This economic evaluation investigates the cost-effectiveness of parathyroid cryopreservation and delayed autotransplantation as a treatment for permanent hypoparathyroidism as a result of thyroid/parathyroid surgery.
Key Points
Question
Is parathyroid cryopreservation and delayed autotransplantation a cost-effective treatment for permanent hypoparathyroidism resulting after thyroid/parathyroid surgery?
Findings
In this forward-looking cost-utility analysis including 10 patients who underwent parathyroid cryopreservation and delayed autotransplantation, 70% of parathyroid autografts were either partially or fully functional, and the marginal cost of cryopreservation and delayed autotransplantation of parathyroid tissue for 10 patients was estimated to be nearly $620 000 (2022 dollars). This equates to an additional 8.75 quality-adjusted life-years (QALY) over 10 years, resulting in a cost per marginal QALY of just over $70 000.
Meaning
Using a willingness-to-pay threshold of $100 000 per QALY, parathyroid cryopreservation and autotransplantation subsequent to thyroid/parathyroid surgery were considered cost-effective at a large, academic center.
Abstract
Importance
Delayed autotransplantation of cryopreserved parathyroid tissue (DACP) is the only surgical treatment for permanent postoperative hypoparathyroidism. Studies suggest that only a small minority of cryopreserved samples are ultimately autotransplanted with highly variable outcomes. For these reasons, many have questioned the economic utility of the process, although, to the authors’ knowledge, this has never been formally studied.
Objective
To report the clinical outcomes of parathyroid cryopreservation and DACP at a large academic institution and to determine the cost-effectiveness of this treatment.
Design, Setting, and Participants
An institutional review board–approved, retrospective review of patients at a single institution who underwent DACP over a 17-year period was conducted with a median follow-up of 48.2 months. A forward-looking cost-utility analysis was then performed to determine the economic utility of cryopreservation/DACP vs usual care (monitoring and supplementation). Patients who had parathyroid tissue in cryopreserved storage between August 2005 to September 2022 at a single-center, academic, quaternary care center were identified.
Exposure
Parathyroid cryopreservation and DACP.
Main Outcomes and Measures
Graft functionality, clinical outcomes, and cost utility using a willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY).
Results
A total of 591 patients underwent cryopreservation. Of these, 10 patients (1.7%; mean [SD] age, 45.6 [17.9] years; 6 male [60%]) underwent DACP. A minority of autografts (2 [20%]) were subsequently fully functional, one-half (5 [50%]) were partially functional, and 3 (30%) were not functional. The cost-utility model estimated that at a large academic center over 10 years, the additional cost of 591 patients undergoing cryopreservation and 10 patients undergoing autotransplantation would be $618 791.64 (2022 dollars) and would add 8.75 QALYs, resulting in a cost per marginal QALY of $70 719.04, which is less than the common willingness-to-pay threshold of $100 000/QALY.
Conclusions and Relevance
The reimplantation rate of cryopreserved tissue was low (<2%), but when implanted, autografts were at least partially functional 70% of the time. In the first-ever, to the authors’ knowledge, formal cost analysis for this treatment, results of the current model suggest that cryopreservation and autotransplantation were cost-effective compared with the usual care for hypoparathyroidism at a large, academic institution. It is recommended that each surgical center consider whether the economic and logistical commitments necessary for cryopreservation are worthwhile for their individual needs.
Introduction
Postoperative permanent hypoparathyroidism (accounting for 75% of all cases of permanent hypoparathyroidism) is defined as low serum calcium level in the presence of a low or inappropriately normal parathyroid hormone (PTH) level, persisting more than 12 months after surgery.1,2,3 Hypoparathyroidism is associated with morbidity (cardiovascular,1,4,5,6 kidney,1,4,7 neurologic,1,8,9 psychiatric,6,10,11 and skeletal1,12,13,14) and reduced quality of life.15,16,17,18,19 Thankfully, permanent hypoparathyroidism is a rare postoperative complication, with a risk of less than 1% to 2% after index neck operations.20,21 Total and subtotal parathyroidectomy,20,22,23 central neck dissections,24,25 and reoperative neck operations23,26,27,28 place patients at higher risk.
Parathyroid autotransplantation, first performed in canines by William Halsted, MD, in 1909 and in humans by Frank Lahey, MD, in 1926, is commonly used during thyroid/parathyroid surgery to reduce rates of hypoparathyroidism.29,30,31 However, most cases of postoperative hypoparathyroidism are only transient. Predicting which patients will develop permanent postoperative hypoparathyroidism is difficult.1 Delayed autotransplantation of cryopreserved parathyroid tissue (DACP) was developed in the 1970s by Samuel Wells Jr, MD, to attempt to restore parathyroid function in patients who develop permanent hypoparathyroidism.32 Currently, there are no standardized indications for cryopreservation of parathyroid tissue, but common reasons include multiple gland hyperplasia due to secondary/tertiary hyperparathyroidism (HPT), familial HPT, and reoperative anterior neck surgery.20
Although DACP is conceptually appealing, it is seldom actually performed. Most studies demonstrate that the utilization rate, defined as the percentage of cryopreserved tissue samples that are actually autotransplanted, is approximately 1.0% to 2.5%.33,34,35,36 Success rates of DACP have been widely variable in the literature, due in part to a lack of consistency regarding the definition of a fully functioning autograft. The majority of published data on DACP come from small, single institution case series from 1979 to the 2000s that have reported success rates ranging from 8% to 71%,23,27,34,37,38,39,40,41,42 with the majority falling in the 20% to 50% range. In 2010, Borot et al36 reported the first multicenter case series from 9 French tissue banks, including over 1300 cryopreserved parathyroid samples, in which 22 DACP procedures were performed, and the fully functional autograft rate was 10%. Shepet et al35 described the Wisconsin experience of over 400 patients who underwent parathyroid cryopreservation, revealing a tissue reimplantation rate less than 1% and only a single patient of the 4 who had DACP procedures was considered to have been surgically cured with a PTH level of 14 pg/mL (to convert to nanograms per liter, multiply by 1). Conversely, Schneider et al33 reported a German case series of 15 DACP procedures, in which 100% of the patients reportedly had functioning autografts at a mean follow-up of 78 months. Schneider et al33 posit that their unusually high success rate may be due to the microbiological and histological examinations of the cryopreserved samples before completing DACP.
In addition to the added costs associated with increased morbidity, permanent hypoparathyroidism is associated with increased hospital readmission rates,25,43,44 increased emergency department and outpatient visits,15,45 longer hospital lengths of stay,25 and the need for lifelong medications and laboratory testing.20,46 Although these factors increase health care costs, given the low tissue utilization rate and unpredictable autograft functionality, many have previously questioned the utility of DACP from a public health and economic standpoint.23,33,35,36 Currently, published DACP financial data are sparse and include only very limited cost information based on estimations of a few steps in the DACP process.33,47 To our knowledge, a formal cost analysis of cryopreservation and DACP has not previously been reported in the literature. Based on the history of cryopreservation at our institution, the lack of large case series reported in the last decade, and the absence of studies investigating the cost efficiency of DACP, we have herein reported our experience with cryopreservation over the past 17 years along with a forward-looking cost-utility analysis to help investigate the cost-effectiveness of parathyroid cryopreservation and DACP.
Methods
Clinical Data Collection
We performed a Washington University School of Medicine institutional review board (IRB)–approved, retrospective review of all patients who underwent parathyroid cryopreservation between August 2005 (when the cryopreservation laboratory began electronic recordkeeping) and September 2022, at a single, high-volume parathyroid surgery center. An exemption for informed consent of study participants was obtained by the IRB due to the use of deidentified patient data. Among this cohort, patients who underwent DACP were identified and analyzed. Information on patient race and ethnicity was not included in this study because of the small sample size, and these data were not originally collected during initial data capture. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guidelines were followed for this study.
Graft Functionality Categorization
The autograft functionality categorization defined in this study was based on the definitions described by Cohen et al39 in 2005. In this schema, autografts were categorized as fully, partially, or not functional, defined by PTH level and calcium and vitamin D (including calcitriol) supplementation:
Fully functional: post-DACP PTH level of 15 pg/mL or greater AND calcium/vitamin D supplements discontinued.
Partially functional: post-DACP PTH level of 15 pg/mL or greater OR calcium/vitamin D supplements reduced.
Not functional: post-DACP PTH level less than 15 pg/mL AND calcium/vitamin D supplements unchanged.
Of note, for the few patients who had PTH levels greater than 15 pg/mL pre-DACP (the lower limit of normal at our institution), the PTH criterion was considered to be met only if the post-DACP PTH level was higher than the pre-DACP PTH level. Additionally, for the 2 most remote parathyroid explanations (1994 and 2003), exact preoperative PTH levels were not available in the medical record, therefore, PTH level was assumed to be less than 15 pg/mL based on clinical notes stating that the patient was biochemically hypoparathyroid. Detailed information on the cryopreservation and autotransplantation logistics protocol is available in eMethods 1 in Supplement 1.
Statistical Analysis
Normality of Continuous Variables and Reporting of Statistical Averages
The Shapiro-Wilk test was used to determine normality of the continuous demographic data, where P < .05 suggests nonnormality. Age was determined to be normally distributed, whereas cryopreserved storage time for all patients in the biobank, time from cryopreservation to autotransplantation for the patients who underwent DACP, and patient follow-up time were nonnormally distributed. The averages of these continuous data were reported as either mean with SD (for normally distributed data) or median with IQR (for nonnormally distributed data).
Retrospective Variable Statistical Analyses
Univariate analyses of all demographic data from the patients who underwent DACP were performed to determine associations with autograft functionality. For these analyses, fully functional autografts were compared with nonfully functional autografts, which included both partially and not functional autografts. Normally distributed variables were analyzed with the Mann-Whitney U test, whereas nonnormally distributed variables were analyzed with the unpaired t test. Categorical data were analyzed with the Fisher exact test. Statistical significance for all tests was considered at a 2-sided P value < .05.
Forward-Looking Cost-Utility Analysis
A forward-looking cost-utility analysis was performed to compare the economic utility of hypoparathyroidism usual care vs cryopreservation and autotransplantation at our center. The term forward looking describes handling of all costs in current terms and considering the future over a 10-year time horizon for run-out of cost and utility. A blended societal perspective was used: in brief, our internal organizational costs were determined using a time-driven activity-based production costing strategy,48 whereas referenced subsequent treatment costs and quality-adjusted life-years (QALYs) gains may reflect patient and societal views.
All costs were reported in 2022 US dollars. Historical costs were normalized to 2022 dollars using annual observed health care inflation rates reported by the US Bureau of Labor Statistics.49 All costs and QALYs accounted for more than 12 months in the future were brought back to a current time frame using 3% annual discounting, a typical benchmark rate for health care analyses. A willingness-to-pay (WTP) threshold of $100 000 per QALY was used, although there is some controversy over the ideal WTP for the US.50,51,52,53
We performed the analysis using the experience from the cohort of patients who had undergone parathyroid cryopreservation in our retrospective review, applying those outcomes in our prospective model. In this analysis, 2 scenarios were compared. In the cryopreservation scenario, the total number of patients was presumed to undergo parathyroid surgery with cryopreservation, and a portion of those patients (the same number in the retrospective review) was presumed to develop permanent hypoparathyroidism treated with DACP. In the usual-care scenario, the same total number of patients was considered to have undergone parathyroid surgery without cryopreservation, and a portion of these patients was presumed to develop permanent hypoparathyroidism treated with usual care only. The usual-care scenario acted as the base case in our model, such that the outcomes of interest were the marginal costs and QALYs from the cryopreservation scenario that were added on top of the usual care scenario.
In these scenarios, the discounted cost of hypoparathyroidism usual care from time zero (assumed to start at the point of DACP) was calculated to be $51 944.86 per patient per 10 years based on data from Chomsky-Higgins et al.46 This value incorporates the costs associated with calcium and vitamin D (including calcitriol) supplementation, along with outpatient office visits, and was discounted appropriately.46 Fully curing a patient with permanent hypoparathyroidism was considered to add 0.222 QALYs per year per patient, based on a baseline 0.778 QALY per year for patients with permanent hypoparathyroidism undergoing usual care46,54 to 1.0 QALY per year associated with a normal quality of life. Partially curing a patient was assumed to restore one-half that amount: 0.111 QALY per year per patient. All cost and quality of life inputs used in our cost-utility analysis are listed in the eTable in Supplement 1. More details on the cost-utility analysis are available in eMethods 2 in Supplement 1.
Results
DACP Case Series Descriptive Data
A total of 591 patients underwent cryopreservation between August 2005 and September 2022. Median (IQR) cryopreservation time was 23.0 (13.0-47.0) months. Among the 591 patients, 10 (1.7%; mean [SD] age, 45.6 [17.9] years; 6 male [60%]; 4 female [40%]) underwent DACP. The DACP case series is summarized in Table 1, and the demographics, surgical details, and outcomes are described in Table 2. One patient (patient 4 in Table 1) had multiple endocrine neoplasia type 1. The median (IQR) time from parathyroid cryopreservation to autotransplantation was 7.5 (6.0-32.4) months, with the longest being 150.7 months.
Table 1. Delayed Autotransplantation of Cryopreserved Parathyroid Tissue (DACP) Case Seriesa.
| Patient | Year of harvest | Year of DACP | Age, y (sex) | HPT diagnosis | Cryopreserved storage time, mo | Pre-DACP PTH level, pg/mL | Post-DACP PTH level, pg/mL | Post-DACP calcium /vitamin D supplementation |
Graft function |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 1994 | 2007 | 37 (M) | Secondary | 150.7 | <15b | 17 | Reduced | Partially functional |
| 2 | 2003 | 2011 | 55 (M) | Secondary | 48.7 | <15b | 11 | Unchanged | Not functional |
| 3 | 2004 | 2006 | 34 (M) | Secondary | 26.9 | 2 | 8-28 | Reduced | Partially functional |
| 4 | 2008 | 2008 | 23 (F) | Primary | 2.5 | 3-5 | 95 | Discontinued | Fully functional |
| 5 | 2015 | 2015 | 65 (M) | Primary | 7.7 | 20-22 | 21 | Reduced | Partially functional |
| 6 | 2015 | 2016 | 40 (F) | Primary | 6.7 | 2-3 | 3 | Unchanged | Not functional |
| 7 | 2015 | 2016 | 28 (F) | Secondary | 7.3 | 14 | 61-94 | Reduced | Partially functional |
| 8 | 2021 | 2021 | 42 (M) | Secondary | 5.2 | <15c | 80 | Discontinued | Fully functional |
| 9 | 2021 | 2022 | 50 (F) | Primary | 7.8 | 16-17 | 4-12 | Reduced | Partially functional |
| 10 | 2022 | 2022 | 82 (M) | Primary | 6.2 | 14-15 | 4-14 | Unchanged | Not functional |
Abbreviations: F, female; HPT, hyperparathyroidism; M, male; PTH, parathyroid hormone.
SI conversion factor: To convert PTH level to nanograms per liter, multiply by 1.
Descriptive and clinical outcomes data are listed for each DACP case.
Actual pre-DACP PTH levels were not available for these patients due to limitations in the electronic medical record, however operative notes described the clinical state of hypoparathyroidism, so it is assumed that the pre-DACP PTH level was less than 15 pg/mL.
This level was drawn at a different laboratory where the undetectable level was reported as less than 15 pg/mL.
Table 2. Patient Demographics, Surgical Details, and Clinical Outcomes of 10 Patients Who Underwent Delayed Autotransplantation of Cryopreserved Parathyroid Tissue (DACP).
| Dates of study | August 2005 to September 2022 |
|---|---|
| Patients cryopreserved, No. | 591 |
| Patients status-post DACP, No. (%) | 10 (1.7) |
| Age at DACP, mean (SD), y | 45.6 (17.9) |
| Sex, No. (%) | |
| Female | 4 (40) |
| Male | 6 (60) |
| Index operation indication, No. (%) | |
| Primary HPT | 5 (50) |
| Secondary HPT | 5 (50) |
| Time of cryopreserved storage to autotransplantation, median (IQR), mo | 7.5 (6.0-32.4) |
| Anatomical site of DACP | |
| Upper extremity | 5 (50) |
| Abdominal wall | 3 (30) |
| Chest wall | 2 (20) |
| Depth of implantation of DACP | |
| Subcutaneous | 6 (60) |
| Intramuscular | 4 (40) |
| Follow-up time, median (IQR), mo | 48.2 (8.2-78.5) |
| Post-DACP PTH level ≥15 pg/mL, No. (%)a | 5 (50) |
| Post-DACP calcium/vitamin D supplementation discontinued, No. (%) | 2 (20) |
| Graft function, No. (%) | |
| Fully functional | 2 (20) |
| Partially functional | 5 (50) |
| Not functional | 3 (30) |
Abbreviations: HPT, hyperparathyroidism; PTH, parathyroid hormone.
For patients with PTH level of 15 pg/mL or greater preoperatively, this criterion was only met if post-DACP PTH level was higher than pre-DACP PTH level.
DACP Case Series Clinical Outcome Data
Five patients (50%) had a normalization of PTH level after autotransplantation. Median (IQR) follow-up from DACP to the last laboratory or medication review was 48.2 (8.2-78.5) months. Post-DACP, 2 patients (20%) had their calcium and vitamin D supplements discontinued completely, 5 patients (50%) had reductions in supplementation, and 3 patients (30%) had no changes in their supplementation. Using the graft function criteria defined previously, 2 patients (20%) had fully functioning DACP grafts, 5 (50%) had partially functioning grafts, and 3 (30%) had nonfunctional grafts (Table 2).
Fully functioning grafts were associated with a significantly shorter cryopreserved storage time, compared with partially functioning and nonfunctioning grafts (median [IQR], 3.85 [2.50-5.20] months vs 7.75 [6.85-43.25] months; P = .04) (eFigure in Supplement 1). No statistically significant associations with graft function classification were found when comparing age, sex, type of HPT, anatomic site of autotransplantation, and depth (subcutaneous vs intramuscular) of autotransplantation, but cohort size limited this analysis.
Cost-Utility Analysis
In our forward-looking cost-utility analysis (Table 3), the total cost of care in the usual care scenario, comprising 10 patients receiving usual care for 10 years, was predicted to be $519 448.60. The cryopreservation and DACP scenario included the freezing and cryopreservation costs for 591 patients, the costs of DACP for 10 patients, and the costs of usual care for the patients who would not be cured by DACP, totaling $1 138 240.24. The marginal quality of life (added on top of the base case usual care scenario) in the cryopreservation and DACP scenario was 8.75 QALY (2 patients × 0.222 QALY per year and 5 patients × 0.11 QALY per year, discounted over 10 years). Thus, the total cost per 1 QALY added by cryopreservation and autotransplantation was predicted to be $70 719.04 per QALY. This value is less than the common WTP of $100 000 per QALY (Figure). This conclusion was stable under most scenarios tested in our sensitivity analyses, including the cost of hypoparathyroidism usual care being halved (Table 4). If partially cured patients were considered to receive a lower gain-back in quality of life (25% vs 50%), the conclusion remained positive but closer to the $100 000 threshold. Cryopreservation was no longer considered cost-effective if the success rate of the DACP procedure decreased to 10% full cure and 30% partial cure. Threshold values resulting in exactly a $100 000 cost per QALY included the following: marginal cost of index surgery increasing to $673 (from $239), sample freezing cost increasing to $1321 (from $878), or the DACP procedure cost increasing to $28 363 (from $2742). Further detail is provided in the eResults in Supplement 1.
Table 3. 10-Year Prediction of Health Care Costs With and Without Parathyroid Cryopreservation and Delayed Autotransplantation of Cryopreserved Parathyroid Tissue (DACP)a.
| Usual care | Cryopreservation and DACP | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Patient subset | Cost description | Unit cost per patient, $ | Patient multiplier | Marginal cost (in 2022), $ | Patient subset | Cost description | Unit cost per patient, $ | Patient multiplier | Marginal cost (in 2022), $ |
| 591 Patients who would have undergone cryopreservation | No cost of cryopreservation | 0 | 591 Patients who underwent cryopreservation | Index surgery | 239.14 | 591 | 141 331.74 | ||
| Sample freezing | 887.56 | 591 | 524 547.96 | ||||||
| Cryo preserved storage for 31.0 moa | 144.91 | 591 | 85 641.81 | ||||||
| 581 Patients who did not undergo DACP | Costs cancel out between groups | 581 Patients who did not undergo DACP | Costs cancel out between groups | ||||||
| 10 Patients with permanent hypoparathyroidism treated with usual care | Usual care for 10.0 yb | 51 944.86 | 10 | 519 448.60 | 10 Patients with permanent hypoparathyroidism treated with DACP | Usual care for 7.5 mo until surgery | 3709.28 | 10 | 37 092.80 |
| DACP preop care | 1436.96 | 10 | 14 369.60 | ||||||
| Sample thawing | 1003.33 | 10 | 10 033.30 | ||||||
| DACP day of surgery care | 3368.02 | 10 | 33 680.20 | ||||||
| DACP postop care | 584.61 | 10 | 5846.10 | ||||||
| 2 Patients fully cured | No further care costs | 0 | 0 | 0 | |||||
| 0.222 QALY added/y × 10 yb × 2 pts | 3.89 QALY | ||||||||
| 5 Patients partially cured | Half usual care for 10 yb | 25 972.43 | 5 | 129 862.15 | |||||
| 0.111 added QALY/y × 10 yb × 5 pts | 4.86 QALY | ||||||||
| 3 Patients not cured | Full usual care for 10 yb | 51 944.86 | 3 | 155 834.58 | |||||
| Continue at usual care QALY | 0 QALY added | ||||||||
| Total cost of care without Cryo + DACP | 519 448.60 | Total cost of care with Cryo + DACP | 1 138 240.24 | ||||||
| Marginal cost added from Cryo + DACP = 618 791.64 | |||||||||
| Marginal QALY added from Cryo + DACP = 8.75 QALY | |||||||||
| Cost of 1 QALY added from Cryo + DACP = 70 719.04 | |||||||||
Abbreviations: Cryo, cryopreservation; postop, postoperative; preop, preoperative; QALY, quality-adjusted life-years.
A 10-year time horizon comparing 2 scenarios of with and without cryopreservation is shown. The base case scenario assumes no parathyroid cryopreservation or DACP. In this scenario, costs included hypoparathyroidism usual care for 10 years for 10 patients. The cryopreservation and DACP scenario is informed by the clinical outcomes from the retrospective institutional case series. Assumptions for this scenario include 591 patients undergoing cryopreservation and 10 patients undergoing DACP, with 2 patients being fully cured, 5 patients partially cured, and 3 patients not cured. All costs are in 2022 dollars.
Denotes that 3% annual discounting was applied.
Figure. Forward-Looking Cost-Utility Analysis of Parathyroid Cryopreservation vs Usual Care.
Costs associated with the parathyroid tissue cryopreservation of 591 patients and delayed autotransplantation of cryopreserved parathyroid tissue (DACP) of 10 patients are shown in the orange ovals. The cost savings associated with usual care reduction for the 10 patients who underwent DACP is shown in the green oval. The overall marginal cost added by cryopreservation and DACP is shown in the brown oval. Added quality-adjusted life-years (QALYs) are shown in the orange boxes. The overall cost of 1 QALY added by cryopreservation and DACP is shown in the blue box.
Table 4. Cost-Utility Sensitivity Analysisa.
| Sensitivity analysis | Adjusted cost of 1 QALY added from Cryo + DACP, $ | Considered cost-effective? |
|---|---|---|
| Cost of usual care doubles from $5934.84/y/patient to $11 869.68/y/patient | 48 243.72 | Yes |
| Cost of usual care cut in half from $5934.84/y/patient to $2967.42/y/patient | 81 956.71 | Yes |
| DACP success rate increases from 20% full and 50% partial cure to 30% full and 70% partial cure | 40 768.16 | Yes |
| DACP success rate decreases from 20% full and 50% partial cure to 10% full and 30% partial cure | 149 006.47 | No |
| Partially cured patient quality of life decreases from 50% QALY gain back to 25% QALY gain back | 97 910.07 | Yes (close to threshold) |
| Partially cured patient quality of life increases from 50% QALY gain back to 75% QALY gain back | 55 348.09 | Yes |
| Marginal cost of index surgery increases from $239.14 to $672.66 | 100 000.00 | (At threshold) |
| Sample freezing cost increases from $887.56 to $1321.08 | 100 000.00 | (At threshold) |
| DACP procedure cost increases from $2742.24 to $28 363.08 | 100 000.00 | (At threshold) |
Abbreviations: Cryo, cryopreservation; DACP, delayed autotransplantation of cryopreserved parathyroid tissue; QALY, quality-adjusted life-years.
Various alternative scenarios and adjustments were considered to test the stability of the cost-utility analysis conclusion. The model was considered cost-effective if the cost per one QALY added was less than the willingness-to-pay threshold of approximately $100 000.
Discussion
In this cost-utility analysis, our data suggest a low (<2%) overall reimplantation rate of cryopreserved parathyroid tissue, but the majority (70%) of subsequent delayed parathyroid autografts were at least partially functional. Furthermore, parathyroid cryopreservation and autotransplantation does seem to be cost-effective compared with usual care at our academic center. To our knowledge, this was the largest US parathyroid cryopreservation case series reported to date, with nearly 600 patients undergoing cryopreservation and 10 patients undergoing DACP over a 17-year period. Additionally, this study was the first cost analysis, to our knowledge, investigating the economic utility of cryopreservation and autotransplantation. eDiscussion 1 in Supplement 1 contains information on the clinical outcomes from our retrospective case review.
With a $100 000 WTP threshold, this cost-utility analysis suggests that cryopreservation and DACP are cost-effective at a large academic center compared with usual care. This conclusion remained stable under several alternative scenarios considered in sensitivity analyses, although notably, the conclusion was not upheld when the observed success rates of DACP were halved. Although a $100 000 WTP threshold is commonly used in the US, defining the value of quality of life in economic terms is controversial.50,51,52,53 Some suggest a smaller number should be used, such as $50 000 per QALY,55 a value taken from an estimation of Medicaid expenditures for a year of dialysis, whereas others advocate for a larger WTP threshold,56 and still others argue that the WTP and QALY paradigm is altogether flawed.57 Our results must be interpreted in this context, as using a lower WTP threshold such as $50 000 would render cryopreservation and autotransplantation not cost-effective.
Based on our results, there are 3 main recommendations warranted to assist surgeons and health care systems further reduce the cost per QALY from cryopreservation and DACP. First, cryopreserved parathyroid tissue should be discarded as soon as it is clear that the patient has a low likelihood of developing permanent hypoparathyroidism. Typically, parathyroid tissue can be discarded relatively early if the PTH level is greater than 10 pg/mL within 12 to 24 hours postoperatively, as this has been shown to be a reliable predictor that permanent hypoparathyroidism is unlikely to occur.1 Second, given the consistent finding in the literature that the vast majority of cryopreserved parathyroid samples are never autotransplanted and that the cost of explanting and freezing parathyroid tissue for a single patient is high ($1126.70), surgeons should reserve parathyroid cryopreservation for only those patients who have a high risk of permanent hypoparathyroidism. Third, for parathyroid tissue that has already been cryopreserved, a lower threshold to perform autotransplantation might be considered in appropriately selected patients. In our analysis, each additional appropriately selected DACP performed for qualified candidates could save the health care system on average almost $17 000 over 10 years and also slightly improve the patient’s quality of life. Independently, each of these recommendations, if applied to the cryopreservation and DACP scenario of our economic analysis, would have resulted in a favorable reduction in the cost per added QALY by approximately $6000 to $9000. Further details are available in eDiscussion 2 in Supplement 1.
There are also some general recommendations for surgeons and surgical centers considering cryopreservation based on this experience. First, cryopreservation and autotransplantation involve complicated logistics that are time and resource intensive for a modest improvement in clinical outcome. For these reasons, this therapeutic approach likely should not be used at centers with low parathyroid surgery volume and individual institutions should consider whether to commit the time, effort, and monetary resources. Second, surgical centers could consider creating standardized indications for parathyroid cryopreservation to help prevent unnecessary costs. Third, from our data and other studies, longer cryopreserved storage time is associated with reduced parathyroid autograft function.20,27,35,39,40,41,58 Thus, surgeons would be wise to proceed with autotransplantation as early as possible after cryopreservation (when clinically necessary) to reduce the risk of autograft nonfunctionality, while simultaneously decreasing ongoing storage costs. Lastly, our center also has early experience in avoiding the costs of cryopreservation altogether by storing explanted parathyroid tissue in refrigerated sterile saline or histidine-tryptophan-ketoglutarate solution overnight and then considering early autotransplantation vs discarding the tissue based on PTH values on postoperative day 1. We do not yet have an extensive series of such cases, but this is feasible and can be effective, and we hope to study this further in the future.
Limitations
Our study is not without limitations. It is retrospective in nature, and although it included many patients who underwent cryopreservation, the sample size of 10 patients undergoing DACP was small, thereby limiting statistical power. The fact that this study was performed at a single-center, high-volume, academic institution may limit applicability of the results to other thyroid/parathyroid surgery centers. The cost-utility analysis itself also has limitations, primarily related to assumptions made for the model inputs, which are further discussed in eDiscussion 3 in Supplement 1. Lastly, although our cost analysis was performed from a blended societal perspective, there are costs to the system at large that may not have been captured, such as more frequent health care utilization and increased comorbidities that are known to be associated with permanent hypoparathyroidism.1,9,45
Conclusions
In summary, although rare, postoperative permanent hypoparathyroidism is both debilitating for patients and costly for the health care system. Almost 50 years after its development, parathyroid cryopreservation and delayed autotransplantation remains one of the few treatment options. Overall use of DACP is low but the majority of autografts reimplanted do have some functionality. Only a small proportion of patients who undergo DACP have their calcium and vitamin D supplementation discontinued completely. At our single, large-volume academic center, parathyroid cryopreservation and delayed autotransplantation was predicted to be cost-effective compared with hypoparathyroidism usual care at approximately $71 000 per added QALY. Each surgical center should strongly consider their individual patient population and surgical needs before implementing DACP, as the economic and logistical costs associated with this approach may not be justified for all centers.
eMethods 1. Cryopreservation and Autotransplantation Logistics Protocol
eMethods 2. Cryopreservation and Usual Care Scenario Details
eResults. Cost-Utility Analysis Further Details
eDiscussion 1. Discussion of Retrospective Case Review Clinical Outcomes
eDiscussion 2. Cost Saving Recommendations Details
eDiscussion 3. Further Discussion Regarding the Limitations of Assumptions of the Economic Model
eTable. Cost-Utility Analysis Model Inputs
eFigure. Cryopreservation Storage Time by DACP Graft Function Classification
eReferences
Data Sharing Statement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods 1. Cryopreservation and Autotransplantation Logistics Protocol
eMethods 2. Cryopreservation and Usual Care Scenario Details
eResults. Cost-Utility Analysis Further Details
eDiscussion 1. Discussion of Retrospective Case Review Clinical Outcomes
eDiscussion 2. Cost Saving Recommendations Details
eDiscussion 3. Further Discussion Regarding the Limitations of Assumptions of the Economic Model
eTable. Cost-Utility Analysis Model Inputs
eFigure. Cryopreservation Storage Time by DACP Graft Function Classification
eReferences
Data Sharing Statement.