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RED CELLS
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
Regular monitoring of left ventricular ejection fraction (LVEF) for thalassemia major
is widely practiced, but its informativeness for iron chelation treatment is unclear. Eighty-one patients with thalassemia major but no history of cardiac
disease underwent quantitative annual
LVEF monitoring by radionuclide ventriculography for a median of 6.0 years (interquartile range, 2-12 years). Intraobserver
and interobserver reproducibility for LVEF
determination were both less than 3%.
LVEF values before and after transfusion
did not differ, and exercise stress testing
did not reliably expose underlying cardiomyopathy. An absolute LVEF of less than
45% or a decrease of more than 10 percentage units was significantly associated with subsequent development of
symptomatic cardiac disease (P < .001)
and death (P ⴝ .001), with a median interval between the first abnormal LVEF findings and the development of symptomatic heart disease of 3.5 years, allowing
time for intervention. In 34 patients in
whom LVEF was less than 45% or decreased by more than 10 percentage units,
intensified chelation therapy was recom-
mended (21 with subcutaneous and 13
with intravenous deferoxamine). All 27
patients who complied with intensification survived, whereas the 7 who did not
comply died (P < .0001). The KaplanMeier estimate of survival beyond 40 years
of age for all 81 patients is 83%. Sequential quantitative monitoring of LVEF is
valuable for assessing cardiac risk and
for identifying patients with thalassemia
major who require intensified chelation
therapy. (Blood. 2004;104:263-269)
© 2004 by The American Society of Hematology
Introduction
Cardiac disease caused by transfusional iron overload remains the
principal cause of death in patients with ␤-thalassemia major,
despite improvements in iron chelation therapy during the past 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 noninvasive monitoring of cardiac function in the
management of thalassemia.12-14
Although recovery is possible in a proportion of patients with
established CHF,15,16 overall long-term prognosis remains poor.17
Cardiac monitoring should, therefore, ideally identify patients at
highest risk for 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 patients at high risk.
Radionuclide ventriculography using multigated acquisition
(MUGA) gives a highly reproducible quantification of LVEF in
normal and abnormal hearts.18-21 MUGA has been used prospec-
tively as part of annual assessments at our center since 1981, and
the value of these prospective data is addressed in this paper. For 20
years, we have used LVEF changes (absolute value less than 45%
or decrease by more than 10 percentage units below baseline for
each patient) to identify patients at greatest risk for cardiac
decompensation. Here we report the outcome of this approach
using sequential quantitative LVEF monitoring in 81 patients with
thalassemia major and no cardiac disease history.
From the Department of Haematology, Royal Free and University College
Medical School, London; and the Department of Research and Development
and the Institute of Nuclear Medicine, University College London Hospitals,
United Kingdom.
Reprints: John B. Porter, Department of Haematology, Royal Free and
University College Medical School, 98 Chenies Mews, London WC1E 6HX,
United Kingdom; e-mail: [email protected].
Submitted August 18, 2003; accepted January 27, 2004. Prepublished online
as Blood First Edition Paper, March 4, 2004; DOI 10.1182/blood-2003-08-2841.
J.B.P. currently acts on the safety board for Cox 189 (Novartis) and on advisory
boards for ICL670 (Novartis).
BLOOD, 1 JULY 2004 䡠 VOLUME 104, NUMBER 1
Patients, materials, and methods
Study design
The predictive value of sequential quantitative LVEF monitoring by
MUGA for subsequent cardiac morbidity and mortality was examined in 81
patients with ␤-thalassemia major born between 1957 and 1987. Between
March 1981 and February 2001, a strategy was adopted at University
College London Hospitals for yearly MUGA monitoring of LVEF. MUGA
data are available for 85 of 103 patients from this clinic for whom survival
data have been previously reported.2 Eighty-one of the 85 patients had no
history of cardiac disease at the time of study entry and are, therefore, those
for whom the predictive value of MUGA monitoring is analyzed. Thirtynine patients are men and 42 are women, and the median age at which
MUGA was initially performed was 19 years (interquartile range, 16-23
years). All patients underwent regular transfusions to maintain pretransfusion hemoglobin levels higher than 10.5 g/dL before 1995 and higher than
9.5 g/dL thereafter.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2004 by The American Society of Hematology
263
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264
BLOOD, 1 JULY 2004 䡠 VOLUME 104, NUMBER 1
DAVIS et al
Routine cardiac evaluation consisted of a detailed clinical history,
physical examination, resting and exercise electrocardiography (ECG),
echocardiography, and MUGA. Twenty-four–hour Holter monitoring was
performed in patients with palpitations or in patients with arrhythmias
demonstrated by clinical examination, routine ECG, or both. Impaired left
ventricular (LV) function was defined as a decrease in resting LVEF either
to a value below the lower reference limit of 45% or by more than 10
percentage units between 2 consecutive measurements, regardless of the
LVEF value. Thirty-four patients had evidence of LV dysfunction on at least
one occasion during the period of observation (LVEF less than 45% in 28
patients and decrease by more than 10 percentage units in 6 patients).
Chelation therapy was performed exclusively with deferoxamine mesylate (DFO), which, in the absence of high-risk clinical features, consisted of
a standard regimen (30-50 mg/kg per day by subcutaneous infusion 8-12
h/d, 5-7 d/wk). DFO treatment was intensified in the event of objective
evidence of asymptomatic LV dysfunction at rest to prevent progression to
frank CHF. Treatment was intensified using 1 of 3 modalities. The first
modality was continuous intravenous DFO through an indwelling line at a
dose of 50 to 100 mg/kg per 24 hours, as previously described in 17
patients,15 11 of whom were eligible for inclusion in this study because they
had no preexisting cardiac disease. Data from 2 additional patients have
also been included. The second modality was improvement in the subcutaneous DFO regimen, achieved by increasing the frequency, duration, or
dose of administration. In the early years of the study, maximal 12-hour
infusions were possible through mechanical pumps (up to 60 mg/kg per
day). After 1994, subcutaneous DFO was given through 24-hour disposable
balloon infusers22 at doses of 40 to 60 mg/kg per day up to 7 days a week.
The third modality was continuous 24-hour intravenous infusion of DFO
(100 mg/kg) diluted in 500 to 1000 mL 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. Dosing intensification
was reduced as serum ferritin values decreased in line with the
therapeutic index, as previously described.15 The decision about which
approach to adopt was based on extended interviews between the lead
clinician and the patient and on the practicalities of each modality; the
first was our preferred approach.
In addition, after 1995, this modality included interviews with a clinical
psychologist, through whom underlying psychological issues pertinent to
poor compliance were explored and rectified. Subsequent LVEF and serum
ferritin findings were relayed to each patient as part of a sustained follow-up
program. Compliance was monitored by patient interview, with the mean
number of infusions per week used as a compliance end point.23
MUGA assessment
All LVEF studies were performed in the left anterior oblique position using
IGE Portacamera (GE Medical Systems, Waukesha, WI)/Informatek Simis
III (Informatek, Buc, France) and IGE Optima/Star 4000i (GE Medical
Systems) configurations as previously described.15 The red cell labeling
method15 had an efficiency of 98%. Image processing was carried out on the
Portacamera/Informatek system as follows: after smoothing the raw data,
Fourier phase, amplitude images, and end-diastolic and end-systolic images
were displayed. A region of interest around the left ventricle was then
assigned manually on the end-diastolic frame, always taking into account
the end-systolic phase and amplitude image limits. After background
correction of the region of interest using the method of Goris et al,24
ventricular time-activity curves were generated and LVEFs were calculated.
Informatek supplied the data processing software. Data analysis on the
Optima/Star configuration was broadly similar to the method described,
except that SAGE software was used to determine the ventricular center
(automatically) and the edge (semiautomatically). SAGE software was
supplied by the manufacturer (GE Medical Systems) and was used
unmodified.
The reproducibility of LVEF measurements was assessed on the 2 study
configurations. On the IGE Portacamera/Informatek configuration, the
interobserver correlation coefficient for a range of LVEF values (n ⫽ 60
patients) between 7% and 71% was 0.99 (P ⫽ .001), with a standard error
of 2.79% between the results of 2 observers. Intraobserver reproducibility
for a range of LVEF values (n ⫽ 66 patients) between 7% and 71% gave a
correlation coefficient of 1.00 (P ⫽ .001), with a standard error of 2.57%
between the results. On the IGE Optima/Star configuration, LVEF values
calculated from 3 acquisitions carried out by the same observer on a range
of values from 22% to 79% (n ⫽ 75 patients) gave a correlation coefficient
of 0.98 (P ⬍ .001), with a standard error between the results of 2%. LVEF
values calculated from 3 acquisitions by 2 independent observers at 2
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 2
systems. Changeover from the Portacamera/Informatek to the Optima/
Star was effected in 1993 to 1994, with no systematic difference for
LVEF values among approximately 50 patients without thalassemia
studied on both configurations.
The reference range for the resting LVEF by MUGA in patients without
thalassemia at our institution was 50% to 70%, with a 95% confidence
interval for the lower value of 45% to 55%. The limits of reproducibility for
the resting LVEF was 5 percentage units; thus, a change of more than 5
percentage units between serial measurements was defined as clinically
significant. However, in this study, a change of more than 10 percentage
units between serial measurements of resting LVEF was used as the trigger
for treatment intensification because this is the limit of biologic variability
in healthy subjects.21 Additionally, absolute LVEF values less than 45%
were considered abnormal and triggered treatment intensification.
For exercise stress tests, LVEF measurements were obtained at rest,
then after 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 W, the load
was increased in 25-W stages, each stage lasting 3 minutes, with continuous
ECG monitoring using lead II and with pulse rate and blood pressure
measurements at the end of each stage. Exercise was continued until
maximum workload was achieved or until the patient developed fatigue,
angina, dyspnea, significant hypotension, or ventricular arrhythmia. Data
were acquired for the final 2 minutes of each stage. A normal response to
dynamic exercise was defined as an increase in LVEF by more than 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 a patient’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 to 11.7 years
and a maximum of 20 years.
Summary data are presented as median or as mean ⫾ 1 SD. Pearson ␹2
and Fisher exact tests were used to test the relationship between categorical
variables. Differences between means of samples were analyzed using
paired t tests. Survival was calculated using Kaplan-Meier survival
analysis, and differences in survival between different groups of patients
were 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).
Results
Initial evaluation of MUGA for LVEF monitoring.
Effect of blood transfusion on LVEF. To determine whether it
was necessary to stipulate when MUGA was performed during the
blood transfusion cycle, paired measurements of LVEF were
undertaken in 10 patients immediately before and 24 hours after
transfusion. Mean pretransfusion and posttransfusion hemoglobin
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BLOOD, 1 JULY 2004 䡠 VOLUME 104, NUMBER 1
concentrations were 11.56 ⫾ 1.16 g/dL and 15.0 ⫾ 1.61 g/dL
(P ⬍ .0001), with mean hematocrits of 0.34 ⫾ 0.03 and 0.46 ⫾ 0.06
(P ⬍ .0001). There was no significant difference between resting
LVEF before (52% ⫾ 14%) and 24 hours after (51% ⫾ 15%) blood
transfusion (P ⫽ .36) (Figure 1). The relatively high pretransfusion
mean hemoglobin value reflects the transfusion policy used at the
time (to keep pretransfusion hemoglobin levels higher than 10.5
g/dL) and reflects that some patients in this study underwent
transfusion in mid-cycle. There was no relationship between the
change in LVEF before and after transfusion and either the
hemoglobin increment with transfusion or the pretransfusion
hemoglobin value.
Effect of dynamic exercise on LVEF. Sixty paired LVEF
exercise studies were performed sequentially on 27 patients with
thalassemia major in a 5-year period. Fatigue and dyspnea were the
reasons for terminating exercise, and in more than half of these
tests patients failed to achieve 85% of the predicted heart rate after
exercise. In those with normal resting LVEF, the mean peak
exercise load achieved was 78 ⫾ 21 W. By contrast, the mean peak
exercise level attained in 25 control subjects (4 healthy volunteers
and 21 patients with angiographically normal hearts) was 155 W
(range, 125-200 W), with only 5 of the 25 subjects failing to
achieve the desired hemodynamic response.26 Forty tests showed
abnormal responses (with failure to show an increased LVEF of
more than 5 percentage units), and 20 showed normal responses.
In all 27 thalassemia patients, there was no significant difference between LVEF values before and after exercise (52% ⫾ 8%
and 53% ⫾ 11%; P ⫽ .47) (Figure 2). Exercise-induced changes in
the subgroup of patients with normal resting LVEF (n ⫽ 19) again
showed no difference between in LVEF values before and after
exercise (54% ⫾ 7% and 54% ⫾ 12%; P ⫽ .91). In the 25 control
subjects, mean LVEF values increased from 64% ⫾ 10% to
73% ⫾ 8% (P ⬍ .01).26
Investigation of cardiac outcomes after each of the 60 studies in
the 27 patients using logistic regression analysis 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.
Value of LVEF in predicting and managing cardiac disease.
Relationship between impaired LVEF and long-term survival
(Table 1). The Kaplan-Meier estimate of survival beyond 40 years
of age was 83% in the entire cohort of 81 patients monitored
Figure 1. Effect of blood transfusion on LVEF measurement by MUGA. LVEF by
MUGA at rest is shown in 10 patients with thalassemia major before and 24 hours
after blood transfusion. There was no significant difference between mean pretransfusion and mean posttransfusion LVEF (P ⫽ .36).
SEQUENTIAL LVEF MONITORING IN THALASSEMIA MAJOR
265
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 was no significant difference in mean LVEF before and after exercise
(P ⫽ .47).
regularly with resting MUGA for LVEF (Figure 3A). In patients in
whom LV dysfunction was demonstrated by MUGA, subsequent
symptomatic heart disease and cardiac death occurred more
frequently. Thus, in patients with asymptomatic LVEF changes, as
defined in “Patients, materials, and methods,” the odds of subsequent heart disease were 25 times those of patients with normal
LVEF (P ⬍ .001). Only 1 of 47 patients for whom there was no
decrease 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 ⫽ .001).
The median time interval between the first abnormal LVEF value
and the development of symptomatic heart disease was 3.5 years
(range, 1.7-10.9 years), and 7 of these patients died after a median
of 3.8 years (range, 2.9-9.3 years) from the time of the initial LVEF
decrease. 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 an LVEF less than 45%
or a decrease of more than 10 percentage units, we also retrospectively examined the relative importance of absolute LVEF less than
45% compared with a decrement of more than 10 percentage units
with respect to subsequent survival and cardiac complications. This
comparison showed that whereas there were no deaths or cardiac
disease among patients whose LVEF decreased by more than 10
percentage units while absolute values remained greater than 45%,
only 57% of patients in whom LVEF decreased 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 2 groups, those
with resting LVEF less than 45% or more than a 10 percentage unit
drop (category 1) and those with resting LVEF greater than 45%
(category 2), in accordance with predetermined criteria for DFO
intensification (“Patients, materials, and methods”). When survival
was compared between both groups of patients based on LVEF, it
was 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 did not sustain improvements in compliance with intensified DFO therapy after the LVEF
abnormality had been identified. Median survival in this group with
abnormal LVEF plus poorly sustained compliance with intensification was only 3.8 years from the initial deterioration in resting
LVEF. This is in contrast to those patients who adhered to sustained
intervention with DFO (n ⫽ 27), none of whom have died during a
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266
BLOOD, 1 JULY 2004 䡠 VOLUME 104, NUMBER 1
DAVIS et al
Table 1. Variables associated with long-term survival in thalassemia major
CHF, arrhythmia,
or both
No.
patients
Yes
No
Dead
LVEF decreased to absolute value below 45% or by more than 10%
34
12
22
7
27
LVEF never decreased to absolute value below 45% or by more than 10%
47
1
46
0
47
Variable
Alive
Total no. patients
81
13
68
7
74
Subcutaneous DFO started after age 10 y
30
11
19
7
23
Subcutaneous DFO started before age 10 y
48
5
43
2
46
Total no. patients
78
16
62
9
69
Serum ferritin greater than 2500 ␮g/L for at least one third of follow-up time*
47
13
34
10
37
Serum ferritin greater than 2500 ␮g/L for less than one third of follow up-time
38
4
34
0
38
Total no. patients
85
17
68
10
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 ⬍ .001) and death (P ⫽ .001) was significantly more likely in patients who displayed LVEF less than 45% or decreases exceeding 10 percentage units. Symptomatic heart
disease occurred more frequently in patients who were older than 10 when subcutaneous DFO therapy was started than in those in whom this treatment was started at an
earlier age (P ⫽ .005). This was also true of death from cardiac causes (P ⫽ .01). Cardiac complications (P ⫽ .05) and death (P ⫽ .002) were significantly greater in patients
who did not maintain ferritin levels lower than 2500 ␮g/L on at least two thirds of occasions.
*Serum ferritin data were available for a median period of 8 years (interquartile range, 4-16 years).
follow-up period of up to 20 years (median, 11.7 years) after the
initial decrease in LVEF.
The influence of the DFO route (subcutaneous or intravenous) used for therapy intensification on outcomes among the 34
category 1 patients was also examined (Table 2). As previously
reported, there is a significant improvement in LVEF after
intravenous DFO through the Port-A-Cath (Pharmacia Deltec,
St Paul, MN).15 However, Table 2 clearly shows that there was
significant improvement in LVEF after subcutaneous DFO
intensification. These findings show that sustained responses
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 cardiac function stabilized was estimated in 22
patients for whom adequate records are available. The median
cumulative DFO dose was 36 g/kg body weight (range, 16-139
g/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 43 mg/kg per day, suggesting that conventional doses of DFO are efficacious in preventing and reversing LV
dysfunction, provided there is sustained patient compliance with
the prescribed regimen.
Relationship between other risk factors and
cardiac complications
Patient age at the start of standard subcutaneous DFO therapy27 and
serum ferritin levels27 have been identified as predictors of cardiac
risk in patients with thalassemia major. Therefore, we examined
their predictive value for cardiac risk in relation to that of
sequential LVEF monitoring. Although myocarditis has been
identified as a precipitant of heart failure in a small portion of
thalassemia patients, no patients in this study had evidence of
myocarditis as a precipitant of cardiac decompensation.28
Effect of age on cardiac risk at initiation of subcutaneous
DFO therapy. As seen in Table 1, 78 patients had evaluable data
with respect to age of DFO commencement. Therapy started when
42 of these patients were younger than 10 years of age and for 36 of
these patients when they were older than 10. Symptomatic heart
disease occurred more frequently in patients who started subcutaneous DFO after age 10 than in those in whom this treatment was
started at an earlier age (odds ratio, 5.0; P ⫽ .005). This was also
true of death from cardiac causes (odds ratio, 7.0; P ⫽ .01)
Serum ferritin and cardiac risk. To examine the relationship
between serum ferritin concentration and cardiac risk, we divided
the study cohort into 2 groups using the risk stratification criteria
identified by Olivieri et al.27 This analysis examines the effect of
consistently high ferritin values (higher than 2500 ␮g/L) on at least
two thirds of occasions on survival. Table 1 shows that cardiac
outcome was significantly better in those patients who maintained
serum ferritin values lower than 2500 ␮g/L on at least two thirds of
occasions. The odds ratio for cardiac complications in patients who
failed to maintain ferritin levels lower than 2500 ␮g/L on at least
two thirds of occasions was 3.25 (P ⫽ .05). The risk for death from
iron overload was also significantly increased in this group
(P ⫽ .002).
Figure 3. Survival in 81 patients with thalassemia major monitored regularly with MUGA for LVEF. (A) 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. (B) Kaplan-Meier estimates of survival in category 1 (n ⫽ 34) and category 2 (n ⫽ 47). 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. (C) Kaplan-Meier
estimates of survival are shown in 34 category 1 patients subdivided on the basis of compliance with DFO intensification therapy. All deaths (n ⫽ 7) occurred in patients who did
not sustain compliance with DFO (P ⬍ .0001, log rank test).
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BLOOD, 1 JULY 2004 䡠 VOLUME 104, NUMBER 1
SEQUENTIAL LVEF MONITORING IN THALASSEMIA MAJOR
Table 2. Outcomes among patients with thalassemia major and
asymptomatic LV impairment treated with intensive DFO therapy
Subcutaneous
n ⴝ 21 (range)
Intravenous
n ⴝ 13 (range)
Median age at first MUGA, y
18 (9-27)
18 (13-24)
Median follow-up, y
12 (3-20)
11 (5-18)
Characteristic
Median age at start of chelation
therapy, y
Mean (⫾SD) baseline LVEF, %
13 (2-24)
9 (2-18)
55 ⫾ 10
54 ⫾ 12
43 ⫾ 6
41 ⫾ 5
Mean (⫾SD) LVEF before
intensification, %
Mean (⫾SD) maximum LVEF after
57 ⫾ 7
55 ⫾ 4
No. patients alive
17
10
No. patients dead
4
3
intensification, %
Outcomes among patients with asymptomatic LV impairment are shown in 34
patients receiving intravenous DFO intensification (n ⫽ 13) and in those receiving
subcutaneous DFO intensification (n ⫽ 21). There were no significant differences in
outcome between subcutaneous and intravenous regimens, but patients at higher
risk generally received intravenous treatment. There was a decrease in LVEF from
baseline before the start of DFO intensification (P ⬍ .0001). After intensification,
maximum LVEF values were significantly higher than before intensification in patients
treated by subcutaneous and intravenous DFO (P ⬍ .0001).
Survival was significantly worse in the group with chronically
elevated serum ferritin values (P ⫽ .02) (not shown). This was also true
in the subgroup of patients in whom decreases in LVEF had been
recorded (n ⫽ 34) and in whom deaths from cardiac disease (n ⫽ 7)
only occurred in patients who failed to maintain ferritin values lower
than 2500 ␮g/L on at least two thirds of occasions. No deaths were seen
in those patients with LVEF decrements in whom ferritin values
remained lower than 2500 ␮g/L on at least two thirds of occasions.
Discussion
Although resting and exercise LVEF responses using MUGA have
been described in the follow-up of small groups of thalassemia
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 with MUGA and serum ferritin
were the regular tools for monitoring and adjusting therapy.
Although this approach was adopted for all patients beginning in
the early 1980s, the procedure was not set up through a formal,
prospective study; consequently, there is heterogeneity in patients’
follow-up times and prior chelation histories. 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, using MUGA, a decrease in LVEF of more than
10 percentage units or an absolute value below the reference range
is associated with progression to clinical heart failure within a
median of 3.5 years and to 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 decrease to an absolute value of less than
45% is more discriminatory for survival than a relative decrement
of more than 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%
267
of the patients being observed between 12 and 20 years. It is
clear that detectable changes in systolic function precede the
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 1
patient in the present study, LVEF changes were demonstrable
before cardiac symptoms appeared.
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 during childhood or early adolescence. Thus, a decrease in
LVEF of 10 percentage units or more from the true baseline value
could have been overlooked, and intensification might have been
delayed. Indeed, among patients born after 1975 who were exposed
to DFO early in life and have been monitored from an earlier age,
survival is 100% at 25 years.2 These data contrast strikingly with
the survival of patients in the United Kingdom as a whole, in whom
survival is only 50% by the age of 35 years,33 and they reflect the
effectiveness of DFO therapy when used in a center in which
monitoring and intervention are given high priority. However, the
optimal age at which monitoring of ventricular function should be
started remains unclear. In the prechelation-era study by Engle et
al,34 the first signs of cardiac involvement emerged at approximately 10 years of age, with patients becoming symptomatic in
middle to late adolescence. 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 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 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 interobserver
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 In
addition, the earliest echocardiographic studies were conducted
before current standard subcutaneous and intensive intravenous
DFO regimens were available and used either no chelation or
subtherapeutic 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 function3,36 and, more recently, to examine
regional wall motion.37 Although abnormalities in diastolic function and regional wall motion can be identified before those of
systolic dysfunction, no studies have been conducted on 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 for assessing
ventricular function was demonstrated by its selection as the
method of choice for several major cardiac intervention studies in
the 1980s and 1990s.38-41 The intraobserver and interobserver
reproducibility of less than 3% for resting LVEF in our hands is
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268
BLOOD, 1 JULY 2004 䡠 VOLUME 104, NUMBER 1
DAVIS et al
comparable to that reported by other workers.18,19,21 Although
MUGA was the tool available for sequential quantitative monitoring from the early 1980s, quantitative monitoring of LVEF is now
possible with magnetic resonance imaging (MRI),42-44 which also
has excellent reproducibility. Recently, MRI techniques have been
used to estimate myocardial iron and, by inference, cardiac risk.45,46
However, the long-term prognostic significance of this modality
has yet to be verified, and it is unclear how chelation treatment
should be stratified based on such a measurement. Our study, on the
other hand, shows that LVEF can be used as an easily available and
effective tool for treatment stratification and intervention and that it
has 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 pretransfusion hemoglobin level
exceeding 10.5 g/dL was policy at the time of the paired measurements and was relatively high compared with current transfusion
practice. However, analysis of the individual changes in LVEF with
transfusion shows that these are unaffected by the variability in
pretransfusion hemoglobin values seen in this study. These results
are in keeping with electrocardiography findings observed by
Henry et al,9 who found no change in LVEF 2 to 4 hours after
transfusion in thalassemia major patients in whom pretransfusion
values were lower than in our patient group.
Exercise stress testing appeared to be of limited additional value
in our patient group. LVEF values determined by MUGA were
reported to be abnormal after exercise compared with at rest in a
higher proportion of thalassemia patients who had not undergone
chelation therapy, with an invariable increase in LVEF noted in
control subjects.32 However, subsequent work showed a wide
variation in exercise responses in healthy persons, and exerciseinduced 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 a
follow up of 1 to 4 years was reported by Freeman et al29,31 in 23
thalassemia major patients receiving subcutaneous DFO. Although
a minority of patients had abnormal resting LVEF values, most
showed abnormal exercise responses, 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 than in those at rest. A confounding
factor in our study was that peak exercise load, an independent
determinant of the exercise response,47 was variable between and
within patients. Because 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 was unlikely because pretransfusion values were
typically greater than 10.5 g/dL. It has been suggested that
pharmacologic stressing might reduce variability related to patient
cooperation during exercise testing. In our hands, dobutamine at
doses up to 40 ␮g/kg per minute often led to unacceptable
symptoms such as flushing and lightheadedness. Although lowdose dobutamine (5 ␮g/kg per minute) has been reported to expose
underlying cardiomyopathy in thalassemia patients using echocardiography,50 no peer-reviewed papers have been published 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 as serum
ferritin,27 liver iron,51 and treatment compliance.23,51 Although our
findings support a relationship between serum ferritin and outcome,
we recognize the limitations of using serum ferritin, particularly as
a single measurement at an arbitrary time point, because many
factors other than body iron burden affect serum ferritin. It is of
note that the association of ferritin with prognosis in this study and
in a previous study by Olivieri et al27 linked prognosis to sustained
increases in serum ferritin over many years, not simply single
ferritin measurements. The relationship between liver iron and
prognosis has not been examined in this paper because 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 Brittenham analysis,51 in which survival was examined in
relation to the ratio between cumulative transfusional iron loading
and DFO use over time.
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
prognoses in patients with thalassemia major. Contrary to some
traditional thinking, 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 must 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 new or established
monitoring tools are used to identify cardiac risk, sequential
changes of the marker in question and full transfusional and
chelation histories should be taken into account.
References
1. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al.
Survival and disease complications in thalassemia
major. Ann N Y Acad Sci. 1998;850:227-231.
2. Porter JB, Davis BA. Monitoring chelation therapy
to achieve optimal outcome in the treatment of
thalassaemia. Best Pract Res Clin Haematol.
2002;15:329-368.
3. Spirito P, Lupi G, Melevendi C, Vecchio C. Restrictive diastolic abnormalities identified by
Doppler echocardiography in patients with thalassemia major. Circulation. 1990;82:88-94.
4. Kremastinos DT, Tsiapras DP, Tsetsos GA, Rentoukas EI, Vretou HP, Toutouzas PK. Left ventricular diastolic Doppler characteristics in betathalassemia major. Circulation. 1993;88:11271135.
5. Yaprak I, Aksit S, Ozturk C, Bakiler AR, Dorak C,
Turker M. Left ventricular diastolic abnormalities
in children with beta-thalassemia major: a Doppler echocardiographic study. Turk J Pediatr. 1998;
40:201-209.
6. Ehlers KH, Levin AR, Markenson AL, et al. Longitudinal study of cardiac function in thalassemia major. Ann N Y Acad Sci. 1980;344:397404.
7. Engle MA, Ehlers KH, O’Loughlin JE, Giardina
PJ, Hilgartner MW. Beta thalassemia and heart
disease: three decades of gradual progress.
Trans Am Clin Climatol Assoc. 1984;96:24-33.
8. Giardina PJ, Ehlers KH, Engle MA, Grady RW,
Hilgartner MW. The effect of subcutaneous deferoxamine on the cardiac profile of thalassemia
major: a five-year study. Ann N Y Acad Sci. 1985;
445:282-292.
9. Henry WL, Nienhuis AW, Wiener M, Miller DR,
Canale VC, Piomelli S. Echocardiographic abnormalities in patients with transfusion-dependent
anemia and secondary myocardial iron deposition. Am J Med. 1978;64:547-555.
10. Kremastinos DT, Toutouzas PK, Vyssoulis GP,
Venetis CA, Vretou HP, Avgoustakis DG. Global
and segmental left ventricular function in betathalassemia. Cardiology. 1985;72:129-139.
11. Nienhuis AW, Griffith P, Strawczynski H, et al.
Evaluation of cardiac function in patients with
thalassemia major. Ann N Y Acad Sci. 1980;344:
384-396.
12. Borow KM, Propper R, Bierman FZ, Grady S,
From www.bloodjournal.org by guest on June 12, 2017. For personal use only.
BLOOD, 1 JULY 2004 䡠 VOLUME 104, NUMBER 1
Inati A. The left ventricular end-systolic pressuredimension relation in patients with thalassemia
major: a new noninvasive method for assessing
contractile state. Circulation. 1982;66:980-985.
13. Jessup M, Manno CS. Diagnosis and management of iron-induced heart disease in Cooley’s
anemia. Ann N Y Acad Sci. 1998;850:242-250.
14. Liu P, Olivieri N. Iron overload cardiomyopathies:
new insights into an old disease. Cardiovasc
Drugs Ther. 1994;8:101-110.
15. Davis BA, Porter JB. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk betathalassemia. Blood. 2000;95:1229-1236.
16. Miskin H, Yaniv I, Berant M, Hershko C, Tamary
H. Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive
iron chelation. Eur J Haematol. 2003;70:398-403.
17. Kremastinos DT, Tsetsos GA, Tsiapras DP, Karavolias GK, Ladis VA, Kattamis CA. Heart failure in
beta thalassemia: a 5-year follow-up study. Am J
Med. 2001;111:349-354.
18. Hecht HS, Josephson MA, Hopkins JM, Singh
BN. Reproducibility of equilibrium radionuclide
ventriculography in patients with coronary artery
disease: response of left ventricular ejection fraction and regional wall motion to supine bicycle
exercise. Am Heart J. 1982;104:567-574.
19. Pfisterer ME, Ricci DR, Schuler G, et al. Validity
of left-ventricular ejection fractions measured at
rest and peak exercise by equilibrium radionuclide angiography using short acquisition times.
J Nucl Med. 1979;20:484-490.
20. Pfisterer ME, Battler A, Swanson SM, Slutsky R,
Froelicher V, Ashburn WL. Reproducibility of ejection-fraction determinations by equilibrium radionuclide angiography in response to supine bicycle exercise: concise communication. J Nucl
Med. 1979;20:491-495.
21. Wackers FJ, Berger HJ, Johnstone DE, et al. Multiple gated cardiac blood pool imaging for left ventricular ejection fraction: validation of the technique and assessment of variability. Am J Cardiol.
1979;43:1159-1166.
22. Araujo A, Kosaryan M, MacDowell A, et al. A
novel delivery system for continuous desferrioxamine infusion in transfusional iron overload. Br J
Haematol. 1996;93:835-837.
23. Gabutti V, Piga A. Results of long-term iron-chelating therapy. Acta Haematol. 1996;95:26-36.
24. Goris ML, Daspit SG, McLaughlin P, Kriss JP. Interpolative background subtraction. J Nucl Med.
1976;17:744-747.
25. Guidelines for the diagnosis of heart failure: the
Task Force on Heart Failure of the European Society of Cardiology. Eur Heart J. 1995;16:741751.
26. Underwood SR, Walton S, Laming PJ, Ell PJ,
Emanuel RW, Swanton RH. Quantitative phase
analysis in the assessment of coronary artery disease. Br Heart J. 1989;61:14-22.
SEQUENTIAL LVEF MONITORING IN THALASSEMIA MAJOR
27. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994;331:
574-578.
28. Kremastinos DT, Tiniakos G, Theodorakis GN,
Katritsis DG, Toutouzas PK. Myocarditis in betathalassemia major: a cause of heart failure. Circulation. 1995;91:66-71.
29. Freeman AP, Giles RW, Berdoukas VA, Talley PA,
Murray IP. Sustained normalization of cardiac
function by chelation therapy in thalassaemia major. Clin Lab Haematol. 1989;11:299-307.
30. Aldouri MA, Wonke B, Hoffbrand AV, et al. High
incidence of cardiomyopathy in beta-thalassaemia patients receiving regular transfusion and
iron chelation: reversal by intensified chelation.
Acta Haematol. 1990;84:113-117.
31. Freeman AP, Giles RW, Berdoukas VA, Walsh
WF, Choy D, Murray PC. Early left ventricular
dysfunction and chelation therapy in thalassemia
major. Ann Intern Med. 1983;99:450-454.
32. Leon MB, Borer JS, Bacharach SL, et al. Detection of early cardiac dysfunction in patients with
severe beta-thalassemia and chronic iron overload. N Engl J Med. 1979;301:1143-1148.
33. Modell B, Khan M, Darlison M. Survival in betathalassaemia major in the UK: data from the UK
Thalassaemia Register. Lancet. 2000;355:20512052.
34. Engle MA, Erlandson M, Smith CH. Late cardiac
complications of chronic, severe, refractory anemia with hemochromatosis. Circulation. 1964;30:
698-705.
35. Himelman RB, Cassidy MM, Landzberg JS,
Schiller NB. Reproducibility of quantitative twodimensional echocardiography. Am Heart J.
1988;115:425-431.
36. Kremastinos DT, Rentoukas E, Mavrogeni S,
Kyriakides ZS, Politis C, Toutouzas P. Left ventricular filling pattern in beta-thalassaemia major:
a Doppler echocardiographic study. Eur Heart J.
1993;14:351-357.
37. Vogel M, Anderson LJ, Holden S, Deanfield JE,
Pennell DJ, Walker JM. Tissue Doppler echocardiography in patients with thalassaemia detects
early myocardial dysfunction related to myocardial iron overload. Eur Heart J. 2003;24:113-119.
38. Morgan CD, Roberts RS, Haq A, et al. Coronary
patency, infarct size and left ventricular function
after thrombolytic therapy for acute myocardial
infarction: results from the tissue plasminogen
activator: Toronto (TPAT) placebo-controlled trial.
TPAT Study Group. J Am Coll Cardiol. 1991;17:
1451-1457.
39. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of
captopril on mortality and morbidity in patients
with left ventricular dysfunction after myocardial
infarction: results of the Survival and Ventricular
Enlargement Trial: the SAVE Investigators.
N Engl J Med. 1992;327:669-677.
40. Ritchie JL, Cerqueira M, Maynard C, Davis K,
Kennedy JW. Ventricular function and infarct size:
269
the Western Washington Intravenous Streptokinase in Myocardial Infarction Trial. J Am Coll Cardiol. 1988;11:689-697.
41. Waagstein F, Bristow MR, Swedberg K, et al.
Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy: Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet.
1993;342:1441-1446.
42. Semelka RC, Tomei E, Wagner S, et al. Normal
left ventricular dimensions and function: interstudy reproducibility of measurements with cine
MR imaging. Radiology. 1990;174:763-768.
43. Semelka RC, Tomei E, Wagner S, et al. Interstudy reproducibility of dimensional and functional measurements between cine magnetic
resonance studies in the morphologically abnormal left ventricle. Am Heart J. 1990;119:13671373.
44. Gaudio C, Tanzilli G, Mazzarotto P, et al. Comparison of left ventricular ejection fraction by
magnetic resonance imaging and radionuclide
ventriculography in idiopathic dilated cardiomyopathy. Am J Cardiol. 1991;67:411-415.
45. Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for
the early diagnosis of myocardial iron overload.
Eur Heart J. 2001;22:2171-2179.
46. Jensen PD, Jensen FT, Christensen T, Eiskjaer
H, Baandrup U, Nielsen JL. Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine:
indication of close relation between myocardial
iron content and chelatable iron pool. Blood.
2003;101:4632-4639.
47. Gibbons RJ, Lee KL, Cobb F, Jones RH. Ejection
fraction response to exercise in patients with
chest pain and normal coronary arteriograms.
Circulation. 1981;64:952-957.
48. Rozanski A, Diamond GA, Jones R, et al. A format for integrating the interpretation of exercise
ejection fraction and wall motion and its application in identifying equivocal responses. J Am Coll
Cardiol. 1985;5:238-248.
49. Borer JS, Bacharach SL, Green MV, Kent KM,
Epstein SE, Johnston GS. Real-time radionuclide
cineangiography in the noninvasive evaluation of
global and regional left ventricular function at rest
and during exercise in patients with coronaryartery disease. N Engl J Med. 1977;296:839-844.
50. Mariotti E, Agostini A, Angelucci E, Lucarelli G,
Sgarbi E, Picano E. Reduced left ventricular contractile reserve identified by low dose dobutamine
echocardiography as an early marker of cardiac
involvement in asymptomatic patients with thalassemia major. Echocardiography. 1996;13:463472.
51. Brittenham GM, Griffith PM, Nienhuis AW, et al.
Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia
major. N Engl J Med. 1994;331:567-573.
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2004 104: 263-269
doi:10.1182/blood-2003-08-2841 originally published online
March 4, 2004
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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