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The combined treatment did not have any effect on serum ferritin and left ventricular ejection fraction.

Publisher's Note: There is an Inside Commentary on this article in this issue.

Abstract

Cardiovascular disease resulting from iron accumulation is still a major cause of death in patients with thalassemia major (TM). Voltage-gated calcium-channel blockade prevents iron entry into cardiomyocytes and may provide an adjuvant treatment to chelation, reducing myocardial iron uptake. We evaluated whether addition of amlodipine to chelation strategies would reduce myocardial iron overload in TM patients compared with placebo. In a multicenter, double-blind, randomized, placebo-controlled trial, 62 patients were allocated to receive oral amlodipine 5 mg/day or placebo in addition to their current chelation regimen. The main outcome was change in myocardial iron concentration (MIC) determined by magnetic resonance imaging at 12 months, with patients stratified into reduction or prevention groups according to their initial T2* below or above the normal human threshold of 35 ms (MIC, 0.59 mg/g dry weight). At 12 months, patients in the reduction group receiving amlodipine (n = 15) had a significant decrease in MIC compared with patients receiving placebo (n = 15) with a median of −0.26 mg/g (95% confidence interval, −1.02 to −0.01) vs 0.01 mg/g (95% confidence interval, −0.13 to 0.23), = .02. No significant changes were observed in the prevention group (treatment–effect interaction with = .005). The same findings were observed in the subgroup of patients with T2* <20 ms. Amlodipine treatment did not cause any serious adverse events. Thus, in TM patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone. Because this conclusion is based on subgroup analyses, it needs to be confirmed in ad hoc clinical trials. This trial was registered at www.clinicaltrials.gov identifier as # NCT01395199 .

Introduction

Myocardial iron overload affects up to 50% of patients with thalassemia major (TM) in many parts of the world. Despite significant reductions in death rates because of early diagnosis and improved chelation treatment, iron cardiomyopathy is still responsible for a high proportion of deaths and hospitalization from arrhythmias and heart failure, especially in patients with high myocardial iron concentrations (MIC). Noninvasive assessment of MIC with magnetic resonance imaging (MRI) and early, more intensive chelation to reduce iron levels in the heart have been the main goal of most recent trials in this disease, with a corresponding reduction in the incidence of clinical events. Despite these advances, current options for treatment of myocardial iron overload are restricted to a limited number of chelation strategies, with important constraints from the need for elevated doses, concomitant side effects, heterogeneous access worldwide resulting from relatively high cost, or limited market availability.

Once iron is taken up by cardiomyocytes, its removal from within these cells is slow. Myocardial clearance may take several years to occur even with very intensive chelation because of the specific mechanisms of iron handling in the heart. Experiments in mice suggest the possibility of preventing iron uptake by cardiomyocytes through voltage-gated calcium-channel blockade. Amlodipine is an inexpensive, widely available calcium-channel blocker with a well-known safety profile in both adults and children, and a first small, open-label study in humans showed its use reduced MIC as measured by MRI in TM patients. In this randomized trial, we sought to study whether the use of oral amlodipine in addition to standard iron chelation regimens in patients with TM can reduce MIC after 1 year of treatment.

Study design and participants

The study was designed as a multicenter, randomized, placebo-controlled, double-blind trial with an allocation rate of 1:1. Participants with TM were included if they were 6 years of age or older and had been receiving regular blood transfusions for at least 2 years (total lifetime red blood cell transfusions above 20 units). Exclusion criteria were a scheduled or already expected change in chelation strategy within the next 12 months (specifically, a change in chelator drug or change from monotherapy to combined therapy, for example); advanced clinical heart failure or ejection fraction below 35%; and formal contraindication for undergoing a MRI examination. The local ethics committees approved the study, and all participants (or their legal guardian) gave written informed consent. All authors had access to the primary clinical trial data.

Randomization and masking

Randomization was performed using a predefined computer-generated list without specific restrictions of blocks, which was kept by the pharmacy responsible for manufacturing the pills for the study (Formula Cia, Campinas, Brazil). Allocation of patients and pill distribution were done by the central pharmacy, with the drug/placebo being shipped directly to the patient in tablets with identical appearance. Compliance was checked monthly during the outpatient/transfusion visits as well as through telephone contacts by a study technician. Concealment of the type of intervention was kept during the whole study for patients and health personnel involved in diagnosis, examination interpretation, and treatment.

Procedures

Patients were invited to participate during their routine outpatient appointments in 6 hematology centers in Brazil. Once selected, peripheral venous blood samples were collected for chemistry and hematology analyses and an MRI scan was performed if the patient had not undergone the examination within 30 days before enrollment in the trial. MRI scans were acquired according to a specific protocol to determine liver and myocardial T2* as well as left ventricular parameters in 1.5 T scanners following standardized techniques (details of the MRI protocols are described in the supplemental Data, available on the Web site). Patients were stratified according to their initial MIC values: they were placed in the reduction group if baseline MIC was initially above the normal mean human threshold for iron concentrations (MIC >0.59 mg/g dry weight or T2*<35 ms) or the prevention group if MIC was below those values at baseline (MIC ≤0.59 mg/g or T2* ≥35 ms). After undergoing MRI scans, patients in each group were randomized to receive either oral placebo or amlodipine (5 mg/day for patients weighing more than 30 kg or 2.5 mg/day for patients weighing 30 kg and less). During the study, amlodipine/placebo doses could be lowered if the patient complained of adverse events commonly expected with the use of calcium-channel blockers. Changes in chelation therapy were allowed during follow-up at the primary physician’s discretion, especially in cases when patients had potentially dangerous levels of MIC or liver iron concentration (LIC). After 12 months, all patients repeated the MRI scan with the same parameters as the baseline examination. At 6 months, an additional MRI examination was also performed in a subgroup of patients that lived geographically close to 1 of the MRI centers. A central core laboratory concealed to treatment allocation and identity of the patient performed interpretation of the all MRI scans using a dedicated workstation (Circle Cardiovascular Imaging, Calgary, Canada; details in the supplemental data). MIC and LIC values were derived from myocardium and liver T2*, respectively, according to previously published reports. All MRI data were available to the primary physician throughout the study.

Outcomes

The primary outcome of the study was the change in MIC at 12 months from baseline in both arms (placebo and amlodipine) as defined by T2* values, with the comparison of effect of the treatment between the 2 subgroups based on subgroup–treatment effect interaction. This outcome was changed to evaluate change in MIC instead of T2* values after the publication of the correlation curves between myocardial T2* and MIC during the course of the trial because they showed a nonlinear correlation between these parameters with a more appropriate clinical use for MIC. The use of MIC allows for a more direct assessment of the linear changes in iron concentrations of the heart, as has been used in the liver in previous trials using LIC as the main outcome and not liver T2*. Secondary outcomes were change in MIC at 6 months, change in LIC at 12 months, serum ferritin, left ventricular ejection fraction, and incidence of adverse events at 6 and 12 months.

Statistical analysis

Sample size was defined based on previous pilot study data that showed a 27% reduction in myocardial iron in patients treated with amlodipine. For a power of 80% and α error of 0.05 to detect a similar difference in the primary outcome between groups assuming a 30% drop-out rate, the total number of patients for enrollment was calculated to be 62 for a final number of 43 patients to be analyzed (PASS 11, Kaysville, UT). The expected difference used in the power calculation was based on patients with initially high myocardial iron because patients with normal baseline MICs did not show significant follow-up changes in previous studies. We acknowledge that this might limit possible interpretations of our findings from underpowering of the subgroup analysis.

All data were analyzed on an intention to treat basis with a 2-tailed significance level of 5% (Medcalc Statistical Software, version 15.8, Ostend, Belgium). Baseline differences among the groups were compared using Student test, χ test with Fisher’s exact test for proportions and Mann-Whitney in case of nonparametric variables (specifically, serum ferritin, myocardial T2*, MIC, and LIC). The respective changes in MIC, LIC, and serum ferritin were not normally distributed and were compared using Wilcoxon test. Subgroup–treatment effect interaction was analyzed using 2-way analysis of variance including treatment arm and subgroup classification as independent factors.

Seventy-seven patients were screened for the trial and 62 patients were randomized from October 1, 2011, to February 10, 2014 ( Figure 1 ). The main reasons for exclusion during screening were prediction of chelation therapy change in the next 12 months and patients declining to participate. In the amlodipine arm, 1 patient was excluded from analysis from a lack of follow-up MRI scans; in the placebo arm, 1 patient was lost to follow-up and 1 patient was excluded because of review of the initial diagnosis from TM to hemoglobulin S/β thalassemia.

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/ 2017 October

STATISTICS SPOTLIGHT

Constructive consensus-building strategies for people with different perspectives

by Christine M. Anderson-Cook

Disagreements in the workplace or elsewhere are inevitable, particularly when several individuals must make decisions. Differences in opinions at the water cooler have much less impact compared to a team needing to unite to determine what action to take.

While debate and conflict are sometimes unavoidable, there are some strategies that I have found that can help enable constructive progress toward consensus and resolution. One just needs to look at the current U.S. political climate to see how easily differences can lead to gridlock and the inability to move forward productively.

A productive path forward

First, I think it is helpful to consider what is at the heart of disagreements because this perspective can be helpful when trying to move past them constructively. One source of conflict is people may be operating based on different information. Often when preliminary choices are made, they are based on incomplete information. Different people may prefer different options based on the information they have available. With more complete knowledge, however, opinions might change.

The second quite different source of disagreement stems from our backgrounds, experiences and priorities. Most decisions involve balancing different criteria and evaluating which tradeoff feels best when we can’t get everything we want. In rare (does this ever happen?) situations in which there is only a single objective, finding the best choice is rarely controversial. We are good at optimizing based on a single metric. The problem is that most often we must simultaneously consider quality, cost, time and risk. Even when having the same information, if we prioritize the criteria differently, different choices can be preferred.

Based on these contributors to disagreements, here are a few ideas about how to establish a productive path forward when faced with disagreement on a decision-making team:

Patience and due process

Disagreements and difficult choices in decision making are not going to disappear from the fabric of our work and personal lives. But with some structure and intentional choices to make discussions and decisions revolve around data, while honoring different priorities of the criteria considered, there are opportunities to reach consensus and concentrate on making the right choice.

Conflict—when focused on the best interests of the business—can elevate performance, author Patrick Lencioni wrote. The key is to handle disagreements in a way that recognizes how individuals prioritized the criteria and allows all participants to be included and heard. With patience and due process, there are strategies that can help people with different perspectives reach a mutually acceptable and ideal choice.

References

Christine M. Anderson-Cook is a research scientist in the Statistical Sciences Group at Los Alamos National Laboratory in Los Alamos, NM. She earned a doctorate in statistics from the University of Waterloo in Ontario. Anderson-Cook is a fellow of ASQ and the American Statistical Association.

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