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Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Kevin F. Erickson, MD, MS; Glenn M. Chertow, MD, MPH; and Jeremy D. Goldhaber-Fiebert, PhD
[+] Article, Author, and Disclosure Information

From the Centers for Health Policy and Primary Care and Outcomes Research, Stanford University School of Medicine, Stanford, California.

Grant Support: By the Agency for Healthcare Research and Quality (F32 HS019178) and National Institutes of Health (DK085446 and AG037593).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0381.

Reproducible Research Statement: Study protocol and data set: Available from Dr. Erickson (e-mail, kevine1@stanford.edu). Statistical code: Not available.

Requests for Single Reprints: Kevin Erickson, MD, MS, Stanford University School of Medicine, 117 Encina Commons, Stanford, CA 94305-6019; e-mail, kevine1@stanford.edu.

Current Author Addresses: Drs. Erickson and Goldhaber-Fiebert: Stanford University School of Medicine, 117 Encina Commons, Stanford, CA 94305-6019.

Dr. Chertow: Division of Nephrology, Stanford University School of Medicine, 777 Welch Road, Suite DE, Palo Alto, CA 94304.

Author Contributions: Conception and design: K.F. Erickson, G.M. Chertow, J.D. Goldhaber-Fiebert.

Analysis and interpretation of the data: K.F. Erickson, G.M. Chertow, J.D. Goldhaber-Fiebert.

Drafting of the article: K.F. Erickson.

Critical revision of the article for important intellectual content: K.F. Erickson, G.M. Chertow, J.D. Goldhaber-Fiebert.

Final approval of the article: K.F. Erickson, G.M. Chertow, J.D. Goldhaber-Fiebert.

Statistical expertise: K.F. Erickson, J.D. Goldhaber-Fiebert.

Administrative, technical, or logistic support: K.F. Erickson, G.M. Chertow.

Collection and assembly of data: K.F. Erickson.

Ann Intern Med. 2013;159(6):382-389. doi:10.7326/0003-4819-159-6-201309170-00004
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Chinese translation

Background: In the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial, tolvaptan significantly reduced expansion of kidney volume and loss of kidney function.

Objective: To determine how the benefits of tolvaptan seen in TEMPO may relate to longer-term health outcomes, such as progression to end-stage renal disease (ESRD) and death, and cost-effectiveness.

Design: A decision-analytic model.

Data Sources: Published literature from 1993 to 2012.

Target Population: Persons with early autosomal dominant polycystic kidney disease.

Time Horizon: Lifetime.

Perspective: Societal.

Intervention: Patients received tolvaptan therapy until death, development of ESRD, or liver complications or no tolvaptan therapy.

Outcome Measures: Median age at ESRD onset, life expectancy, discounted quality-adjusted life-years and lifetime costs (in 2010 U.S. dollars), and incremental cost-effectiveness ratios.

Results of Base-Case Analysis: Tolvaptan prolonged the median age at ESRD onset by 6.5 years and increased life expectancy by 2.6 years. At $5760 per month, tolvaptan cost $744 100 per quality-adjusted life-year gained compared with standard care.

Results of Sensitivity Analysis: For patients with autosomal dominant polycystic kidney disease that progressed more slowly, the cost per quality-adjusted life-year gained was even greater for tolvaptan.

Limitation: Although TEMPO followed patients for 3 years, the main analysis assumed that clinical benefits persisted over patients' lifetimes.

Conclusion: Assuming that the benefits of tolvaptan persist in the longer term, the drug may slow progression to ESRD and reduce mortality rates. However, barring an approximately 95% reduction in price, cost-effectiveness does not compare favorably with many other commonly accepted medical interventions.

Primary Funding Source: National Institutes of Health and Agency for Healthcare Research and Quality.


Grahic Jump Location
Figure 1.

Schematic of the Markov model of kidney disease.

Stage 3 CKD was subdivided into stages 3A and 3B (not shown). We used SAS, version 9.2 (SAS Institute, Cary, North Carolina), in our microsimulation to convert estimated GFR progression to CKD stage progression in autosomal dominant polycystic kidney disease and then used TreeAge Pro 2009 (TreeAge Software, Williamstown, Massachusetts) to do cost-effectiveness analyses. CKD = chronic kidney disease; ESRD = end-stage renal disease; GFR = glomerular filtration rate.

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Grahic Jump Location
Figure 2.

Simulated mortality and age of ESRD onset with and without tolvaptan.

Tolvaptan therapy prolongs median age to development of ESRD by 6.5 years and extends life by an average of 2.6 years. ESRD = end-stage renal disease.

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Grahic Jump Location
Figure 3.

Cost-effectiveness under different model assumptions.

Tolvaptan was less cost-effective with slower rates of baseline kidney disease progression. Tolvaptan cost less than $100 000 per QALY gained if 95 mg per day were offered at $1155 or less per month (approximately where the dotted $100 000 WTP line crosses the lines for men and women). The decline in estimated GFR from a cohort of patients with ADPKD was −2.4 mL/min/1.73 m2 per year (3). Base-case decline in eGFR was −3.7 mL/min/1.73 m2 per year, which was seen in the placebo group of TEMPO (7). The $50 000 and $100 000 WTP lines represent societal WTP thresholds (the amount of money society would be willing to pay to increase quality-adjusted life expectancy by 1 year). The assumed base-case cost of $5760 per month for 95 mg of tolvaptan equals the current cost of 30-mg tablets. The current cost of 95 mg of tolvaptan was $18 240 based on the current cost of 30-mg tablets. ADPKD = autosomal dominant polycystic kidney disease; CKD = chronic kidney disease; GFR = glomerular filtration rate; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year; TEMPO = Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes; WTP = willingness to pay.

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Comment on “Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease”
Posted on October 8, 2013
James Lineen MB MSc, David MJ Naimark MD MSc, on behalf of the Sunnybrook Nephrology Journal Club
Sunnybrook Health Sciences Centre, and The Institute of Health Policy, Management, and Evaluation University of Toronto
Conflict of Interest: None Declared
[Note; our greek letter “delta” was omitted]: Erickson et al. [1] have published an elegant Markov-based cost effectiveness analysis which extended the results of the TEMPO trial [2] of Tolvaptan for the treatment of adult polycystic kidney disease (PCKD). The authors indicate that a key input parameter was the change in estimated glomerular filtration rate (deltaeGFR) in patients who would or would not receive chronic tolvaptan therapy. In fact, the parameter that was modeled was the change in actual glomerular filtration rate (deltaGFR). However, since eGFR is a non-linear function of GFR, deltaeGFR is not numerically equal to deltaGFR. For example, taking the average starting serum creatinine value and GFR that were observed in TEMPO, and assuming that net creatinine production would be constant over a one-year time frame, it is possible to calculate the expected change in serum creatinine concentration for a given deltaGFR and to use the CKD-EPI equation [3] to compute the resulting expected deltaeGFR . The observed difference in deltaeGFR between the tolvaptan and placebo groups in TEMPO of 0.98 ml/min/year corresponds to a difference in deltaGFR of 0.88 ml/min/year. While the latter discrepancy is small over a one-year time frame, when extrapolated over the decades that patients are likely to live with PCKD, the beneficial effect of tolvaptan to retard progression to end-stage renal disease (ESRD) would therefore be significantly over-estimated by the authors´ model. In cost-effectiveness analyses, a key model outcome is the incremental cost-effectiveness ratio (ICER). For the tolvaptan model, where the numerator of the ICER (incremental, discounted, lifetime costs) is large and the denominator (incremental, discounted, quality-adjusted, life-years) is small, a further reduction in the denominator would produce a large increase the computed ratio. The result of the above consideration is that the authors may have underestimated the ICER for tolvaptan therapy of PCKD: however this would only bolster their conclusion that, given current cost of the drug, it is not a cost-effective treatment strategy. In general, lack of numerical equivalence between deltaeGFR and deltaGFR is likely of little significance when deltaeGFR is used as a surrogate for ESRD since deltaeGFR and deltaGFR are highly correlated . However, we believe that in clinical trials where the primary outcome of interest is deltaGFR per se, the use of deltaeGFR may lead to an inaccurate estimate of benefit.

1. Erickson KF, Chertow GM, Goldhaber-Fiebert JD. “Cost-effectiveness of Tolvaptan in Autosomla Dominant Polycystic Kidney Disease”. Ann, Int. Med. 2013; 159: 382-9.
2. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. “Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease”. New Eng. J. Med. 2012; 376: 2407-18.
3. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Int. Med. 2009;150:604-12.
Posted on October 31, 2013
Christopher M. Blanchette, PhD, MBA, Benjamin Gutierrez, PhD, Keith Friend, MD
Otsuka America Pharmaceutical Inc
Conflict of Interest: None Declared
We acknowledge Erickson et al. for their assessment of the cost-effectiveness of tolvaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) and moreover for their effort to study this disease for which there is no approved treatment. Tolvaptan, as compared to placebo, was found to slow the increase in total kidney volume and decline in kidney function and led to a greater number of aquaresis events (excretion of electrolyte-free water) and hepatic adverse events over a 3-year period in patients with ADPKD. (1)While a cost-effectiveness analysis of tolvaptan is necessary, it is premature to complete at this time, as several key data points are not yet known. We discuss these points below.

Tolvaptan is available in the US(2) but is not approved for the treatment of ADPKD, and therefore, a price for this treatment cannot be determined at this time. The price assumed in this study was based on the daily price for the current indication of tolvaptan in the United States. Any new indication that may be approved in the future will require an independent pricing assessment, particularly in the context of a chronic indication such as the treatment of ADPKD. Further, the price of tolvaptan used in this analysis does not account for patent expiration and generic availability within the time horizon proposed. This constant price assumption significantly biases the results against the cost-effectiveness of tolvaptan.

Some assumptions of this study have led to the underestimation of the true cost of managing this disease. For example, this study did not account for costly and burdensome renal-related symptoms (hematuria, kidney stones, renal pain and infections).(3)

Also, the cost of any recommended safety monitoring or treatment-related adverse events would also have to be fully included to provide a balanced assessment of cost-effectiveness.

While the placebo arm of the TEMPO trial represents an adequate sample for comparison of the safety and efficacy of tolvaptan, established longitudinal cohorts,(4,5) may more accurately represent the natural course of disease. Moreover, this study did not evaluate cost-effectiveness in specific ADPKD patient subgroups (such as younger age, larger kidneys or early stage of disease).

Although the current analysis is thought-provoking, conclusions of this study should be viewed with caution until such time that these important data points are addressed.

(1) Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. NEJM. 2012;367(25):2407-18.

(2) Tolvaptan Full Prescribing Information, including Boxed WARNING; April 2013. Accessed at US Food and Drug Administration at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022275s007lbl.pdf on October 9, 2013.

(3) Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes. Clin J Am Soc Nephrol. 2006;1(1):148-57.

(4) Schrier RW, McFann KK, Johnson AM. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease. Kidney Int. 2003;63(2):678-85.

(5) Thong KM, Ong AC. The natural history of autosomal dominant polycystic kidney disease: 30-year experience from a single centre. QJM. 2013;106(7):639-46.

Christopher M. Blanchette, PhD, MBA
Health Economics & Outcomes Research, Otsuka America Pharmaceutical, Inc., Princeton, NJ

Benjamin Gutierrez, PhD
Health Economics & Outcomes Research, Otsuka America Pharmaceutical, Inc., Princeton, NJ

Keith Friend, MD
Medical Affairs, Otsuka America Pharmaceutical, Inc., Princeton, NJ
Author's Response
Posted on November 12, 2013
Kevin F. Erickson, MD, Glenn M Chertow, MD, Jeremy D. Goldhaber-Fiebert, PhD
Stanford University
Conflict of Interest: None Declared

We agree with Professors Lineen and Naimark that the estimated glomerular filtration rate (eGFR) is an imperfect surrogate for actual GFR, and that declines in GFR are not identical to declines in eGFR. It may also be the case that the treatment benefit described by the TEMPO investigators appears greater when assessed using eGFR than true GFR, although measuring the latter would have been quite challenging given the relative large sample size and dispersed geography described in the TEMPO trial. The eGFR necessarily introduces regression error; ideally, we could relate our model inputs (e.g., mortality rates, health-related quality of life and health care costs) to true, rather than estimated GFR, though we note that our model of eGFR matches the progression rates to end-stage renal disease observed in large cohorts of patients with polycystic kidney disease. However, measures of true GFR (e.g., inulin or iothalamate clearance) are not without imprecision themselves. Moreover, GFR itself does not encompass the totality of what the kidneys contribute to human health, as kidney function modulates volume and blood pressure, biochemical and hormonal balance, and pro- and anti-inflammatory and oxidant status, among other life sustaining tasks above and beyond the filtration of solutes. Use of eGFR is an imperfect but necessary simplification. Whether one employs eGFR or true GFR or a more comprehensive assessment of kidney function, our analysis and the input of our Canadian colleagues highlight the challenges of drawing firm conclusions about long-term risks and benefits of complex, sometimes costly interventions from clinical trials or related modeling exercises.

We agree with Dr. Blanchette that it would have been ideal to know the prices of brand name and generic tolvaptan for treatment of autosomal dominant polycystic kidney disease prior to conducting our cost-effectiveness analysis. Despite these price uncertainties, we believe that our analysis provides important information to inform decision makers regarding the use of tolvaptan for several reasons. First, the TEMPO trial relied on intermediate outcomes (i.e., growth in kidney volume and change in eGFR) and did not assess the long-term benefits of treatment using endpoints such as ESRD and mortality. By combining trial information with longitudinal studies like those cited by Dr. Blanchette, our analysis bridges intermediate and long-term endpoints. Second, our analysis determines price points at which tolvaptan would likely be deemed good value for money relative to other commonly used interventions; we find that a price reduction of >95% compared to the current price per milligram (for the hyponatremia indication) would likely be required to achieve reasonable cost-effectiveness.
The potential availability of a generic does not guarantee the cost-effectiveness of tolvaptan. Although our analysis did not consider generic availability explicitly, our price point analysis provides information on a price at which a generic should be considered. Furthermore, the relevance of considering non-generics remains even after a generic alternative becomes available. Based on experiences with other medications such as statins, many patients continue to use brand name formulations even after generics are on the market. For example, one survey of physicians found that approximately 4 in 10 physicians reported sometimes or often providing brand name drugs when a generic is available.1
We believe that many of the other concerns raised by Blanchette and colleagues are in fact addressed in the sensitivity analyses we reported. For instance, we demonstrate that varying our assumptions about the cost of polycystic kidney disease did not materially change our conclusions. Since quality of life from tolvaptan was not reported in the TEMPO trial, we were limited in our ability to account for changes in quality of life resulting from use of tolvaptan. In our base case, we assumed that the quality of life benefit from tolvaptan reducing polycystic kidney disease symptoms equaled the QALY loss from the medication (in terms of increased thirst and polyuria). Again, our main findings showed no particular sensitivity to variations on this assumption.

Erickson, Chertow, Goldhaber-Feibert

1. Campbell EG, Pham-Kanter G, Vogeli C, Iezzoni LI. Physician acquiescence to patient demands for brand-name drugs: results of a national survey of physicians. JAMA Internal Medicine. Feb 11 2013;173(3):237-239.

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