What Groups of Patients on Dialysis Who Have Secondary Hyperparathyroidism Might Not Benefit from Calcimimetics?

In the assessment of chronic kidney disease–mineral bone disorder (CKD-MBD), serial measurements of serum calcium, phosphorus, and parathyroid hormone (PTH) occur, and attempts are made to bring these levels into the normal range. However, the optimal level of PTH in dialysis patients is not known. Kidney Disease Improving Global Outcomes recommends that, in dialysis patients requiring PTH-lowering therapy, calcimimetics, calcitriol, vitamin D analogs, or a combination of these drugs be prescribed (1). However, which patients need these drugs? The indications may include prevention or treatment of severe unremitting hyperparathyroidism (hyper-PTH) or prevention of major clinical events (cardiovascular events or fractures). Calcimimetics may be given orally (cinacalcet) or intravenously (etelcalcetide). Recently, it was reported that etelcalcetide in one trial of patients on dialysis with secondary hyper-PTH reduced PTH from a baseline of 849 to 384 pg/mL after 20 to 27 weeks of therapy and in a second trial, from 845 to 363 pg/mL (2).

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Prevention of severe, unremitting hyper-PTH

Cinacalcet is approved for the treatment of secondary hyper-PTH, and it is very effective in the prevention of severe unremitting hyper-PTH. This has been defined as plasma PTH >1000 pg/mL with sustained hypercalcemia or a decision to undertake a parathyroidectomy (PTX). The relative hazard comparing patients randomized to cinacalcet compared with those randomized to placebo in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) Study was 0.31 and significant regardless of whether the baseline PTH was 300 to 600, 600 to 900, 900 to 1200, or >1200 pg/mL (3).

However, in patients with PTH levels below 900 pg/mL, these hyper-PTH events took time to occur and were relatively infrequent in the first 2 years. Consequently, I would not prescribe cinacalcet for PTH levels below 900 pg/mL if the intent was the prevention of severe unremitting hyper-PTH.

Treatment of severe hyper-PTH

In patients with PTH >900 pg/mL, severe unremitting hyper-PTH is highly likely to occur, and treatment choices are PTX or cinacalcet. PTX is clearly a more definitive treatment than cinacalcet, but its harms may outweigh its benefits in some subgroups, particularly the frail elderly and those with severe comorbidity. There is no head-to-head randomized, controlled clinical trial of PTX versus calcimimetics. Consequently, I would likely not prescribe cinacalcet in those patients who can undergo an invasive surgery and are at mild to moderate surgical risk. However, these patients should be permitted to choose their preferred therapy when provided information on harms and benefits of each choice.

Prevention of cardiovascular events

In the EVOLVE Study of cinacalcet versus placebo for the treatment of secondary hyper-PTH, the unadjusted primary composite end point (death or nonfatal cardiovascular events) showed a nonsignificant reduction (relative risk [RR] = 0.93) but when adjusted for imbalances in baseline characteristics, showed a nominally significant reduction in the primary composite end point (RR = 0.88; p = 0.007) (4). Of particular interest was the observation in a pre-specified analysis of age that cinacalcet in patients >65 years old reduced the primary end point by 26% (p < 0.001) and mortality by 27% (p < 0.001) but had no effect on the primary end point in patients younger than 65 years old (5). In my opinion, trials should not be judged by the result of a single analysis and a single p value, but inferences should be on the basis of the totality of the data (6). Consequently, I would not prescribe cinacalcet in patients younger than 65 years old with PTH levels <900 pg/mL.

In older patients with PTH levels <900 pg/mL, I would prescribe cinacalcet, but I would not prescribe it in patients with substantial comorbidity and a short life expectancy.

Prevention of fractures

In the EVOLVE Study, the results for fractures were very similar to those for the primary end point: nonsignificant reduction in the risk of clinical fractures in the unadjusted analyses (RR = 0.93), nominally significant reduction in risk when adjusted for age (RR = 0.88; p = 0.007), and a treatment effect that was strongly age dependent (7). The adjusted RR for clinical fracture was 0.92 (NS) in patients younger than 65 years old and 0.69 (95% confidence interval, 0.49 to 0.95) in patients 65 years or older. These data support the recommendations for limiting cinacalcet use in younger patients discussed in the previous paragraph.

Treatment of calcific uremic arteriolopathy

Cinacalcet reduced the incidence of calcific uremic arteriolopathy in the EVOLVE Study, implying that hyper-PTH was implicated in its cause (8). However, that does not mean that cinacalcet would be an effective treatment of calcific arteriolopathy.

Balance of benefits versus harms

Nausea and vomiting occur quite frequently when using either oral cinacalcet (4) or intravenous etelcalcetide (2). Of interest, with the intravenous compound, nausea occurred in 12% of patients (compared with 7% of controls), and vomiting occurred in 9% of patients (compared with 5% of controls) (2). This may be occasionally severe enough to withdraw calcimimetics (9). Furthermore, hypocalcemia may occur (8), although it is usually asymptomatic, and in the EVOLVE Study, rarely engendered a therapeutic response (P. Parfrey, unpublished data). Consequently, the decision to prescribe or maintain cinacalcet requires an assessment of the likelihood that potential important clinical benefits will be achieved and that the drug will be tolerated in individual patients.

Economic evaluation of cinacalcet in the US

Cinacalcet does not represent a cost-effective use of health care resources when using the unadjusted intention to treat analysis from the EVOLVE Study and a willingness to pay a threshold of $100,000 (10). However, when using the covariate-adjusted treatment effect, which probably represents the least biased estimate, cinacalcet is a cost-effective therapy for patients with moderate to severe hyper-PTH. If used in the more targeted manner described above, cinacalcet becomes much more cost effective.

Conclusion

Calcimimetrics are unlikely to provide important clinical benefits in patients younger than 65 years old, other than those who have severe hyper-PTH and cannot have PTX. In older patients, treatment of moderate to severe hyper-PTH may be more beneficial, but prescription of calcimimetics should take account of like expectancy.

July 2017 (Vol. 9, Number 7)

References

1. KDIGO. Clinical practice guideline update on diagnosis, evaluation, prevention and treatment of CKD-MBD, 2016.

2. Block GA, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: Two randomized controlled trials. JAMA 2017; 317:146–155.

3. Parfrey PS, et al. The clinical course of treated hyperparathyroidism among patients receiving hemodialysis and the effect of cinacalcet. J Clin Endocrinol Metab 2013; 98:4834–4844.

4. Chertow GM, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:2482–2494.

5. Parfrey PS, et al. The effects of cinacalcet in older and younger patients on hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Clin J Am Soc Nephrol 2015; 10:791–799.

6. Parfrey PS, et al. Lessons learned from EVOLVE for planning of future randomized trials in patients on dialysis. Clin J Am Soc Nephrol 2016; 11:539–546.

7. Moe SM, et al. Effects of cinacalcet on fracture events in patients receiving hemodialysis: The EVOLVE trial. J Am Soc Nephrol 2015; 26:1466–1475.

8. Floege J, et al. The effect of cinacalcet on calcific uremic arteriolopathy events in patients receiving hemodialysis: The EVOLVE trial. Clin J Am Soc Nephrol 2015; 10:800–807.

9. Bover J, et al. Clinical and practical use of calcimimetics in dialyisis patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol 2016; 11:161–174.

10. Belozeroff V, et al. Economic evaluation of cinacalcet in the United States: The EVOLVE trial. Value Health 2015; 18:1079–1087.