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PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

Akizawa T, Kurita N, Mizobuchi M, Fukagawa M, Onishi Y, Yamaguchi T, Ellis AR, Fukuma S, Alan Brookhart M, Hasegawa T, Kurokawa K, Fukuhara S - Sci Rep (2016)

Bottom Line: To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders.Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT.In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82).

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

ABSTRACT
Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43-1.06). These findings indicate that decisions about using cinacalcet should take into account the severity of SHPT.

No MeSH data available.


Related in: MedlinePlus

Study design of the MBD-5D.The study has a “whole cohort” (large solid circle) comprising all patients enrolled and a “subcohort” (dotted circle) comprising a randomly selected 40% of the whole cohort. From 86 facilities, all 8,229 dialysis patients with secondary hyperparathyroidism were registered, and 3,276 were selected into the subcohort. Data were collected prospectively from the subcohort, and retrospectively from those outside the subcohort who died. In total, there were 1,226 deaths due to any cause (small solid circle with gray color) and 462 deaths due to cardiovascular disease. As for death due to any cause, data from 3,996 patients (3,276 patients in the subcohort, among whom there were 506 deaths, together with 720 deaths among patients outside the subcohort) were analyzed as a case-cohort study. Similarly, as for death due to cardiovascular disease, data from 3,547 patients (3,276 patients in the subcohort, among whom there were 191 deaths, together with 271 deaths among patients outside the subcohort) were analyzed as a case-cohort study. As for cardiovascular hospitalization or death due to any cause, 1,054 cases were observed in the subcohort, and data from 3,276 subcohort patients were analyzed as a cohort study. CV: cardiovascular.
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f3: Study design of the MBD-5D.The study has a “whole cohort” (large solid circle) comprising all patients enrolled and a “subcohort” (dotted circle) comprising a randomly selected 40% of the whole cohort. From 86 facilities, all 8,229 dialysis patients with secondary hyperparathyroidism were registered, and 3,276 were selected into the subcohort. Data were collected prospectively from the subcohort, and retrospectively from those outside the subcohort who died. In total, there were 1,226 deaths due to any cause (small solid circle with gray color) and 462 deaths due to cardiovascular disease. As for death due to any cause, data from 3,996 patients (3,276 patients in the subcohort, among whom there were 506 deaths, together with 720 deaths among patients outside the subcohort) were analyzed as a case-cohort study. Similarly, as for death due to cardiovascular disease, data from 3,547 patients (3,276 patients in the subcohort, among whom there were 191 deaths, together with 271 deaths among patients outside the subcohort) were analyzed as a case-cohort study. As for cardiovascular hospitalization or death due to any cause, 1,054 cases were observed in the subcohort, and data from 3,276 subcohort patients were analyzed as a cohort study. CV: cardiovascular.

Mentions: As the MBD-5D study was designed to answer more than one research question (associations between mineral abnormalities and outcomes, and associations between cinacalcet and outcomes), the sample size was not determined for specific treatments14. However, sample size was determined as follows: for death due to cardiovascular disease, (1) the expected rate was 2.5 deaths per 100 person-years during the 3-year follow up period, (2) the effect size of a drug was 20% to 25% of the relative risk, (3) the proportion of patients to whom the drug was prescribed was one-third. With those values, 6000–7500 patients would be required for 80% power with a two-sided alpha of 0.05. We did not have the financial resources needed to hire clinical research coordinators to collect data repeatedly from all of the patients (the “whole cohort”, n = 8229), and therefore we conducted a case-cohort study. Patients were randomly sampled from the whole cohort to yield a “subcohort”. Although data were prospectively and repeatedly collected only from patients in the subcohort, drug’s effect could be estimated by analyzing data from the whole cohort1429. (Figure 3) Specifically, the case-cohort analysis included records of all patients in whom an outcome event occurred as well as all records of subcohort patients in whom an outcome event did not occur. The former received a weight of 1.0 and the latter received a weight determined by the inverse of the sampling fraction, to account for the fact that non-cases outside the subcohort were not observed29. The case-cohort design was used for “death due to cardiovascular disease” and for “death due to any cause” (cases) (Fig. 3). To examine whether a drug was associated with reduced cardiovascular hospitalization or death due to any cause in the subcohort, the sampling fraction used was 0.4 (i.e. the subcohort n = 3276) based on the following assumptions: (1) the expected rate of cardiovascular hospitalization or death due to any cause was assumed to be 13.0 events per 100 person-years during the 3-year follow-up period, (2) the effect size of a drug was assumed to be 20% to 25% of the relative risk, and (3) the proportion of patients to whom the drug was prescribed was one-third. With those values, 3000 patients would be required for 80% power with a two-sided alpha of 0.0514. A cohort design was used for cardiovascular hospitalization or death due to any cause. Details of the participants in each part of the study are given in Figure S3. As reported previously, the randomly-selected subcohort and the whole cohort were similar in terms of age, gender, and iPTH at baseline10.


PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

Akizawa T, Kurita N, Mizobuchi M, Fukagawa M, Onishi Y, Yamaguchi T, Ellis AR, Fukuma S, Alan Brookhart M, Hasegawa T, Kurokawa K, Fukuhara S - Sci Rep (2016)

Study design of the MBD-5D.The study has a “whole cohort” (large solid circle) comprising all patients enrolled and a “subcohort” (dotted circle) comprising a randomly selected 40% of the whole cohort. From 86 facilities, all 8,229 dialysis patients with secondary hyperparathyroidism were registered, and 3,276 were selected into the subcohort. Data were collected prospectively from the subcohort, and retrospectively from those outside the subcohort who died. In total, there were 1,226 deaths due to any cause (small solid circle with gray color) and 462 deaths due to cardiovascular disease. As for death due to any cause, data from 3,996 patients (3,276 patients in the subcohort, among whom there were 506 deaths, together with 720 deaths among patients outside the subcohort) were analyzed as a case-cohort study. Similarly, as for death due to cardiovascular disease, data from 3,547 patients (3,276 patients in the subcohort, among whom there were 191 deaths, together with 271 deaths among patients outside the subcohort) were analyzed as a case-cohort study. As for cardiovascular hospitalization or death due to any cause, 1,054 cases were observed in the subcohort, and data from 3,276 subcohort patients were analyzed as a cohort study. CV: cardiovascular.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829837&req=5

f3: Study design of the MBD-5D.The study has a “whole cohort” (large solid circle) comprising all patients enrolled and a “subcohort” (dotted circle) comprising a randomly selected 40% of the whole cohort. From 86 facilities, all 8,229 dialysis patients with secondary hyperparathyroidism were registered, and 3,276 were selected into the subcohort. Data were collected prospectively from the subcohort, and retrospectively from those outside the subcohort who died. In total, there were 1,226 deaths due to any cause (small solid circle with gray color) and 462 deaths due to cardiovascular disease. As for death due to any cause, data from 3,996 patients (3,276 patients in the subcohort, among whom there were 506 deaths, together with 720 deaths among patients outside the subcohort) were analyzed as a case-cohort study. Similarly, as for death due to cardiovascular disease, data from 3,547 patients (3,276 patients in the subcohort, among whom there were 191 deaths, together with 271 deaths among patients outside the subcohort) were analyzed as a case-cohort study. As for cardiovascular hospitalization or death due to any cause, 1,054 cases were observed in the subcohort, and data from 3,276 subcohort patients were analyzed as a cohort study. CV: cardiovascular.
Mentions: As the MBD-5D study was designed to answer more than one research question (associations between mineral abnormalities and outcomes, and associations between cinacalcet and outcomes), the sample size was not determined for specific treatments14. However, sample size was determined as follows: for death due to cardiovascular disease, (1) the expected rate was 2.5 deaths per 100 person-years during the 3-year follow up period, (2) the effect size of a drug was 20% to 25% of the relative risk, (3) the proportion of patients to whom the drug was prescribed was one-third. With those values, 6000–7500 patients would be required for 80% power with a two-sided alpha of 0.05. We did not have the financial resources needed to hire clinical research coordinators to collect data repeatedly from all of the patients (the “whole cohort”, n = 8229), and therefore we conducted a case-cohort study. Patients were randomly sampled from the whole cohort to yield a “subcohort”. Although data were prospectively and repeatedly collected only from patients in the subcohort, drug’s effect could be estimated by analyzing data from the whole cohort1429. (Figure 3) Specifically, the case-cohort analysis included records of all patients in whom an outcome event occurred as well as all records of subcohort patients in whom an outcome event did not occur. The former received a weight of 1.0 and the latter received a weight determined by the inverse of the sampling fraction, to account for the fact that non-cases outside the subcohort were not observed29. The case-cohort design was used for “death due to cardiovascular disease” and for “death due to any cause” (cases) (Fig. 3). To examine whether a drug was associated with reduced cardiovascular hospitalization or death due to any cause in the subcohort, the sampling fraction used was 0.4 (i.e. the subcohort n = 3276) based on the following assumptions: (1) the expected rate of cardiovascular hospitalization or death due to any cause was assumed to be 13.0 events per 100 person-years during the 3-year follow-up period, (2) the effect size of a drug was assumed to be 20% to 25% of the relative risk, and (3) the proportion of patients to whom the drug was prescribed was one-third. With those values, 3000 patients would be required for 80% power with a two-sided alpha of 0.0514. A cohort design was used for cardiovascular hospitalization or death due to any cause. Details of the participants in each part of the study are given in Figure S3. As reported previously, the randomly-selected subcohort and the whole cohort were similar in terms of age, gender, and iPTH at baseline10.

Bottom Line: To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders.Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT.In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82).

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

ABSTRACT
Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43-1.06). These findings indicate that decisions about using cinacalcet should take into account the severity of SHPT.

No MeSH data available.


Related in: MedlinePlus