Meta-Analysis of Biochemical and Patient-Level Effects of Calcimimetic Therapy - Article Review
This was a systematic review performed to assess available efficacy and safety data as well as to highlight research questions that need additional investigations related to the use of calcimimetic therapy in the dialysis population. The clinically relevant end points were parathyroidectomy rates, fracture, renal osteodystrophy and cardio vascular disease and death as well as surrogate markers which included PTH, serum calcium and phosphorus levels. Another important question was the optimal time for start of calcimimetic therapy, the influence of calcimimetics on standard treatment regimens and the effectiveness of calcimimetics in patients with different stages of CKD and after transplantation.
Study Design and Study Population
All randomized control trials have any calcimimetic agent, cinacalcet hydrochloride or NPS R 308 administration to patients with CKD for the treatment of secondary hyperparathyroidism. Standard electronic searches were performed in MEDLINE, EMBASE and Cochrane Renal Group Specialized Register. Medical subject headings and test words were used. Results of the searches were analyzed in title and abstract form by two authors. Reference list from identified articles were also searched. Information about unpublished or ongoing trials was sought from experts in the field and pharmaceutical companies. There was no language restriction on the randomized controlled trials. Each trial was assessed by two independent authors. From all included trials, data was extracted for study sample characteristics included type of agent, dose, and route administration as well as trial methods and outcomes. The following outcome measures were considered: end-of-treatment values for PTH, 30% or greater decrease in PTH levels from baseline, serum calcium level, hypocalcemia, serum phosphorus, calcium phosphate product, cardiovascular events, cardiovascular and all-cause mortality, fractures at any site, bone hisomorphometry, bone mineral density, bone pain, muscle pain or weakness, paresthesias, nausea, vomiting, dyspnea, hospitalization, and quality of life.
Methods and quality of included trials were assessed by standard criteria which include allocation of concealment; blinding of participants, investigators, and outcome assessors, analysis by intention to treat and completeness of follow-up. Standard statistical analysis was used. Forest pots were used for graphical representation of data.
186 articles were identified which 148 excluded after title and abstract review. Reason for exclusion included non-randomized studies, randomized trials of interventions not related to secondary hyperparathyroidism, non-calcimimetic interventions, duplicate articles of the same trials or review articles. Of the remaining 38 eligible studies, 30 additional studies were excluded as they did not conform from the full text analysis or from contacting the investigators if they were randomized trials or duplicate publication. Therefore, 8 trials enrolling a total of 1429 patients were included for final analysis. These trials compared cinacalcet hydrochloride and 845 patients versus placebo in 584 patients. One trial reported on the first generation calcimimetic R-568 which has subsequently been withdrawn from the market due to poor bioavailability and other problems. As there is no difference on the results of the analysis, this trial was included in the final report.
Most patients were administered an active vitamin D sterol for suppression of PTH and phosphate binders as co interventions in all trials in a non randomized fashion, however there were no significant difference in the proportion of patients prescribed cinacalcet, calcitriol, vitamin D analogs and phosphate binders when comparing the calcimimetic and placebo groups of the trial. Mean age of the patients enrolled raged from 47 to 55 years of age with all patients having secondary hyperparathyroidism. On average there were a greater proportion of males enrolled in the trails. Follow-up studies ranged from 3 weeks to 26 weeks. Figure 1 provides a flow chart indicating the number of citations retrieved, along with the final number of included trials and the reasons for exclusion.
Method Quality of Included Studies (Table 3)
Only two trials met the quality standards, although all trails were published after release of the consolidated standards for reporting trials (consort). Allocation concealment was unclear in 75% of the trials, even though all studies were reported as double blinded. Intention to treat analysis was performed in 3 of the 8 trials. The proportion of patients lost a follow of range from 0-56%. The measure of persistence of medication was unclear from most trials and either not reported or reported to be minimal.
Trail Results / Patient Level Outcomes (Table 4)
- All cause of mortality was not significantly different with calcimimetics compared to placebo.
- Factures and other clinically important measure of renal bone measures were not reported by any trial except for two abstracts.
- There was no report that rates of hospitalization admission study withdrawal treatment of placebo patients.
- Treatment with calcimimetic or placebo did not result in significant differences in the use of phosphate binders, calcitriol or vitamin D analogs.
- Use of calcimimetic increased the risk for nausea and vomiting but hypotension was less common.
- For all of the tests of heterogeneity the I2 statistic was moderate to high or only one study reported the outcome, therefore no forest plot was done to pool the results.
Trial Results / Biomarker Outcomes (Figure 2)
The end of treatment value for PTH was significantly less with calcimimetics compared with placebo.
• End of treatment values for serum calcium, serum phosphate and calcium phosphate product were significantly less with calcimimetics than placebo.
This was a well done meta analysis using standard procedures for the authors of this paper are well known for their expertise in conducting systematic reviews in meta analysis. The reason for doing this when mostly biomarker endpoints were in the study design does not increase the information that is available from these trials.
Impact on Practice
This meta-analysis highlights that the majority of the trials done with the calcimimetic have been to determine efficacy of lowering PTH levels in a wide variety of secondary hyperparathyroidism states. Most of the trials have been done with dialysis patients. The studies have also shown that the use of calcimimetic also decreased phosphate, serum phosphorus and calcium concentrations even with concomitant use of vitamin D analogs.
At the time of publication of this meta-analysis, there were no studies designed to specifically address the efficacy of a calcimimetic in decreasing cardio vascular or other morbidity or mortality outcomes. A recent study called the Advanced Trail investigated the efficacy of cinacalcet decreasing vascular calcification and there was a trend towards decrease calcification in this study. The renal community waits for the results of the Evolve trial which is specifically powered and designed to address the use of calcimimetics and their effect on morbidity and mortality in the dialysis population.
Cinacalcet has not been approved though the common drug review process in Canada due to the lack of outcome data. Therefore, the availability and use is restricted to patients with private insurance or though compassionate programs. It is not anticipated that there will be any further coverage of expansion of coverage until there is good outcome data proving benefit in decreasing morbidity and mortality.
Reviewed by Reviewed by Dr. Steven Soroka
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