Patients with end-stage renal disease (ESRD) have a

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1 At a Glance Original Research Practical Implications e25 Author Information e32 Web Exclusive Costs of Treatment and Clinical Events for Secondary Hyperparathyroidism Andrew Lee, PhD; Vasily Belozeroff, PhD; Xue Song, PhD; David Diakun, BS; and William Goodman, MD ABSTRACT Objectives: To assess the direct costs of treatment for, and clinical events related to, secondary hyperparathyroidism (SHPT) in US patients on chronic dialysis (CD) with commercial or Medicare supplemental insurance. Study Design: Retrospective cohort study of MarketScan claims data from January 1, 2004, to October 31, 2010, constructed from paid medical and prescription drug claims for patients with commercial and Medicare supplemental insurance. Methods: Patients aged >18 years were identifi ed using 2 CD claims at least 30 days apart and treatment with vitamin D analogues or cinacalcet to determine SHPT. We estimated costs of SHPT-related pharmacotherapies, parathyroidectomy procedures, and inpatient cost per fracture or cardiovascular (CV) hospitalization, weighted mean monthly costs during follow-up, and marginal impact of the event on monthly costs in matched case and control patients. To quantify the costs of SHPT-related events, population-attributable fraction was used. Results: A total of 41,927 CD patients were included. The annual additional healthcare cost of SHPT was $5598 per patient. Therapies accounted for 78% of total costs; CV and fracture events accounted for 19% and 3%, respectively, of total costs. Hip fracture rates were highest (11.4 per 1000 patient-years), and cost per event was the most expensive ($23,339) among all fractures. Among CV events, heart failure rates were highest (63.6 per 1000 patient-years), and peripheral vascular disease costs per hospitalization ($25,484) were the most expensive. Conclusions: High direct costs of SHPT-related clinical events refl ect an economic burden to the payer and a substantial quality-oflife burden to the affected patient. Am J Pharm Benefi ts. 2013;5(2):e24-e35 Patients with end-stage renal disease (ESRD) have a high risk of clinical complications that often lead to hospitalizations, which contributes to the overall humanistic 1,2 as well as the economic 3 burden of the illness. Secondary hyperparathyroidism (SHPT) affects the majority of ESRD patients, yet few data exist describing costs of care for SHPT. 4 In an already grievously ill population who often suffer from infections and other acute as well as chronic maladies, the clinical sequelae of SHPT include adverse effects on bone health and increased coronary artery calcification, each corresponding to a higher risk of fractures, 5,6 cardiovascular (CV) events, 7 and surgical parathyroidectomy (PTX), respectively. 5,8 Multiple risk factors for CV disease are present among those with ESRD, but these factors collectively do not account for the very high rates of CV morbidity and mortality in the dialysis population. A number of reports in the literature suggest that disturbances in bone and mineral metabolism, a risk factor unique to patients with SHPT, contribute to increased rates of CV outcomes. 9 The pathophysiology of this relationship is understood in the context of vascular calcification, whereby disturbances in mineral metabolism, (ie, elevated levels of parathyroid hormone [PTH] and particularly of phosphorus and calcium) have been linked to coronary artery calcification. 10,11 Additionally, patients with ESRD suffer an increased incidence of hip and vertebral fractures. 12,13 In a large prospective study using data from the United States Renal Data System, the risk for hip fracture in patients with stage 5 chronic kidney disease was more than 4 times higher than that in the general population. 12 Evidence from several studies based on the Dialysis Outcomes and Practice Patterns Studies (DOPPS) suggests the relationship between bone markers (PTH and alkaline phosphatase) and fracture risk. 6 In DOPPS I and II, risks of new fracture were 42% and 67% in patients with mildly and markedly increased alkaline phosphatase levels, respectively. 14 In addition to increased risk for new e24 The American Journal of Pharmacy Benefi ts March/April 2013

2 Costs of Treatment and Clinical Events fractures, altered mineral metabolism is more likely in patients with a history of fractures. The DOPPS II patients with a history of bone fracture were significantly more likely to have higher serum calcium and phosphorus levels (>10.2 mg/dl and >5.5 mg/dl, respectively) compared with patients without a previous fracture. 6 To fully characterize the economic burden of SHPT in chronic dialysis patients, it is important to understand not only the costs of treating SHPT but also the costs of managing clinical events that represent consequences of the disorder. Therapy for SHPT is generally focused on controlling or correcting the biochemical parameters of bone and mineral metabolism including the blood levels of PTH, phosphorus, and calcium. Costs for SHPT include the direct costs of pharmacotherapies and surgical PTX options. Additionally, because CV events and fractures are associated with poor control of laboratory parameters, a portion of these events and their corresponding medical costs should be included in calculating the cost of illness. 7 Our study examines the healthcare costs of treating SHPT including costs of therapies and acute and chronic costs of related events (ie, CV and fractures) among US chronic dialysis patients with commercial and Medicare supplemental insurance. METHODS This is a retrospective cohort study of the Thomson Reuters MarketScan Commercial Claims and Encounters (Commercial) Database and Medicare Supplemental and Coordination of Benefit (Medicare) Database from January 1, 2004, to October 31, Both claims databases were constructed from commercial and Medicare supplemental paid medical and prescription drug claims. Both the Medicare-covered portion of payment (represented as Coordination of Benefits Amount) and the employer-paid portion were included in the Medicare database. Patients were selected if they were at least 18 years of age and received chronic dialysis, which was identified by the presence of 2 claims for chronic dialysis at least 30 days apart (the first claim was the dialysis initiation date). In order to assess clinical event related costs, 2 cohorts were delineated: case patients who experienced fracture or CV events and control patients who did not experience these events (Figure 1). Among chronic dialysis patients, those with 2 or more claims for therapeutic doses of vitamin D analogues or any dose of cinacalcet were identified as SHPT patients. Therapeutic doses of vitamin D analogues were based on the OPTIMA clinical trial study 15 treatment algorithm and were defined as follows: intravenous PRACTICAL IMPLICATIONS The economic burden associated with management of secondary hyperparathyroidism (SHPT) in end-stage renal disease patients is evidenced by the high incremental healthcare costs, including costs of SHPT therapies and costs of treating SHPT-related clinical events. n Specifically, hip fracture and heart failure hospitalizations within this population entail high costs. n There also is a substantial quality-of-life burden to the patients over long follow-up periods. Calcitriol/Calcijex 0.5 mg or greater per treatment (1.5 mg or more per week based on administration 3 times per week); oral Calcitriol/Calcijex 0.25 mg or more per treatment (0.75 mg or more per week based on administration 3 times per week); Paricalcitol/Zemplar 2 mg or more per treatment (6 mg per week intravenously); oral Paricalcitol/ Zemplar 5 mg or more per week; Doxercalciferol/Hectorol 1 mg per treatment (3 mg per week intravenously); and oral Doxercalciferol/Hectorol 5 mg or more per week. The index date for SHPT patients was defined by the first claim observed for therapeutic doses of vitamin D analogues or any dose of cinacalcet. Demographic characteristics were measured on the index date, and clinical characteristics were measured during the 6 months before the index date. A variable length of follow-up (ending at patient death as identified from the hospital discharge records, end of continuous insurance enrollment, or October 31, 2010, whichever came first) was allowed to measure costs; however, a sensitivity analysis described data with a minimum of 6 months and 12 months of follow-up (post-index date). For direct treatment estimation among SHPT patients, the index date was defined as the first claim for therapeutic doses of a vitamin D analogue or any dose of cinacalcet, whichever came first. To minimize the confounding effects of variable disease progression on costs, we matched SHPT patients to non-shpt patients by time since dialysis initiation (defined by date of first observed dialysis claim). In order to match the patients, dialysis vintage was calculated as the time from dialysis initiation to the SHPT patient s index date. Dialysis vintages for non-shpt patients were randomly drawn from the distribution of SHPT patients dialysis vintage to define non-shpt patients index date. Direct costs for SHPT include pharmacy costs for vitamin D analogues, phosphate binders, and cinacalcet, and inpatient hospitalization costs for surgical PTX. Similarly, we matched each fracture (or CV) case patient to a fracture-free (or CV event free) control patient by Vol. 5, No. 2 The American Journal of Pharmacy Benefits e25

3 n Lee Belozeroff Song Diakun Goodman Figure 1. Diagram of Patient Samples Examined in Study I. Treatment analysis Chronic dialysis patients II. Fracture event analysis a III. CV event analysis a Chronic dialysis patients Case fracture event Matched control Chronic dialysis patients the marginal cost impact of the event holding all other covariates constant between cases and controls). The total marginal cost impact was a sum of inpatient, outpatient, pharmacy, and emergency department costs, and included both acute costs (costs associated with hospitalization) and chronic costs (follow-up costs after the event). Costs were the reimbursed amount, including patients out-of-pocket payments. All costs were adjusted to 2011 dollars using the medical component of the Consumer Price Index. Case CV event propensity score. Patients propensity scores were matched using nearest neighbor matching by a 1:1 ratio composed of sex, geographic region, age, Charlson Comorbidity Index, time since dialysis initiation, and other clinical characteristics including SHPT using a conservative caliper of 0.25 standard deviation for the propensity score. Using the case patients, we estimated the rates of fracture events including hip, vertebral, long bone (humerus, radius and ulna, tibia or fibula, other specified parts of femur, and patella), and other SHPT-related fractures (tarsal, rib, pelvic, clavicle, metacarpal, foot, and ankle fractures) and CV events including myocardial infarction, angina, heart failure, peripheral vascular disease. and stroke. The International Classification of Diseases, Ninth Revision, Clinical Modification codes used to identify these events are listed in Appendix A. Rates were calculated as the number of first fracture or CV events observed over the total number of follow-up months. We estimated mean inpatient cost per fracture or CV hospitalization and weighted mean monthly costs during follow-up (using each patient s length of follow-up as the weight), and then conducted multivariate regressions on the mean monthly costs during followup between matched case and control patients to estimate the marginal impact of the event on monthly costs (ie, Matched control CV indicates cardiovascular. a Cases of fracture (or CV) events were matched by propensity score by a 1:1 ratio composed of sex, geographic region, age, Charlson Comorbidity Index score, time since dialysis initiation, and secondary hyperparathyroidism. SHPT-Related Costs per Patient per Month We estimated the costs of SHPT by summing 100% of SHPT direct costs with a percentage of costs for SHPTrela ted clinical events attributable to SHPT. To calculate the cost attributable to SHPT, we used the population attributable fraction (PAF) based on the published literature to estimate what percentage of the estimated fracture and CV monthly costs should be considered to be SHPT-related costs. Using the study by Block and colleagues, 4 we started with a base case PAF of 17.5%; weighted monthly costs equaled the annualized rate per 1000 patients monthly total costs PAF. Sensitivity Analysis In our base case cost estimations for CV and fracture events, we allowed patients to have variable lengths of follow-up. Although cost estimations would have been easier if we had followed all patients for the same length of time, this type of censoring could potentially have led to biased results given the nonindependence of costs and length of follow-up data. In order to validate our results from the base case analyses, we included a range of sensitivity analyses by artificially imposing a minimum follow-up time. We estimated the difference in costs between matched patients for CV and fracture events who had at least 6 and 12 months of follow-up data for cost calculations. We also estimated the impact of varying PAF between 10% and 25%. Finally, we estimated the rates e26 The American Journal of Pharmacy Benefits March/April 2013

4 Costs of Treatment and Clinical Events Table 1. Demographics and Clinical Characteristics of Chronic Dialysis Patients After Matching CV Event Patient Sample After Matching All Chronic Dialysis Patients % No. or SD Patients With CV % No. or SD Patients Without CV % No. or SD Patients With Fracture % No. or SD Standardized Characteristics Difference a Total number 41, Fracture Event Patient Sample After Matching Patients Without Fracture % No. or SD Standardized Difference a Age, y, mean Male 24, % % % % % 2.59 Residence in an urban area 35, % % % % % 4.74 Geographic region of residence Northeast 3, % 870 9% 900 9% % 152 9% 0.81 North Central 14, % % % % % 0.34 South 15, % % % % % 1.64 West % % % % % 2.76 Unknown % Payer Commercial 19, % % % % % 2.06 Medicare 22, % % % % % 2.06 Length of follow-up, d, mean Charlson Comorbidity Index score, mean SHPT 15, % % % % % 1.45 Dialysis vintage (days between 1st dialysis date and index date), mean End of continuous enrollment , % End of study period % Patient death % Transplant % CV indicates cardiovascular; SD, standard deviation; SHPT, secondary hyperparathyroidism. a Ratio of mean to standard deviation of the difference of 2 random values. of hospitalization and inpatient cost per clinical event by payer type (ie, commercial, Medicare supplemental). RESULTS Estimating Treatment Costs for SHPT A total of 41,927 chronic dialysis patients who met the study inclusion criteria were identified in the data set. Patient demographic and clinical characteristics are presented in Table 1. In summary, mean (standard deviation [SD]) age was 64.4 (14.4) years, and 57.7% of patients were male. Mean (SD) length of follow-up was 469 (486) days or approximately 1.3 years. Mean (SD) Charlson Comorbidity Index score was 3.74 (2.12), and 37% of the chronic dialysis patients had SHPT. Mean (SD) dialysis vintage was 213 (309) days or approximately 7 months. Based on the standardized difference estimates, matched case and control patients had similar demographic and clinical characteristics. Fracture patients, however, had a shorter length of follow-up (419 days vs 501 days) in the data than nonfracture patients. Mean Vol. 5, No. 2 The American Journal of Pharmacy Benefits e27

5 n Lee Belozeroff Song Diakun Goodman Table 2. Frequency, Rates, and Inpatient Costs for Fracture and CV Events Event Number of Hospitalizations Observed Annualized Rate per 1000 Patient-Years Mean Inpatient Cost per Hospitalization, $ SD, $ Any type of fracture ,215 26,068 Hip fracture related hospitalization ,339 28,808 Vertebral fracture related hospitalization ,305 28,202 Long bone fracture related hospitalization ,915 18,379 Other SHPT-related fracture hospitalization ,052 19,476 CV event hospitalization Any type of CV event 17, ,822 40,522 Hospitalization with MI ,293 37,724 Hospitalization with angina ,545 Hospitalization with heart failure ,481 23,085 Hospitalization with PVD ,484 33,341 Hospitalization with stroke ,955 37,131 CV indicates cardiovascular; MI, myocardial infarction; PVD, peripheral vascular disease; SD, standard deviation; SHPT, secondary hyperparathyroidism. (SD) time from first dialysis claim to CV event was 252 (242) days, whereas mean (SD) time to fracture event was 648 (482) days (Table 1). Of the 41,927 chronic dialysis patients identified, mean (SD) monthly SHPT medication (ie, vitamin D analogues, phosphate binders, and cinacalcet) costs were $360 ($2615). Mean (SD) monthly PTX costs were $5 ($136). Mean per patient annual direct costs for SHPT were $4380. The frequency, rates, and hospitalization costs of CV and fracture events are described in Table 2. Among fracture events, hip fracture rates were the highest (11.4 per 1000 patient-years) and the most expensive ($23,339), whereas the vertebral fracture rate was the lowest (2.1 per 1000 patient-years) and long-bone fractures were the least expensive ($14,915). Among the CV events, heart failure rates were the highest (63.6 per 1000 patient-years), and peripheral vascular disease was the most expensive ($25,484 per hospitalization). Angina rates were the lowest (1.5 per 1000 patient-years) and angina was the least expensive ($8543). From the estimated follow-up costs, Table 3 summarizes the marginal impact of each fracture and CV event on total, inpatient, outpatient, pharmacy, and nursing facility costs. Hip fractures had the highest total mean marginal monthly costs at $4490 and annual costs at $53,880, mostly due to inpatient (mean monthly marginal cost, $2385) and outpatient (mean monthly marginal cost, $2093) costs. Nursing facility costs for hip fractures (mean monthly marginal cost, $747) were, however, lower than those for long-bone fractures (mean monthly marginal cost, $913). Other SHPT-related fractures had the highest mean monthly marginal outpatient costs at $1471. Among the CV events, mean monthly total marginal costs for peripheral vascular disease were the highest at $4775, whereas angina had the lowest mean monthly total marginal costs at $2774. The mean monthly nursing facility marginal cost for stroke was $485, which was the costliest CV event, followed by peripheral vascular disease at $252. Using 100% of SHPT treatment costs and applying the PAF to the SHPT-related clinical event costs, Figure 2 summarizes the mean annual per patient economic burden of SHPT. Of the total per patient cost of $5598, 78% and 22% was spent on the treatment and outcomes, respectively. Specifically, vitamin D analogues were the largest cost category at 39%. Cinacalcet and phosphate binders represented 26% and 12%, respectively, of total costs. Cardiovascular events represented the other large cost category at 19% of total costs. Sensitivity Analysis The differences between matched cases and controls for CV and fracture events decreased as the length of follow-up increased. For example, the difference in follow-up mean monthly costs between patients who experienced a hip fracture and those who did not was estimated to be $4359, which decreased to $3206 for patients with at least 6 months of follow-up and to $2565 for patients with at least 12 months of follow-up. Similarly, the difference in mean monthly total cost between those who did and did not experience a stroke went from $4221 in the base case analysis to $3487 for at e28 The American Journal of Pharmacy Benefits March/April 2013

6 Costs of Treatment and Clinical Events Table 3. Mean Monthly per Patient Marginal Costs of Fracture and CV Events Patients With CV/Fracture Hospitalization, $ Patients Without CV/Fracture Hospitalization, $ Event Mean SD Mean SD Difference Marginal Impact of CV/Fracture Hospitalization, $ Fracture hospitalization (n = 1778) All-cause total costs 12, , All-cause inpatient costs , All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility Hip fracture (n = 818) All-cause total costs 12, , All-cause inpatient costs , All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility Vertebral fracture (n = 247) All-cause total costs 12, , All-cause inpatient costs All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility Long bone (n = 226) All-cause total costs 11, , , All-cause inpatient costs All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility Other SHPT-related fracture (n = 352) All-cause total costs 12, , All-cause inpatient costs All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility CV hospitalization (n = 9574) All-cause total costs 13, , , All-cause inpatient costs , All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility Stroke hospitalization (n = 934) All-cause total costs 12, , , All-cause inpatient costs , All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility (Continued) Vol. 5, No. 2 The American Journal of Pharmacy Benefits e29

7 n Lee Belozeroff Song Diakun Goodman Table 3. Mean Monthly per Patient Marginal Costs of Fracture and CV Events (Continued) Patients With CV/Fracture Hospitalization, $ Patients Without CV/Fracture Hospitalization, $ Event Mean SD Mean SD Difference MI hospitalization (n = 1042) Marginal Impact of CV/Fracture Hospitalization, $ All-cause total costs 13, , , All-cause inpatient costs , All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility Heart failure hospitalization (n = 3027) All-cause total costs 12, , , All-cause inpatient costs , All-cause outpatient costs , Total outpatient pharmacy costs Costs of nursing facility PVD hospitalization (n = 772) All-cause total costs 14, , , All-cause inpatient costs , All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility Angina hospitalization (n = 71) All-cause total costs 10, All-cause inpatient costs All-cause outpatient costs Total outpatient pharmacy costs Costs of nursing facility CV indicates cardiovascular; MI, myocardial infarction; PVD, peripheral vascular disease; SD, standard deviation; SHPT, secondary hyperparathyroidism. least 6 months of follow-up and to $3136 for at least 12 months of follow-up. About 70% and 50% of matched patients had at least 6 months and 12 months of followup, respectively. When the PAF was varied between 10% and 25%, the corresponding total annual amount spent on SHPT varied from $5076 to $6120, the percentage spent on treatment varied from 86% to 72%, and the percentage spent on outcomes varied from 14% to 28%. Finally, we estimated rates and inpatient costs per clinical event by payer type (available in Appendix B). Rates of clinical events were lower and cost per clinical event was higher for commercial patients compared with Medicare patients. DISCUSSION Our study is the first to examine more holistically the costs of SHPT in dialysis patients by including both the direct costs of SHPT and the cost of SHPT-related clinical events. For each SHPT-related clinical event, we calculated both acute costs of the event (ie, mean inpatient hospitalization) and chronic costs (ie, estimated marginal costs) by examining the incremental cost for patients who experienced the clinical event compared with that for patients who did not experience the event after matching them by propensity score methods. By doing so, we were able to estimate the annual economic burden of the disease where 100% of SHPT treatment costs were attributed to the disease and a PAF of 17.5%, based on the prior literature, was applied to the costs of SHPT-related clinical event costs. This combined approach using 1 data set and the same set of patients to calculate the economic burden of SHPT ties together 2 otherwise disparate streams of research: 1 that calculates the direct costs of SHPT 16 and 1 that calculates the costs of SHPT-related clinical events. 3 In the sensitivity analysis, we found that our cost estimates for clinical events were sensitive to the length e30 The American Journal of Pharmacy Benefits March/April 2013

8 Costs of Treatment and Clinical Events of follow-up as an inclusion criterion. Cost estimates decreased as we required a longer length of follow-up. Shi and colleagues 17 reported in a study of first-year fracture costs that the most common skeletal fracture, hip fracture in women 65 years or older (52%), had the highest total medical cost ($15,196); by contrast, the rate of vertebral fractures was 12% and the cost was $6701. This may be in part because patients who did not survive for 6 (or 12) months after the clinical event may have incurred high end-of-life care costs that were incorporated into the overall mean costs. Not including these high end-of-life care costs in estimating the cost of the clinical events, however, would underestimate and bias the severity (toward less severe cases) and economic burden of these clinical events. Because our average length of follow-up was more than 1 year, any under- or overestimation of monthly costs should have been very small. Our base case estimates allowing for variable length of follow-up, therefore, reflect the full spectrum of clinical event severity. One limitation of this study is the generalizability of these estimates to the broader US dialysis population because most dialysis patients receive primary coverage through Medicare. Patients in this data set had a mean (SD) length of follow-up from first dialysis claim of 469 (486) days or approximately 1.3 years. This length of follow-up suggests that the data set contained patients who were on dialysis for a shorter duration and perhaps had less severe disease than the broader Medicare dialysis population. However, this is also a unique strength of the study in that other studies that only focus on Medicare patients would not capture dialysis patients costs prior to and during their coordination of benefits. Therefore, these cost estimates may serve as a lower bound of the costs, recognizing that costs for patients with more advanced ESRD may be higher, but not fully represented, in this study. Additionally, the direct costs of SHPT do not contain other disease-related costs (eg, office visits, lab tests, and other unknown events associated with the disease) and again serve as a lower bound of SHPT-related costs. Furthermore, due to the very small sample of patients who underwent PTX, we only estimated their inpatient hospitalization costs and likely underestimated the true cost of the procedure, recognizing that there may be follow-up physician visits, surgical procedures (for failures), medications, and adverse event costs not Figure 2. Mean Annual SHPT-Related Costs by Cost Categories 26% 12% 1% 3% 39% 19% CV indicates cardiovascular; SHPT, secondary hyperparathyroidism. Fracture events CV events Vitamin D analogues Phosphate binders Cinacalcet Parathyroidectomy examined in this study. Similarly, because we identified SHPT patients experiencing a fracture by the initial inpatient claim, our fracture rates may be an underestimation of the true rates within this population. We also recognize the limitation of the PAF approach in deciding what proportion of the related events may be considered related to SHPT. In the absence of other estimates in the literature, we relied on the number reported by Block and colleagues 4 for mortality; thus, we acknowledge that the estimate needs to be interpreted with caution. Because there is only 1 published estimate of the PAF that we are aware of, assumption of the lower (10%) and upper (25%) limits for the sensitivity analysis was somewhat arbitrary. Finally, we needed to rely on treatments for SHPT (ie, therapeutic doses of vitamin D analogues and cinacalcet) to identify patients with SHPT, with the possibility that some patients may have been miscoded. Given the choice of therapeutic doses of vitamin D analogues and number of claims we used to identify SHPT patients, we were more likely to have missed patients with moderate to severe SHPT than to have identified patients who had mild SHPT or who did not have SHPT. Despite these potential limitations, we selected the most conservative approaches to estimate lower bounds of what may be the true economic burden of SHPT among dialysis patients. To complement this analysis, future studies should consider estimating the economic burden of SHPT patients in other data sets that have dialysis and SHPT patients along the rest of the disease spectrum. Vol. 5, No. 2 The American Journal of Pharmacy Benefi ts e31

9 n Lee Belozeroff Song Diakun Goodman Per patient mean annual SHPT direct costs (ie, SHPT medications and PTX) represent approximately threefourths of the disease s annual costs, with CV and fracture event costs making up the remaining one-fourth. Within a 1-year time frame, the chronic costs of the clinical event (for both CV and fractures) are greater than the acute inpatient hospitalization costs of these events. Moreover, what is not captured in estimating the economic impact of these clinical events is the humanistic and potential long-term impact on patients quality of life due to these clinical events. In a long-term follow-up study of vertebral and hip fractures in postmenopausal women, Hallberg and colleagues 18 examined 67 patients who sustained a clinical fracture at baseline; 7 years later 29 of the 67 (43%) had experienced 1 or more low-energy fractures. Among the health-related quality-of-life domains assessed by the SF-36 scale, back pain was the most widely reported symptom and was reported significantly more often in the vertebral fracture group than in the group who experienced hip fractures alone, with 48% and 32% of patients, respectively, regularly taking pain medications at follow-up. Most patients were taking bisphosphonates as well as calcium and vitamin D at baseline and 2 years; 35% continued anti-osteoporosis therapy during the 5-year follow-up period. The relationship between pain and increased morbidity rates in these patients (in particular those who had a vertebral fracture) is consistent with similar data that illustrate the profound devastation for patients that often includes loss of mobility and independence in both younger (<65 years) and older (>65 years) age cohorts. Additionally, hip fractures are known to increase the risk of mortality beyond the follow-up period for our study. 19 Because there is no real treatment for vertebral fractures, therapy is frequently limited to pain management, which poses a significant physical as well as mental burden for patients and subsequently increases the economic responsibility for payers in the form of prescription costs. 20 These costs and their relative distribution are important factors to consider in determining the appropriate reimbursement for the treatment of SHPT. Failure to allocate adequate payment for SHPT to cover both treatments and outcomes may lead to suboptimal levels of SHPT treatment and therefore potential growth in the costs of CV and fracture events that are attributable to the disease, even against the backdrop of cost savings on the treatment side. The increased costs of these SHPT-related clinical events would reflect both an economic burden to the payer and an increased quality-of-life burden that includes increased risk of morbidity and mortality for the patient experiencing these events. Given the various other clinical challenges that dialysis patients encounter, in addition to the exorbitant costs associated with frequent hospitalizations, the importance of properly treating and preventing SHPT-related clinical events cannot be overemphasized. Acknowledgment The authors wish to thank Holly Tomlin (employee and stockholder, Amgen Inc) for her medical writing assistance and journal submission support. Author Affiliations: From Amgen Inc (AL, VB, WG), Thousand Oaks, CA; Thomson Reuters (XS, DD), Washington, DC. Funding Source: This study was supported by Amgen Inc. Author Disclosures: Drs Lee, Belozeroff, and Goodman report employment and stock ownership in Amgen Inc. Mr Song and Mr Diakun are employees of Thomson Reuters who contract with Amgen Inc. Authorship Information: Concept and design (AL, VB, XS, DD, WG); acquisition of data (DD); analysis and interpretation of data (AL, VB, XS, DD, WG); drafting of the manuscript (AL, WG); critical revision of the manuscript for important intellectual content (AL, VB, XS, DD); statistical analysis (AL, XS); and obtaining funding (VB). Address correspondence to: Vasily Belozeroff, PhD, Amgen Inc, One Amgen Center Dr, M/S B A, Thousand Oaks, CA vasilyb@amgen.com. REFERENCES 1. Gabbay E, Meyer KB, Griffith JL, Richardson MM, Miskulin DC. Temporal trends in health-related quality of life among hemodialysis patients in the United States. Clin J Am Soc Nephrol. 2010;5(2): Malindretos P, Sarafidis P, Lazaridis A, Nikolaidis P. A study of the association of higher parathormone levels with health-related quality of life in hemodialysis patients. Clin Nephrol. 2012;77(3): Doan QV, Gleeson M, Kim J, Borker R, Griffiths R, Dubois RW. Economic burden of cardiovascular events and fractures among patients with end-stage renal disease. Curr Med Res Opin. 2007;23(7): Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15(8): Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int. 2005;68(4): Jadoul M, Albert JM, Akiba T, et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2006;70(7): Slinin Y, Foley RN, Collins AJ. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol. 2005;16(6): Kestenbaum B, Andress DL, Schwartz SM, et al. Survival following parathyroidectomy among United States dialysis patients. Kidney Int. 2004;66(5): Kestenbaum B, Belozeroff V. Mineral metabolism disturbances in patients with chronic kidney disease. Eur J Clin Invest. 2007;37(8): Raggi P. Coronary-calcium screening to improve risk stratification in primary prevention. J La State Med Soc. 2002;154(6): Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients: a link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol. 2002;39(4): Alem AM, Sherrard DJ, Gillen DL, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000;58(1): Inaba M, Okuno S, Kumeda Y, Yamakawa T, Ishimura E, Nishizawa Y. Increased incidence of vertebral fracture in older female hemodialyzed patients with type 2 diabetes mellitus. Calcif Tissue Int. 2005;76(4): e32 The American Journal of Pharmacy Benefits March/April 2013

10 Costs of Treatment and Clinical Events 14. Blayney MJ, Pisoni RL, Bragg-Gresham JL, et al. High alkaline phosphatase levels in hemodialysis patients are associated with higher risk of hospitalization and death. Kidney Int. 2008;74(5): Messa P, Macário F, Yaqoob M, et al. The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2008;3(1): Joy MS, Karagiannis PC, Peyerl FW. Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct costs of treatment. J Manag Care Pharm. 2007;13(5): Shi N, Foley K, Lenhart G, Badamgarav E. Direct healthcare costs of hip, vertebral, and non-hip, non-vertebral fractures. Bone. 2009;45(6): Hallberg I, Bachrach-Lindström M, Hammerby S, Toss G, Ek AC. Health-related quality of life after vertebral or hip fracture: a seven-year follow-up study. BMC Musculoskelet Disord. 2009;10: National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. Updated Accessed February 20, Salaffi F, Cimmino MA, Malavolta N, et al; Italian Multicentre Osteoporotic Fracture Study Group. The burden of prevalent fractures on health-related quality of life in postmenopausal women with osteoporosis: the IMOF study. J Rheumatol. 2007;34(7): Vol. 5, No. 2 The American Journal of Pharmacy Benefits e33

11 n Lee Belozeroff Song Diakun Goodman Appendix A. Codes for Cardiovascular and Fracture Events Type of Event Codes Cardiovascular Myocardial infarction ICD-9-CM: 410.x0-410.x2, 411.0x, 412.xx Angina ICD-9-CM: 411.1x, 413.0x, 413.1x, 413.9x Heart failure ICD-9-CM: , , , , , , , , , 428.0x, 428.1x, , , , 428.9x Peripheral vascular disease ICD-9-CM: 440.2x, , , , , , , , , 442.0x, 442.3x, , 443.9x Stroke ICD-9-CM: 430.xx-432.xx, 433.x1, 434.x1, 435.xx-437.xx Other cardiovascular events ICD-9-CM: 411.8x, 414.9x, 414.0x , 414.1x, 414.2x, 426.7x, 427.1x, 427.3x, 427.4x, 427.6x, , , 427.9x, 429.3x ICD-9-CM: procedure: , 0061, 0062, 0066, 3601, 3602, , , 3619, 362, 387, 390, 391, 3929, 3950, 398, 3990, , , , , 3539, 3542, , , , , , 3598, 3599, 3603, 3609, 3616, , 3639, 3691, 3699, , 3724, , , , , , 3779, 3780, , 3791, , 3818, 3821, 3829, , 3855, 3857, 3859, , , , , , 3949, , 3965, , 3979 HCPCS: G0290, G0291, S2205-S2209 Fracture Hip ICD-9-CM: , 820.xx Vertebral ICD-9-CM: , 805.0x-805.1x, 805.2x-805.9x Long bone ICD-9-CM: , , , , , 812.xx, 813.xx, 821.xx, 822.xx, 823.xx Other SHPT-related fracture ICD-9-CM: , 807.xx, 808.xx, 810.xx, 811.xx, 814.xx, 815.xx, 817.xx, 824.xx, 825.xx, 826.xx Other fracture ICD-9-CM: , , , 800.xx-804.xx, 816.xx, 829.xx HCPCS indicates Healthcare Common Procedure Coding System; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; SHPT, secondary hyperparathyroidism. e34 The American Journal of Pharmacy Benefits March/April 2013

12 Costs of Treatment and Clinical Events Appendix B. Rates and Cost per Clinical Event by Payer Type Number of Hospitalizations Annualized Rate Mean Inpatient Cost Type of Event Observed per 1000 Patient-Years per Hospitalization, $ SD, $ Commercial Any type of fracture ,122 36,456 Hip fracture related hospitalization ,568 42,907 Vertebral fracture related hospitalization ,990 50,177 Long bone fracture related hospitalization ,720 19,045 Other SHPT-related fracture hospitalization ,198 29,379 Any type of CV event ,260 31,107 Hospitalization with MI ,336 31,107 Hospitalization with angina ,232 Hospitalization with heart failure ,384 29,476 Hospitalization with PVD ,060 36,017 Hospitalization with stroke ,104 49,244 Medicare Supplemental Any type of fracture ,269 20,910 Hip fracture related hospitalization ,078 23,466 Vertebral fracture related hospitalization ,547 17,827 Long bone fracture related hospitalization ,378 18,005 Other SHPT-related fracture hospitalization ,940 12,581 Any type of CV event 10, ,798 40,374 Hospitalization with MI ,559 40,374 Hospitalization with angina ,005 Hospitalization with heart failure ,309 18,662 Hospitalization with PVD ,726 31,207 Hospitalization with stroke ,283 24,997 CV indicates cardiovascular; MI, myocardial infarction; PVD, peripheral vascular disease; SD, standard deviation; SHPT, secondary hyperparathyroidism. Vol. 5, No. 2 The American Journal of Pharmacy Benefits e35