Effect of L-type calcium channel blocker (amlodipine) on myocardial iron deposition in patients with thalassaemia with moderate-to-severe myocardial iron deposition: protocol for a randomised, controlled trial

Abstract

Introduction: Sideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca(2+) channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy.

Outcomes: The primary outcome is to compare the efficacy of amlodipine+chelation (intervention) versus standard chelation (control) in retarding myocardial iron deposition. Secondary outcomes include the effect of amlodipine therapy on systolic and diastolic function, strain and strain rate and liver iron content.

Methods and analysis: This is a single-centre, parallel-group, prospective randomised control trial. Twenty patients will be randomised in a 1:1 allocation ratio into the intervention and control arms. In addition to conventional echocardiography, MRI T2* values for assessment of cardiac and liver iron load will be obtained at baseline and at 6 and 12 months. Cardiac T2* will be reported as the geometric mean and per cent coefficient of variation, and an increase in cardiac T2* values from baseline will be used as an end point to compare the efficacy of therapy. A p Value of <0.05 will be considered significant.

Study setting: Department of Pediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan.

Ethics and dissemination: This study has been approved by the Ethics Review Committee and Clinical Trials Unit at The Aga Khan University with respect to scientific content and compliance with applicable research and human subjects regulations. Findings will be reported through scientific publications and research conferences and project summary papers for participants.

Trial registration number: ClinicalTrials.Gov. Registration no: NCT02065492.

Figure 1

Adapted from Carpenter et al. This graph shows signal intensity (arbitrary units) plotted against echocardiography time (milliseconds) for the hearts shown on top. Heart 1 (with normal iron levels) has a shallow decay curve with a T2* value of >20 ms. Heart 2, owing to severe iron loading, has a much more rapid decay with T2* <10 ms.

Figure 2

Adapted from Carpenter et al correlated T2* values to myocardial iron content. The regression (solid line) and 95% confidence bands (dotted lines) are shown and derived from analysis of the log-log data shown in E. (A) R2* plotted versus myocardial iron concentration measured from each myocardial region of interest (ROI). (B) R2* versus myocardial iron concentration excluding heart 4. (C) Mean R2* plotted versus mean iron concentration for each heart. (D) Mean R2* versus mean iron concentration excluding heart 4. (E) ln(R2*) plotted versus ln((Fe)) for all ROIs, including heart 4, showing the best-fit linear regression line. (F) Mean midseptal R2* versus mean whole-heart R2* plotted against the line of identity showing that the septal R2* value is highly representative of the whole-heart R2*.

Figure 3

Sample showing ventricular strain assessment using speckle tracking. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.