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Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)
W P Te Rijdt1,2, E T Hoorntje3,4, R de Brouwer5
1Department of Genetics, University of Groningen, Groningen UMC, Groningen, The Netherlands. w.p.te.rijdt@umcg.nl.
Insights
Eplerenone may prevent or delay cardiomyopathy in presymptomatic carriers of the phospholamban (PLN) p.Arg14del variant. This study investigates if early eplerenone treatment can reduce disease progression in these individuals.
Area of Science:
- Cardiology
- Genetics
- Pharmacology
Background:
- The phospholamban (PLN) p.Arg14del variant is a founder mutation causing dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM).
- Presymptomatic carriers face increased risk of arrhythmias and heart failure due to early cardiac fibrosis.
- No current evidence-based treatments exist for presymptomatic carriers of this monogenic cardiomyopathy.
Purpose of the Study:
- To evaluate if pre-emptive eplerenone treatment can reduce disease progression in presymptomatic PLN p.Arg14del carriers.
- To determine if eplerenone can postpone the onset of overt DCM and ACM.
- To assess the antifibrotic effects of eplerenone in this patient population.
Main Methods:
- A multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) trial (iPHORECAST).
- Presymptomatic PLN p.Arg14del carriers randomized to receive daily eplerenone (50 mg) or no treatment.
- Primary endpoint: multiparametric assessment of disease progression over 3 years, including cardiac MRI, ECG, and clinical outcomes.
Main Results:
- 84 presymptomatic carriers enrolled (42 per group), with no significant baseline differences.
- All participants initially presented with NYHA class I, LVEF >45%, and <2500 ventricular ectopies per 24h.
- The study is ongoing, with final participant data expected in 2021.
Conclusions:
- The iPHORECAST trial is a prospective randomized controlled trial investigating eplerenone's efficacy in presymptomatic PLN p.Arg14del carriers.
- The study aims to determine if pre-emptive eplerenone treatment can prevent or delay cardiomyopathy onset.
- Registered on clinicaltrials.gov (NCT01857856).
Background:
The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers.
Aims:
The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease.
Methods:
iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years.
Baseline Results:
A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021.
Conclusion:
iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).
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