- Email: [email protected]
Comparing Microvascular Decompression with Gamma Knife Radiosurgery for Trigeminal Neuralgia. A Cost-Effectiveness Analysis
Doing More with Less
Comparing Microvascular Decompression with Gamma Knife Radiosurgery for Trigeminal Neuralgia. A Cost-Effectiveness Analysis Gurpreet S. Gandhoke1, Kenneth J. Smith2, Ajay Niranjan3, Raymond F. Sekula3, L. Dade Lunsford3
BACKGROUND AND OBJECTIVE: Both microvascular decompression (MVD) and Gamma Knife radiosurgery (GKRS) are time-tested treatment modalities for trigeminal neuralgia (TN). There is little evidence in the literature studying these modalities head to head in a costeffectiveness comparison.
-
OBJECTIVE: To evaluate the cost-effectiveness of MVD compared with GKRS for treating patients with TN.
-
METHODS: We developed a Markov cost-effectiveness model for the U.S. health care system to account for all costs related to MVD and GKRS as treatment modalities for TN, from the health care system perspective, over a patient lifetime horizon. A base case was estimated using data from previous studies, from our own GKRS experience, and from a current data analysis of patients undergoing MVD. We derived model inputs, including health care costs, survival, and utility estimates, from the literature. We used age-specific, sex-specific, and race-specific mortality from national registries. Costs studied included those for MVD, for GKRS, for treating complications from either procedure, and for medications throughout patient lifetimes. We performed multiple 1-way, 2-way, and probabilistic sensitivity analyses to confirm the robustness of model assumptions and results. The incremental cost-effectiveness ratio (ICER), with a threshold of $50,000 per quality-adjusted lifeyear (QALY) gained, defined cost-effectiveness.
-
RESULTS: The base case had an ICER of $12,154 per QALY for MVD compared with GKRS. Probabilistic
-
Key words - Cost-effectiveness - Gamma Knife radiosurgery - Microvascular decompression - Trigeminal neuralgia Abbreviations and Acronyms BNI: Barrow Neurological Institute GKRS: Gamma Knife radiosurgery ICER: Incremental cost-effectiveness ratio MVD: Microvascular decompression PRGR: Percutaneous retrogasserian rhizotomy QALY: Quality-adjusted life-year QAPFY: Quality-adjusted pain-free year TN: Trigeminal neuralgia WTP: Willingness to pay
WORLD NEUROSURGERY 125: 207-216, MAY 2019
sensitivity (Monte Carlo) analysis showed that MVD was cost-effective in 70% of model iterations. GKRS was favored when the willingness to pay threshold was <$12,000 per QALY gained. CONCLUSIONS: In patients medically eligible for either procedure, we found MVD to be the most cost-effective modality to treat TN, primarily because of its reported greater durability. MVD remained the most cost-effective strategy across a broad range of model input values in sensitivity analyses.
-
INTRODUCTION
T
rigeminal neuralgia (TN) is a neuropathic pain disorder marked by evoked and spontaneous attacks in the distribution of the trigeminal nerve. The disorder is further associated with periods of partial or complete remission but there is recurrence in most patients. The pain of TN is considered to be among the most debilitating types of pain. Neurovascular compression of the trigeminal nerve has been accepted as the cause of classical TN in most patients by the International Headache Society. Because of its minimally invasive nature, stereotactic radiosurgery using the Gamma Knife (Elekta, Stockholm, Sweden) has, in the past 2 decades, emerged as an alternative to initial microvascular decompression (MVD) of the trigeminal nerve. The reasons for the increasing use of radiosurgery in the management of TN include an avoidance of general anesthesia and its attendant risks, absence From the 1Marion Bloch Neuroscience Institute, Saint Luke’s Hospital, Kansas City, Missouri; and Departments of 2Medicine and 3Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA To whom correspondence should be addressed: Gurpreet S. Gandhoke, M.D., M.S. [E-mail: [email protected]] Raymond F. Sekula and L. Dade Lunsford have contributed equally as senior authors in the evolution of this manuscript. Citation: World Neurosurg. (2019) 125:207-216. https://doi.org/10.1016/j.wneu.2018.12.204 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
www.journals.elsevier.com/world-neurosurgery
207
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 1. The Markov state transition model. BNI, Barrow Neurological Institute; GKRS, Gamma Knife
of radiographically apparent neurovascular compression,1 decreased overall cost, and a lower major morbidity profile (e.g., stroke or death).2 Arguments against the use of radiosurgery for TN include the superior durability of MVD3 and its efficacy and safety even in elderly patients.4 In this study, we sought to evaluate the cost-effectiveness of Gamma Knife radiosurgery (GKRS) compared with MVD for patients with TN. METHODS Study Design and Model Inputs This study was exempt from review by the University of Pittsburgh institutional review board, and informed consent was waived because patient data were de-identified. We developed a Markov cost-effectiveness model to compare MVD with GKRS for the treatment of TN from the health care system perspective over a patient lifetime horizon. We obtained model inputs from the literature and our own data on patients with TN treated with MVD or GKRS. We applied this model to our institution’s cohort of representative patients treated for TN. The MVD data were obtained from the personal series of the senior author (R.F.S.) from treating 208 consecutive patients with TN (173 typical and 35 atypical) from 2011 to 2018. The mean age of these patients was 60 years. None of these patients had previous surgery. The GKRS data2 were obtained from published data from our institutional experience of treating 503 medically refractory patients with idiopathic TN. Mean age was 69 years. GKRS was the first surgical procedure in 288/503 patients. Surgery had been performed previously in 215 patients. We also analyzed our
208
www.SCIENCEDIRECT.com
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
radiosurgery; MVD, microvascular decompression; PRGR, percutaneous retrogasserian rhizotomy.
model with probabilities obtained from Wang et al.’s5 experience of treating 764 patients with TN (364 GKRS and 316 MVD). The model follows a patient from time of diagnosis of TN through treatment with either MVD or GKRS, postoperative pain relief based on the Barrow Neurological Institute (BNI) score, requiring additional procedures, and also accounting for recurrence of symptoms of pain after initial relief. This strategy continues for the remainder of life of the patient. The primary outcome was the incremental cost-effectiveness ratio (ICER), representing the cost paid by the health care system in dollars per quality-adjusted life-year (QALY) gained comparing MVD with GKRS for treating TN. The ICER was calculated as the difference in cost between the 2 strategies divided by the difference in effectiveness. We applied an ICER threshold of $50,000, which is a generally accepted value of costeffective medical interventions in the developed world.6,7
Decision Analytic Markov Model We developed a decision analytic tree model with a decision point choosing either MVD or GKRS as a treatment strategy for treating TN. Patients entered the Markov model at age 50 years with either MVD or GKRS as the initial treatment choice. Surviving patients either had a BNI IeIIIB outcome and remained pain free thereafter or had a BNI IVeV outcome and entered 1 of 3 Markov transition states of having another MVD or GKRS, having a percutaneous retrogasserian rhizotomy (PRGR) or remaining in a BNI IVeV state, with probabilities of those events based on published literature. Patients could then progress through each Markov cycle
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Table 1. The Probabilities Used in the Base Case Model and Their Ranges Applied for Sensitivity Analyses Variable
Base Case Value
Sensitivity Analysis Range
Distribution
Source
BNI IeIIIB score with GKRS
0.8 at 1 year 0.7 at 2 years 0.5 at 5 years 0.3 at 10 years
20%
Beta
Kondziolka et al.2
BNI IeIIIB score with MVD
0.93 at 1 year 0.89 at 2 years 0.80 at 5 years 0.44 at 10 years
20%
Beta
Sekula dataset Sekula dataset Sekula dataset Wang et al.5
0.18
0.05e0.18
Beta
Kondziolka et al.2
0.91 at 1 year
0.6e0.91
Beta
Cohen et al.8
Redo MVD
0.05
0.01e0.05
Beta
Sekula dataset
BNI IeIIIB with redo MVD
0.7
0.5e0.7
Beta
Bruce Pollock et al.9
MVD after GKRS
0.04
0.01e0.04
Beta
Kondziolka et al.2
BNI IeIIIB score with MVD after GKRS
0.83
0.4e0.83
Beta
Cheng et al.10
Probabilities
Redo GKRS BNI IeIIIB with redo GKRS
GKRS after MVD
0.02
0.01e0.04
Beta
Sekula dataset
BNI IeIIIB score GKRS after MVD
0.7954
0.5e0.7954
Beta
Yi Wang et al.11
PRGR after GKRS
0.131
0.05e0.131
Beta
Kondziolka et al.2
BNI IeIIIB score with PRGR after GKRS
0.36
0.25e0.36
Beta
Pollock et al.9
PRGR after MVD
0.48
0.35e0.5
Beta
Sekula dataset
BNI IeIIIB score with PRGR after MVD
0.57
0.45e0.6
Beta
Kang Ho et al.12
Complication with MVD
0.03
0.01e0.03
Beta
Sekula dataset
Complication with GKRS
0.11
0.05e0.15
Beta
Kondziolka et al.2
Complication with PRGR
0.52
0.2e0.5
Beta
Holland et al.13
Multiplication Factor for BNI IeIIIB yearly rates with GKRS
1
0.8e1.2
Gamma
NA
Multiplication Factor for BNI IeIIIB yearly rates with MVD
1
0.8e1.2
Gamma
NA
All probabilities were constructed as beta distributions for application in the Monte Carlo sensitivity analyses. BNI IeIIIB outcome for MVD at the 10-year mark was not available from the Sekula dataset. We used the BNI I outcome from Wang et al.5 for this calculation. We constructed a gamma distribution for a 20% range for the yearly probabilities of BNI IeIIIB outcomes for GKRS and MVD. BNI, Barrow Neurological Institute; GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression; PRGR, percutaneous retrogasserian rhizotomy, NA, not applicable.
either surviving an additional cycle or dying, with death representing a self-absorbing health state (Figure 1). Model Assumptions We populated decision branch points with probabilities of discrete mutually exclusive events. The probability of going through the MVD or GKRS arm was fixed at 0.5. We used linear regression to calculate yearly probabilities of recurrence of pain with GKRS and MVD from 1-year, 2-year, 5-year, and 10-year probabilities of painfree status for both groups. We assumed that the pain status at the 10-year follow-up mark was constant and patients in both groups would not transition to another state after this time point. We have depicted the probabilities used in the decision tree in Table 1. We obtained the annual probability of mortality from U.S. life tables, with a 0% mortality attributed to both GKRS and MVD by virtue of the procedure itself. A base case was estimated
WORLD NEUROSURGERY 125: 207-216, MAY 2019
using our published data for GKRS from Kondziolka et al.,2 and our own data bank of patients undergoing MVD, from 1 of the senior author’s (R.F.S.) personal series of 208 patients. Base case inputs included a mean age of 50 years, mean time for GKRS, MVD, and PRGR mean length of stay with each procedure, incidence of complications with MVD (cerebrospinal fluid leak and wound infection) and GKRS (facial dysesthesia). The Markov cycle length was set to 1 year, and a 3% discount rate was applied to costs and QALYs. Cost Costs in the model include costs for GKRS, MVD, medications, and complication management for each procedure. All economic inputs represent estimated expenditures to the hospital, rather than charges. Costs for surgical procedures (MVD, GKRS, and PRGR) were obtained from the finance department of our
www.journals.elsevier.com/world-neurosurgery
209
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Table 2. The Cost Data Obtained from the Finance Department at the University of Pittsburgh Medical Center Variable
Base Case Value ($)
Sensitivity Analysis Range
Distribution
Source
Cost of MVD
10,597
8000e15,000
Gamma
Finance department
Cost of GKRS
2916
2500e4000
Gamma
Finance department
Cost of percutaneous retrogasserian rhizotomy
1090
1000e2500
Gamma
Finance department
Cost redo MVD
10,597
8000e15,000
Gamma
Finance department
Cost redo GKRS
2916
2500e4000
Gamma
Finance department
Cost data
Cost of complication with GKRS
180
100e500
Gamma
Patient interview
Cost of complication with MVD
6470
5000e8000
Gamma
Finance department
Cost of medication with GKRS
180 (15*12)
100e500
Gamma
Patient interview
Cost of medication with MVD
180 (15*12)
100e500
Gamma
Patient interview
A gamma distribution was constructed for all cost-related variables for the sensitivity analyses. Data on cost of medications for the treatment of face pain for both groups (MVD and GKRS) were obtained by patient interview and insurance cost for generic medication ($15/month) was used as cost of medications. Because the Markov cycle length used was 1 year, this cost amounted to a total of $180. GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression; PRGR, percutaneous retrogasserian rhizotomy.
university hospital. Yearly medication cost for management of TN or for facial dysesthesia resulting as a complication from any of the 3 surgical procedures were obtained by patient interview. The yearly cost of the generic medication to the insurance company was used for the base case calculations. Costs for management of a complication resulting from MVD, GKRS, or PRGR were also obtained from the hospital finance department (Table 2). Health Outcomes Health outcomes were evaluated as health state utilities in the form of QALYs. Utilities for having any of the 3 procedures (GKRS, MVD, and PRGR) were calculated as the probability of
having a BNI 1 score at 1 month after the procedure multiplied by the utility of a BNI 1 score (1.0).14 Utilities for BNI IeIIIB, BNI IVeV, procedure complications, and medication use were obtained from the literature. The utility for a BNI IeIIIB score was calculated as the mean of BNI I, BNI II, and BNI III state utilities. The utility of the first 1-month after GKRS (waiting for procedure results to occur) was the same as the medication use utility. Losses in QALYs, also known as disutility to the patient, were estimated for those with complications from any procedure, and for the first month after GKRS. These losses were calculated as 1-utility of being in the state of complication (Tables 3 and 4).
Table 3. The Utilities for Each Surgical Procedure, the Barrow Neurological Institute Outcome States, and the State of Being on Medications and Waiting for Gamma Knife Radiosurgery to Take Effect (Month 1 Utility, Which Is the Same as the Utility of Being on Medications During that Time) Variable
Base Case Value
Sensitivity Analysis Range
Distribution
Source
MVD
0.73
0.6e0.8
Triangular
Sekula dataset
GKRS
0.6
0.5e0.8
Triangular
Cohen et al.8
Percutaneous retrogasserian rhizotomy
0.85
0.6e0.9
Triangular
Asplund et al.15
BNI IeIIIB
0.87
0.75e0.95
Triangular
Hunink et al.14 Perez et al.16
BNI IVeV
0.399
0e0.4
Triangular
Perez et al.16
Month 1
0.881
0.5e0.881
Triangular
Berger et al.17
Complication MVD
0.958
0.5e0.958
Triangular
Berger et al.17
Complication GKRS
0.962
0.8e0.962
Triangular
Berger et al.17
Medications
0.881
0.6e0.881
Triangular
Berger et al.17
Utilities
A triangular distribution was constructed for each utility for the probabilistic sensitivity analysis. MVD, microvascular decompression; BNI, Barrow Neurological Institute; GKRS, Gamma Knife radiosurgery.
210
www.SCIENCEDIRECT.com
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Table 4. The Cohort Characteristics, with a Mean Age of Entry into the Marko State Transition Model at 50 Years Variable
Base Case Value
Sensitivity Analysis Range
Distribution
Source
50
NA
NA
Mean age in our cohort GKRS 69 MVD 60
GKRS: 2520 MVD: 1659
365e2520 500e1659
Triangular
Kondziolka et al.2 Sekula dataset
1
0.25e1
Triangular
Kondziolka et al.2 Sekula dataset
Cohort characteristics Start age (years)
Days on medication before GKRS/MVD Days for GKRS MVD
1
1e4
Percutaneous retrogasserian rhizotomy
1
1e2
GKRS
30
30e365
Triangular
Kondziolka et al.2
MVD
4
2e4
Triangular
Sekula dataset
Days with complications
We applied a broad range to the base case value of 30 for the days with complication (facial dysesthesia) because these data were not available in the literature. Despite the broad range (1 month to 1 year), this variable had no significant impact on the incremental cost-effectiveness ratio as shown in the Tornado diagram. GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression.
Sensitivity Analyses We performed multiple sensitivity analyses to evaluate the robustness of our model assumptions and results. One-way sensitivity analysis was performed across all model variables. The most influential variables were selected for 2-way sensitivity analysis to evaluate the effect of varying both inputs simultaneously. Probabilistic sensitivity analysis was performed, varying all parameters simultaneously over distributions, over 1000 Monte Carlo simulations. A cost-effectiveness acceptability curve was generated to evaluate the proportion of Monte Carlo iterations in which strategies are favored across a range of ICER threshold values. Stata version 15 (StataCorp LLC, College Station, Texas, USA) was used for statistical analysis, and TreeAgePro version
2018 (TreeAge Software Inc. Williamstown, Massachusetts, USA) was used for cost-effectiveness modeling. RESULTS The base case showed higher cost and greater effectiveness for MVD compared with GKRS, resulting in an ICER of $12,154/QALY for MVD compared with GKRS (Table 5). One-way sensitivity analysis showed that the probability of maintaining a BNI score of IeIIIB over a period of time for both GKRS and MVD were the most influential model inputs (Figure 2). Two-way sensitivity analysis showed that if the probability of recurrence of pain with MVD is >89% then GKRS is always favored at a $50,000/QALY
Table 5. The Incremental Cost and Incremental Quality-Adjusted Life-Years Provided by Microvascular Decompression Compared with Gamma Knife Radiosurgery
Strategy
Cost ($)
Incremental Cost ($)
Effectiveness
11,289
13.68
Incremental Effectiveness
Incremental Cost-Effectiveness Ratio
0.93
12,154
0.93
12,084
Base case GKRS
8073
MVD
19,362
12.75
Sensitivity analysis GKRS
8073
MVD
19261
14.29 11,188
15.21
Both the base case incremental cost-effectiveness ratio ($12,154/quality-adjusted life-year) and the incremental cost-effectiveness ratio calculated from probabilistic sensitivity analyses ($12,084/quality-adjusted life-year) are close to one another, reiterating the robustness of the calculation and reliability of the results. GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression.
WORLD NEUROSURGERY 125: 207-216, MAY 2019
www.journals.elsevier.com/world-neurosurgery
211
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 2. The Tornado diagram with multiple 1-way sensitivity analyses. Size of bars represents relative influence of each model variable on the incremental cost-effectiveness ratio (ICER) across the range of values tested in sensitivity analysis. This diagram provides evidence that the
threshold, whereas if recurrence of pain with MVD is <47%, then MVD is always favored (Figure 3). Probabilistic sensitivity analysis showed that MVD is the cost-effective strategy in 70% of the iterations at the $50,000/QALY threshold (Figure 4). GKRS became more cost-effective only when the willingness to pay threshold decreased <$12,000. Using Wang et al.’s5 probabilities of BNI I outcome at years 1, 5, and 10 for GKRS and MVD in our model, Monte Carlo probabilistic analysis showed that MVD had 100% cost-effective iterations (Figure 5). Sensitivity analyses were performed to ensure that our results were robust to changes in model assumptions across a range of clinically plausible values. Our base case ICER of $12,154/QALY gained for MVD decreased to $910/QALY when using the probabilities of sustained pain relief from another institution’s experience (Wang et al.5). All sensitivity analyses showed MVD to be the more cost-effective strategy, reiterating the robustness of the base case model. MVD remained the cost-effective strategy until the willingness to pay (WTP) threshold was decreased <$12,000 for the base case model and <$5000 for probabilities of BNI I outcomes (Figures 4 and 5). The generally accepted cost-effectiveness threshold in the United States ranges from $50,000/QALY to
212
www.SCIENCEDIRECT.com
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
probability of maintaining a Barrow Neurological Institute (BNI) IeIIB status with both Gamma Knife radiosurgery (GKRS) and microvascular decompression (MVD) (the longest horizontal bars) are the 2 variables with the maximum impact on the incremental cost-effectiveness ratio.
$100,000/QALY.6,7 Compared with GKRS, MVD was found to provide 1 additional QALY at the cost of approximately $12,000. Both GKRS ($8073 for 12.75 QALYs) and MVD ($19,362 for 13.68 QALYs), by themselves are likely cost-effective compared with no treatment at all. However, comparing head to head, GKRS resulted in 30% cost-effective iterations compared with 70% costeffective iterations of MVD in probabilistic sensitivity analyses. DISCUSSION Almost 8000 patients with TN undergo surgery every year in the United States at an estimated cost of $100 million.18,19 Pollock et al.9 compared MVD, PRGR, and GKRS for the treatment of TN. They obtained data from a prospective nonrandomized trial including 126 patients undergoing 153 operations (MVD, n ¼ 33; PRGR, n ¼ 51; and GKRS, n ¼ 69). Mean follow-up was 20.6 months. The outcome measure that these investigators used was a quality-adjusted pain-free year (QAPFY). This measure was determined by multiplying the length of follow-up after each operation by the adjusted facial pain outcome. Facial pain outcomes were adjusted as excellent
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 3. Two-way sensitivity analysis of probability of recurrence of pain with Gamma Knife radiosurgery (GKRS) and probability of recurrence of pain with microvascular decompression (MVD). Blue area represents pairs
(no pain, no medications), 1.0; good (no pain, reduced medications), 0.7; fair (>50% pain reduction, 0.5; and poor, 0.1. The investigators found that the cost per QAPFY was $6342, $8174, and $8269 for PRGR, MVD, and GKRS, respectively. Comparing GKRS with MVD, we found that the cost per QALY for MVD was $12,154, close to the value obtained by Pollock et al. Our model was different in that the time horizon was over the lifetime of the patient and not confined to the follow-up interval as in the Pollock et al. study. We also discounted for both cost and QALYs, which was not performed in the study by Pollock et al. We used a standardized outcome measures in the form of the BNI score and QALYs in contrast to the QAPFY score. Despite these differences, similar results of the 2 studies reiterate the robustness of the analyses and the dependability of the results of the costeffectiveness frontier. Sivakanthan et al.20 used Medicare claims data in conjunction with a literature review to assess the use, effectiveness, and cost-effectiveness of MVD, GKRS, and PRGR in the treatment of TN. These investigators extracted claim data for the treatment of TN from the 2011 Medicare Data Bank. They used Kaplan-Meier survival curves from 3 articles in their estimation of QALYs. They found the average weighted costs for MVD, GKRS, and PRGR to be $40,434, $38,062, and $3910, respectively. The QALYs were 8.2 for MVD, 4.9 for SRS, and 6.5 for PRGR. The ICER was calculated as $4931, $7767, and $601 for MVD, GKRS, and PRGR, respectively. Sivakanthan et al. calculated QALYs by importing
WORLD NEUROSURGERY 125: 207-216, MAY 2019
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
of these values where Gamma Knife radiosurgery is more cost-effective and red areas represent pairs of these values where microvascular decompression is more cost-effective.
Kaplan-Meier curves from their 3 selected articles into Adobe Photoshop and used the Magic Wand tool to select the area under the curve out to 0 years and normalized to the total area available at 10 years. Because they defined their investigation over a 10-year follow-up period, the graphically derived QALY was multiplied by 10. In our study, with a lifetime horizon and use of the hospital perspective for our economic analysis, and with the use of 3% discounting for both cost and QALYs, we found the cost and QALYs for MVD to be $19,362 and 13.68, respectively. GKRS cost $8073 for 12.75 QALYs. Despite the difference in calculation of QALYs, Sivakanthan et al. also found MVD to be more costeffective (ICER $4931) than was GKRS ($7767). PRGR came out to be the most cost-effective in their study; we did not compare PRGR with MVD and GKRS in our study but based on the higher durability of pain relief with MVD compared with PRGR, this comparison would be an interesting endeavor. Berger et al.17 performed a decision analysis comparing the effectiveness of MVD and GKRS for TN. These investigators modeled pain relief and complication outcomes over a 7-year horizon. Costs were not taken into consideration. One assumption for their model states that “all cases in which pain recurs, does so after 2.5 years and has a BNI IVeV score after pain returns.” Berger et al.17 do not discount for utilities in their study. At 7 years after the procedure, they found that MVD provided 6 QALYs compared with 5.4 QALYs provided by GKRS. They attribute the higher utility of MVD to its higher initial success rate and lower
www.journals.elsevier.com/world-neurosurgery
213
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 4. Cost-effectiveness acceptability curve across a range of cost-effectiveness thresholds from probabilistic sensitivity analysis. Microvascular decompression (MVD) is cost-effective in 70% of iterations
pain recurrence rate compared with GKRS. In our lifetime horizon study, we found MVD to provide 13.68 QALYs compared with 12.75 QALYs with GKRS. This again reiterates the robustness of our decision model and the reliability of the result. A European cost-minimization study (assuming that the effectiveness of both MVD and CyberKnife radiosurgery [(Accuray, Sunnyvale, California, USA)] is the same) by Tarricone et al.21 found Cyber Knife radiosurgery (V4388) to be the cost-saving alternative to MVD (V6641). A cost-minimization study such as this is considered to be the lowest in the hierarchy of evidence in the domain of economic analyses and reports results based on a 6- month follow-up interval. The results may thus not hold strength in the presence of solid evidence that it is the durability of relief from pain that makes MVD more economically viable than radiosurgery in the long run. We do not have experience with using CyberKnife radiosurgery and, thus, we could not study this treatment modality in a head-to-head comparison with GKRS and MVD. The results of this study aim to assist decision making for the treatment of medically refractory TN in cases in which either MVD or GKRS could be appropriate. The less invasive GKRS option is
214
www.SCIENCEDIRECT.com
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
at $50,000 per quality-adjusted life-year, whereas Gamma Knife radiosurgery (GKRS) has more cost-effective iterations only when the cost-effectiveness threshold is <$12,000/quality-adjusted life-year.
appealing to many patients and most often outweighs any discussion regarding comparative effectiveness between various surgical options. Our study reiterates the appropriateness of the current approach used in the management of medically refractory TN. We also used our decision analytical model to compare MVD and GKRS results from another single-institution experience. We used the percentages of patients with BNI pain intensity score of I at 1, 5, and 10 years after MVD of 83%, 61%, and 44%, and the corresponding percentages after GKRS of 71%, 47%, and 27%, respectively, as reported by Wang et al.5 from their experience of treating 764 patients with TN at the University of California, San Francisco. These probabilities in our model yielded an ICER of $900/QALY with a Monte Carlo analysis yielding 100% costeffective iterations in favor of MVD at a WTP threshold of $50,000/QALY (Figure 5). This result also helped reinforce the reliability and dependability of our model. Limitations Establishing clinical equipoise outside an assumption is near impossible because of patient heterogeneity. The attributes of
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 5. Cost-effectiveness acceptability curve across a range of cost-effectiveness thresholds from probabilistic sensitivity analysis for Barrow Neurological Institute I outcome with Gamma Knife radiosurgery (GKRS) and microvascular decompression (MVD) from Wang et al.5
the patient (life expectancy and comorbidities) and the operating surgeon (complication rate and efficacy) affect the cost-benefit analysis. Cost-effectiveness models require variable inputs derived from existing data and literature. This process requires many assumptions, and the results are specific to these data and assumptions. The data used for model inputs came from a variety of sources across varied populations and time periods, assuming that each is representative of patients with TN. We did perform several sensitivity analyses to evaluate the robustness of our conclusions to variations in these data and assumptions, which showed similar results. The costs, complications, and base case results are based on a neurosurgical practice at a quaternary-care center performing many TN operations (both MVD and GKRS) every year. Another surgeon performing fewer
REFERENCES 1. Maarbjerg S, Wolfram F, Gozalov A, Olesen J, Bendtsen L. Significance of neurovascular contact in classical trigeminal neuralgia. Brain. 2015;138: 311-319.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Microvascular decompression is cost-effective in 100% of iterations at $50,000 per quality-adjusted life-year, whereas Gamma Knife radiosurgery has more cost-effective iterations only when the cost-effectiveness threshold is <$5000/quality-adjusted life-year.
procedures may have worse facial pain outcomes and/or a higher complication rate. CONCLUSIONS By U.S. society standards, we are willing to pay $50,000/ QALY. Thus, the current neurosurgical protocol for management of medically refractory TN is economically viable. Our cost-effectiveness study shows that over a long follow-up period, MVD as the initial surgical management of TN is more cost-effective than is GKRS as the initial surgical procedure. This finding is primarily related to the reported increased durability of pain relief after MVD compared with GKRS. This finding is applicable to patients considered medically eligible for either procedure.
4. Sekula RF Jr, Frederickson AM, Jannetta PJ, Quigley MR, Aziz KM, Arnone GD. Microvascular decompression for elderly patients with trigeminal neuralgia: a prospective study and systematic review with meta-analysis. J Neurosurg. 2011;114: 172-179.
2. Kondziolka D, Zorro O, Lobato-Polo J, et al. Gamma Knife stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg. 2010;112: 758-765.
5. Wang DD, Raygor KP, Cage TA, et al. Prospective comparison of long-term pain relief rates after first-time microvascular decompression and stereotactic radiosurgery for trigeminal neuralgia. J Neurosurg. 2018;128:68-77.
3. Barker FG 2nd, Jannetta PJ, Bissonette DJ, Larkins MV, Jho HD. The long-term outcome of microvascular decompression for trigeminal neuralgia. New Engl J Med. 1996;334:1077-1083.
6. Braithwaite RS, Meltzer DO, King JT Jr, Leslie D, Roberts MS. What does the value of modern medicine say about the $50,000 per qualityadjusted life-year decision rule? Med Care. 2008; 46:349-356.
WORLD NEUROSURGERY 125: 207-216, MAY 2019
7. Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness–the curious resilience of the $50,000-per-QALY threshold. New Engl J Med. 2014;371:796-797. 8. Cohen J, Mousavi SH, Faraji AH, et al. Stereotactic radiosurgery as initial surgical management for elderly patients with trigeminal neuralgia. Stereotact Funct Neurosurg. 2017;95:158-165. 9. Pollock BE, Ecker RD. A prospective costeffectiveness study of trigeminal neuralgia surgery. Clin J Pain. 2005;21:317-322. 10. Cheng J, Liu W, Hui X, Lei D, Zhang H. Microvascular decompression for trigeminal neuralgia in patients with failed gamma knife surgery:
www.journals.elsevier.com/world-neurosurgery
215
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
analysis of efficacy and safety. Clin Neurol Neurosurg. 2017;161:88-92.
treatment of trigeminal neuralgia. Neurosurgery. 2016;78:421-428 [discussion: 428].
Claims Database. Neurosurgery. 2014;75:220-226 [discussion: 225-226].
11. Wang Y, Zhang S, Wang W, et al. Gamma Knife surgery for recurrent trigeminal neuralgia in cases with previous microvascular decompression. World Neurosurg. 2018;110:e593-e598.
16. Perez C, Navarro A, Saldana MT, Martinez S, Rejas J. Patient-reported outcomes in subjects with painful trigeminal neuralgia receiving pregabalin: evidence from medical practice in primary care settings. Cephalalgia. 2009;29:781-790.
21. Tarricone R, Aguzzi G, Musi F, Fariselli L, Casasco A. Cost-effectiveness analysis for trigeminal neuralgia: Cyberknife vs microvascular decompression. Neuropsychiatr Dis Treat. 2008;4: 647-652.
17. Berger I, Nayak N, Schuster J, Malhotra NR. Microvascular versus stereotactic radiosurgery neuralgia: a decision analysis. e1000.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
12. Kang IH, Park BJ, Park CK, Malla HP, Lee SH, Rhee BA. A clinical analysis of secondary surgery in trigeminal neuralgia patients who failed prior treatment. J Korean Neurosurg Soc. 2016;59:637-642. 13. Holland M, Noeller J, Buatti J, He W, Shivapour ET, Hitchon PW. The cost-effectiveness of surgery for trigeminal neuralgia in surgically naive patients: a retrospective study. Clin Neurol Neurosurg. 2015;137:34-37. 14. Hunink MGMGP. Decision Making in Health and Medicine: Integrating Evidence and Values. Cambridge, United Kingdom: Cambridge University Press; 2001. 15. Asplund P, Blomstedt P, Bergenheim AT. Percutaneous balloon compression vs percutaneous retrogasserian glycerol rhizotomy for the primary
216
www.SCIENCEDIRECT.com
Lee J, Stein S, decompression for trigeminal Cureus. 2017;9:
Received 16 September 2018; accepted 26 December 2018 18. American Association of Neurological Surgeons. National Neurosurgical Statistics. 1999 Procedural Statistics. Rolling Meadows, IL: American Association of Neurological Surgeons (AANS); 2000.
Citation: World Neurosurg. (2019) 125:207-216. https://doi.org/10.1016/j.wneu.2018.12.204
19. Leksell Gamma Knife Treatment Statistics [press release]. Norcross, GA: Elekta Instruments Inc.; 2000.
Available online: www.sciencedirect.com
20. Sivakanthan S, Van Gompel JJ, Alikhani P, van Loveren H, Chen R, Agazzi S. Surgical management of trigeminal neuralgia: use and costeffectiveness from an analysis of the Medicare
Journal homepage: www.journals.elsevier.com/worldneurosurgery 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
Comparing Microvascular Decompression with Gamma Knife Radiosurgery for Trigeminal Neuralgia. A Cost-Effectiveness Analysis Gurpreet S. Gandhoke1, Kenneth J. Smith2, Ajay Niranjan3, Raymond F. Sekula3, L. Dade Lunsford3
BACKGROUND AND OBJECTIVE: Both microvascular decompression (MVD) and Gamma Knife radiosurgery (GKRS) are time-tested treatment modalities for trigeminal neuralgia (TN). There is little evidence in the literature studying these modalities head to head in a costeffectiveness comparison.
-
OBJECTIVE: To evaluate the cost-effectiveness of MVD compared with GKRS for treating patients with TN.
-
METHODS: We developed a Markov cost-effectiveness model for the U.S. health care system to account for all costs related to MVD and GKRS as treatment modalities for TN, from the health care system perspective, over a patient lifetime horizon. A base case was estimated using data from previous studies, from our own GKRS experience, and from a current data analysis of patients undergoing MVD. We derived model inputs, including health care costs, survival, and utility estimates, from the literature. We used age-specific, sex-specific, and race-specific mortality from national registries. Costs studied included those for MVD, for GKRS, for treating complications from either procedure, and for medications throughout patient lifetimes. We performed multiple 1-way, 2-way, and probabilistic sensitivity analyses to confirm the robustness of model assumptions and results. The incremental cost-effectiveness ratio (ICER), with a threshold of $50,000 per quality-adjusted lifeyear (QALY) gained, defined cost-effectiveness.
-
RESULTS: The base case had an ICER of $12,154 per QALY for MVD compared with GKRS. Probabilistic
-
Key words - Cost-effectiveness - Gamma Knife radiosurgery - Microvascular decompression - Trigeminal neuralgia Abbreviations and Acronyms BNI: Barrow Neurological Institute GKRS: Gamma Knife radiosurgery ICER: Incremental cost-effectiveness ratio MVD: Microvascular decompression PRGR: Percutaneous retrogasserian rhizotomy QALY: Quality-adjusted life-year QAPFY: Quality-adjusted pain-free year TN: Trigeminal neuralgia WTP: Willingness to pay
WORLD NEUROSURGERY 125: 207-216, MAY 2019
sensitivity (Monte Carlo) analysis showed that MVD was cost-effective in 70% of model iterations. GKRS was favored when the willingness to pay threshold was <$12,000 per QALY gained. CONCLUSIONS: In patients medically eligible for either procedure, we found MVD to be the most cost-effective modality to treat TN, primarily because of its reported greater durability. MVD remained the most cost-effective strategy across a broad range of model input values in sensitivity analyses.
-
INTRODUCTION
T
rigeminal neuralgia (TN) is a neuropathic pain disorder marked by evoked and spontaneous attacks in the distribution of the trigeminal nerve. The disorder is further associated with periods of partial or complete remission but there is recurrence in most patients. The pain of TN is considered to be among the most debilitating types of pain. Neurovascular compression of the trigeminal nerve has been accepted as the cause of classical TN in most patients by the International Headache Society. Because of its minimally invasive nature, stereotactic radiosurgery using the Gamma Knife (Elekta, Stockholm, Sweden) has, in the past 2 decades, emerged as an alternative to initial microvascular decompression (MVD) of the trigeminal nerve. The reasons for the increasing use of radiosurgery in the management of TN include an avoidance of general anesthesia and its attendant risks, absence From the 1Marion Bloch Neuroscience Institute, Saint Luke’s Hospital, Kansas City, Missouri; and Departments of 2Medicine and 3Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA To whom correspondence should be addressed: Gurpreet S. Gandhoke, M.D., M.S. [E-mail: [email protected]] Raymond F. Sekula and L. Dade Lunsford have contributed equally as senior authors in the evolution of this manuscript. Citation: World Neurosurg. (2019) 125:207-216. https://doi.org/10.1016/j.wneu.2018.12.204 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
www.journals.elsevier.com/world-neurosurgery
207
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 1. The Markov state transition model. BNI, Barrow Neurological Institute; GKRS, Gamma Knife
of radiographically apparent neurovascular compression,1 decreased overall cost, and a lower major morbidity profile (e.g., stroke or death).2 Arguments against the use of radiosurgery for TN include the superior durability of MVD3 and its efficacy and safety even in elderly patients.4 In this study, we sought to evaluate the cost-effectiveness of Gamma Knife radiosurgery (GKRS) compared with MVD for patients with TN. METHODS Study Design and Model Inputs This study was exempt from review by the University of Pittsburgh institutional review board, and informed consent was waived because patient data were de-identified. We developed a Markov cost-effectiveness model to compare MVD with GKRS for the treatment of TN from the health care system perspective over a patient lifetime horizon. We obtained model inputs from the literature and our own data on patients with TN treated with MVD or GKRS. We applied this model to our institution’s cohort of representative patients treated for TN. The MVD data were obtained from the personal series of the senior author (R.F.S.) from treating 208 consecutive patients with TN (173 typical and 35 atypical) from 2011 to 2018. The mean age of these patients was 60 years. None of these patients had previous surgery. The GKRS data2 were obtained from published data from our institutional experience of treating 503 medically refractory patients with idiopathic TN. Mean age was 69 years. GKRS was the first surgical procedure in 288/503 patients. Surgery had been performed previously in 215 patients. We also analyzed our
208
www.SCIENCEDIRECT.com
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
radiosurgery; MVD, microvascular decompression; PRGR, percutaneous retrogasserian rhizotomy.
model with probabilities obtained from Wang et al.’s5 experience of treating 764 patients with TN (364 GKRS and 316 MVD). The model follows a patient from time of diagnosis of TN through treatment with either MVD or GKRS, postoperative pain relief based on the Barrow Neurological Institute (BNI) score, requiring additional procedures, and also accounting for recurrence of symptoms of pain after initial relief. This strategy continues for the remainder of life of the patient. The primary outcome was the incremental cost-effectiveness ratio (ICER), representing the cost paid by the health care system in dollars per quality-adjusted life-year (QALY) gained comparing MVD with GKRS for treating TN. The ICER was calculated as the difference in cost between the 2 strategies divided by the difference in effectiveness. We applied an ICER threshold of $50,000, which is a generally accepted value of costeffective medical interventions in the developed world.6,7
Decision Analytic Markov Model We developed a decision analytic tree model with a decision point choosing either MVD or GKRS as a treatment strategy for treating TN. Patients entered the Markov model at age 50 years with either MVD or GKRS as the initial treatment choice. Surviving patients either had a BNI IeIIIB outcome and remained pain free thereafter or had a BNI IVeV outcome and entered 1 of 3 Markov transition states of having another MVD or GKRS, having a percutaneous retrogasserian rhizotomy (PRGR) or remaining in a BNI IVeV state, with probabilities of those events based on published literature. Patients could then progress through each Markov cycle
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Table 1. The Probabilities Used in the Base Case Model and Their Ranges Applied for Sensitivity Analyses Variable
Base Case Value
Sensitivity Analysis Range
Distribution
Source
BNI IeIIIB score with GKRS
0.8 at 1 year 0.7 at 2 years 0.5 at 5 years 0.3 at 10 years
20%
Beta
Kondziolka et al.2
BNI IeIIIB score with MVD
0.93 at 1 year 0.89 at 2 years 0.80 at 5 years 0.44 at 10 years
20%
Beta
Sekula dataset Sekula dataset Sekula dataset Wang et al.5
0.18
0.05e0.18
Beta
Kondziolka et al.2
0.91 at 1 year
0.6e0.91
Beta
Cohen et al.8
Redo MVD
0.05
0.01e0.05
Beta
Sekula dataset
BNI IeIIIB with redo MVD
0.7
0.5e0.7
Beta
Bruce Pollock et al.9
MVD after GKRS
0.04
0.01e0.04
Beta
Kondziolka et al.2
BNI IeIIIB score with MVD after GKRS
0.83
0.4e0.83
Beta
Cheng et al.10
Probabilities
Redo GKRS BNI IeIIIB with redo GKRS
GKRS after MVD
0.02
0.01e0.04
Beta
Sekula dataset
BNI IeIIIB score GKRS after MVD
0.7954
0.5e0.7954
Beta
Yi Wang et al.11
PRGR after GKRS
0.131
0.05e0.131
Beta
Kondziolka et al.2
BNI IeIIIB score with PRGR after GKRS
0.36
0.25e0.36
Beta
Pollock et al.9
PRGR after MVD
0.48
0.35e0.5
Beta
Sekula dataset
BNI IeIIIB score with PRGR after MVD
0.57
0.45e0.6
Beta
Kang Ho et al.12
Complication with MVD
0.03
0.01e0.03
Beta
Sekula dataset
Complication with GKRS
0.11
0.05e0.15
Beta
Kondziolka et al.2
Complication with PRGR
0.52
0.2e0.5
Beta
Holland et al.13
Multiplication Factor for BNI IeIIIB yearly rates with GKRS
1
0.8e1.2
Gamma
NA
Multiplication Factor for BNI IeIIIB yearly rates with MVD
1
0.8e1.2
Gamma
NA
All probabilities were constructed as beta distributions for application in the Monte Carlo sensitivity analyses. BNI IeIIIB outcome for MVD at the 10-year mark was not available from the Sekula dataset. We used the BNI I outcome from Wang et al.5 for this calculation. We constructed a gamma distribution for a 20% range for the yearly probabilities of BNI IeIIIB outcomes for GKRS and MVD. BNI, Barrow Neurological Institute; GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression; PRGR, percutaneous retrogasserian rhizotomy, NA, not applicable.
either surviving an additional cycle or dying, with death representing a self-absorbing health state (Figure 1). Model Assumptions We populated decision branch points with probabilities of discrete mutually exclusive events. The probability of going through the MVD or GKRS arm was fixed at 0.5. We used linear regression to calculate yearly probabilities of recurrence of pain with GKRS and MVD from 1-year, 2-year, 5-year, and 10-year probabilities of painfree status for both groups. We assumed that the pain status at the 10-year follow-up mark was constant and patients in both groups would not transition to another state after this time point. We have depicted the probabilities used in the decision tree in Table 1. We obtained the annual probability of mortality from U.S. life tables, with a 0% mortality attributed to both GKRS and MVD by virtue of the procedure itself. A base case was estimated
WORLD NEUROSURGERY 125: 207-216, MAY 2019
using our published data for GKRS from Kondziolka et al.,2 and our own data bank of patients undergoing MVD, from 1 of the senior author’s (R.F.S.) personal series of 208 patients. Base case inputs included a mean age of 50 years, mean time for GKRS, MVD, and PRGR mean length of stay with each procedure, incidence of complications with MVD (cerebrospinal fluid leak and wound infection) and GKRS (facial dysesthesia). The Markov cycle length was set to 1 year, and a 3% discount rate was applied to costs and QALYs. Cost Costs in the model include costs for GKRS, MVD, medications, and complication management for each procedure. All economic inputs represent estimated expenditures to the hospital, rather than charges. Costs for surgical procedures (MVD, GKRS, and PRGR) were obtained from the finance department of our
www.journals.elsevier.com/world-neurosurgery
209
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Table 2. The Cost Data Obtained from the Finance Department at the University of Pittsburgh Medical Center Variable
Base Case Value ($)
Sensitivity Analysis Range
Distribution
Source
Cost of MVD
10,597
8000e15,000
Gamma
Finance department
Cost of GKRS
2916
2500e4000
Gamma
Finance department
Cost of percutaneous retrogasserian rhizotomy
1090
1000e2500
Gamma
Finance department
Cost redo MVD
10,597
8000e15,000
Gamma
Finance department
Cost redo GKRS
2916
2500e4000
Gamma
Finance department
Cost data
Cost of complication with GKRS
180
100e500
Gamma
Patient interview
Cost of complication with MVD
6470
5000e8000
Gamma
Finance department
Cost of medication with GKRS
180 (15*12)
100e500
Gamma
Patient interview
Cost of medication with MVD
180 (15*12)
100e500
Gamma
Patient interview
A gamma distribution was constructed for all cost-related variables for the sensitivity analyses. Data on cost of medications for the treatment of face pain for both groups (MVD and GKRS) were obtained by patient interview and insurance cost for generic medication ($15/month) was used as cost of medications. Because the Markov cycle length used was 1 year, this cost amounted to a total of $180. GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression; PRGR, percutaneous retrogasserian rhizotomy.
university hospital. Yearly medication cost for management of TN or for facial dysesthesia resulting as a complication from any of the 3 surgical procedures were obtained by patient interview. The yearly cost of the generic medication to the insurance company was used for the base case calculations. Costs for management of a complication resulting from MVD, GKRS, or PRGR were also obtained from the hospital finance department (Table 2). Health Outcomes Health outcomes were evaluated as health state utilities in the form of QALYs. Utilities for having any of the 3 procedures (GKRS, MVD, and PRGR) were calculated as the probability of
having a BNI 1 score at 1 month after the procedure multiplied by the utility of a BNI 1 score (1.0).14 Utilities for BNI IeIIIB, BNI IVeV, procedure complications, and medication use were obtained from the literature. The utility for a BNI IeIIIB score was calculated as the mean of BNI I, BNI II, and BNI III state utilities. The utility of the first 1-month after GKRS (waiting for procedure results to occur) was the same as the medication use utility. Losses in QALYs, also known as disutility to the patient, were estimated for those with complications from any procedure, and for the first month after GKRS. These losses were calculated as 1-utility of being in the state of complication (Tables 3 and 4).
Table 3. The Utilities for Each Surgical Procedure, the Barrow Neurological Institute Outcome States, and the State of Being on Medications and Waiting for Gamma Knife Radiosurgery to Take Effect (Month 1 Utility, Which Is the Same as the Utility of Being on Medications During that Time) Variable
Base Case Value
Sensitivity Analysis Range
Distribution
Source
MVD
0.73
0.6e0.8
Triangular
Sekula dataset
GKRS
0.6
0.5e0.8
Triangular
Cohen et al.8
Percutaneous retrogasserian rhizotomy
0.85
0.6e0.9
Triangular
Asplund et al.15
BNI IeIIIB
0.87
0.75e0.95
Triangular
Hunink et al.14 Perez et al.16
BNI IVeV
0.399
0e0.4
Triangular
Perez et al.16
Month 1
0.881
0.5e0.881
Triangular
Berger et al.17
Complication MVD
0.958
0.5e0.958
Triangular
Berger et al.17
Complication GKRS
0.962
0.8e0.962
Triangular
Berger et al.17
Medications
0.881
0.6e0.881
Triangular
Berger et al.17
Utilities
A triangular distribution was constructed for each utility for the probabilistic sensitivity analysis. MVD, microvascular decompression; BNI, Barrow Neurological Institute; GKRS, Gamma Knife radiosurgery.
210
www.SCIENCEDIRECT.com
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Table 4. The Cohort Characteristics, with a Mean Age of Entry into the Marko State Transition Model at 50 Years Variable
Base Case Value
Sensitivity Analysis Range
Distribution
Source
50
NA
NA
Mean age in our cohort GKRS 69 MVD 60
GKRS: 2520 MVD: 1659
365e2520 500e1659
Triangular
Kondziolka et al.2 Sekula dataset
1
0.25e1
Triangular
Kondziolka et al.2 Sekula dataset
Cohort characteristics Start age (years)
Days on medication before GKRS/MVD Days for GKRS MVD
1
1e4
Percutaneous retrogasserian rhizotomy
1
1e2
GKRS
30
30e365
Triangular
Kondziolka et al.2
MVD
4
2e4
Triangular
Sekula dataset
Days with complications
We applied a broad range to the base case value of 30 for the days with complication (facial dysesthesia) because these data were not available in the literature. Despite the broad range (1 month to 1 year), this variable had no significant impact on the incremental cost-effectiveness ratio as shown in the Tornado diagram. GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression.
Sensitivity Analyses We performed multiple sensitivity analyses to evaluate the robustness of our model assumptions and results. One-way sensitivity analysis was performed across all model variables. The most influential variables were selected for 2-way sensitivity analysis to evaluate the effect of varying both inputs simultaneously. Probabilistic sensitivity analysis was performed, varying all parameters simultaneously over distributions, over 1000 Monte Carlo simulations. A cost-effectiveness acceptability curve was generated to evaluate the proportion of Monte Carlo iterations in which strategies are favored across a range of ICER threshold values. Stata version 15 (StataCorp LLC, College Station, Texas, USA) was used for statistical analysis, and TreeAgePro version
2018 (TreeAge Software Inc. Williamstown, Massachusetts, USA) was used for cost-effectiveness modeling. RESULTS The base case showed higher cost and greater effectiveness for MVD compared with GKRS, resulting in an ICER of $12,154/QALY for MVD compared with GKRS (Table 5). One-way sensitivity analysis showed that the probability of maintaining a BNI score of IeIIIB over a period of time for both GKRS and MVD were the most influential model inputs (Figure 2). Two-way sensitivity analysis showed that if the probability of recurrence of pain with MVD is >89% then GKRS is always favored at a $50,000/QALY
Table 5. The Incremental Cost and Incremental Quality-Adjusted Life-Years Provided by Microvascular Decompression Compared with Gamma Knife Radiosurgery
Strategy
Cost ($)
Incremental Cost ($)
Effectiveness
11,289
13.68
Incremental Effectiveness
Incremental Cost-Effectiveness Ratio
0.93
12,154
0.93
12,084
Base case GKRS
8073
MVD
19,362
12.75
Sensitivity analysis GKRS
8073
MVD
19261
14.29 11,188
15.21
Both the base case incremental cost-effectiveness ratio ($12,154/quality-adjusted life-year) and the incremental cost-effectiveness ratio calculated from probabilistic sensitivity analyses ($12,084/quality-adjusted life-year) are close to one another, reiterating the robustness of the calculation and reliability of the results. GKRS, Gamma Knife radiosurgery; MVD, microvascular decompression.
WORLD NEUROSURGERY 125: 207-216, MAY 2019
www.journals.elsevier.com/world-neurosurgery
211
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 2. The Tornado diagram with multiple 1-way sensitivity analyses. Size of bars represents relative influence of each model variable on the incremental cost-effectiveness ratio (ICER) across the range of values tested in sensitivity analysis. This diagram provides evidence that the
threshold, whereas if recurrence of pain with MVD is <47%, then MVD is always favored (Figure 3). Probabilistic sensitivity analysis showed that MVD is the cost-effective strategy in 70% of the iterations at the $50,000/QALY threshold (Figure 4). GKRS became more cost-effective only when the willingness to pay threshold decreased <$12,000. Using Wang et al.’s5 probabilities of BNI I outcome at years 1, 5, and 10 for GKRS and MVD in our model, Monte Carlo probabilistic analysis showed that MVD had 100% cost-effective iterations (Figure 5). Sensitivity analyses were performed to ensure that our results were robust to changes in model assumptions across a range of clinically plausible values. Our base case ICER of $12,154/QALY gained for MVD decreased to $910/QALY when using the probabilities of sustained pain relief from another institution’s experience (Wang et al.5). All sensitivity analyses showed MVD to be the more cost-effective strategy, reiterating the robustness of the base case model. MVD remained the cost-effective strategy until the willingness to pay (WTP) threshold was decreased <$12,000 for the base case model and <$5000 for probabilities of BNI I outcomes (Figures 4 and 5). The generally accepted cost-effectiveness threshold in the United States ranges from $50,000/QALY to
212
www.SCIENCEDIRECT.com
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
probability of maintaining a Barrow Neurological Institute (BNI) IeIIB status with both Gamma Knife radiosurgery (GKRS) and microvascular decompression (MVD) (the longest horizontal bars) are the 2 variables with the maximum impact on the incremental cost-effectiveness ratio.
$100,000/QALY.6,7 Compared with GKRS, MVD was found to provide 1 additional QALY at the cost of approximately $12,000. Both GKRS ($8073 for 12.75 QALYs) and MVD ($19,362 for 13.68 QALYs), by themselves are likely cost-effective compared with no treatment at all. However, comparing head to head, GKRS resulted in 30% cost-effective iterations compared with 70% costeffective iterations of MVD in probabilistic sensitivity analyses. DISCUSSION Almost 8000 patients with TN undergo surgery every year in the United States at an estimated cost of $100 million.18,19 Pollock et al.9 compared MVD, PRGR, and GKRS for the treatment of TN. They obtained data from a prospective nonrandomized trial including 126 patients undergoing 153 operations (MVD, n ¼ 33; PRGR, n ¼ 51; and GKRS, n ¼ 69). Mean follow-up was 20.6 months. The outcome measure that these investigators used was a quality-adjusted pain-free year (QAPFY). This measure was determined by multiplying the length of follow-up after each operation by the adjusted facial pain outcome. Facial pain outcomes were adjusted as excellent
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 3. Two-way sensitivity analysis of probability of recurrence of pain with Gamma Knife radiosurgery (GKRS) and probability of recurrence of pain with microvascular decompression (MVD). Blue area represents pairs
(no pain, no medications), 1.0; good (no pain, reduced medications), 0.7; fair (>50% pain reduction, 0.5; and poor, 0.1. The investigators found that the cost per QAPFY was $6342, $8174, and $8269 for PRGR, MVD, and GKRS, respectively. Comparing GKRS with MVD, we found that the cost per QALY for MVD was $12,154, close to the value obtained by Pollock et al. Our model was different in that the time horizon was over the lifetime of the patient and not confined to the follow-up interval as in the Pollock et al. study. We also discounted for both cost and QALYs, which was not performed in the study by Pollock et al. We used a standardized outcome measures in the form of the BNI score and QALYs in contrast to the QAPFY score. Despite these differences, similar results of the 2 studies reiterate the robustness of the analyses and the dependability of the results of the costeffectiveness frontier. Sivakanthan et al.20 used Medicare claims data in conjunction with a literature review to assess the use, effectiveness, and cost-effectiveness of MVD, GKRS, and PRGR in the treatment of TN. These investigators extracted claim data for the treatment of TN from the 2011 Medicare Data Bank. They used Kaplan-Meier survival curves from 3 articles in their estimation of QALYs. They found the average weighted costs for MVD, GKRS, and PRGR to be $40,434, $38,062, and $3910, respectively. The QALYs were 8.2 for MVD, 4.9 for SRS, and 6.5 for PRGR. The ICER was calculated as $4931, $7767, and $601 for MVD, GKRS, and PRGR, respectively. Sivakanthan et al. calculated QALYs by importing
WORLD NEUROSURGERY 125: 207-216, MAY 2019
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
of these values where Gamma Knife radiosurgery is more cost-effective and red areas represent pairs of these values where microvascular decompression is more cost-effective.
Kaplan-Meier curves from their 3 selected articles into Adobe Photoshop and used the Magic Wand tool to select the area under the curve out to 0 years and normalized to the total area available at 10 years. Because they defined their investigation over a 10-year follow-up period, the graphically derived QALY was multiplied by 10. In our study, with a lifetime horizon and use of the hospital perspective for our economic analysis, and with the use of 3% discounting for both cost and QALYs, we found the cost and QALYs for MVD to be $19,362 and 13.68, respectively. GKRS cost $8073 for 12.75 QALYs. Despite the difference in calculation of QALYs, Sivakanthan et al. also found MVD to be more costeffective (ICER $4931) than was GKRS ($7767). PRGR came out to be the most cost-effective in their study; we did not compare PRGR with MVD and GKRS in our study but based on the higher durability of pain relief with MVD compared with PRGR, this comparison would be an interesting endeavor. Berger et al.17 performed a decision analysis comparing the effectiveness of MVD and GKRS for TN. These investigators modeled pain relief and complication outcomes over a 7-year horizon. Costs were not taken into consideration. One assumption for their model states that “all cases in which pain recurs, does so after 2.5 years and has a BNI IVeV score after pain returns.” Berger et al.17 do not discount for utilities in their study. At 7 years after the procedure, they found that MVD provided 6 QALYs compared with 5.4 QALYs provided by GKRS. They attribute the higher utility of MVD to its higher initial success rate and lower
www.journals.elsevier.com/world-neurosurgery
213
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 4. Cost-effectiveness acceptability curve across a range of cost-effectiveness thresholds from probabilistic sensitivity analysis. Microvascular decompression (MVD) is cost-effective in 70% of iterations
pain recurrence rate compared with GKRS. In our lifetime horizon study, we found MVD to provide 13.68 QALYs compared with 12.75 QALYs with GKRS. This again reiterates the robustness of our decision model and the reliability of the result. A European cost-minimization study (assuming that the effectiveness of both MVD and CyberKnife radiosurgery [(Accuray, Sunnyvale, California, USA)] is the same) by Tarricone et al.21 found Cyber Knife radiosurgery (V4388) to be the cost-saving alternative to MVD (V6641). A cost-minimization study such as this is considered to be the lowest in the hierarchy of evidence in the domain of economic analyses and reports results based on a 6- month follow-up interval. The results may thus not hold strength in the presence of solid evidence that it is the durability of relief from pain that makes MVD more economically viable than radiosurgery in the long run. We do not have experience with using CyberKnife radiosurgery and, thus, we could not study this treatment modality in a head-to-head comparison with GKRS and MVD. The results of this study aim to assist decision making for the treatment of medically refractory TN in cases in which either MVD or GKRS could be appropriate. The less invasive GKRS option is
214
www.SCIENCEDIRECT.com
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
at $50,000 per quality-adjusted life-year, whereas Gamma Knife radiosurgery (GKRS) has more cost-effective iterations only when the cost-effectiveness threshold is <$12,000/quality-adjusted life-year.
appealing to many patients and most often outweighs any discussion regarding comparative effectiveness between various surgical options. Our study reiterates the appropriateness of the current approach used in the management of medically refractory TN. We also used our decision analytical model to compare MVD and GKRS results from another single-institution experience. We used the percentages of patients with BNI pain intensity score of I at 1, 5, and 10 years after MVD of 83%, 61%, and 44%, and the corresponding percentages after GKRS of 71%, 47%, and 27%, respectively, as reported by Wang et al.5 from their experience of treating 764 patients with TN at the University of California, San Francisco. These probabilities in our model yielded an ICER of $900/QALY with a Monte Carlo analysis yielding 100% costeffective iterations in favor of MVD at a WTP threshold of $50,000/QALY (Figure 5). This result also helped reinforce the reliability and dependability of our model. Limitations Establishing clinical equipoise outside an assumption is near impossible because of patient heterogeneity. The attributes of
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204
DOING MORE GURPREET S. GANDHOKE ET AL.
Figure 5. Cost-effectiveness acceptability curve across a range of cost-effectiveness thresholds from probabilistic sensitivity analysis for Barrow Neurological Institute I outcome with Gamma Knife radiosurgery (GKRS) and microvascular decompression (MVD) from Wang et al.5
the patient (life expectancy and comorbidities) and the operating surgeon (complication rate and efficacy) affect the cost-benefit analysis. Cost-effectiveness models require variable inputs derived from existing data and literature. This process requires many assumptions, and the results are specific to these data and assumptions. The data used for model inputs came from a variety of sources across varied populations and time periods, assuming that each is representative of patients with TN. We did perform several sensitivity analyses to evaluate the robustness of our conclusions to variations in these data and assumptions, which showed similar results. The costs, complications, and base case results are based on a neurosurgical practice at a quaternary-care center performing many TN operations (both MVD and GKRS) every year. Another surgeon performing fewer
REFERENCES 1. Maarbjerg S, Wolfram F, Gozalov A, Olesen J, Bendtsen L. Significance of neurovascular contact in classical trigeminal neuralgia. Brain. 2015;138: 311-319.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
Microvascular decompression is cost-effective in 100% of iterations at $50,000 per quality-adjusted life-year, whereas Gamma Knife radiosurgery has more cost-effective iterations only when the cost-effectiveness threshold is <$5000/quality-adjusted life-year.
procedures may have worse facial pain outcomes and/or a higher complication rate. CONCLUSIONS By U.S. society standards, we are willing to pay $50,000/ QALY. Thus, the current neurosurgical protocol for management of medically refractory TN is economically viable. Our cost-effectiveness study shows that over a long follow-up period, MVD as the initial surgical management of TN is more cost-effective than is GKRS as the initial surgical procedure. This finding is primarily related to the reported increased durability of pain relief after MVD compared with GKRS. This finding is applicable to patients considered medically eligible for either procedure.
4. Sekula RF Jr, Frederickson AM, Jannetta PJ, Quigley MR, Aziz KM, Arnone GD. Microvascular decompression for elderly patients with trigeminal neuralgia: a prospective study and systematic review with meta-analysis. J Neurosurg. 2011;114: 172-179.
2. Kondziolka D, Zorro O, Lobato-Polo J, et al. Gamma Knife stereotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg. 2010;112: 758-765.
5. Wang DD, Raygor KP, Cage TA, et al. Prospective comparison of long-term pain relief rates after first-time microvascular decompression and stereotactic radiosurgery for trigeminal neuralgia. J Neurosurg. 2018;128:68-77.
3. Barker FG 2nd, Jannetta PJ, Bissonette DJ, Larkins MV, Jho HD. The long-term outcome of microvascular decompression for trigeminal neuralgia. New Engl J Med. 1996;334:1077-1083.
6. Braithwaite RS, Meltzer DO, King JT Jr, Leslie D, Roberts MS. What does the value of modern medicine say about the $50,000 per qualityadjusted life-year decision rule? Med Care. 2008; 46:349-356.
WORLD NEUROSURGERY 125: 207-216, MAY 2019
7. Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness–the curious resilience of the $50,000-per-QALY threshold. New Engl J Med. 2014;371:796-797. 8. Cohen J, Mousavi SH, Faraji AH, et al. Stereotactic radiosurgery as initial surgical management for elderly patients with trigeminal neuralgia. Stereotact Funct Neurosurg. 2017;95:158-165. 9. Pollock BE, Ecker RD. A prospective costeffectiveness study of trigeminal neuralgia surgery. Clin J Pain. 2005;21:317-322. 10. Cheng J, Liu W, Hui X, Lei D, Zhang H. Microvascular decompression for trigeminal neuralgia in patients with failed gamma knife surgery:
www.journals.elsevier.com/world-neurosurgery
215
DOING MORE GURPREET S. GANDHOKE ET AL.
WITH
LESS
COST-EFFECTIVENESS OF MVD & GKRS FOR TN
analysis of efficacy and safety. Clin Neurol Neurosurg. 2017;161:88-92.
treatment of trigeminal neuralgia. Neurosurgery. 2016;78:421-428 [discussion: 428].
Claims Database. Neurosurgery. 2014;75:220-226 [discussion: 225-226].
11. Wang Y, Zhang S, Wang W, et al. Gamma Knife surgery for recurrent trigeminal neuralgia in cases with previous microvascular decompression. World Neurosurg. 2018;110:e593-e598.
16. Perez C, Navarro A, Saldana MT, Martinez S, Rejas J. Patient-reported outcomes in subjects with painful trigeminal neuralgia receiving pregabalin: evidence from medical practice in primary care settings. Cephalalgia. 2009;29:781-790.
21. Tarricone R, Aguzzi G, Musi F, Fariselli L, Casasco A. Cost-effectiveness analysis for trigeminal neuralgia: Cyberknife vs microvascular decompression. Neuropsychiatr Dis Treat. 2008;4: 647-652.
17. Berger I, Nayak N, Schuster J, Malhotra NR. Microvascular versus stereotactic radiosurgery neuralgia: a decision analysis. e1000.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
12. Kang IH, Park BJ, Park CK, Malla HP, Lee SH, Rhee BA. A clinical analysis of secondary surgery in trigeminal neuralgia patients who failed prior treatment. J Korean Neurosurg Soc. 2016;59:637-642. 13. Holland M, Noeller J, Buatti J, He W, Shivapour ET, Hitchon PW. The cost-effectiveness of surgery for trigeminal neuralgia in surgically naive patients: a retrospective study. Clin Neurol Neurosurg. 2015;137:34-37. 14. Hunink MGMGP. Decision Making in Health and Medicine: Integrating Evidence and Values. Cambridge, United Kingdom: Cambridge University Press; 2001. 15. Asplund P, Blomstedt P, Bergenheim AT. Percutaneous balloon compression vs percutaneous retrogasserian glycerol rhizotomy for the primary
216
www.SCIENCEDIRECT.com
Lee J, Stein S, decompression for trigeminal Cureus. 2017;9:
Received 16 September 2018; accepted 26 December 2018 18. American Association of Neurological Surgeons. National Neurosurgical Statistics. 1999 Procedural Statistics. Rolling Meadows, IL: American Association of Neurological Surgeons (AANS); 2000.
Citation: World Neurosurg. (2019) 125:207-216. https://doi.org/10.1016/j.wneu.2018.12.204
19. Leksell Gamma Knife Treatment Statistics [press release]. Norcross, GA: Elekta Instruments Inc.; 2000.
Available online: www.sciencedirect.com
20. Sivakanthan S, Van Gompel JJ, Alikhani P, van Loveren H, Chen R, Agazzi S. Surgical management of trigeminal neuralgia: use and costeffectiveness from an analysis of the Medicare
Journal homepage: www.journals.elsevier.com/worldneurosurgery 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.12.204