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Blood First Edition
Paper, prepublished
online
March
4, 2004;
DOI 10.1182/blood-2003-08-2841
TITLE PAGE
Article title:
Value of sequential monitoring of left ventricular ejection fraction in
the management of thalassemia major
Running title:Sequential LVEF monitoring in thalassemia major
Authors:
Bernard A Davis*, Caoimhe O’Sullivan†, Peter H Jarritt‡, John B Porter*
*Department of Haematology, Royal Free and University College Medical
School, London.
†
Department of Research and Development, University College London
Hospitals, London.
‡
Institute of Nuclear Medicine, University College London Hospitals,
London.
Correspondence to: Professor John B. Porter, Department of Haematology, Royal Free and
University College Medical School, 98 Chenies Mews, London WC1E
6HX, U.K; e-mail: j.porter @ ucl.ac.uk.
Word Count:
4850
Abstract word count:
Scientific Heading: Red Cells.
Copyright (c) 2004 American Society of Hematology
200
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Abstract
Regular monitoring of left ventricular ejection fraction (LVEF) for thalassemia major (TM) is
widely practiced, but its value in informing iron chelation treatment is unclear. 81 TM patients
without previous cardiac history received quantitative yearly LVEF monitoring by radionuclide
ventriculography for a median of 6.0 years (inter-quartile range: 2-12 years). Intra-and interobserver reproducibility for LVEF determination were both <3%. LVEF values pre- and posttransfusion did not differ and exercise stressing did not reliably expose underlying
cardiomyopathy. An absolute LVEF of <45% or fall of >10 percentage units was significantly
associated with subsequent development of symptomatic cardiac disease (p<0.001) and death
(p=0.001), with a median interval between the first abnormal LVEF and development of
symptomatic heart disease of 3.5 years, allowing time for intervention. In 34 patients where the
LVEF was <45% or fell by >10 percentage units, intensification of chelation was recommended
(21 with subcutaneous and 13 with intravenous deferoxamine). All 27 patients who complied
with intensification survive, while the 7 who failed to comply died (p<0.0001). The KaplanMeier estimate of survival beyond 40 years for all 81 patients is 83%. Sequential quantitative
monitoring of LVEF is valuable for assessing cardiac risk and for identifying TM patients
requiring chelation intensification.
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Introduction
Cardiac disease due to transfusional iron overload remains the principal cause of death in
β-thalassemia
major, despite improvements in iron chelation therapy over the last 25 years.1 For
this reason, regular evaluation of cardiac function is recommended for all patients with
thalassemia major2 and is now an integral part of their management. However, the value of
monitoring cardiac function to the long-term management of thalassemia is unclear. This is
partly because the prognostic significance of diastolic abnormalities, which appear early in the
disease process, is unknown.3-5 Additionally, congestive heart failure (CHF) is often already
present by the time systolic abnormalities have become manifest using echocardiography.6-11
These observations have led some workers to question the value of non-invasive monitoring of
cardiac function in the management of thalassemia.12-14
15,16
Although recovery is possible in a proportion of patients with established CHF,
overall
long-term prognosis remains poor.17 Cardiac monitoring should therefore ideally identify patients
at highest risk of cardiac decompensation before CHF develops. Sequential and reproducible
quantification of ventricular function can in principle identify early changes in the left ventricular
ejection fraction (LVEF) from baseline for each patient and could be used as a rationale for
identifying high-risk cases. Radionuclide ventriculography using multi-gated acquisition
(MUGA) gives a highly reproducible quantification of LVEF in normal and abnormal hearts,18-21
MUGA has been used prospectively as a part of annual assessment at our center since 1981, and
it is the value of these prospective data which is addressed in this paper. Over a 20-year period,
we have used LVEF changes (absolute value <45% or a fall >10 percentage units below baseline
for each patient) to identify patients at greatest risk of cardiac decompensation. Here we report
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the outcome of this approach using sequential quantitative LVEF monitoring in 81 thalassemia
major patients with no previous cardiac history.
Methods
Study design
The predictive value of sequential quantitative LVEF monitoring by MUGA for
subsequent cardiac morbidity and mortality has been examined in 81 patients with β-thalassemia
major born between 1957 and 1987. Between March 1981 and February 2001 a strategy was
adopted at University College London Hospitals for yearly monitoring of LVEF by MUGA.
Data from MUGA are available from 85 of 103 patients from this clinic in whom survival data
have been previously reported.2 81 of the 85 patients had no previous cardiac history at the time
of entry into the study and are therefore those in whom the predictive value of MUGA
monitoring is analyzed. 39 patients were male and 42 were female and the median age at which
MUGA was initially performed was 19 years (inter-quartile range: 16-23 years). All patients
were regularly transfused to maintain pre-transfusion hemoglobin levels of >10.5 g/dl prior to
1995 and >9.5g/dl thereafter.
Routine cardiac evaluation consisted of a detailed clinical history, physical examination,
resting and exercise electrocardiography (ECG), echocardiography and MUGA. 24-hour Holter
monitoring was performed in patients with palpitations or in patients with arrhythmias
demonstrated by clinical examination and/or on routine ECG. Impaired left ventricular (LV)
function was defined as a fall in the resting LVEF either to a value below the lower reference
limit of 45% or by >10 percentage units between two consecutive measurements, regardless of
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the LVEF value. 34 patients showed evidence of LV dysfunction on at least one occasion during
the period of observation (LVEF <45% in 28 and drop by >10 percentage units in 6).
Chelation therapy was exclusively with deferoxamine mesylate (DFO), which in the
absence of high-risk clinical features, consisted of a standard regimen (30-50mg/kg/d by
subcutaneous infusion 8-12h/d, 5-7d/wk). DFO treatment was intensified in the event of
objective evidence of asymptomatic LV dysfunction at rest, in an attempt to prevent progression
to frank CHF. Treatment intensification was with one of three modalities. The first was
continuous intravenous DFO through an indwelling line at a dose of (50-100 mg/kg/24h) as
previously described in 17 patients,15 11 of whom were eligible for inclusion in this paper, as they
had no pre-existing cardiac disease. Data from 2 additional patients have also been included. The
second was improvement in the subcutaneous DFO regimen, achieved by increasing the
frequency, duration or dose of administration. In early years of the study, a maximum of 12-hour
infusions were possible through mechanical pumps (up to 60mg/kg/day).
After 1994,
22
subcutaneous DFO was given through 24-hour disposable balloon infusers at doses of 40-
60mg/kg/24h up to 7 days a week. The third was continuous 24-hour intravenous infusion of
DFO (100mg/kg) diluted in 500-1000mls of normal saline and delivered though a peripheral vein
on an inpatient basis for up to 1 week at a time, to supplement ongoing subcutaneous treatment.
Intensification dosing was reduced as serum ferritin values fell in line with the therapeutic index,
as previously described.15 The decision about which approach to adopt was made on the basis of
extended interviews between the lead clinician with the patient and on the practicalities of each
option; option 1 being our preferred approach.
In addition, after 1995, this included interviews with a clinical psychologist, where
underlying psychological issues pertinent to poor compliance were explored and rectified.
Results of subsequent LVEF or serum ferritin were fed back to each patient as part of a sustained
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follow up program. Compliance was monitored by patient interview with the mean number of
infusions/week being used as a compliance endpoint.23
MUGA assessment
All LVEF studies were performed in the left anterior oblique position using IGE
Portacamera/Informatek Simis III and IGE Optima/Star 4000I configurations as previously
15
15
described. The red cell labeling method had an efficiency of 98%. Image processing was
carried out on the Portacamera/Informatek system as follows: after smoothing the raw data,
Fourier phase and amplitude images as well as the end-diastolic and end-systolic images were
displayed. A region of interest around the left ventricle was then assigned manually on the enddiastolic frame, always taking into account the end-systolic phase and amplitude image limits.
Following background correction of the region of interest using the method of Goris,24 ventricular
time-activity curves were generated and LVEFs calculated. Data processing software was
supplied by Informatek, Buc, France.
Data analysis on the Optima/Star configuration was
broadly similar to the method described above, except that SAGE software was used to determine
the ventricular center (automatically) and edge (semi-automatically). The SAGE software was
supplied by the manufacturers (GE Medical Systems, WI) and used unmodified.
The reproducibility of LVEF measurements was assessed on the two configurations used
during the study.
On the IGE Portacamera/Informatek configuration, the inter-observer
correlation coefficient for a range of LVEF values (n=60 patients) between 7-71% was 0.99 (p =
0.001), with a standard error of 2.79% between the results of two observers. Intra-observer
reproducibility for a range of LVEF values (n=66 patients) between 7-71% gave a correlation
coefficient of 1.00 (p=0.001), with a standard error of 2.57% between the results. On the IGE
Optima/Star configuration, LVEF values calculated from three acquisitions carried out by the
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same observer on a range of values from 22-79% (n=75 patients) gave a correlation coefficient of
0.98 (p<0.001) with a standard error between the results of 2%. LVEF values calculated from
three acquisitions by two independent observers at two different times on the same patients also
showed a high correlation (r=0.99) with a standard error of 1.8% between the results. Thus, there
was no appreciable difference in reproducibility between the two systems. Changeover from the
Portacamera/Informatek to the Optima/Star was effected in 1993-1994, with no systematic
difference for LVEF values among approximately 50 non-thalassemic subjects studied on both
configurations.
The reference range for the resting LVEF by MUGA in non-thalassemic patients at our
institution was 50-70%, with a 95% confidence interval for the lower value of 45-55%. The
limits of reproducibility for the resting LVEF was 5 percentage units; thus a change of >5
percentage units between serial measurements was defined as clinically significant. However, in
this study, a change in the resting LVEF by >10 percentage units between serial measurements
was used as the trigger for treatment intensification as this is the limit of biological variability in
21
normal subjects. Additionally, absolute LVEF values <45% were considered to be abnormal and
a trigger for treatment intensification.
For exercise stress tests, LVEF measurements were obtained at rest, then following
dynamic exercise in the supine position on a mechanically-braked bicycle. Chest movements
during exercise were minimized by the use of shoulder restraints, chest straps and handgrips.
Starting at 25 watts, the load was increased in 25-watt stages, each stage lasting three minutes,
with continuous ECG monitoring using lead II and measurement of the pulse rate and blood
pressure at the end of each stage. Exercise was continued until maximum workload was achieved,
or the patient developed fatigue, angina, dyspnoea, significant hypotension, or ventricular
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arrhythmia. Data were acquired for the final two minutes of each stage. A normal response to
dynamic exercise was defined as a rise in LVEF by >5 percentage units at maximal exercise.
Serum ferritin measurements were generally measured monthly as previously described.15
Outcome measures and statistical analysis
The outcome measures were CHF or arrhythmia requiring cardiac medication, and cardiac
death attributable to iron overload. CHF was defined by the criteria of the Task Force on Heart
Failure of the European Society of Cardiology.25 The period of follow up began on the date of an
individual’s first MUGA, and the cut-off point for follow up was February 28 2001. Patients
leaving the study center for treatment abroad or in other centers were censored for analysis at the
point of exit. The median follow-up period for the 81 patients was 5.8 years, with an interquartile range of 2.4-11.7 years and a maximum of 20 years.
Summary data are presented either as median or mean ± 1 standard deviation. Pearson’s
chi squared and Fisher’s exact tests have been used to test the relationship between categorical
variables.
Differences between means of samples have been analyzed using paired t-tests.
Survival has been calculated using Kaplan-Meier survival analysis and differences in survival
between different groups of patients compared using the log rank test. A logistic regression
model, adjusted for serial tests on patients, was used to investigate the association between
exercise response and subsequent CHF. All statistical analyses were performed using Stata
software, version 7 (Stata Corporation, TX).
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Results
1. Initial evaluation of MUGA for LVEF monitoring.
Effect of blood transfusion on LVEF
To determine whether it was necessary to stipulate the point in the blood transfusion cycle
when MUGA was performed, paired measurements of LVEF were undertaken in 10 patients
immediately pre- and 24 hours post-transfusion. Mean pre- and post-transfusion hemoglobin
concentrations were 11.56 ± 1.16g/dl and 15.0 ± 1.61g/dl (p<0.0001), with mean hematocrits of
0.34 ± 0.03 and 0.46 ± 0.06 (p<0.0001). There was no significant difference between resting
LVEF pre (52 ± 14%) and 24 hours post (51 ± 15%) blood transfusion (p=0.36) (Figure 1). The
relatively high ‘pre-transfusion’ mean hemoglobin value partly reflects the transfusion policy
used at the time (to keep pre-transfusion hemoglobin >10.5g/dl) and partly that some patients in
this study were transfused mid-cycle. There was no relationship between the change in LVEF
pre- and post-transfusion and either the hemoglobin increment with transfusion or the pretransfusion hemoglobin value.
Effect of dynamic exercise on LVEF
A total of 60 paired LVEF exercise studies were performed sequentially on 27
thalassemia major patients over a 5-year period. Fatigue and dyspnoea were the reasons for
termination of the exercise and there was a failure to achieve 85% of the predicted heart rate postexercise in over half of these. In those with normal resting LVEF, the mean peak exercise load
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achieved was 78 ± 21 watts. By contrast, the mean peak exercise level attained in 25 control
subjects, comprising 4 healthy volunteers and 21 patients with angiographically normal hearts,
was 155 watts (range 125-200 watts), with only 5 of the 25 subjects failing to achieve the desired
hemodynamic response.26 40 tests showed an abnormal response (with failure to show an
increased LVEF of >5 percentage units) and 20 had a normal response.
In all 27 thalassaemia patients, there was no significant difference between LVEF values
pre- and post-exercise (52 ± 8% and 53 ± 11%; p=0.47) (Figure 2). Exercise-induced changes in
the subgroup of patients with normal resting LVEF (n=19) again showed no difference between
pre- and post-exercise LVEF (54 ± 7% versus 54 ± 12%; p=0.91). In the 25 control subjects, the
mean LVEF increased from 64 ± 10% to 73 ± 8% (p<0.01).26
Investigation of cardiac outcome following each of the 60 studies in the 27 patients, using
logistic regression adjusted for serial tests on patients, provided no evidence to support an added
prognostic value of exercise testing. Exercise response was not significantly associated with
subsequent heart failure, even after adjusting for peak exercise load.
2. Value of LVEF in prediction and management of cardiac disease.
Relationship between impaired LVEF and long-term survival (Table 1).
The Kaplan-Meier estimate of survival beyond 40 years of age is 83%, in the entire cohort
of 81 patients monitored regularly with resting MUGA for LVEF (Figure 3a). Where LV
dysfunction was demonstrated by MUGA, subsequent symptomatic heart disease and cardiac
death were more frequent. Thus, in patients with asymptomatic LVEF changes, as defined in
methods, the odds of subsequent heart disease were 25 times those of patients with normal LVEF
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(p<0.001). Only 1 out of 47 patients who never recorded a drop in LVEF experienced a cardiac
event. There was also a significant difference in the frequency of cardiac death between the
groups with and without asymptomatic LVEF changes (p=0.001). The median time interval
between the first abnormal LVEF and development of symptomatic heart disease was 3.5 years
(range: 1.7-10.9 years) and 7 of these died after a median of 3.8 years (range: 2.9-9.3 years) from
the time of initial LVEF drop. These findings show that LVEF changes identified with sequential
quantitative monitoring generally precede and predict subsequent significant clinical cardiac
decompensation by a sufficient period to allow treatment intensification. Although all treatment
decisions were made on the basis of either LVEF <45% or fall of >10 percentage units, we have
also retrospectively examined the relative importance of absolute LVEF <45% compared with a
decrement of >10 percentage units to subsequent survival and cardiac complications This showed
that whereas there were no deaths or cardiac disease among patients who dropped LVEF >10
percentage units while maintaining absolute values >45%, only 57% of patients in whom LVEF
fell below this value had no cardiac disease, with only 75% surviving long-term.
Interventional treatment with DFO based on LVEF and long-term survival.
Patients were categorized into those with a resting LVEF <45% or >10 percentage unit
drop (category 1) or >45% (category 2) in line with pre-determined criteria for DFO
intensification (see Methods). When survival is compared between category 1 and category 2
patients based on LVEF, it can be seen that all deaths occurred in category 1 patients (Table
1)(Figure 3b). Figure 3c shows that among the 34 category 1 patients, all deaths (n=7) occurred
in those who failed to sustain an improvement in compliance with intensified DFO after the
LVEF abnormality had been identified. Median survival in this group with abnormal LVEF plus
poor sustained compliance to intensification was only 3.8 years from the initial deterioration in
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resting LVEF. This contrasts with those patients who adhered to sustained intervention with
DFO (n=27), none of whom have died with a follow up period of up to 20 years (median 11.7
years) after the initial fall in LVEF.
The influence of the route of DFO used for intensification (subcutaneous or intravenous)
on outcome among the 34 category 1 patients was also examined (Table 2). As previously
reported, there is a significant improvement in LVEF following intravenous DFO through Port-a15
Cath. However it is also clear from Table 2 that there is significant improvement in LVEF
following subcutaneous DFO intensification. These findings show that sustained response can be
achieved with either route, provided compliance is maintained.
Among the 27 surviving patients who received treatment intensification on the basis of
LVEF, the cumulative DFO dose to the point when their cardiac function stabilized was
estimated in 22 in whom adequate records are available. The median cumulative DFO dose was
36g/kg body weight (range: 16-139g/kg) over a median of 3 years (range: 1.3-8 years). When the
cumulative dose for each patient was calculated on a daily basis, the median value was
43mg/kg/day, suggesting that conventional doses of DFO are efficacious both in preventing and
reversing LV dysfunction, provided there is sustained patient compliance to the prescribed
regimen.
3. Relationship between other risk factors and cardiac complications.
Age of commencement of standard subcutaneous DFO,27 and serum ferritin levels27 have
been previously identified as predictors of cardiac risk in patients with thalassemia major. We
therefore examined their predictive value for cardiac risk in relation to that of sequential LVEF
monitoring. While myocarditis has been identified as a precipitant of heart failure in a small
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portion of thalassemia patients, no patients in this study had evidence of myocarditis as a
precipitant of cardiac decompensation.28
Effect of age at subcutaneous DFO commencement on cardiac risk (Table 1).
78 patients had evaluable data with respect to age of DFO commencement. 42 of these
patients had started therapy at <10 years of age and 36 patients at >10 years of age. Symptomatic
heart disease occurred more frequently in patients commencing subcutaneous DFO >10 years of
age than in those in whom this treatment was started at an earlier age (odds ratio: 5.0, p=0.005).
This was also true of death from cardiac causes (odds ratio: 7.0, p=0.01)
Serum ferritin and cardiac risk.
To examine the relationship between serum ferritin concentration and cardiac risk, we
divided the study cohort into two groups using the risk stratification criteria identified by
27
Olivieri. This analysis examines the effect of consistently high ferritin values (>2500µg/L) on at
least 2/3 of occasions on survival. Table 1 shows that cardiac outcome was significantly better in
those patients who maintained serum ferritin values <2500µg/L on at least 2/3 of occasions. The
odds for cardiac complications in patients who failed to maintain ferritin <2500µg/L on at least
2/3 of occasions was 3.25 (p=0.05). The risk of dying from iron overload was also significantly
increased in this group (p=0.002).
Survival was significantly worse in the group with chronically elevated serum ferritin
values (p=0.02) (not shown). This was also true in the subgroup of patients in whom a fall in
LVEF had been recorded (n=34), where deaths from cardiac disease (n=7) only occurred in
subjects who failed to maintain ferritin values <2500µg/L on at least 2/3 of occasions. No deaths
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were seen in those patients with LVEF decrements, in whom ferritin values were maintained at
<2500µg/L on at least 2/3 of occasions.
Discussion
Although resting and exercise response of LVEF using MUGA have been previously
described in follow-up of small groups of thalassaemia patients for periods up to 4 years,11,29 this
is the first study to investigate the long-term prognostic value of monitoring for asymptomatic
LV dysfunction in a large group of thalassemia patients with unlimited access to DFO chelation
therapy. In our group of patients, LVEF performed by MUGA and serum ferritin were the
regularly used tools for monitoring and adjustment of therapy. Whilst this approach was adopted
in all patients since the early 1980s, this was not set up as a formal prospective study and
consequently there is heterogeneity in patients’ follow up time and prior chelation history. It is
clear, however, that the overall survival is excellent (83% at 40 years) and indeed is the best so
far reported, suggesting that this approach is useful. Our findings show that a fall in LVEF by
MUGA of >10 percentage units or to an absolute value below the reference range is associated
with progression to clinical heart failure within a median period of 3.5 years and death within a
median of 3.8 years if DFO intensification is not achieved. Further analysis of the data suggested
that under the conditions of observation and intervention adopted in this study, a fall to an
absolute value of <45% is more discriminatory for survival than a relative decrement of >10
percentage units.
Previous studies in thalassemia major using MUGA suggested that systolic dysfunction
may precede frank CHF and that a successful clinical outcome may be achieved with appropriate
intensification of DFO therapy.
15,29-32
In this paper, we have observed LVEF changes over a
median period of 6 years, with 25% of the patients being observed for between 12-20 years. It is
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clear that detectable changes in systolic function precede development of clinical heart failure
sufficiently early for a useful intervention strategy to be adopted.
After an initial rapid
improvement in systolic function with intensification of DFO as previously described,15 there was
characteristically a more gradual improvement that took several years of sustained treatment for
maximal effect (data not shown). In all but one patient in the present study, LVEF changes were
demonstrable prior to the development of cardiac symptoms.
Our findings may underestimate the effectiveness of the strategy used for LVEF
monitoring and treatment intensification because in the older patients, ‘baseline’ LVEF values
were not obtained in childhood or in early teenage years. Thus, a fall of LVEF of 10 percentage
units or more from the true baseline value could have been missed and intensification delayed.
Indeed, survival among patients born after 1975, who were exposed to DFO early in life and have
2
been monitored from an earlier age, shows 100% survival at 25 years. These data compare
strikingly with survival of patients in the United Kingdom as a whole where survival is only 50%
by the age of 35 years,33 and reflect the effectiveness of DFO therapy if used in a center where
monitoring and intervention such as described in this paper are considered a high priority.
However, the optimal age at which monitoring of ventricular function should be commenced
remains unclear. In Engle’s pre-chelation era study,34 the first signs of cardiac involvement
emerged at about 10 years of age, with patients becoming symptomatic in mid- to late teens. In
our study, one patient already had a reduced LVEF of 39% when her initial MUGA was
performed at 13 years of age, although she was clinically asymptomatic at the time. We suggest
that yearly quantitative LVEF monitoring of patients should begin ideally by 10 years of age.
Longitudinal monitoring of LV systolic function in thalassemia was traditionally
considered to be of limited value because changes were only demonstrable as late events using
echocardiography.6,8,9,12 However, the limitations of echocardiography for sequential quantitative
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LVEF measurement are well-recognized: the technique is heavily reliant on operator skill and
assumptions have to be made about ventricular geometry, resulting in greater inter-observer
variability for LVEF,35 more so in severely impaired ventricles. Indeed, early studies in
thalassemia major showed that MUGA was a more sensitive indicator of declining cardiac
function than M-mode echocardiography, both at rest and on exercise.
7
Also, the
echocardiographic studies were conducted before current standard subcutaneous and intensive
intravenous DFO regimens were available, and used either no chelation, or sub-therapeutic doses
of DFO.6,8,9,12
Thus, there was no effective salvage therapy for patients with deteriorating
ventricular function and mortality was high.
Doppler echocardiography has been used to
evaluate diastolic function,3,36 and more recently for examining regional wall motion.37 While
abnormalities in diastolic function and regional wall motion can be identified before those of
systolic dysfunction, there have been no studies of how these affect prognosis or how these might
be used as a trigger for treatment intensification. Unlike echocardiography, MUGA does not
require any geometric assumptions about ventricular shape; it is thus highly reproducible for
quantification of LVEF, even for abnormal hearts. The recognized reliability of MUGA in the
assessment of ventricular function is demonstrated by its selection as the method of choice for
several major cardiac intervention studies in the 1980s and 1990s.
38-41
The intra- and inter-
observer reproducibility of <3% for resting LVEF in our hands is comparable to that reported by
other workers.18,19,21 While MUGA was the tool available for sequential quantitative monitoring
from the early 1980s, quantitative monitoring of LVEF is now possible with MRI,42-44 which also
has excellent reproducibility.
Recently, MRI techniques have been also used to estimate
45,46
myocardial iron and by inference cardiac risk.
However, the long-term prognostic significance
of this modality has yet to be verified and it is presently unclear how chelation treatment should
be stratified based on such a measurement. Our study, on the other hand, shows that LVEF can
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be used as an easily available and effective tool for treatment stratification and intervention with
a demonstrable impact on cardiac disease and survival.
Our findings show that the excellent reproducibility achieved with MUGA is unaffected
by blood transfusion under the conditions of this study. A mean pre-transfusion hemoglobin of
>10.5g/dl, was policy at the time of the paired measurements and was relatively high compared
to current transfusion practice. However, analysis of the individual changes in LVEF with
transfusion shows that these are unaffected by the variability in pre-transfusion hemoglobin
values seen in this study. These findings are in keeping with those observed by Henry et al9
using echocardiography, who found no change in LVEF 2-4 hours after transfusion in
thalassemia major patients, where pre-transfusion values were lower than in our patient group.
Exercise stressing appeared to be of limited additional value in our patient group. LVEF
by MUGA was originally reported to be abnormal in a higher proportion of hitherto unchelated
thalassemia patients following exercise than at rest, with an invariable rise in LVEF noted in
32
control subjects. However, subsequent work showed a wide variation in exercise responses in
normal individuals and exercise-induced increments are not invariably seen.47 Furthermore, a
wide overlap between LVEF responses of subjects with angiographically normal hearts and those
with coronary artery disease is now recognized,48 whereas invariable increases in LVEF had been
reported initially.49 Exercise LVEF testing using MUGA with follow up of 1-4 years was reported
by Freeman et al29,31 in 23 thalassemia major patients receiving subcutaneous DFO. Whereas a
minority of patients had abnormal resting LVEF, the majority showed an abnormal exercise
response, suggesting an increased sensitivity of exercise compared with resting LVEF. However,
neither increased specificity nor prognostic significance was demonstrated. In our own study,
subsequent clinical heart failure or cardiac death, were no more common in those with
abnormalities demonstrated with exercise compared with those at rest. A confounding factor in
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our study was that peak exercise load, an independent determinant of the exercise response,47 was
variable both between and within patients. Since exercise testing was undertaken at variable
points in the transfusion cycle, in principle this could have contributed to the variation in exercise
tolerance.
In practice, however, this is unlikely as pre-transfusion values were typically
>10.5g/dl. It has been suggested that pharmacological stressing might reduce variability related
to patient cooperation during exercise testing.
In our hands, dobutamine at doses up to
40µg/kg/minute often led to unacceptable symptoms such as flushing and lightheadedness.
Although low dose dobutamine (5µg/kg/minute) has been reported to expose underlying
cardiomyopathy in thalassaemia patients using echocardiography,50 there are no peer-reviewed
papers on its effects on LVEF in thalassemia patients using MUGA.
Clearly there are a number of useful approaches to monitoring iron overload in
thalassemia major, some of which have been shown to have prognostic value with DFO use, such
27
51
23,51
Although our findings support a
as serum ferritin, liver iron and treatment compliance.
relationship between serum ferritin and outcome, we recognize the limitations of using serum
ferritin, particularly as a single measurement at an arbitrary time point, as many factors other than
body iron burden affect serum ferritin. It is of note that the association of ferritin with prognosis
in both this study and the previous study of Olivieri27, linked prognosis to sustained rises of
serum ferritin over many years and not simply single ferritin measurements. The relationship of
liver iron to prognosis has not been examined in this paper as this was not one of the
determinants used for regular monitoring and thus for chelation stratification. Outcome however
is likely to include a component of the duration of exposure to high liver iron levels as in the
51
Brittenham analysis, where survival was examined in relation to the ratio between cumulative
transfusional iron loading and DFO use over time.
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In conclusion, it is clear that sequential quantitative monitoring of LVEF, combined with
timely and sustained intensification of DFO where necessary, can be used to achieve excellent
long-term prognosis in thalassemia major. Contrary to some traditional thinking, it is clear that
changes can be identified sufficiently early to prevent further deterioration of LVEF, to reverse
cardiac dysfunction and to achieve excellent long-term survival. For this approach to be effective,
however, LVEF measurements need to be quantitative, highly reproducible and performed
regularly (at least annually). Our data show that single measurements at arbitrary time points will
have less prognostic value than those obtained by sequential analysis. We suggest that when
either new or established monitoring tools are used to identify cardiac risk, the sequential
changes of the marker in question, as well as the full transfusional and chelation history should
be taken into account.
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Table 1. Variables associated with long-term survival in thalassemia major
CHF and/or Arrhythmia
Variable
No. of
patients
Dead
Alive
Yes
No
LVEF fell to absolute value below 45% or by more than 10%
LVEF never fell to absolute value below 45% or by more than 10%
Total number of patients
34
47
81
12
1
13
22
46
68
7
0
7
27
47
74
Subcutaneous DFO commenced after 10 years of age
Subcutaneous DFO commenced before 10 years of age
Total number of patients
30
48
78
11
5
16
19
43
62
7
2
9
23
46
69
Serum ferritin over 2500µg/l for at least a third of follow up time*
Serum ferritin over 2500µg/l for less than a third of follow up time
Total number of patients
47
38
85
13
4
17
34
34
68
10
0
10
37
38
85
Cardiac disease free survival is shown in patients as a function of LVEF, age of DFO commencement and serum ferritin.
Subsequent development of heart disease (p<0.001) and death (p=0.001) were significantly more likely in those patients who
displayed a LVEF <45% or drop by >10 percentage units. Symptomatic heart disease occurred more frequently in patients
commencing subcutaneous DFO >10 years of age than in those in whom this treatment was started at an earlier age (p=0.005).
This was also true of death from cardiac causes (p=0.01). Cardiac complications (p=0.05) and death (p=0.002) were significantly
greater in patients who failed to maintain ferritin <2500µg/L on at least 2/3 of occasions.
*Serum ferritin data were available for a median period of 8 years (inter-quartile range: 4-16 years)
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Table 2. Outcomes among thalassemia major patients with asymptomatic left ventricular
impairment treated with intensive deferoxamine therapy.
Characteristic
Subcutaneous
n=21
Intravenous
n=13
Median age at first MUGA (years)
18 (9-27)*
18 (13-24)
Median follow up (years)
12 (3-20)
11 (5-18)
Median age at start of chelation therapy (years)
13 (2-24)
9 (2-18)
Mean (±SD) “baseline” LVEF (%)
55 ± 10
54 ± 12
Mean (±SD) LVEF pre-intensification (%)
43 ± 6
41 ± 5
Mean (±SD) maximum LVEF post intensification (%)
57 ± 7
55 ± 4
17
10
4
3
Number of patients alive
Number of deceased patients
Outcomes among patients with asymptomatic LV impairment are shown in 34 patients receiving intravenous
intensification with DFO (n=13) and those receiving DFO intensification by the subcutaneous route (n=21).
There are no significant differences in outcome between subcutaneous and intravenous regimens but patients
of higher risk generally received intravenous treatment. There is a fall in LVEF from baseline prior to
commencement of intensification of DFO (p<0.0001). Post intensification maximum LVEF values are
significantly higher than pre-intensification values in patients treated by both subcutaneous and intravenous
DFO (p<0.0001).
*Ranges are in parentheses
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Figure Legends.
Figure 1. Effect of blood transfusion on LVEF measurement by MUGA. LVEF by MUGA at
rest is shown in 10 thalassemia major patients pre- and 24 hours post blood transfusion. There is
no significant difference between mean pre- and mean post-transfusion LVEF (p=0.36).
Figure 2. Effect of dynamic exercise on LVEF measurement by MUGA. LVEF is shown
before and after fatigue-limited exercise in 60 paired observations in 27 patients. There is no
significant difference in mean LVEF pre- and post-exercise (p=0.47).
Figure 3. Survival in 81 thalassemia major patients monitored regularly with MUGA for
LVEF. Figure 3a shows that the Kaplan-Meier estimate of survival beyond 40 years of age is
83%, in the entire cohort of 81 patients monitored regularly with MUGA for LVEF. KaplanMeier estimates of survival in category 1 (n=34) and category 2 (n=47) are shown in figure 3b. It
can be seen that all deaths (n=7) occurred in category 1 patients, namely, patients with
demonstrable left ventricular dysfunction during the period of observation. In figure 3c, KaplanMeier estimates of survival are shown in 34 category 1 patients subdivided on the basis of
compliance with intensification with deferoxamine. All deaths (n=7) occurred in patients who
failed to sustain compliance with deferoxamine (log rank p< 0.0001).
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80
70
60
LVEF (% )
p = 0 .36
M ean =52
50
M ean =51
40
30
20
0 .4
0 .6
0 .8
P1 .0
re
1 .2
1 .4
1 .6
1 .8 2 4h
2 .0
post
Figure 1
2 .2
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80
70
p = 0.47
LVEF (%)
60
M ean = 53
50
M ean = 52
40
30
20
0.4
Figure 2
At rest
1.4
M ean load
75 Watts
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1.00
Survival probability
.75
.50
.25
0.00
0
10
20
Year s fr om bir t h
Figure 3a
30
40
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1.00
No LVEF impairment
Survival probability
.75
LVEF impairment
.50
.25
0.00
0
5
10
Years from first MUGA
Figure 3b
15
20
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1.00
Complied well with
DFO
Survival probability
.75
.50
.25
Complied poorly with DFO
0.00
0
5
10
15
Years from start of DFO intensificat ion
Figure 3c
20
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Prepublished online March 4, 2004;
doi:10.1182/blood-2003-08-2841
Value of sequential monitoring of left ventricular ejection fraction in the
management of thalassemia major
Bernard A Davis, Caoimhe O'Sullivan, Peter H Jarritt and John B Porter
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