The clinical course of treated hyperparathyroidism among patients receiving hemodialysis and the effect of cinacalcet: the EVOLVE trial.

CONTEXT: The clinical course of secondary hyperparathyroidism (sHPT) in patients on hemodialysis is not well described, and the effect of the calcimimetic cinacalcet on disease progression is uncertain. OBJECTIVE: Our objective was to describe 1) the clinical course of sHPT in patients treated with phosphate binders and/or vitamin D sterols and 2) the impact of cinacalcet on the occurrence of severe unremitting HPT, defined by the persistence of markedly elevated PTH concentrations together with hypercalcemia or parathyroidectomy (PTX). DESIGN AND SETTING: This was a randomized, double-blind, placebo-controlled, global, multicenter clinical trial. PATIENTS: Of 5755 patients screened with moderate to severe sHPT, 3883 patients on hemodialysis were included in the trial. MAIN OUTCOME MEASURES: Outcomes included PTX; severe, unremitting HPT; and use of commercial cinacalcet (a protocol violation). INTERVENTION: Intervention was cinacalcet (30-180 mg daily) or placebo for up to 64 months. RESULTS: In the 1935 patients randomized to placebo, 278 patients (14%) underwent PTX (median PTH 1872 pg/mL within the previous 12 weeks from surgery). Age, sex, geographic region, co-morbidity, calcium-containing phosphate binder use, and baseline serum calcium, phosphorus, and PTH concentrations were associated with PTX. Commercial cinacalcet was started in 443 (23%) patients (median PTH 1108 pg/mL before treatment began). Severe unremitting HPT developed in 470 patients (24%). In a multivariable Cox model, the relative hazard (comparing patients randomized to cinacalcet versus placebo) of severe unremitting HPT was 0.31 (95% confidence interval = 0.26-0.37). The relative hazard differed little when adjusted by baseline clinical characteristics. CONCLUSIONS: Severe unremitting HPT develops frequently in patients on hemodialysis despite conventional therapy, and cinacalcet substantially reduces its occurrence.

Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis.

OBJECTIVE: To examine the safety of anakinra when added to a background of standard rheumatoid arthritis (RA) medications in patients with RA with active disease. METHODS: This analysis further evaluates data from the first 6 months of a blinded, placebo controlled safety trial that had a subsequent 30 month, open label portion (not reported here). Patients with RA with a wide range of comorbid conditions, disease activity, and background medications were randomly assigned in a 4:1 allocation ratio to treatment with anakinra 100 mg or placebo administered daily by injection. Safety was assessed by comparing adverse event profiles between anakinra and placebo patients according to concomitant medications received. RESULTS: Anakinra patients (n = 1116) showed no difference in the incidence of upper respiratory infections or overall serious adverse events compared with placebo patients (n = 283). The anakinra group had more injection site reactions (72.6% vs 32.9% in placebo) and a small increase in serious infections (2.1% vs 0.4% in placebo). Anakinra's safety profile did not differ in patients receiving antihypertensive, antidiabetic, or statin drugs. CONCLUSION: This study indicates that anakinra has a good safety profile in patients typically seen in a rheumatology practice who are considered candidates for therapy with agents that are immunomodulatory and disease modifying. Except for injection site reactions and a nonstatistically although potentially clinically significant increase in serious infections in the anakinra versus the placebo groups, the addition of anakinra to a stable background regimen of RA medications introduced no other important safety risk in patients with RA.

Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial.

OBJECTIVE: To evaluate the safety of anakinra (a recombinant human interleukin-1 receptor antagonist) in a large population of patients with rheumatoid arthritis (RA), typical of those seen in clinical practice. METHODS: A total of 1,414 patients were randomly assigned to treatment with 100 mg of anakinra or placebo, administered daily by subcutaneous injection. Background medications included disease-modifying antirheumatic drugs, corticosteroids, and nonsteroidal antiinflammatory drugs, alone or in combination. The primary end point was safety, which was evaluated by adverse events (including infections), discontinuation from study due to adverse events, and death. RESULTS: Safety was evaluated in 1,399 patients (1,116 in the anakinra group and 283 in the placebo group; 15 patients were randomized but did not receive any study drug) during the initial 6-month, double-blind, placebo-controlled phase of this long-term safety study. Baseline demographics, disease characteristics, and concomitant medications were similar between the 2 groups. The study group included patients with numerous comorbid conditions and a wide range of RA disease activity. Serious adverse events occurred at a similar rate in the anakinra group and the placebo group (7.7% and 7.8%, respectively). Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group). The rate of withdrawal due to adverse events was 13.4% in the anakinra group and 9.2% in the placebo group. CONCLUSION: Results from this large, placebo-controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA, including those with comorbid conditions and those using multiple combinations of concomitant therapies. Although the frequency of serious infection was slightly higher in the anakinra group, no infection was attributed to opportunistic microorganisms or resulted in death.