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An economic comparison of surgical and medical therapy in patients with secondary hyperparathyroidism—the German perspective
An economic comparison of surgical and medical therapy in patients with secondary hyperparathyroidism—the German perspective Ralph Schneider, MD,a Georgios Kolios, MD,b Benjamin M. Koch,a Emilio Domınguez Fern andez, MD,c Detlef K. Bartsch, MD,a and Katja Schlosser, MD,a Marburg, Bremen, and Hannover, Germany
Background. Treatment options for secondary hyperparathyroidism were significantly amended with the introduction of cinacalcet and paricalcitol. Limitations of resources in public health systems demand detailed analyses of accruing costs. The aim of this study was to compare the costs of these new treatment modalities to surgery. Methods. Patients who underwent initial parathyroidectomy (n = 91) and patients treated with cinacalcet or paricalcitol (n = 100) at an ambulatory dialysis center between 01/2003 and 12/2006 were analyzed. The revenues of both therapies for the funding agencies were calculated by a cost-cost analysis. The real arising costs of the supplier were analyzed and compared to the revenues. Results. Treatment costs for cinacalcet (60 mg/day/year) were 5828.40V and 4485.20V for paricalcitol (15 mg/week/year). Revenues for inpatient surgical treatment according to the German DRG system were 3755.38V/case. Additionally, costs for postoperative ambulatory therapies were 545.05V for the first year and 384.97V for the following. Conclusion. Due to linearly increases, expenses of medical treatment with cinacalcet for more than 9 months or paricalcitol for more than 12 months exceeded the costs of surgical therapy. The indication of these new medical therapies should be restricted to patients as an interim solution ahead of surgery or in patients considered unfit for surgery. (Surgery 2010;148:1091-9.) From the Department of Visceral, Thoracic and Vascular Surgery,a Philipps University, Marburg, Department of Plastic, Reconstructive and Aesthetic Surgery,b University of Bremen, and Department of General, Visceral and Vascular Surgery,c Clinical Centre Nordstadt, Hannover, Germany
SECONDARY HYPERPARATHYROIDISM (sHPT) is a common sequel of chronic kidney disease (CKD) developing in response to high phosphate, low calcium and low 1,25-dihydroxyvitamin D3 (calcitriol) levels. High levels of parathyroid hormone (PTH) accelerate bone turnover, with efflux of calcium and phosphate leading to vascular calcifications and renal osteopathy.1 Until the beginning of this century, the medical treatment of sHPT comprised the application of calcitriol and calcium-based phosphate binders. A successful kidney transplantation is the only causal treatment available to correct the abnormalities in mineral R.S. and G.K. contributed equally to this work. Accepted for publication December 18, 2010. Reprint requests: Ralph Schneider, MD, Philipps University Marburg, Department of Visceral, Thoracic and Vascular Surgery, Baldingerstrasse, 35043 Marburg, Germany. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2010.09.009
metabolism.2 However, limited availability of kidney transplants or high comorbidities preventing transplantation led to a high percentage of patients requiring operative intervention with total parathyroidectomy (PTX) with autotransplantation or subtotal PTX, both worldwide accepted equivalent standard procedures in the surgical treatment of sHPT.3 The introduction of vitamin D analogs and calcimimetics in 2004 and 2005 was considered as a ‘‘breakthrough’’ in the medical treatment of sHPT.4 Vitamin D analogs such as paricalcitol (ZemplarÒ) inhibit PTH gene transcription and parathyroid hyperplasia and have the advantage of a reduced calcemic activity when compared to vitamin D. Several such analogs are now in use, and analogs with even greater selectivity than those currently available are in development.5 However, the role of vitamin D analogs and PTX needs to be re-evaluated in the calcimimetic era.6 Cinacalcet (SensiparÒ/MimparaÒ) is the first of the new class of calcimimetic drugs approved for the treatment of sHPT. Calcimimetics suppress the SURGERY 1091
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secretion of PTH by sensitizing the parathyroid calcium receptor to extracellular calcium.2 Combined with higher doses of calcium-based oral phosphate binders, it is mostly well tolerated and already considered as an effective alternative to standard medical treatments such as vitamin D derivatives together with non--calcium-based oral phosphate binders.2 Clinical trials demonstrated cinacalcet to be effective in suppressing PTH secretion in uremic patients with severe sHPT in whom formerly PTX might have been considered. Therefore, calcimimetics were claimed to be an alternative to PTX.2 However, evidence for an impact on clinical events such as mortality, cardiovascular events or fractures is based on short-term post hoc analyses7 and most of the trials with cinacalcet are supported by the industry merchandising this drug. Whether the application of cinacalcet will translate in improved outcomes remains to be demonstrated and adequately powered prospective controlled randomized studies independently performed from industrial influence are needed.6 Reports about PTX rates before and after the introduction of either one of these new drugs are unavailable and the rate of patients requiring PTX after unsuccessful treatment with either calcimimetics or vitamin D analogs needs to be evaluated.8 At present, the rising costs of vitamin D analogs and cinacalcet are refunded without any restrictions in Germany, and consecutively decision-making between medical or surgical therapy often depends on personal interests and experiences of both patients and nephrologists. To the best of our knowledge, no analysis is available comparing the costs of the surgical treatment and the costs of these new medical treatments with either cinacalcet or paricalcitol. The aim of this study was to obtain objective information allowing a transparent estimation of costs associated with cinacalcet or paricalcitol medication as well as with surgical therapy to find out which therapy is more cost effective. Consequently, the results should facilitate the decision-making process in reference to resources, regulations, and developmental processes. MATERIALS AND METHODS Data of the present study refer to a retrospective analysis of a prospective database regarding the patients who underwent surgery and to a retrospective review of outpatient files of patients who received a medical therapy with either cinacalcet or paricalcitol in 2 dialysis centers. The inpatient surgical sector taken for economic evaluation comprised all patients with advanced
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sHPT who underwent initial PTX between January 2003 and January 2006 at a tertiary referral surgical center (n = 91). The standard surgical procedure was a total PTX with a parathyroid autotransplantation into the forearm. The costs of surgical therapy comprised inpatient costs, as well as costs for special postoperative ambulatory measures including blood examinations and calcium and calcitriol supplementation. The revenues were calculated on the basis of the German diagnosis related grouping (DRG) calculation system, where base-case values are multiplied with a relative weight. To find out if the inpatient surgical therapy can be performed costcovering, the real arising costs for the supplier (hospital) were analyzed and compared to the revenues. An activity-based costing approach based on clinical pathways, which allocated the individual and overhead costs to processes, was chosen for an appropriate real cost accounting. Therefore, primary, secondary, and tertiary processes were defined. Primary processes comprised main activities including personal and material costs, which were directly related to the treatment. The nursing related activity was calculated summarizing the daily allocation of each patient with correlated working minutes. Nursing related activities comprised admission examinations, transport of patients (x-ray, electrocardiogram, operation theater), preoperative preparation of patients as well as documentation and other nursing activities on the ward. Nursing efforts in the operation theater were defined in a special ‘‘operation pathway’’ including the efforts of 1 anesthetic and 2 surgical nurses. The personnel costs of the nurses were calculated on the basis of the salaries and the working minutes at 0.50V per minute. The physician related activity was calculated on the working minutes for every process per patient on the ward (interviews, examinations, ward rounds, documentations). In the operation theater, the efforts of 2 surgeons and 1 anesthetist were taken into consideration. The calculated minutes were multiplied with personnel costs on the basis of the mean salaries of 2 residents (1 surgeon and 1 anesthetist) and 1 consultant of 1.05V per minute. Material costs were calculated considering wound dressing materials, surgical drapes, anesthetic materials, and drugs and disposable items like clips and sutures, as well as costs for sterilization of surgical instruments. The working minutes of physicians and nurses on the ward were extrapolated from estimates based on interviews to all nurses and physicians involved in the care of patients with
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sHPT. The working minutes in the operation theater were extrapolated as the mean of the precise data provided by both the surgical and anesthetic protocols of all 91 patients who underwent a PTX. Secondary processes comprised personal and material costs provided by other departments of the hospital. The costs of medical functional services such as laboratory, radiology, pathology, nuclear medicine, and others were calculated according to a catalog listing the equivalencenumeral-calculations of the German Hospital Society (DKG-NT-table), where a point system of inpatient and outpatient services for hospitals is depicted. Every department is given a score which is calculated on the total costs for the department divided by the sum of all scores provided over a period of 1 year. Afterwards this score is multiplied with the points of the DKG-NT-table. The files of all patients who underwent surgery were screened for these services, and the costs for every service in each patient were calculated. The mean costs were used for the final calculation. Tertiary processes were defined as activities of the hospital infrastructure without direct relation to the treatment (technical service, kitchen, cleaning service, energy costs). These estimates refer to the costs which arise for any patient admitted to the hospital per treatment day independently from the reason of admission. The sum of all overhead costs of 2006 was divided by the sum of all treatment days of 2006 and multiplied by the individual hospital stay of each of the 91 patients who underwent surgery. The mean costs were used for the final calculation. These primary, secondary, and tertiary processes were summarized for every individual patient in order to optimally display the clinical pathways and then to calculate the real costs for the inpatient therapy. Costs for reoperations due to postoperative complications or recurrent/persistent disease were added into the calculation. A reoperation rate of 5% was chosen as a result of a follow-up study not yet published concerning 479 patients who underwent surgery at our department between the years 1976 and 2003. This study revealed a rate of persistent sHPT of 0.6% and a rate of recurrent sHPT of 4.6% after a mean follow-up of 57.6 months. Patients who underwent initial PTX for sHPT in the following years (2007--2009) were counted to achieve information about the trend in the numbers of PTX performed in the era after the initiation of vitamin D analogs and calcimimetics.
Number of patients undergoing initial PTX for sHPT
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40 35 30 25 20 15 10 5 0 2003
2004
2005
2006
2007
2008
2009
Years
Fig 1. Number of patients undergoing initial PTX for sHPT per year.
The ambulatory medical sector comprised all patients who were treated with cinacalcet or paricalcitol in 2 dialysis centers (n = 100) between January 2003 and January 2006. The costs of both medical therapies for the funding agencies were calculated depending on their dosage and on costs for laboratory measures. Considering a typical discount of 5% for funding agencies, the costs were correspondingly reduced. The dosages per patient were analyzed, leading to a mean dosage of 60mg/ day for cinacalcet and of 3 ml/week for paricalcitol. The costs were summarized per month over a time period of 2 years. Physical or other examinations which were necessary due to dialysis were not taken into consideration. An analysis comparing the costs for surgical and the costs for medical therapies was then performed (cost-cost analysis). RESULTS Ninety-one patients with sHPT who underwent initial PTX between January 2003 and January 2006 were analyzed. Of these 91 patients, 29 had a failed treatment attempt with cinacalcet or paricalcitol prior to surgery. The number of patients who underwent initial parathyroid surgery for sHPT decreased from 37 in 2003 to 28 in 2004, 21 in 2005, and 5 in 2006. The number of initial PTX for sHPT increased thereafter with 12, 13, and 20 patients in the years 2007, 2008 and 2009, respectively (Fig 1). The mean duration of hospital stay of the patients considered for economic evaluation was 7.3 ± 4.31 days. One patient had to undergo a cervical revision for persistent sHPT due to a missed fifth gland within the carotid sheath. Within a follow-up period of 3 years after surgery, 2 patients
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Table I. Revenues for our hospital for the treatment of sHPT Year
DRG text
DRG code
Relative weights
Base-casevalue (V)
Revenue/ case (V)
Number of patients
K05Z 1.179 3169.83 3737.23 ‘‘Parathyroid surgery’’ or ‘‘other 901Z 1.479 4688.18 disorders resulting from impaired L09B 2.137 6773.93 renal tubular function’’ or ‘‘secondary hyperparathyroidism of renal origin’’ Average revenue per case (2003) 2004 ‘‘Procedures on the thyroid the L09B 1.405 3054.43 4291.47 parathyroids or the thyroglottic duct’’ K12Z 1.390 4245.66 or ‘‘other procedures for kidney and urinary tract disorders’’ Average revenue per case (2004) 2954.71 3714.07 1.257 K11Z 2005 ‘‘Parathyroid disorders’’ or ‘‘Procedures 3454.06 1.169 L09B on the thyroid the parathyroids or 3932.72 1.331 L18Z the thyroglottic duct’’ or ‘‘Other 1997.38 0.676 K64C disorders resulting from impaired 5551.90 1.879 901D renal tubular function’’ or ‘‘secondary hyperparathyroidism of renal origin’’ Average revenue per case (2005) 2006 ‘‘Parathyroid disorders’’ or ‘‘procedures K11Z 1.217 2806.35 3415.33 on the thyroid the parathyroids or L09B 1.285 3606.16 the thyroglottic duct’’ or X06B 1.146 3216.08 ‘‘parathyroid procedures’’ Average revenue per case (2006) Mean revenues per case for the whole period, calculated from the mean annual revenues and the number of patients treated per year 2003
developed recurrent sHPT at the parathyroid autograft and had to undergo an autograft reduction. The ambulatory medical sector comprised 50 patients who were treated with cinacalcet and 50 patients who were treated with paricalcitol in 2 dialysis centers (n = 100) between 01/2003 and 01/2006. An interview with the nephrologists in charge addressing the outcome of these 100 patients revealed a high lost to follow-up rate of 18%, another 13% underwent PTX after a mean medical treatment duration of 25.6 months with either cinacalcet or paricalcitol, 38% achieved a significant (>50%) reduction in PTH levels, and 31% patients exhibited minor or no response regarding PTH. The latter are considered unfit for surgery, refuse surgical intervention, or are already scheduled for PTX in the meantime. The calculation of the mean annual inpatient revenues is shown in Table I. The mean revenues per case for the whole period, calculated from the mean annual revenues and the number of patients treated per year, were 3559.79V ± 484.22V. Considering a reoperation rate of 5% due to postoperative complications or recurrent/persistent disease the revenues increased to 3755.38V for Germany. Additional costs for postoperative ambulatory therapies
Overall revenue (V)
35 1 1
130 830.03 4 688.18 6 773.93
8 20
3 845.00 34 331.79 84 913.15
6 11 1 1 2
4 258.75 22 284.42 37 994.62 3 932.72 1 997.38 11 103.80
2 2 1
3 6 7 3
681.57 830.66 212.32 216.08
3 451.81 3 559.79 ± 484.22
were 545.05V for the first and maximum 384.97V for the following year. The sensitivity analyses considering the different base-case values estimated a ‘‘worst-case’’ revenue of 3589.77V and a ‘‘bestcase’’ revenue of 3983.96V. Costs of primary processes arising from nursing related activities were 571.50V per case assuming 663 working minutes per patient on the ward and 480 minutes per surgery in the operation theater. Time for physician related work was 243 minutes per patient on the ward and 541 minutes in the operation theater resulting in a total amount of 823.20V per case (Fig 2). Material costs were 643.66V per case. Costs of 1118.27V ± 650.40V per case were calculated for secondary processes and of 685.89V ± 407.45V per case for tertiary processes. The summation of the costs for primary, secondary and tertiary processes revealed 3842.52V per case as the real arising costs for the inpatient surgical treatment. The mean revenues from the agencies for our hospital were 3912.99V per case, leading to a costcovering situation with a mean benefit of 70.47V per case over all years analyzed (Table II). Neither the costs of the operative treatment nor the costs of the medical therapy varied over the years
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Fig 2. Timeline of primary processes to physician and nurse related activities to estimate the real arising costs.
analyzed. However, the revenues decreased over the years mainly attributed to a reduction of the basecase values. The cost-revenue relation per case for every year analyzed is depicted in Table II. However, the cost-revenue analysis per year observed revealed an increasing unprofitable relation between these measures, leading to resumed negotiations between the hospital, the funding agencies, and the nephrologists in charge to compile a treatment plan in the aim to regain a cost-covering situation. The costs of the ambulatory medical therapies mainly depended on the dosages of the drugs. Cinacalcet (28 tablets/package) was offered with 30, 60, and 90 mg at 232.72V, 421.47V, and 627.39V, respectively. Paricalcitol was offered in packages containing 5 3 1-ml (5 mg/ml) at 130.47V and 5 3 2 ml (5 mg/ml) at 251.29V. Monthly and yearly costs for cinacalcet and paricalcitol are displayed in Tables III and IV. The cost-intensive inpatient hospital stay caused higher expenses for the surgical therapy within the first months. Due to linearly rising costs and lifelong application of the drugs the surgical expenses were exceeded by cinacalcet after 9 months and by paricalcitol after 12 months (Fig 3). The postoperative costs remained almost constant within the outpatient period. These costs were depended on the dosages of calcium and vitamin D supplementation and the numbers of laboratory measures needed to control calcium and PTH levels and are displayed in Tables V and VI. We additionally performed a
sensitivity analysis considering different dosages of the drugs to differentiate between best and worstcase scenarios. In the worst case scenarios all patients were treated with the highest dosage of each drug (cinacalcet 180 mg, paricalcitol 3 3 2 ml). In contrast, the best case scenario was based on the lowest dosages of each drug (cinacalcet 30mg, paricalcitol 1 3 1-ml). The costs of surgical therapy were exceeded by the costs for cinacalcet in the worst case scenario after 3 months (Fig 4, A) and for paricalcitol after 6 months (Fig 4, B). Based on the best case scenario surgical therapy has to be preferred from an economic point of view after 16 months (C) treatment with cinacalcet and after 31 months (D) treatment with paricalcitol. DISCUSSION According to the third National Health and Nutrition Examination Survey, CKD affected as many as 19 million adults in the U.S. in 2003, with 20 million more at risk.9 The economic burden associated with CKD was recently analyzed in an observational study of 13,796 predialytic patients,10 the determined costs to treat CKD related comorbidities were almost twice of those treating CKD alone ($14,000 vs $8,000) and the cumulative costs of CKD plus comorbidities were greater than their simple sum ($26,000 vs $22,000). However, these findings underscored the importance of an active treatment of underlying risk factors for comorbidities.10
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Table II. The cost-revenue relation per case for every year analyzed Mean revenue per case Mean cost per case Mean cost-revenue relation per case
2003--2006
2003/2004
2005
2006
3912.99 3842.52 70.47
4258.75 3842.52 416.23
3681.57 3842.52 160.95
3451.81 3842.52 390.71
All costs are in Euros.
Table III. Dosage dependent costs of medical treatment with cinacalcet Dose/day cinacalcet
30 mg
60 mg
90 mg
180 mg
Medical/month Laboratory/month Total therapy/month Total therapy/year
240.17 50.70 290.87 3 490.44
434.96 50.70 485.66 5 827.92
647.46 50.70 698.16 8 377.92
1 294.93 50.70 1 345.63 16 147.56
All costs are in Euros.
Table IV. Dosage dependent costs of medical treatment with paricalcitol Dose/week paricalcitol (5 mg/ml)
1 3 1 ml
3 3 1 ml
3 3 2 ml
Medical/month Laboratory/month Total therapy/month Total therapy/year
107.42 50.70 158.12 1 897.44
322.26 50.70 372.96 4 475.52
620.69 50.70 671.39 8 056.68
All costs are in Euros.
Prior to the development of newer drugs such as vitamin D analogs and calcimimetics, medical treatment results of sHPT as the most important sequela of CKD remained inadequate. Less than 30% of all patients achieved 3 and only 5% of all patients all 4 Kidney Disease Outcomes and Initiative (KDOQI) target ranges (phosphate, calcium, PTH, calcium-phosphate product)11 leading to a high rate of PTX over time. The introduction of cinacalcet and vitamin D analogs into clinical practice opened a novel pathway in the treatment of patients with sHPT.12,13 Cinacalcet acts as an allosteric activator of the calcium-sensing receptor of parathyroid cells and therefore represents an appealing molecular target for therapeutic agents designed to control sHPT.14 Paricalcitol as a new analog of vitamin D suppresses synthesis and secretion of PTH as effectively as calcitriol but has a lower tendency to raise serum calcium and phosphorus.15,16 Several retrospective studies reported a significant reduction in the need to undergo PTX in patients receiving either cinacalcet or vitamin D analogs or both.17 Although we experienced a
decreasing frequency of surgical interventions for sHPT in the years 2003--2006, the numbers of surgeries increased thereafter. The decreasing number of surgeries within the study period at our hospital can be explained by the introduction of cinacalcet and paricalcitol into the armamentarium of the medical treatment options in patients with sHPT and the increased usage of these new drugs during that time. Due to the first studies published, which reported excellent results for both cinacalcet and paricalcitol, and to an aggressive advertisement of the pharmaceutical industry merchandising these drugs, many nephrologists considered the new medical treatments as alternatives to the surgical treatment of sHPT. The clinical courses and results of laboratory measures in the following years demonstrated a treatment failure in some of the patients who received either cinacalcet or paricalcitol or both which consecutively led to an increased assignment of patients for surgery. Almost all of the patients who underwent surgery at our hospital within the last 3 years had undergone an attempt to treat sHPT with cinacalcet, vitamin D analogs, or both for several years (unpublished data), and therefore, had undergone an unnecessary and costly medical therapy. Thus, drug resistances to cinacalcet or vitamin D analogs are possible, already described in the literature and usually attributed to either nodular hyperplasia or patient incompliance.18 In a recent large observational study patients with mild disease prior to treatment with cinacalcet (PTH 300--500 pg/ml) were more likely to achieve the KDOQI PTH target ranges than those with more severe disease (PTH >800 pg/ml).19 Moreover, patients with nodular hyperplasia have been
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7.000 € 6.500 €
Surgery (average base-case-value nationwide)
6.000 €
Paricalcitol (5μg/ml) 3 x 1ml/week
5.500 €
Cinacalcet 60mg/day
5.000 €
costs
4.500 € 4.000 € 3.500 € 3.000 € 2.500 € 2.000 € 1.500 € 1.000 € 500 € -€
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
months
Fig 3. Average treatment costs of treatment modalities over time.
Table V. Costs for calcitriol and calcium supplementation within the postoperative ambulatory setting Drug Costs Per Per Per Per
day week month year
Calcitriol (vitamin D)
Calcium
.53 3.73 16.18 194.18
.19 1.33 5.78 69.35
All costs are in Euros.
reported to have a higher risk for cinacalcet resistance.20 Thus, the severity of sHPT and the degree of nodular transformation potentially induce the development of resistance to the new drugs. Very few reports exist about the proposed length of treatment and dosage titration for cinacalcet or paricalcitol to achieve KDOQI targets.17 These articles report successful reductions in PTH already after 3 months of treatment.11,19-21 Accordingly, the National Institute for Health and Clinical Excellence of the United Kingdom recommended a continuation of medication only in patients who achieved a reduction in PTH levels of 30% or more within 4 months of treatment, including dose escalation if appropriate.22 Our study demonstrated that the costs for surgical therapy were exceeded by the linearly rising costs for medical therapy already after a 9-month treatment with cinacalcet and after a 12-month treatment with paricalcitol. Our findings are in accordance to those of Narayan et al who found the surgical intervention to be more cost effective after 8 months when compared to a treatment with cinacalcet.23 In addition, Narayan showed that PTX was more cost effective after 16 to 19 months even after calculating a combination of maximum
possible surgical costs and minimum cinacalcet costs.23 To the best of our knowledge, this is the first study which provides a detailed cost-cost analysis together with an estimate of the real arising costs concerning the treatment options in patients with sHPT. Based on our results one has to suggest that medical therapy may be optimal in patients with an anticipated short time on dialysis therapy (<12 months) and mild sHPT. This group includes patients with a high expected mortality due to comorbid illness or poor general health, patients who expect to undergo transplantation in less than 1 year, dialysis patients with living donors, and those who do decline operative therapy, respectively. However, it is not known whether control of PTH will be sustained after cessation of cinacalcet or paricalcitol. It is possible that underlying disease progression still occurs or that effectiveness may not be sustained over the long-term.24 Moreover, cinacalcet is not approved in patients after kidney transplantation and it needs to be elucidated how many of those requiring pretransplant cinacalcet will have to undergo PTX or necessitate ongoing costly off-label administered cinacalcet therapy thereafter. Because our study referred to 2 different medical treatment arms, the group of patients observed was unfortunately too small and heterogeneous to gain reliable data about the treatment successes. To evaluate the outcome of these treatments, prospective randomized multicenter trials with a structured follow-up protocol have to be conducted. However, the wise use of medical resources is paramount to delivering cost-effective care and our study adds a helpful piece of information to enable the development of a reasonable duration and dosage recommendation for the medical
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Table VI. Costs for laboratory measures within the postoperative ambulatory setting Laboratory parameters
Costs/laboratory measure (V) Number of laboratory measures in the 1st year postsurgery Total costs for laboratory measures in the 1st year postsurgery (V) Number of laboratory measures in the 2nd year postsurgery Total costs for laboratory measures in the 2nd year postsurgery (V)
Calcium
PTH
Total
2.76 78 215.28
33.12 2 66.24
35.88 80 281.52
20 55.20
2 66.24
22 121.44
Fig 4. Sensitivity analysis considering different dosages of the drugs compared to costs for surgical therapy over time.
therapies. A combination of our results and the results of future prospective trials comparing the success of medical and surgical treatments will help to facilitate the ever pressing challenge to surgeons in choosing the right patient to undergo surgery, choosing the right surgical technique, and then making the operative treatment more successful, less complicated, and less expensive. In conclusion, sHPT is an important sequela of CKD. The treatment options of sHPT have expanded substantially in the last years, with vitamin D analogs and calcimimetics being the most recent addition. From an economic point of view surgical therapy should be preferred whenever possible. Especially in patients with only little effect on improving mineral balance by cinacalcet or
vitamin D analogs, a prolongation of medical therapy over the recommended length of 4 months seems to be unjustifiable and should not be remunerated by the funding agencies. Randomized studies are needed to predict which patients will most likely gain benefit from early parathyroid surgery in order to avoid unnecessary, prolonged, and costly medical therapy.
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without autotransplantation and without thymectomy versus total parathyroidectomy with autotransplantation and with thymectomy for secondary hyperparathyroidism: TOPAR PILOT-Trial. Trials 2007;8:22. Felsenfeld AJ. Considerations for the treatment of secondary hyperparathyroidism in renal failure. J Am Soc Nephrol 1997;8:993-1004. Brown AJ, Slatopolsky E. Drug insight: vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Nat Clin Pract Endocrinol Metab 2007;3:134-44. Evenepoel P. Calcimimetics in chronic kidney disease: evidence, opportunities and challenges. Kidney Int 2008;74:265-75. 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;68:1793-800. Tominaga Y, Matsuoka S, Uno N. Surgical and medical treatment of secondary hyperparathyroidism in patients on continuous dialysis. World J Surg 2009;33:2335-42. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41:1-12. 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;13:397-411. Portol es J, Tato A, L opez-Sanchez P, Gruss E, Cava F, Ortigosa A, et al. [Cinacalcet in patients on peritoneal dialysis with moderate to severe hyperparathyroidism resistant to conventional treatment, a one-year, prospective study]. Nefrologia 2008;28:419-24. Szczech LA. The impact of calcimimetic agents on the use of different classes of phosphate binders: results of recent clinical trials. Kidney Int Suppl 2004:S46-8. Block GA. The impact of calcimimetics on mineral metabolism and secondary hyperparathyroidism in end-stage renal disease. Kidney Int Suppl 2003:S131-6. Nemeth EF, Steffey ME, Fox J. The parathyroid calcium receptor: a novel therapeutic target for treating hyperparathyroidism. Pediatr Nephrol 1996;10:275-9.
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15. Lindberg J, Martin KJ, Gonzalez EA, Acchiardo SR, Valdin JR, Soltanek C. A long-term, multicenter study of the efficacy and safety of paricalcitol in end-stage renal disease. Clin Nephrol 2001;56:315-23. 16. Llach F, Yudd M. Paricalcitol in dialysis patients with calcitriol-resistant secondary hyperparathyroidism. Am J Kidney Dis 2001;38:S45-50. 17. Lazar E, Hebert K, Poma T, Stankus N. Long-term outcomes of cinacalcet and paricalcitol titration protocol for treatment of secondary hyperparathyroidism. Am J Nephrol 2007;27:274-8. 18. Fukagawa M, Taniguchi M. Can calcimimetics inhibit nodular hyperplasia of parathyroid glands? Nephrol Dial Transplant 2008;23:407-8. 19. Ure~ na P, Jacobson SH, Zitt E, Vervloet M, Malberti F, Ashman N, et al. Cinacalcet and achievement of the NKF/KDOQI recommended target values for bone and mineral metabolism in real-world clinical practice--the ECHO observational study. Nephrol Dial Transplant 2009;24:2852-9. 20. Hirai T, Nakashima A, Takasugi N, Yorioka N. Response of secondary hyperparathyroidism to cinacalcet depends on parathyroid size. Nephron Clin Pract 2010;114:c187-93. 21. Kakuta T, Tanaka R, Kanai G, Sawaya A, Hirukawa T, Sato A, et al. Can cinacalcet replace parathyroid intervention in severe secondary hyperparathyroidism? Ther Apher Dial 2009;13(Suppl 1):S20-7. 22. National Institute for Health and Clinical Excellence. Understanding NICE guidance. Information for people who use NHS services Cinacalcet for treating secondary hyperparathyroidism in people with kidney disease who are on dialysis. January 2007. Available at: http://www. nice.org.uk/nicemedia/pdf/TA117publicinfo.pdf. 23. Narayan R, Perkins RM, Berbano EP, Yuan CM, Neff RT, Sawyers ES, et al. Parathyroidectomy versus cinacalcet hydrochloride-based medical therapy in the management of hyperparathyroidism in ESRD: a cost utility analysis. Am J Kidney Dis 2007;49:801-13. 24. Garside R, Pitt M, Anderson R, Mealing S, D’Souza R, Stein K. The cost-utility of cinacalcet in addition to standard care compared to standard care alone for secondary hyperparathyroidism in end-stage renal disease: a UK perspective. Nephrol Dial Transplant 2007;22:1428-36.
Background. Treatment options for secondary hyperparathyroidism were significantly amended with the introduction of cinacalcet and paricalcitol. Limitations of resources in public health systems demand detailed analyses of accruing costs. The aim of this study was to compare the costs of these new treatment modalities to surgery. Methods. Patients who underwent initial parathyroidectomy (n = 91) and patients treated with cinacalcet or paricalcitol (n = 100) at an ambulatory dialysis center between 01/2003 and 12/2006 were analyzed. The revenues of both therapies for the funding agencies were calculated by a cost-cost analysis. The real arising costs of the supplier were analyzed and compared to the revenues. Results. Treatment costs for cinacalcet (60 mg/day/year) were 5828.40V and 4485.20V for paricalcitol (15 mg/week/year). Revenues for inpatient surgical treatment according to the German DRG system were 3755.38V/case. Additionally, costs for postoperative ambulatory therapies were 545.05V for the first year and 384.97V for the following. Conclusion. Due to linearly increases, expenses of medical treatment with cinacalcet for more than 9 months or paricalcitol for more than 12 months exceeded the costs of surgical therapy. The indication of these new medical therapies should be restricted to patients as an interim solution ahead of surgery or in patients considered unfit for surgery. (Surgery 2010;148:1091-9.) From the Department of Visceral, Thoracic and Vascular Surgery,a Philipps University, Marburg, Department of Plastic, Reconstructive and Aesthetic Surgery,b University of Bremen, and Department of General, Visceral and Vascular Surgery,c Clinical Centre Nordstadt, Hannover, Germany
SECONDARY HYPERPARATHYROIDISM (sHPT) is a common sequel of chronic kidney disease (CKD) developing in response to high phosphate, low calcium and low 1,25-dihydroxyvitamin D3 (calcitriol) levels. High levels of parathyroid hormone (PTH) accelerate bone turnover, with efflux of calcium and phosphate leading to vascular calcifications and renal osteopathy.1 Until the beginning of this century, the medical treatment of sHPT comprised the application of calcitriol and calcium-based phosphate binders. A successful kidney transplantation is the only causal treatment available to correct the abnormalities in mineral R.S. and G.K. contributed equally to this work. Accepted for publication December 18, 2010. Reprint requests: Ralph Schneider, MD, Philipps University Marburg, Department of Visceral, Thoracic and Vascular Surgery, Baldingerstrasse, 35043 Marburg, Germany. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2010.09.009
metabolism.2 However, limited availability of kidney transplants or high comorbidities preventing transplantation led to a high percentage of patients requiring operative intervention with total parathyroidectomy (PTX) with autotransplantation or subtotal PTX, both worldwide accepted equivalent standard procedures in the surgical treatment of sHPT.3 The introduction of vitamin D analogs and calcimimetics in 2004 and 2005 was considered as a ‘‘breakthrough’’ in the medical treatment of sHPT.4 Vitamin D analogs such as paricalcitol (ZemplarÒ) inhibit PTH gene transcription and parathyroid hyperplasia and have the advantage of a reduced calcemic activity when compared to vitamin D. Several such analogs are now in use, and analogs with even greater selectivity than those currently available are in development.5 However, the role of vitamin D analogs and PTX needs to be re-evaluated in the calcimimetic era.6 Cinacalcet (SensiparÒ/MimparaÒ) is the first of the new class of calcimimetic drugs approved for the treatment of sHPT. Calcimimetics suppress the SURGERY 1091
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secretion of PTH by sensitizing the parathyroid calcium receptor to extracellular calcium.2 Combined with higher doses of calcium-based oral phosphate binders, it is mostly well tolerated and already considered as an effective alternative to standard medical treatments such as vitamin D derivatives together with non--calcium-based oral phosphate binders.2 Clinical trials demonstrated cinacalcet to be effective in suppressing PTH secretion in uremic patients with severe sHPT in whom formerly PTX might have been considered. Therefore, calcimimetics were claimed to be an alternative to PTX.2 However, evidence for an impact on clinical events such as mortality, cardiovascular events or fractures is based on short-term post hoc analyses7 and most of the trials with cinacalcet are supported by the industry merchandising this drug. Whether the application of cinacalcet will translate in improved outcomes remains to be demonstrated and adequately powered prospective controlled randomized studies independently performed from industrial influence are needed.6 Reports about PTX rates before and after the introduction of either one of these new drugs are unavailable and the rate of patients requiring PTX after unsuccessful treatment with either calcimimetics or vitamin D analogs needs to be evaluated.8 At present, the rising costs of vitamin D analogs and cinacalcet are refunded without any restrictions in Germany, and consecutively decision-making between medical or surgical therapy often depends on personal interests and experiences of both patients and nephrologists. To the best of our knowledge, no analysis is available comparing the costs of the surgical treatment and the costs of these new medical treatments with either cinacalcet or paricalcitol. The aim of this study was to obtain objective information allowing a transparent estimation of costs associated with cinacalcet or paricalcitol medication as well as with surgical therapy to find out which therapy is more cost effective. Consequently, the results should facilitate the decision-making process in reference to resources, regulations, and developmental processes. MATERIALS AND METHODS Data of the present study refer to a retrospective analysis of a prospective database regarding the patients who underwent surgery and to a retrospective review of outpatient files of patients who received a medical therapy with either cinacalcet or paricalcitol in 2 dialysis centers. The inpatient surgical sector taken for economic evaluation comprised all patients with advanced
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sHPT who underwent initial PTX between January 2003 and January 2006 at a tertiary referral surgical center (n = 91). The standard surgical procedure was a total PTX with a parathyroid autotransplantation into the forearm. The costs of surgical therapy comprised inpatient costs, as well as costs for special postoperative ambulatory measures including blood examinations and calcium and calcitriol supplementation. The revenues were calculated on the basis of the German diagnosis related grouping (DRG) calculation system, where base-case values are multiplied with a relative weight. To find out if the inpatient surgical therapy can be performed costcovering, the real arising costs for the supplier (hospital) were analyzed and compared to the revenues. An activity-based costing approach based on clinical pathways, which allocated the individual and overhead costs to processes, was chosen for an appropriate real cost accounting. Therefore, primary, secondary, and tertiary processes were defined. Primary processes comprised main activities including personal and material costs, which were directly related to the treatment. The nursing related activity was calculated summarizing the daily allocation of each patient with correlated working minutes. Nursing related activities comprised admission examinations, transport of patients (x-ray, electrocardiogram, operation theater), preoperative preparation of patients as well as documentation and other nursing activities on the ward. Nursing efforts in the operation theater were defined in a special ‘‘operation pathway’’ including the efforts of 1 anesthetic and 2 surgical nurses. The personnel costs of the nurses were calculated on the basis of the salaries and the working minutes at 0.50V per minute. The physician related activity was calculated on the working minutes for every process per patient on the ward (interviews, examinations, ward rounds, documentations). In the operation theater, the efforts of 2 surgeons and 1 anesthetist were taken into consideration. The calculated minutes were multiplied with personnel costs on the basis of the mean salaries of 2 residents (1 surgeon and 1 anesthetist) and 1 consultant of 1.05V per minute. Material costs were calculated considering wound dressing materials, surgical drapes, anesthetic materials, and drugs and disposable items like clips and sutures, as well as costs for sterilization of surgical instruments. The working minutes of physicians and nurses on the ward were extrapolated from estimates based on interviews to all nurses and physicians involved in the care of patients with
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sHPT. The working minutes in the operation theater were extrapolated as the mean of the precise data provided by both the surgical and anesthetic protocols of all 91 patients who underwent a PTX. Secondary processes comprised personal and material costs provided by other departments of the hospital. The costs of medical functional services such as laboratory, radiology, pathology, nuclear medicine, and others were calculated according to a catalog listing the equivalencenumeral-calculations of the German Hospital Society (DKG-NT-table), where a point system of inpatient and outpatient services for hospitals is depicted. Every department is given a score which is calculated on the total costs for the department divided by the sum of all scores provided over a period of 1 year. Afterwards this score is multiplied with the points of the DKG-NT-table. The files of all patients who underwent surgery were screened for these services, and the costs for every service in each patient were calculated. The mean costs were used for the final calculation. Tertiary processes were defined as activities of the hospital infrastructure without direct relation to the treatment (technical service, kitchen, cleaning service, energy costs). These estimates refer to the costs which arise for any patient admitted to the hospital per treatment day independently from the reason of admission. The sum of all overhead costs of 2006 was divided by the sum of all treatment days of 2006 and multiplied by the individual hospital stay of each of the 91 patients who underwent surgery. The mean costs were used for the final calculation. These primary, secondary, and tertiary processes were summarized for every individual patient in order to optimally display the clinical pathways and then to calculate the real costs for the inpatient therapy. Costs for reoperations due to postoperative complications or recurrent/persistent disease were added into the calculation. A reoperation rate of 5% was chosen as a result of a follow-up study not yet published concerning 479 patients who underwent surgery at our department between the years 1976 and 2003. This study revealed a rate of persistent sHPT of 0.6% and a rate of recurrent sHPT of 4.6% after a mean follow-up of 57.6 months. Patients who underwent initial PTX for sHPT in the following years (2007--2009) were counted to achieve information about the trend in the numbers of PTX performed in the era after the initiation of vitamin D analogs and calcimimetics.
Number of patients undergoing initial PTX for sHPT
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40 35 30 25 20 15 10 5 0 2003
2004
2005
2006
2007
2008
2009
Years
Fig 1. Number of patients undergoing initial PTX for sHPT per year.
The ambulatory medical sector comprised all patients who were treated with cinacalcet or paricalcitol in 2 dialysis centers (n = 100) between January 2003 and January 2006. The costs of both medical therapies for the funding agencies were calculated depending on their dosage and on costs for laboratory measures. Considering a typical discount of 5% for funding agencies, the costs were correspondingly reduced. The dosages per patient were analyzed, leading to a mean dosage of 60mg/ day for cinacalcet and of 3 ml/week for paricalcitol. The costs were summarized per month over a time period of 2 years. Physical or other examinations which were necessary due to dialysis were not taken into consideration. An analysis comparing the costs for surgical and the costs for medical therapies was then performed (cost-cost analysis). RESULTS Ninety-one patients with sHPT who underwent initial PTX between January 2003 and January 2006 were analyzed. Of these 91 patients, 29 had a failed treatment attempt with cinacalcet or paricalcitol prior to surgery. The number of patients who underwent initial parathyroid surgery for sHPT decreased from 37 in 2003 to 28 in 2004, 21 in 2005, and 5 in 2006. The number of initial PTX for sHPT increased thereafter with 12, 13, and 20 patients in the years 2007, 2008 and 2009, respectively (Fig 1). The mean duration of hospital stay of the patients considered for economic evaluation was 7.3 ± 4.31 days. One patient had to undergo a cervical revision for persistent sHPT due to a missed fifth gland within the carotid sheath. Within a follow-up period of 3 years after surgery, 2 patients
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Table I. Revenues for our hospital for the treatment of sHPT Year
DRG text
DRG code
Relative weights
Base-casevalue (V)
Revenue/ case (V)
Number of patients
K05Z 1.179 3169.83 3737.23 ‘‘Parathyroid surgery’’ or ‘‘other 901Z 1.479 4688.18 disorders resulting from impaired L09B 2.137 6773.93 renal tubular function’’ or ‘‘secondary hyperparathyroidism of renal origin’’ Average revenue per case (2003) 2004 ‘‘Procedures on the thyroid the L09B 1.405 3054.43 4291.47 parathyroids or the thyroglottic duct’’ K12Z 1.390 4245.66 or ‘‘other procedures for kidney and urinary tract disorders’’ Average revenue per case (2004) 2954.71 3714.07 1.257 K11Z 2005 ‘‘Parathyroid disorders’’ or ‘‘Procedures 3454.06 1.169 L09B on the thyroid the parathyroids or 3932.72 1.331 L18Z the thyroglottic duct’’ or ‘‘Other 1997.38 0.676 K64C disorders resulting from impaired 5551.90 1.879 901D renal tubular function’’ or ‘‘secondary hyperparathyroidism of renal origin’’ Average revenue per case (2005) 2006 ‘‘Parathyroid disorders’’ or ‘‘procedures K11Z 1.217 2806.35 3415.33 on the thyroid the parathyroids or L09B 1.285 3606.16 the thyroglottic duct’’ or X06B 1.146 3216.08 ‘‘parathyroid procedures’’ Average revenue per case (2006) Mean revenues per case for the whole period, calculated from the mean annual revenues and the number of patients treated per year 2003
developed recurrent sHPT at the parathyroid autograft and had to undergo an autograft reduction. The ambulatory medical sector comprised 50 patients who were treated with cinacalcet and 50 patients who were treated with paricalcitol in 2 dialysis centers (n = 100) between 01/2003 and 01/2006. An interview with the nephrologists in charge addressing the outcome of these 100 patients revealed a high lost to follow-up rate of 18%, another 13% underwent PTX after a mean medical treatment duration of 25.6 months with either cinacalcet or paricalcitol, 38% achieved a significant (>50%) reduction in PTH levels, and 31% patients exhibited minor or no response regarding PTH. The latter are considered unfit for surgery, refuse surgical intervention, or are already scheduled for PTX in the meantime. The calculation of the mean annual inpatient revenues is shown in Table I. The mean revenues per case for the whole period, calculated from the mean annual revenues and the number of patients treated per year, were 3559.79V ± 484.22V. Considering a reoperation rate of 5% due to postoperative complications or recurrent/persistent disease the revenues increased to 3755.38V for Germany. Additional costs for postoperative ambulatory therapies
Overall revenue (V)
35 1 1
130 830.03 4 688.18 6 773.93
8 20
3 845.00 34 331.79 84 913.15
6 11 1 1 2
4 258.75 22 284.42 37 994.62 3 932.72 1 997.38 11 103.80
2 2 1
3 6 7 3
681.57 830.66 212.32 216.08
3 451.81 3 559.79 ± 484.22
were 545.05V for the first and maximum 384.97V for the following year. The sensitivity analyses considering the different base-case values estimated a ‘‘worst-case’’ revenue of 3589.77V and a ‘‘bestcase’’ revenue of 3983.96V. Costs of primary processes arising from nursing related activities were 571.50V per case assuming 663 working minutes per patient on the ward and 480 minutes per surgery in the operation theater. Time for physician related work was 243 minutes per patient on the ward and 541 minutes in the operation theater resulting in a total amount of 823.20V per case (Fig 2). Material costs were 643.66V per case. Costs of 1118.27V ± 650.40V per case were calculated for secondary processes and of 685.89V ± 407.45V per case for tertiary processes. The summation of the costs for primary, secondary and tertiary processes revealed 3842.52V per case as the real arising costs for the inpatient surgical treatment. The mean revenues from the agencies for our hospital were 3912.99V per case, leading to a costcovering situation with a mean benefit of 70.47V per case over all years analyzed (Table II). Neither the costs of the operative treatment nor the costs of the medical therapy varied over the years
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Fig 2. Timeline of primary processes to physician and nurse related activities to estimate the real arising costs.
analyzed. However, the revenues decreased over the years mainly attributed to a reduction of the basecase values. The cost-revenue relation per case for every year analyzed is depicted in Table II. However, the cost-revenue analysis per year observed revealed an increasing unprofitable relation between these measures, leading to resumed negotiations between the hospital, the funding agencies, and the nephrologists in charge to compile a treatment plan in the aim to regain a cost-covering situation. The costs of the ambulatory medical therapies mainly depended on the dosages of the drugs. Cinacalcet (28 tablets/package) was offered with 30, 60, and 90 mg at 232.72V, 421.47V, and 627.39V, respectively. Paricalcitol was offered in packages containing 5 3 1-ml (5 mg/ml) at 130.47V and 5 3 2 ml (5 mg/ml) at 251.29V. Monthly and yearly costs for cinacalcet and paricalcitol are displayed in Tables III and IV. The cost-intensive inpatient hospital stay caused higher expenses for the surgical therapy within the first months. Due to linearly rising costs and lifelong application of the drugs the surgical expenses were exceeded by cinacalcet after 9 months and by paricalcitol after 12 months (Fig 3). The postoperative costs remained almost constant within the outpatient period. These costs were depended on the dosages of calcium and vitamin D supplementation and the numbers of laboratory measures needed to control calcium and PTH levels and are displayed in Tables V and VI. We additionally performed a
sensitivity analysis considering different dosages of the drugs to differentiate between best and worstcase scenarios. In the worst case scenarios all patients were treated with the highest dosage of each drug (cinacalcet 180 mg, paricalcitol 3 3 2 ml). In contrast, the best case scenario was based on the lowest dosages of each drug (cinacalcet 30mg, paricalcitol 1 3 1-ml). The costs of surgical therapy were exceeded by the costs for cinacalcet in the worst case scenario after 3 months (Fig 4, A) and for paricalcitol after 6 months (Fig 4, B). Based on the best case scenario surgical therapy has to be preferred from an economic point of view after 16 months (C) treatment with cinacalcet and after 31 months (D) treatment with paricalcitol. DISCUSSION According to the third National Health and Nutrition Examination Survey, CKD affected as many as 19 million adults in the U.S. in 2003, with 20 million more at risk.9 The economic burden associated with CKD was recently analyzed in an observational study of 13,796 predialytic patients,10 the determined costs to treat CKD related comorbidities were almost twice of those treating CKD alone ($14,000 vs $8,000) and the cumulative costs of CKD plus comorbidities were greater than their simple sum ($26,000 vs $22,000). However, these findings underscored the importance of an active treatment of underlying risk factors for comorbidities.10
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Table II. The cost-revenue relation per case for every year analyzed Mean revenue per case Mean cost per case Mean cost-revenue relation per case
2003--2006
2003/2004
2005
2006
3912.99 3842.52 70.47
4258.75 3842.52 416.23
3681.57 3842.52 160.95
3451.81 3842.52 390.71
All costs are in Euros.
Table III. Dosage dependent costs of medical treatment with cinacalcet Dose/day cinacalcet
30 mg
60 mg
90 mg
180 mg
Medical/month Laboratory/month Total therapy/month Total therapy/year
240.17 50.70 290.87 3 490.44
434.96 50.70 485.66 5 827.92
647.46 50.70 698.16 8 377.92
1 294.93 50.70 1 345.63 16 147.56
All costs are in Euros.
Table IV. Dosage dependent costs of medical treatment with paricalcitol Dose/week paricalcitol (5 mg/ml)
1 3 1 ml
3 3 1 ml
3 3 2 ml
Medical/month Laboratory/month Total therapy/month Total therapy/year
107.42 50.70 158.12 1 897.44
322.26 50.70 372.96 4 475.52
620.69 50.70 671.39 8 056.68
All costs are in Euros.
Prior to the development of newer drugs such as vitamin D analogs and calcimimetics, medical treatment results of sHPT as the most important sequela of CKD remained inadequate. Less than 30% of all patients achieved 3 and only 5% of all patients all 4 Kidney Disease Outcomes and Initiative (KDOQI) target ranges (phosphate, calcium, PTH, calcium-phosphate product)11 leading to a high rate of PTX over time. The introduction of cinacalcet and vitamin D analogs into clinical practice opened a novel pathway in the treatment of patients with sHPT.12,13 Cinacalcet acts as an allosteric activator of the calcium-sensing receptor of parathyroid cells and therefore represents an appealing molecular target for therapeutic agents designed to control sHPT.14 Paricalcitol as a new analog of vitamin D suppresses synthesis and secretion of PTH as effectively as calcitriol but has a lower tendency to raise serum calcium and phosphorus.15,16 Several retrospective studies reported a significant reduction in the need to undergo PTX in patients receiving either cinacalcet or vitamin D analogs or both.17 Although we experienced a
decreasing frequency of surgical interventions for sHPT in the years 2003--2006, the numbers of surgeries increased thereafter. The decreasing number of surgeries within the study period at our hospital can be explained by the introduction of cinacalcet and paricalcitol into the armamentarium of the medical treatment options in patients with sHPT and the increased usage of these new drugs during that time. Due to the first studies published, which reported excellent results for both cinacalcet and paricalcitol, and to an aggressive advertisement of the pharmaceutical industry merchandising these drugs, many nephrologists considered the new medical treatments as alternatives to the surgical treatment of sHPT. The clinical courses and results of laboratory measures in the following years demonstrated a treatment failure in some of the patients who received either cinacalcet or paricalcitol or both which consecutively led to an increased assignment of patients for surgery. Almost all of the patients who underwent surgery at our hospital within the last 3 years had undergone an attempt to treat sHPT with cinacalcet, vitamin D analogs, or both for several years (unpublished data), and therefore, had undergone an unnecessary and costly medical therapy. Thus, drug resistances to cinacalcet or vitamin D analogs are possible, already described in the literature and usually attributed to either nodular hyperplasia or patient incompliance.18 In a recent large observational study patients with mild disease prior to treatment with cinacalcet (PTH 300--500 pg/ml) were more likely to achieve the KDOQI PTH target ranges than those with more severe disease (PTH >800 pg/ml).19 Moreover, patients with nodular hyperplasia have been
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7.000 € 6.500 €
Surgery (average base-case-value nationwide)
6.000 €
Paricalcitol (5μg/ml) 3 x 1ml/week
5.500 €
Cinacalcet 60mg/day
5.000 €
costs
4.500 € 4.000 € 3.500 € 3.000 € 2.500 € 2.000 € 1.500 € 1.000 € 500 € -€
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
months
Fig 3. Average treatment costs of treatment modalities over time.
Table V. Costs for calcitriol and calcium supplementation within the postoperative ambulatory setting Drug Costs Per Per Per Per
day week month year
Calcitriol (vitamin D)
Calcium
.53 3.73 16.18 194.18
.19 1.33 5.78 69.35
All costs are in Euros.
reported to have a higher risk for cinacalcet resistance.20 Thus, the severity of sHPT and the degree of nodular transformation potentially induce the development of resistance to the new drugs. Very few reports exist about the proposed length of treatment and dosage titration for cinacalcet or paricalcitol to achieve KDOQI targets.17 These articles report successful reductions in PTH already after 3 months of treatment.11,19-21 Accordingly, the National Institute for Health and Clinical Excellence of the United Kingdom recommended a continuation of medication only in patients who achieved a reduction in PTH levels of 30% or more within 4 months of treatment, including dose escalation if appropriate.22 Our study demonstrated that the costs for surgical therapy were exceeded by the linearly rising costs for medical therapy already after a 9-month treatment with cinacalcet and after a 12-month treatment with paricalcitol. Our findings are in accordance to those of Narayan et al who found the surgical intervention to be more cost effective after 8 months when compared to a treatment with cinacalcet.23 In addition, Narayan showed that PTX was more cost effective after 16 to 19 months even after calculating a combination of maximum
possible surgical costs and minimum cinacalcet costs.23 To the best of our knowledge, this is the first study which provides a detailed cost-cost analysis together with an estimate of the real arising costs concerning the treatment options in patients with sHPT. Based on our results one has to suggest that medical therapy may be optimal in patients with an anticipated short time on dialysis therapy (<12 months) and mild sHPT. This group includes patients with a high expected mortality due to comorbid illness or poor general health, patients who expect to undergo transplantation in less than 1 year, dialysis patients with living donors, and those who do decline operative therapy, respectively. However, it is not known whether control of PTH will be sustained after cessation of cinacalcet or paricalcitol. It is possible that underlying disease progression still occurs or that effectiveness may not be sustained over the long-term.24 Moreover, cinacalcet is not approved in patients after kidney transplantation and it needs to be elucidated how many of those requiring pretransplant cinacalcet will have to undergo PTX or necessitate ongoing costly off-label administered cinacalcet therapy thereafter. Because our study referred to 2 different medical treatment arms, the group of patients observed was unfortunately too small and heterogeneous to gain reliable data about the treatment successes. To evaluate the outcome of these treatments, prospective randomized multicenter trials with a structured follow-up protocol have to be conducted. However, the wise use of medical resources is paramount to delivering cost-effective care and our study adds a helpful piece of information to enable the development of a reasonable duration and dosage recommendation for the medical
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Table VI. Costs for laboratory measures within the postoperative ambulatory setting Laboratory parameters
Costs/laboratory measure (V) Number of laboratory measures in the 1st year postsurgery Total costs for laboratory measures in the 1st year postsurgery (V) Number of laboratory measures in the 2nd year postsurgery Total costs for laboratory measures in the 2nd year postsurgery (V)
Calcium
PTH
Total
2.76 78 215.28
33.12 2 66.24
35.88 80 281.52
20 55.20
2 66.24
22 121.44
Fig 4. Sensitivity analysis considering different dosages of the drugs compared to costs for surgical therapy over time.
therapies. A combination of our results and the results of future prospective trials comparing the success of medical and surgical treatments will help to facilitate the ever pressing challenge to surgeons in choosing the right patient to undergo surgery, choosing the right surgical technique, and then making the operative treatment more successful, less complicated, and less expensive. In conclusion, sHPT is an important sequela of CKD. The treatment options of sHPT have expanded substantially in the last years, with vitamin D analogs and calcimimetics being the most recent addition. From an economic point of view surgical therapy should be preferred whenever possible. Especially in patients with only little effect on improving mineral balance by cinacalcet or
vitamin D analogs, a prolongation of medical therapy over the recommended length of 4 months seems to be unjustifiable and should not be remunerated by the funding agencies. Randomized studies are needed to predict which patients will most likely gain benefit from early parathyroid surgery in order to avoid unnecessary, prolonged, and costly medical therapy.
REFERENCES 1. Schlieper G, Floege J. Calcimimetics in CKD-results from recent clinical studies. Pediatr Nephrol 2008;23:1721-8. 2. Lewin E, Wang W, Olgaard K. Reversibility of experimental secondary hyperparathyroidism. Kidney Int 1997;52:1232-41. 3. Schlosser K, Veit JA, Witte S, Fernandez ED, Victor N, Knaebel HP, et al. Comparison of total parathyroidectomy
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