1.8.1. interpreting the evidence
1.8.1.1. The results that matter most
The panel considered quality of life and health-related mortality outcomes as critical outcomes for decision-making. Other important outcomes included renal function, fractures, kidney stones, persistent hypercalcemia, bone mineral density (lumbar spine or distal radius), cardiovascular events, cancer incidence, and adverse events. The panel was interested in cardiovascular and cancer outcomes, as there is some observational evidence to suggest that the risk of these future events is greater in untreated primary hyperparathyroidism.
No evidence was found for the effects of renal dysfunction, fractures, occurrence of kidney stones, cardiovascular events or cancer incidence.
1.8.1.2. The quality of evidence
There was evidence from 3 studies comparing cinacalcet with placebo. Cinacalcet is an oral calcimimetic used in the treatment of primary hyperparathyroidism. No data are available comparing calcimimetics with surgery, bisphosphonates, or combination therapy (calcimimetics and bisphosphonates).
For the comparison of cinacalcet with placebo, most of the evidence was of very low quality due to risk of bias and imprecision. This reduces our confidence in the estimate of the effect of cinacalcet.
All studies included patients with hypercalcemia. No evidence was found for normocalcemia primary hyperparathyroidism or outcome strata for pregnant women.
1.8.1.3. benefits and harms
Of the three included studies, two included patients with mild to moderately severe primary hyperparathyroidism (serum calcium 2.62 to 3.13 mmol/liter) and, in one study, all participants met criteria for parathyroid surgery (adjusted total serum calcium ≥ 2.85 mmol/liter). liter), but could not be submitted to parathyroidectomy. The committee argued that the latter study population reflected the current approved indications for cinacalcet in primary hyperparathyroidism. It is also the population considered in a recent UK NHS clinical commissioning document for 'Cinacalcet for complex primary hyperparathyroidism in adults'.26
Evidence suggests that the clinical benefits of cinacalcet outweigh the harms. The panel highlighted the clinical benefit of cinacalcet on quality of life outcomes, achieving normal calcium levels, and short-term adverse effects. There was clinical harm of cinacalcet on the long-term outcome of side effects. Mortality data were based on a single event and the fatal event in the study was considered unrelated to the intervention. For this reason, the panel did not consider data on the critical outcome of mortality. No clinical differences were found for the outcomes of serious adverse events, BMD of the lumbar spine and distal radius.
Data were also available from a small subset of the population who had had previous unsuccessful surgery. The panel noted that there was clinical benefit from using cinacalcet to achieve normal calcium levels. No other results were available for this population.
Cinacalcet works to lower serum calcium and therefore the panel considered that the greatest benefit would be in people with an adjusted serum calcium level above the reference range. Therefore, the greatest benefit will be achieved in individuals with elevated serum calcium levels and symptoms resulting from their hypercalcemia. It will also reduce the risk of target organ damage. However, the committee noted that cinacalcet should be an option in people who cannot undergo surgery alone and not as an alternative to surgery, as parathyroidectomy is the only definitive treatment option in people with primary hyperparathyroidism without surgical contraindication. Cinacalcet does not immediately stop bone loss or kidney problems due to primary hyperparathyroidism.
Based on their experience, the panel discussed that there is a group of patients who will not undergo surgery because of patient choice or because they are not suitable for surgery. In these cases, cinacalcet may lower serum calcium levels and prevent episodes of hypercalcemic crisis. The committee also noted that there is a small group of patients with primary hyperparathyroidism after failed one or more surgeries who are likely to benefit from cinacalcet. There are often very few other options for these people, and they may report an improvement in general well-being. Therefore, the committee recommended that cinacalcet be considered in these groups of people with primary hyperparathyroidism.
The panel agreed to make specific recommendations for cinacalcet, as data were only available for this type of calcium mimetic. They also felt that if another calcium mimetic becomes available for use in primary hyperparathyroidism in the future, the criteria for its use may be different. Therefore, they agreed that these recommendations should only apply to cinacalcet.
The panel discussed cutoff values for hypercalcemia and the use of cinacalcet. The clinical benefit on quality of life in this review was considered in subjects with an adjusted serum calcium level greater than 2.85 mmol/liter. Therefore, the limit was set at 2.85 mmol/liter for people with symptoms of hypercalcemia. When determining the cut-off point for hypercalcemia in the presence or absence of symptoms, the committee agreed, based on clinical experience, that it should be set above 3.0 mmol/liter, mainly due to the increased risk of hypercalcemic crisis. degree. of hypercalcemia. In the absence of data, the panel could not make a recommendation for people with normal calcemia.
The panel discussed that for individuals with albumin-adjusted serum calcium levels below 3.0 mmol/liter, continued treatment should be based on symptom relief. For individuals with an albumin-adjusted baseline serum calcium level of 3.0 mmol/L or greater, continuation of therapy should be based on a reduction in serum calcium or improvement in symptoms. Again, this distinction was made largely because of the increased risk of hypercalcemic attacks that can be seen with this degree of hypercalcemia.
The panel noted that albumin-adjusted serum calcium levels should be measured prior to initiation of cinacalcet therapy and within 1 week of initiation of therapy or dose adjustment. It was recognized that the dose of cinacalcet could be increased to achieve an optimal effect in lowering serum calcium and possibly improving the patients' symptoms. They agreed that albumin-adjusted serum calcium level should be measured every 2 to 3 months as stated in the British National Formulary (BNF). The committee, agreeing with the opinion of the BNF, decided that continuous biochemical monitoring should be done regardless of symptoms. The committee, based on their experience, stated that if there is improvement and the cinacalcet-adjusted serum calcium reference range is restored, treatment should be continued at the lowest effective dose to maintain this condition, as discontinuation of cinacalcet will lead to a increase in calcium and symptoms are likely to return. If cinacalcet is effective, it will become a potentially chronic treatment.
The panel argued based on clinical experience that cinacalcet is unlikely to have a beneficial effect in bone disease or kidney stones, as they do not act directly to reduce calcium excretion or bone loss. Therefore, they agreed that there is no benefit in prescribing cinacalcet if there are symptoms of end-organ damage.
1.8.2. Profitability and resource utilization
No financial data found for this question.
Cinacalcet is the only calcimimetic licensed for PHPT in the UK. It is an expensive drug costing around £3,278 per patient per year with an average dose of 60 mg per day (30 mg twice daily).
In the clinical review, it was observed that there is compensation in cases where an intervention is more effective and has more adverse effects. However, side effects noted in the studies were nausea, headache, muscle spasms and paraesthesia. Such side effects are not uncommon with many other drug treatments, and the panel judged that the benefits of the treatment outweighed the possible side effects.
However, cinacalcet is an expensive treatment and the cost-effectiveness of treatment for this population is highly uncertain.
A simple calculation was made using the results of those who achieved normal calcemia to estimate profitability. The example assumed a population of 1000, each subject received either cinacalcet or placebo, and outcomes were measured if normal calcemia was achieved. The absolute values of the results were obtained from the clinical review. The utility value assumptions were 0.8 and 0.6 for those who achieved normal calcemia and those who did not, respectively. A 6-month time horizon was used to maintain consistency with the time frame for the clinical outcome used.
The committee discussed that patients often receive cinacalcet for longer than 6 months, which was the maximum duration in some of the clinical review trials. However, as cinacalcet remains effective as long as it is taken, a time horizon of 6 months is considered sufficient for the purposes of this calculation, as the cost-effectiveness is likely to remain similar thereafter. Only the cost of cinacalcet (at a dose of 60 mg daily) was included. the cost of the placebo was considered zero.
The analysis described above generated an ICER of approximately £31,000. This is profitable at the highest NICE limit limit. However, it should be noted that incremental quality of life estimates of 0.2 between a normocalcemic and an abnormally calcemic patient are considered generous. It is unclear whether the patients included in the studies are symptomatic and, if so, to what extent. If the true difference in quality of life were smaller, the ICER would be higher than previously estimated.
The panel noted that cinacalcet side effects are also likely to affect quality of life. When people experience side effects as a result of using cinacalcet, it is likely that their actual improvement in quality of life will be less than estimated in the above calculations. Furthermore, if such side effects require the use of health resources, e.g. hospitalization, then the additional cost of calcium mimetics could potentially be greater than previously estimated. However, as mentioned above, the adverse effects reported in the studies are unlikely to cause significant patient disutility or significant additional costs.
The panel also argued that the above calculation does not take into account changes in resource use for those not receiving treatment. The committee noted that the cost of not receiving treatment would be greater in current practice because of the cost of rehydration as a result of hypercalcemia, which often requires hospitalization for intravenous fluids and treatment of symptoms and other consequences of hypercalcemia. In addition, there is the potential for long-term reduction in resource use after successful treatment with calcimimetic drugs due to reduced symptoms of hypercalcemia and reduced number of blood tests and doctor visits, as well as prevention of possible organ disease. -target. such as kidney stones and weakness. fractures
Furthermore, the committee noted that patients with untreated hypercalcemia are at increased risk of hypercalcemic crisis. This requires urgent hospitalization and consequently leads to very high levels of utilization of health resources, as well as a significant reduction in quality of life, together with a high risk of mortality. Although considered a rare occurrence, the relatively high cost and reduced QALYs due to the hypercalcemic crisis raise the possibility that cinacalcet is cost-effective. Overall, therefore, this is likely to reduce the incremental cost and QALY difference between drug and placebo, thereby lowering the ICER and making cinacalcet more cost-effective.
In general, the cost-effectiveness of calcimimetics is very uncertain due to poor quality clinical evidence. However, the committee noted that, for patients who cannot undergo surgery, calcium mimetics would likely be the last remaining option to manage primary hyperparathyroidism and control their hypercalcemia and avoid potentially serious episodes of intensive medical care. Therefore, despite the fact that the cost-effectiveness of calcimimetics is highly uncertain, they should be considered for individuals when appropriate.
The committee noted that the recommendations made were in line with current NHS England clinical commissioning policy practice and therefore no significant impact on resources is expected.
1.8.3. Other factors considered by the committee
The panel discussed that cinacalcet was initially licensed for the treatment of hyperparathyroidism secondary to renal failure and for the treatment of hypercalcemia in parathyroid carcinoma. It was later approved for use in patients with primary hyperparathyroidism who meet hypercalcemia criteria for parathyroidectomy but refuse or are unable to undergo surgery.26
Lay committee members noted that there is concern among patients that cinacalcet is being offered as an alternative when surgery must be used. Because cinacalcet treats the symptoms rather than the cause, many patients are concerned about the long-term consequences of primary hyperparathyroidism if the underlying cause is left untreated.
The panel debated whether a validated objective assessment of symptoms was necessary, but decided that the potential benefit was minimal compared to the time it would take to administer a questionnaire. The panel noted that the number of people unable to undergo surgery has declined with advances in surgical practice and anesthesia.
While the panel acknowledges that the cost-effectiveness of cinacalcet is unclear, in many cases cinacalcet intervention is the only available option for patients who cannot undergo surgery.