NDT Advance Access originally published online on September 4, 2007
Nephrology Dialysis Transplantation 2007 22(11):3357-3358; doi:10.1093/ndt/gfm456
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Reply
Email: Ruth.Garside{at}PenTAG.nhs.ukSir,
We write in response to the comments by Ray et al. on our paper The cost-utility of cinacalcet in addition to standard care compared to standard care alone for secondary hyperparathyroidism: a UK perspective. As a general point, please note that data used in this economic analysis were identified through systematic searches of electronic databases, where possible [1]. Only if such published data were not available did we rely on the input of a clinical, expert advisory group. We do not consider it appropriate to criticize work for not using data unavailable at the time it was written. Extensive one-way and probabilistic sensitivity analyses were undertaken to accommodate the inherent uncertainties surrounding any such analysis.
In answer to the specific points raised by Ray et al.
Relative risk of mortality at different levels of PTH
The difference between the relative risk (RR) of mortality described by Block et al. [2], as used in our paper and that suggested by Ray et al. is not totally clear. They quote a 23% increased risk of death for those with PTH levels over 308 pg/ml, while our model used 6.13% for those with PTH >300 pg/ml and 18.24% for those >800 pg/ml based on data from a cohort study of over 40 000 people.
As stated in our paper, one-way sensitivity analysis was carried out to identify thresholds required in order for the ICER to fall below a E30 000 willingness-to-pay threshold. Full details were not included in the original paper for reasons of space. All details can be found in the HTA monograph reporting this project [1]. This showed that the risk of death among those with very uncontrolled levels of PTH would need to be more than doubled (RR = 2.2) for the ICER to fall below E30 000/QALY (Figure 1).
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As we state in our paper, any analysis is limited by the absence of data which describes the relative impact and interaction of PTH, calcium and phosphate levels on risk of fractures, CV events, mortality and quality of life (QoL). Even without this multivariate information, calcium–phosphate product may be a better risk marker of CV event and mortality than PTH level. We attempted to accommodate this in our paper through a scenario analysis, utilizing estimated relative risks by Ca x P levels on which cinacalcet will have an effect if PTH control is increased. This yielded an ICER of E39 000/QALY; however, detailed information about this marker was not available from the trials, so this analysis remains speculative.
Dose of cinacalcet
Dose data was based on that used in the trials—the best available at the time and which, crucially, links observed treatment effect to actual dose used. We calculated using threshold analysis that the cost of cinacalcet, a proxy for dose, would need to be reduced to 55% of the current price for the ICER to fall below a threshold of E30 000/QALY, rather than the 64% suggested by Ray et al. (Figure 2).
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Distribution of patients across the three strata of PTH control
I am unclear as to the point about initial distribution across the three levels of PTH control. As stated in our paper, patients in both arms are identical at the start of the model. After the initial 3 months of treatment with best standard care with or without cinacalcet, they are distributed between the model strata according to the degree of PTH control reported in the literature—pooled patient level data from three published RCTs (n = 1136), show 40% of people treated with cinacalcet achieved target levels of PTH [3]. The suggested figure of 56% of people treated with cinacalcet achieving controlled PTH is not referenced by Ray et al.
Probabilistic analysis does not include the base case of no deterioration of PTH levels with cinacalcet
There is a typo in Table 1—thank you for drawing this to our attention. Range data used in the PSA for ‘the proportion of people with "controlled" PTH becoming "uncontrolled" in the cinacalcet arm (per year)’ and ‘the proportion of people with "uncontrolled" PTH becoming "very uncontrolled" in the cinacalcet arm (per year)’ should be 
0.001, 0.5. In order to ensure that all values used are positive (i.e. people can only deteriorate over time in the model and not improve), sampling is from approaching zero up to the maximum value. A log-normal distribution ensures that the values are sampled from close to zero.
Not clear how model accounts for withdrawal
Apologies if this was unclear. People withdrawing from cinacalcet treatment after the titration period revert to standard care, and pick up those associated costs and benefits which are counted in the cinacalcet arm of the model.
Increased risk of fracture following parathyroidectomy
The comment by Ray et al. is based on opinion. We also found a paucity of published information about the long-term impact of raised PTH levels on fracture rate, and used expert clinical opinion as our data source. They suggested that the risk of fracture was likely to decrease following parathyroidectomy, while the risk of CV event was likely to remain elevated, and these assumptions were used in the model. The absolute numbers of fractures (21 in the cinacalcet arm vs 25 with standard care) and differential fracture rate (0.4%) in the model was small (see Table 6, Garside et al., 2006 [4]) and so this is unlikely to have a large impact on the model.
Utilities in ‘uncontrolled’ PTH health state
QoL for people with ESRD on dialysis is already considerably reduced. Based on published data, we used a value of 0.6735 for this patient group [5]. Any additional impact of raised PTH levels is more difficult to assess. We identified one large study of QoL in 14 800 people with ESRD in the USA using the SF-36. This found no significant association with PTH scores and worsening QoL scores [6]. However, clinical opinion was that there were QoL implications, and that these were likely to impact on those with the highest levels of PTH—we therefore included an additional scaled reduction of 15% in utility for this strata of the model. One-way sensitivity analysis showed that the model was not sensitive to utility values in the ‘uncontrolled’ PTH stratum.
The conclusions are in contrast to those of NICE
Our report is provided as independent research and is just one of many pieces of information which NICE considers when making the decision about adopting treatments under the NHS. We do not make this decision. Other NICE decisions have been positive despite high costs, for such reasons as the selection of subgroups, severity of a condition or the paucity of alternative treatments. A full description of the NICE decision relating to cinacalcet and their reasons are available here: http://guidance.nice.org.uk/TA117/guidance/pdf/English/download.dspx. Finally, as stated in our paper, we used probabilistic sensitivity analysis to account for the uncertainty associated with all the parameters used in the model. This showed cinacalcet was very unlikely to be considered cost-effective at usual levels of willingness to pay (WTP) in the UK—just 6% at a WTP threshold of E30 000/QALY.
Peninsula Technology Assessment Group
Peninsula Medical School
Universities of Exeter & Plymouth
References
- Garside R, Pitt M, Anderson R, et al. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end stage renal disease: a systematic review and economic evaluation. Health Technol Asses (2007) 11.
- Block GA, Klassen P, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintainance hemodialysis. J Am Soc Nephrol (2004) 15:2208–2218.
[Abstract/Free Full Text] - Centre for Drug Evaluation and Research FDA. Cinacalcet Medical Review. (2005) Available at http://www.fda.gov/cder/foi/nda/2004/21-688_Sensipar.htm.
- Garside R, Pitt M, Anderson R, Mealing S, D'Souza R, Stein K. The cost-utility of cinacalcet in addition to standard care compared to standard care alone for secondary hyperparathyroidism in end-stage renal disease: a UK perspective. Nephrol Dial Transplant (2007) 22:1428–1436.
[Abstract/Free Full Text] - de Wit GA, Ramsteijn PG, de Charro FT. Economic evaluation of end stage renal disease treatment. Health Policy (1998) 44:215–232.[CrossRef][Web of Science][Medline]
- Knight EL, Ofsthun N, Teng M, Lazarus JM, Curhan GC. The association between mental health, physical function, and hemodialysis mortality. Kidney Int (2003) 63:1843–1851.[CrossRef][Web of Science][Medline]
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