Paricalcitol Superior for Lowering iPTH
PRAGUE—Paricalcitol is superior to cinacalcet in achieving target parathyroid hormone levels in patients with secondary hyperparathyroidism (SHPT), data show.
Either a vitamin D receptor activator such as paricalcitol or a calcimimetic such as cinacalcet are used to treat elevated serum levels of intact parathyroid hormone (iPTH), which can lead to skeletal and cardiovascular complications.
In a late-breaking trials session here at the 48th Congress of the European Renal Association-European Dialysis and Transplant Association, Markus Ketteler, MD, of the Division of Nephrology at Klinikum Coburg in Coburg, Germany, told delegates that until now, the comparative effectiveness of these two drugs had not been evaluated in patients undergoing hemodialysis (HD).
In an open-label, phase 4, multi-national trial, the IMPACT SHPT (Improved Management of iPTH with Paricalcitol-centered Therapy vs Cinacalcet Therapy with Low-dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism) study, he and his co-investigators evaluated optimal dose titration of paricalcitol (plus cinacalcet if hypercalcemia occurred) versus a combination of cinacalcet with low-dose vitamin D in the management of SHPT.
After a screening and washout period, 272 HD patients were randomly assigned to paricalcitol with cinacalcet for hypercalcemia or to cinacalcet with low-dose vitamin D for 28 weeks, with evaluation during the final 8 weeks. Patients received paricalcitol intravenously (IV stratum, at United States and Russian sites) or orally (oral stratum, all other sites).
Eligible patients required HD thrice weekly for at least three months prior to study entry, had an iPTH level of 300-800 pg/mL, serum calcium of 8.4-10.0 mg/dL, and a phosphorus level no higher than 6.5 mg/dL.
At baseline, patients were well matched within the IV or oral strata for age, gender, duration of dialysis, serum calcium, and iPTH (496-526 pg/mL across both strata and treatment arms). Their co-morbidities were typical of HD populations.
One significant difference between the strata was that more subjects in the paricalcitol IV stratum had type 1 diabetes whereas the oral stratum had more type 2 diabetes. Initial doses were paricalcitol 0.07 μg/kg IV or PTH/80 orally, or cinacalcet 30 mg. The primary endpoint of the trial was the proportion of subjects at a target mean iPTH level of 150-300 pg/mL (normal: 10-65 pg/mL) at weeks 21-28. A secondary endpoint was the proportion with hypocalcemia or hypercalcemia (calcium less than 8.4 mg/dL or 10.5 mg/dL or higher).
IV paricalcitol was superior to IV cinacalcet in getting patients into the target iPTH range that was the primary endpoint and with fewer patients outside the target serum calcium range. Thirty of 52 patients in the IV paricalcitol stratum (58%) achieved the goal compared with 16 of 49 cinacalcet-treated patients (33%), a significant difference between the groups. However, the oral strata of either drug showed no significant difference in the proportion achieving the iPTH efficacy endpoint (54% with paricalcitol compared with 43% for cinacalcet).
A secondary efficacy analysis using the Cochran-Mantel-Haenszel (CMH) statistical test to control for strata showed that 56% of patients on paricalcitol verus 38% on cinacalcet achieved the iPTH range of 150-300 pg/mL.
Paricalcitol treatment worked out to be 40% less expensive than cinacalcet when those drugs and vitamin D preparations were figured in, based on U.S. wholesale pricing, according to the researchers.
Combining the IV and oral strata, three times as many major adverse cardiovascular events occurred with paricalcitol (9/134) as with cinacalcet (3/134), possibly related to differences in risk factors in the groups at baseline. About half of the cinacalcet patients on either IV or oral therapy experienced hypocalcemia compared with none of the paricalcitol patients in the IV stratum and only 3.6% in the oral stratum. Hypercalcemia was minimal, with no significant differences among the treatment groups.
Serious adverse events affected 21%-31% of subjects in the oral stratum and 35%-44% in the IV stratum and led to interruption of the study drugs in 22%-27% of subjects in any of the four arms.
“Paricalcitol showed superiority over cinacalcet in achieving the primary efficacy endpoint using the CMH test,” Dr. Ketteler concluded. "Hypocalcemia developed in almost half of the subjects treated with cinacalcet, [and] hypercalcemia in paricalcitol treated subjects was not significantly different than the cinacalcet treated subjects.”
Johannes Mann, MD, Director of the Department of Nephrology at Munich General Hospitals in Munich, Germany, who moderated the congress session, told Renal & Urology News that he is “totally underwhelmed”looking at trials on changes in iPTH levels. He said more important outcomes, in his view, are hard endpoints such as bone fractures, cardiovascular events, survival, and quality of life, which are what matter to patients.
The study was designed, conducted, and funded by Abbott Laboratories, which markets Zemplar brand of paricalcitol.