NDT Advance Access originally published online on July 22, 2008
Nephrology Dialysis Transplantation 2008 23(10):3371-3372; doi:10.1093/ndt/gfn425
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Reply
Nephrol Dial Transplant 2008; doi:10.1093/ndt/gfn389E-mail: gablock{at}denverneph.net
Sir,
We read with interest the letter by Dr Sane in response to our paper examining the use of combinations of cinacalcet with low-dose vitamin D sterols in the treatment of moderate-to-severe secondary hyperparathyroidism in subjects receiving dialysis [1]. Dr Sane points out that low serum calcium concentrations were observed in this trial, and he raises concern about the cardiovascular safety monitoring and the cardiovascular implications of the use of the treatment strategy examined in this study. We understand and appreciate Dr Sane's concerns.
Because of the potential for decreased serum calcium concentrations to induce alterations in cardiac conduction and left ventricular function, early studies with the calcimimetic R-568 included monitoring of cardiac electrical activity with accompanying ionized calcium levels on a q 4 h basis in a 15-day study of 20 subjects. Despite notable decreases in blood ionized calcium [2], there was only one report of first degree AV block and incomplete bundle branch block with ST changes, which was deemed unrelated to study drug.
The absence of adverse cardiovascular effects of cinacalcet in patients receiving dialysis, even in the presence of hypocalcaemia, was reinforced by the data gathered from the phase 3 trials. Post hoc analyses of the phase 3 data showed a 39% decrease in the risk of hospitalization with cardiovascular disease (relative risk = 0.61) [3] and no clinically significant effect on the QT interval, regardless of the baseline serum calcium concentration. Mean (SE) uncorrected QT intervals from baseline to end of study were similar between cinacalcet and placebo groups. Although the phase 3 trials were neither designed nor powered to examine the effects of cinacalcet on cardiovascular outcomes, these data suggest no difference in cardiovascular events or other complications related to cinacalcet use.
The exposure-adjusted incidence rate for all arrhythmias and for arrhythmias requiring hospitalization was also similar. The incidence of cardiac arrhythmia in the first 30 days after drug initiation or dose increase was 4% for both cinacalcet and placebo, despite a higher rate of hypocalcaemia observed in cinacalcet-treated subjects during this period. Torsades de point was reported in zero cinacalcet-treated and one placebo-treated subject during the trials.
With respect to the TARGET study, Dr Sane requested that information on patient serum calcium concentrations be provided; however, serum calcium concentrations were rarely collected within 24 h of death. Moreover, among the 16 subjects who died (the manuscript reported nine patients in error, and an erratum has been sent to the editor), the most common causes reported for death were infectious (8/16) and included sepsis (5), presumed pneumonia (2) and viral encephalitis (1). Cardiovascular causes of death were implicated in five cases and included myocardial infarction (MI), heart failure secondary to MI, cardiopulmonary arrest and unwitnessed death (2). Of the cardiovascular deaths, there were no reports of arrhythmias. The serum calcium was 9.9 mg/dl in the one case of acute MI, and serum calcium values were not provided at the time of the event in the other reports. Other causes of death (3) included pulmonary embolus, ischaemic bowel and haemorrhagic cerebrovascular accident.
Dr Sane suggests that the vitamin D sterols exert activity outside of the reduction of PTH that is not shared by cinacalcet. It is noteworthy that vitamin D sterols have not been prospectively tested in clinical trials to determine whether they exert favourable or deleterious effects on cardiovascular or other disease processes in CKD. It is troubling that despite the widespread use of intravenous vitamin D sterols in established dialysis patients, we have not observed a decrease in annual mortality rates published by the USRDS [4] over this time or in parathyroidectomy [5], cardiovascular disease or fractures in the dialysis population. The ongoing (and fully enrolled, N = 3883) Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) trial will test whether cinacalcet+standard therapy, including vitamin D sterols, versus standard therapy without cinacalcet reduces mortality and cardiovascular events in haemodialysis patients with secondary hyperparathyroidism.
Finally, we agree with Dr Sane that cardiovascular risk assessment is particularly complex in patients with CKD-MBD. Future studies aimed at evaluating cardiovascular risk should include other biomarkers in addition to parameters of mineral metabolism.
1 Denver Nephrologists, Denver, CO 2 Pines Clinical Research, Pembroke Pines, FL 3 St. Francis Medical Center Honolulu, HI 4 University of California San Francisco, San Francisco, CA 5 Amgen, Inc., Thousand Oaks, CA 6 University of Rochester School of Medicine and Dentistry 601 Elmwood Ave Box 675, Rochester New York 14642
Acknowledgments
The authors would like to thank Drs William G. Goodman, Peter McCroskery and William W. Stark, Jr (Amgen Inc.) for assistance in writing this letter. The writing of this letter was supported by Amgen Inc.
Conflict of interest statement. Dr Block has acted as an advisor to Amgen Inc, and has received research funding from Amgen, Inc. Dr Zeig has nothing to declare. Dr. Sugihara has acted as an advisor to Amgen Inc and holds equity interest in Amgen Inc. Dr Chertow has received research funding from Amgen, Inc, and has acted as an advisor to Amgen Inc. Drs. Turner and Chi are employees of, and hold equity interest in, Amgen Inc. Dr Bushinsky has acted as an advisor to Amgen Inc, has lectured for Amgen Inc, and holds equity interest in Amgen Inc.
References
- Block GA, Zeig S, Sugihara J, et al. Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism. Nephrol Dial Transplant (2008) 1–8.
- Goodman WG, Frazao JM, Goodkin DA, et al. A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int (2000) 58:436–445.[CrossRef][Web of Science][Medline]
- Cunningham J, Danese M, Olson K, et al. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int (2005) 68:1793–1800.[CrossRef][Web of Science][Medline]
- USRDS. (2007) Annual Data Report: 2007 http://www.usrds.org/adr.htm.
- Foley RN, Li S, Liu J, et al. The fall and rise of parathyroidectomy in U.S. hemodialysis patients, 1992 to 2002. J Am Soc Nephrol (2005) 16:210–218.
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