects in patients with Clodronate 94 Table 5.54 : Incidence of Gastrointestinal Side effects in patients with Etidronate (* estimated from total withdrawals) 94 Table 5.55 : Incidence of Gastrointestinal Side effects in patients with Ibandronate 95 vi Table 5.56 : Incidence of Gastrointestinal Side effects in patients with Pamidronate 95 Table 5.57 : Incidence of Gastrointestinal Side effects in patients with Risedronate 95 Table 5.58 : Incidence of Gastrointestinal Side effects in patients with Tiludronate 95 Table 5.59 : Pooled incidence of all gastrointestinal adverse events 96 Table 5.60 : Pooled incidence of serious gastrointestinal side effects 96 Table 5.61 : Patient price of bisphosphonates at various institutions and retail pharmacies 98 Table 5.62 : Costs of bisphosphonate for one year 99 Table 5.63 : Incremental Cost effectiveness ratio of bisphosphonates for Lumbar BMD at year 101 Table 5.64 : Incremental Cost effectiveness ratio of bisphosphonates for Lumbar BMD at years 101 Table 5.65 : Incremental Cost effectiveness ratio of bisphosphonates for Lumbar BMD at years 101 Table 5.66 : Incremental Cost effectiveness ratio of bisphosphonates for Femoral Neck BMD at year 103 Table 5.67 : Incremental Cost effectiveness ratio of bisphosphonates for Femoral Neck BMD at years 103 Table 5.68 : Incremental Cost effectiveness ratio of bisphosphonates for Femoral Neck BMD at years 103 Table 5.69 : Total costs before government subsidy for Hip and Vertebral Fracture DRGs 111 Table 5.70 : Derivation of costs of hip fracture in a one year model 111 Table 5.71 : Derivation of costs of vertebral fracture in a one year model 111 Table 5.72 : Total costs before government subsidy for gastrointestinal side effects DRGs 112 Table 5.73 : Total costs of Intervention with Bisphosphonate, including side effects 112 Table 5.74 : Expected value of treatment with bisphosphonates in a one year decision analytic model 114 Table 5.75 : Expected value of treatment with bisphosphonates in a two year decision analytic model 114 Table 5.76 : Expected value of treatment with bisphosphonates in a two year decision analytic model with discounting 114 Table 5.77 : Expected value of treatment with bisphosphonates in a three year decision analytic model 115 Table 5.78 : Expected value of treatment with bisphosphonates in a three year decision analytic model with discounting 115 vii Table 5.79 : Expected value of treatment with bisphosphonates for geriatric women in a one year decision analytic model 117 Table 5.80 : Expected value of treatment with bisphosphonates for geriatric women in a two year decision analytic model 117 Table 5.81 : Expected value of treatment with bisphosphonates for geriatric women in a two year decision analytic model with discounting 117 Table 5.82 : Expected value of treatment with bisphosphonates for geriatric women in a three year decision analytic model 118 Table 5.83 : Expected value of treatment with bisphosphonates for geriatric women in a three year decision analytic model with discounting 118 Table 5.84 : Expected value of treatment with bisphosphonates for geriatric women in a one year decision analytic model 119 Table 5.85 : Expected value of treatment with bisphosphonates for geriatric women in a two year decision analytic model 119 Table 5.86 : Expected value of treatment with bisphosphonates for geriatric women in a two year decision analytic model with discounting 119 Table 5.87 : Expected value of treatment with bisphosphonates for geriatric women in a three year decision analytic model 119 Table 5.88 : Expected value of treatment with bisphosphonates for geriatric women in a three year decision analytic model with discounting 120 viii LIST OF FIGURES Figure Description Page Figure 2.1 : Average number of defined daily dose of alendronate used per month from Jan to Dec 2001 12 Figure 2.2 : Moving average of defined daily dose of alendronate used per month from Jan 2000 to Dec 2001 13 Figure 4.1 : Flowchart of the overview of the methodology 22 Figure 5.1 : Relative risk of Fracture versus percentage change of bone mineral density from baseline as compared to placebo 84 Figure 5.2 : Relative risk of Fracture versus percentage change of bone mineral density from baseline as compared to placebo 86 Figure 5.3 : Decision tree for cost effectiveness pharmacoeconomic model 100 Figure 5.4 : Monte Carlo simulation for cost effectiveness model 105 Figure 5.5 : Monte Carlo simulation for Cost effectiveness model with willingness to pay value of $1.00 per day 106 Figure 5.6 : Decision analytic model 108 ix 15. 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MIMs Annual. 2001. 184 [...]... osteoporosis A wide range of pharmacological agents indicated for the management of postmenopausal osteoporosis are available in Singapore Examples of such agents include the • Bisphosphonates : Alendronate, Etidronate, Risedronate • Selective estrogen receptor modulators : Raloxifene • Vitamin D analogues : alfacalcidol • Natural and synthetic hormones : Teriparatide, Nasal Calcitonin, Tibolone, estrogens and... between a Singaporean and Swedish study, and extrapolated the rate of vertebral fractures to be of a factor of 0.62 as compared to that reported in the Swedish study 28 Results from another Australian study which reported on the rate of vertebral fracture was available 29 It reported a very similar rate of vertebral fractures in women more than 55 years of age as compared to the extrapolated data from the. .. osteoporosis in women 2 1.2 Incidence of osteoporosis in Singapore There are a number of factors which may predispose an increasing proportion of women in Singapore to postmenopausal osteoporosis Firstly, Singapore sees a trend of increase in life expectancy with improved healthcare standards The Ministry of Health 2001 Annual Report estimates an average increase of 25% in life expectancy of women from... However, the guidelines available are derived from data from Caucasian populations The lower fracture rates in Asian as compared to Caucasian populations with similar BMD could affect the decision to treat and hence, the applicability of these guidelines to Asian populations 37-39 Hence, there may be a need to look at other factors that may affect clinical decision for treatment of osteoporosis in our local... interesting to note that for alendronate, only the 10mg and 70mg preparations are available in Singapore The 5mg preparation, which is approved in the United States for prevention of osteoporosis in postmenopausal women without osteoporosis, is not available and the company, MSD has no plans to bring it into Singapore in the near future 9 2.2 Pharmacological agents for osteoporosis in KK Hospital In KK Women’s... such as the correlation between age of patients and rate of fractures in the Asian population With this analysis, if a unique set of guidelines may be established, it may also be applicable for Asians living among Caucasian populations To establish guidelines, the relative efficacy of the bisphosphonates have first to be established Ideally, in order to determine the most efficacious bisphosphonate, a. .. out The subscription features an automatic selective dissemination of information (SDI), which enables automatic 23 searching of the outlined search strategy for any new citations whenever there is an update to the database and notification via email (see Appendix 3) e A search was then performed on the National Library of Medicine (NLM) Medical Literature Analysis and Retrieval System Online (MEDLINE)... comparing individual bisphosphonates with placebo for prevention of postmenopausal osteoporosis a A manual search of the last 3 years (June 1998 to June 2001) of 3 osteoporosis related journals available in the University Medical library was carried out These 3 journals have relatively high journal impact factor of above 3 53 The 3 journals were : - Osteoporosis International (via Springer Verlag website)... Results of the pooled efficacy and safety data were then applied to a cost-effectiveness analysis as well as a decision analytic model to allowing for comparison between the agents From the meta-analysis of lumbar vertebral and femoral neck BMD results, alendronate had the highest improvement in BMD at one, two and three years There were insufficient data available for tiludronate, pamidronate and ibandronate... 80.0 years) 9 This results in an increase in both the proportion of women living past menopause as well as the average number of years in which they live past menopause It has been shown that the incidence of fracture among women increases with age One study in Australia estimated the proportion of women expected to sustain a fracture to increase from 1.9% of the population under 55 years to 49.1% of women . Incidence of osteoporosis in Singapore There are a number of factors which may predispose an increasing proportion of women in Singapore to postmenopausal osteoporosis. Firstly, Singapore sees a. of follow-up. 22, 23 5 1.4 Financial impact of postmenopausal osteoporotic fractures in Singapore The financial impact of osteoporotic fractures on overall healthcare costs in Singapore. A PHARMACOECONOMIC EVALUATION OF BISPHOSPHONATES IN THE MANAGEMENT OF POSTMENOPAUSAL OSTEOPOROSIS IN SINGAPORE HING WEE CHUAN BSc(Pharm), NUS