eliglustat-tartrate and Cardiovascular-Diseases

The Canadian Fabry disease initiative (CFDI) tracks outcomes of subjects with Fabry disease treated enzyme replacement therapy (ERT) given to subjects who meet evidence-based treatment guidelines and cardiovascular risk factor modification.. We report 5 year follow-up data on 362 subjects for a composite endpoint (death, neurologic or cardiovascular events, development of end-stage renal disease or sustained increase in serum creatinine of 50% from baseline).. At enrollment, 86 subjects had previously received ERT (Cohort 1a) and 67 subjects were newly started (Cohort 1b) and randomized to agalsidase alfa or agalsidase beta. 209 subjects did not initially meet ERT criteria (Cohort 1c), 25 of whom met ERT criteria in follow-up and were moved to Cohort 1b (total N=178 ERT treated subjects). Use of supportive therapies such as aspirin (78%), renin-angiotensin blockade (59%), and statins (55%) was common in ERT treated subjects. In Cohort 1a, 32 subjects met the composite endpoint with 8 deaths. In Cohort 1b, 16 subjects met the composite endpoint with 1 death. Cohort 1b had fewer clinical events than Cohort 1a (p=0.039) suggesting that the treatment protocol was effective in targeting subjects at an earlier stage. 19.4% of Cohort 1b subjects on agalsidase alfa and 13.3% on agalsidase beta had a clinical event (p=0.57). 10 Cohort 1c subjects had clinical events, none of which would have been prevented by earlier use of ERT.. Cardiovascular risk factor modification and targeted use of ERT reduce the risk of adverse outcomes related to Fabry disease.

Topics: Adult; Aged; alpha-Galactosidase; Canada; Cardiovascular Diseases; Cohort Studies; Endpoint Determination; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Kaplan-Meier Estimate; Male; Middle Aged; Recombinant Proteins; Risk Factors; Treatment Outcome

Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement.. To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease.. Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial.. 41 referral centers in 9 countries.. 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent.. Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months).. The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point.. Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group.. The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event.. Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.

Topics: Adult; Aged; alpha-Galactosidase; Cardiovascular Diseases; Cerebrovascular Disorders; Disease Progression; Double-Blind Method; Fabry Disease; Female; Glomerular Filtration Rate; Humans; Isoenzymes; Kidney Diseases; Male; Middle Aged; Proteinuria; Treatment Outcome