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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1229-1236
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Long-term outcome of continuous 24-hour deferoxamine infusion
via indwelling intravenous catheters in high-risk  -thalassemia
Bernard A. Davis and
John B. Porter
From the Department of Hematology, University College London Medical
School, London, England.
 |
Abstract |
The optimal regimen of intravenous deferoxamine for iron overload in
high-risk homozygous  -thalassemia is unknown because only short-term
follow-up has been described in small patient groups. We report the
outcome over a 16-year period of a continuous 24-hour deferoxamine
regimen, with dose adjustment for serum ferritin, delivered via 25 indwelling intravenous lines for 17 patients. Treatment indications
were cardiac arrhythmias, left ventricular dysfunction, gross iron
overload, and intolerability of subcutaneous deferoxamine. Cardiac
arrhythmias were reversed in 6 of 6 patients, and the left ventricular
ejection fraction improved in 7 of 9 patients from a mean (± SEM) of
36 ± 2% to 49 ± 3% (P = .002, n = 9). The
serum ferritin fell in a biphasic manner from a pretherapy mean of
6281 ± 562 µg/L to 3736 ± 466 µg/L (P = .001),
falling rapidly and proportionally to the pretreatment ferritin
(r2 = 0.99) for values >3000 µg/L
but falling less rapidly below this value (at 133 ± 22 µg/L/mo).
The principal catheter-related complications were
infection and thromboembolism (1.15 and 0.48 per 1000 catheter days,
respectively), rates similar to other patient groups. Only one case of
reversible deferoxamine toxicity was observed (retinal) when the
therapeutic index was briefly exceeded. An actuarial survival of 61%
at 13 years with no treatment-related mortality provides evidence of
the value of this protocol.
(Blood. 2000;95:1229-1236)
© 2000 by The American Society of Hematology.
| |
Introduction |
The benefits of long-term discontinuous subcutaneous
(sc) chelation therapy with deferoxamine (DFO) in extending survival and diminishing cardiac complications in transfusion-dependent -thalassemia are well-established.1-4 For the majority
of patients, the administration of 8- to 12-hour sc infusions, at 30-50 mg/kg body weight, 5-6 nights a week titrated against serum ferritin levels5 or hepatic iron concentration6 is
current practice and unlikely to result in chelator-induced toxicity if
used with these precautions.7 However, a subgroup of
patients, who by reason of poor compliance with or delayed commencement
of recommended sc regimens, becomes massively iron overloaded and is at
risk of early death, principally from cardiac
complications.1,2 For such high-risk patients, intensive
intravenous (IV) chelation is indicated, but the optimal regimen
remains uncertain. In particular, it is not clear whether 24-hour
continuous treatment is necessary or whether discontinuous treatment
with shorter infusions is equally effective. Currently, no published
data are available on the effects of intervention with 24-hour
continuous treatment on long-term cardiac outcome and survival in this
group of patients.
Previous reports of the use of IV DFO have either used discontinuous
regimes whereby DFO is infused <24 hours each day8,9 or
have involved relatively small numbers of patients and relatively short
follow-up periods.10-12 It is clear from these studies that IV DFO given by a variety of regimens can decrease the serum ferritin and improve left ventricular function in some cases, but the optimal regime to reverse cardiac complications of iron overload is not known.
The effect of DFO infusion on serious cardiac arrhythmias, which are
common in severely iron-overloaded thalassemia patients and have poor
prognostic significance, has also not been convincingly demonstrated.
Furthermore, a detailed analysis of risk and benefit of continuous DFO
infusion has not been possible because of the small numbers, short
follow-up, and the different regimens employed hitherto. For these
reasons, in contrast to sc therapy, no consensus exists as to what
should constitute standard treatment in high-risk cases.
To establish the optimal regimen in high-risk patients or to select
those who may best benefit from long-term IV chelation, 3 areas of
knowledge need to be enhanced. First, it is necessary to know how
effective the regimen in question is at decreasing iron stores, at
eliminating toxic iron pools such as nontransferrin bound iron (NTBI),
and at reducing the morbidity and mortality arising from these
conditions. Second, it is necessary to understand whether the potential
toxic effects of DFO are best minimized with the use of discontinuous
therapy8,9 at relatively high doses or with the use of
continuous therapy12 at relatively low doses. Finally, it
is important to know the complication rate of the indwelling catheters
themselves in this group of patients and how these complications can be minimized.
In this paper, we describe the response, survival, and complications
associated with long-term continuous IV DFO therapy administered via
indwelling central venous catheters over a 16-year period. The
treatment protocol employed continuous rather than intermittent DFO,
with the aim of clearing toxic iron species for the maximum practical
duration, and the DFO dose was guided by the therapeutic index (mean
daily dose of DFO in mg/kg divided by the serum ferritin in µg/L) to
minimize DFO-related toxicity.5
| |
Patients and methods |
Patient selection
Between March 1983 and October 1998, 25 IV devices (22 Port-A-Cath
and 3 single-lumen Hickman) were inserted into 17 patients with
transfusion-dependent -thalassemia (11 male, 6 female; age range:
14-43 years) attending the Hematology Department of the University
College London Hospitals (Table 1).
Selection of patients for insertion of Port-A-Caths was based on the
presence of one or more of the following four criteria: deteriorating
left ventricular function with or without clinical heart failure,
development of a clinically significant arrhythmia, a persistently high
serum ferritin value associated with poor DFO compliance, and
intolerance of DFO by the sc route because of severe local reactions.
The 17 patients entered into the study form a small minority of the 140 patients followed in the thalassemia clinic over this period. Five
patients had been referred from other hospitals specifically for
consideration of IV therapy.
Left ventricular dysfunction was judged to be present when at least a
5-point drop in the resting left ventricular ejection fraction (LVEF)
had occurred to a value below the reference range (45%-55%) for
radionuclide ventriculography. Patients showing symptoms and signs of
heart failure who were judged well enough to have a Port-A-Cath
inserted for long-term use were included in the study. By its nature,
this study excluded patients who were admitted in extremis and died
from heart failure rapidly before a Port-A-Cath could be inserted for
long-term use. A significant arrhythmia was defined as one that, by
causing or having the potential to cause cardiovascular instability,
posed a threat to life. Atrial fibrillation was the most common
significant arrhythmia recorded in this study, but nonsustained
ventricular tachycardia and supraventricular tachycardia were also
observed in 2 patients (Table 1). The serum ferritin trigger for
inclusion in this study was a level persistently >3000 µg/L in the
presence of noncompliance with or intolerance of sc DFO. Good compliers
with no evidence of cardiac disease were excluded even if their
ferritin levels exceeded this value from time to time.
Patient monitoring
Cardiac follow-up was done yearly unless cardiac disease was evident
when the frequency of reviews was dictated by individual patient needs.
Resting LVEF measurements were obtained by multigated acquisition
(MUGA) scanning after in vivo labeling of the patients' own red cells
with the use of IV injections of 10-15 µg/kg body weight of stannous
ion (as the pyrophosphate) and 20 µCi of technetium-99m pertechnate
given 20 minutes apart.13 Data acquisition was by means of
IGE SFV and Optima gamma cameras (General Electric Medical Systems, Milwaukee, WI), respectively interfaced with Informatek SIMIS
3 and IGE S4000 computers. MUGA scans were performed
routinely on a yearly basis unless deterioration in LVEF was noted, in
which case measurements were performed as clinically indicated. A
change in LVEF readings of 5 points or more was considered to be
clinically significant. Cardiac arrhythmias were assessed by both
resting 12-lead electrocardiography and 24-hour Holter monitoring with the use of the Pathfinder 3 Analysis System (Reynolds Medical Ltd,
Hertford, UK).
Measurements of serum ferritin were carried out generally monthly by
enzyme immunoassay with the use of IMX and AxSYM analyzers (Abbott
Diagnostics, Maidenhead, UK), and all values are referable to the WHO
Ferritin 80/602 First International Standard. Although 24-hour urinary
iron excretion was determined in most patients, this result was not
used as a criterion for treatment modification. Pure tone audiometric
assessments were undertaken yearly as previously described5
to examine for high frequency sensorineural deficits not attributable
to pre-existing middle ear disease. Electroretinography was performed
at Moorfields Eye Hospital, London annually (or more frequently if
abnormalities were detected or if the patient was symptomatic),
according to the protocol developed by Arden et al.14
DFO infusion regimen
Doses of DFO were calculated with reference to the serum ferritin
with a view to maintaining the therapeutic index (mean daily dose of
DFO in mg/kg divided by the serum ferritin in µg/L) < 0.025.5 The usual DFO regime was 6-7 days of continuous
treatment. Patients were instructed to report immediately any symptoms
that might be due to DFO toxicity, in particular visual and auditory disturbances. Only 8 patients received mean daily doses exceeding 50 mg/kg at any one time (Table 2). The
maximum DFO dose given to each patient has decreased since the
commencement of the study in 1983, and since 1994 only one patient has
received a mean daily dose exceeding 50 mg/kg. Battery-operated CADD
pumps (Pharmacia Deltec Inc, Minnesota, MN), which allow continuous
treatment for up to a week at a time, were used for the most part of
the study but were superseded in 1995 by disposable balloon pumps
(Baxter Healthcare Ltd, Newbury, UK). These disposable infusers have
recently been evaluated15 and are generally preferred by
patients because they are lightweight, silent, unobtrusive, and easy to
use. To encourage patient compliance further, a home-care delivery
system was established, whereby the disposable infusers were delivered directly to the patients' homes.
Intravenous therapy was continued in individual patients until the
catheter had to be removed on account of complications. The decision
about whether to insert a second catheter for further IV treatment was
based on the continuing presence or absence of high-risk features, such
as demonstrable heart disease or persistently high serum ferritin
levels, but the decision ultimately depended on patient acceptance.
Eight patients complied with these recommendations, but one of them
refused to have a third catheter inserted (Table 1). We have recently
introduced continuous 24-hour sc DFO infusions with disposable balloon
pumps in some patients who find this an acceptable alternative to
continuous IV therapy.
Catheter care
Patients with indwelling lines were trained in all aspects of
catheter use and care, but the majority preferred to have them accessed by nurses in the hematology day care unit. Although this entailed a weekly visit to the hospital, it provided more opportunities for early intervention if any complications were found. Individuals on
6-day regimens were advised to remove the Huber needles of their
Port-A-Caths on completion of the last infusion, thus allowing a
24-hour needle-free rest period. Entry sites for the Huber needles were
rotated as much as possible to further lessen the risk of infection,
and catheters were flushed with heparinized saline solution each time
they were accessed.
At each visit, patients were asked about symptoms that might indicate a
catheter infection (fever, exudate, pain, erythema, swelling), and the
port site and catheter track were examined for signs of infection. If
an infection was suspected, appropriate swabs were taken and blood
samples were drawn from the catheters and a peripheral vein for
culture. The tips of all catheters removed were sent for culture.
Organisms were identified by standard microbiological methods. The
laboratory diagnosis of catheter-related sepsis depended on the
isolation of identical organisms from blood drawn from a peripheral
vein and from the catheter itself. Catheter-related infections were
treated with a 7-day course of IV antibiotics via a peripheral vein,
followed by a further 7 days through the catheter itself with
antibiotic locking. Antibiotic treatment of infected lines was
considered successful if cultures from the line remained repeatedly
negative for at least 1 month afterward with associated resolution of
clinical signs.
Patients were also assessed for thromboembolic complications at each
visit and were investigated as appropriate with the use of Doppler
ultrasonography, venography, ventilation-perfusion scanning, and spiral
computed tomography.
Data and statistical analysis
All determinations are expressed as the mean ± standard error
unless otherwise stated. Differences between means have been analyzed
by the Student t test and by P values <.05 reported
as statistically significant. Rates of decline of serum ferritin in
response to IV chelation have been calculated by linear regression analysis. For ferritin data showing biphasic kinetics, the initial and
subsequent rates of decline (K1 and K2,
respectively) have been determined separately by linear regression,
having first identified the points of inflexion of the individual
curves. The duration of the initial phase for each curve was defined by
the x-axis intercept of the K1 plot for that particular
curve. Calculations of actuarial survival have been done by the
Kaplan-Meier method.
| |
Results |
Left ventricular ejection fraction
Resting LVEFs improved significantly in 7 of 9 evaluable cases with
previously documented deterioration in LVEF and stabilized in the
remaining 2 cases. Mean initial and final LVEFs of all 9 evaluable
cases were 36 ± 2% and 49 ± 3%, respectively
(P = .002) [Figure 1]. Analysis
of the serial data (not shown) on individuals with improved LVEFs
revealed a >10% increase in LVEF readings in 2 cases after 3 months
and in 3 cases after 6-8 months of treatment. An 11% increase was
recorded in 1 case after 14 months of treatment, although the dose of
DFO had been reduced from 80 mg/kg/d to 26 mg/kg/d during this period
on account of DFO-related toxicity. Serial data were incomplete for the
seventh case. Long-term follow-up measurements confirm that the
improvements in resting LVEF have been sustained with standard sc
regimens after cessation of IV therapy.
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| Fig 1.
Effect of 24-hour continuous intravenous deferoxamine
infusion on resting left ventricular ejection fraction.
Measurements were obtained serially by radionuclide ventriculography in
9 transfusion-dependent -thalassemia patients with cardiac disease,
and the initial and final values are shown.
|
|
Arrhythmias
All 6 cases with cardiac arrhythmias reverted to sinus rhythm with
continuous IV DFO therapy. Five of these patients received conventional
anti-arrhythmic drugs from the outset, but one patient who had
presented with atrial fibrillation cardioverted after 5 days of
treatment with DFO alone. The time to documented cardioversion ranged
from <24 hours to 12 months. In those who continued to comply with
treatment, sinus rhythm was sustained even when conventional anti-arrhythmic agents were discontinued. Two patients who had documented recurrences of atrial fibrillation, coinciding with short
periods of erratic compliance, were successfully cardioverted on
recommencing continuous DFO infusion. Arrhythmia recurrence in one of
this pair had occurred despite prophylaxis with the blocker,
sotalol. A third patient had a recurrence of prolonged palpitations at
home when his infusion pump temporarily malfunctioned, although he was
taking amiodarone and digoxin at the time. The palpitations did not
recur after the malfunction was rectified, and no significant
arrhythmia was recorded when a 24-hour electrocardiogram recording was
done a few days later.
Serum ferritin
Serum ferritin values fell from a pretherapy mean of
6281 ± 562 µg/L to 3736 ± 466 µg/L (P = .001,
n = 25) during the lifetime of the catheters (Table 2). Two distinct
patterns of response to chelation were observed. Biphasic kinetics,
characterized by an initial rapid fall (K1) in the first
few months of treatment followed by a slower rate of decline
(K2), were evident in individuals with elevation of serum
ferritin more than approximately 3000 µg/L (Figure
2A). Mean K1 was
1082 ± 203 µg/L/mo (n = 8), and the median duration of this
phase was 4 months (range: 3-6 months). The serum ferritin level at
which K1 became zero was 2660 µg/L (Figure 2B). In
patients with pretreatment values less than approximately 3000 µg/L,
K1 was not discernible, only the slower K2
being evident. The mean value of K2 was 133 ± 22
µg/L/mo (n = 12). This slower kinetic phase was evident in patients
with pretreatment ferritin values of <3000 µg/L as well as in those
patients with higher pretreatment values once levels <3000 µg/L had
been achieved. Although K2 was relatively constant,
K1 was variable and correlated with the pretherapy serum
ferritin value (r2 = 0.99, P < .0001;
Figure 2B).
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| Fig 2.
Kinetics of decline of serum ferritin levels in response
to continuous intravenous 24-hour deferoxamine infusion.
(A) Pattern of decline in 2 grossly iron-overloaded patients with
homozygous -thalassemia. (B) Correlation of initial rate of serum
ferritin decline, K1, and pretherapy serum ferritin
level.
|
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Effect on long-term survival
The median follow-up for this study is 54 months (range 9.6-153.6 months), representing the longest follow-up reported to date for this
modality of treatment. The actuarial survival is 61% at 13 years in
all patients with no patients dying while complying with the prescribed
regimen (Figure 3). Compliance with
intended treatment was good in all but 3 patients, representing a
marked improvement compared with sc therapy as evidenced by a
progressive and significant fall in the serum ferritin (Table 2). The
reasons for poor compliance were largely psychosocial and were not a
consequence of mechanical or physical problems with the regimen.
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| Fig 3.
Long-term survival following 24-hour continuous
intravenous deferoxamine infusion.
Kaplan-Meier actuarial survival curve at a median follow-up of 4.5 years for 17 patients with high-risk -thalassemia is shown.
|
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Actuarial survival in patients with demonstrable cardiac disease was
62% at 13 years (not shown), which is not significantly different from
the patient group as a whole (Figure 3). Three patients have died from
heart failure since the commencement of this study. The first of these
patients did not comply with IV treatment. The second patient died a
year after removal of her second Port-A-Cath, having refused further IV
therapy. The third patient, who had earlier made a full recovery from
an episode of severe cardiac failure while on IV treatment, died 2 years after his infected catheter had been taken out. All the patients who presented with serious arrhythmias and three of the four who had
heart failure are alive and leading normal lives.
DFO-related toxicity
DFO-related toxicity was limited to a single early case (patient 5)
of reversible retinopathy when the therapeutic index briefly exceeded
0.025 (Table 2). This patient had preexisting diabetes mellitus, and
the ferritin had fallen rapidly from a starting value of 7075 µg/L
before the start of continuous IV therapy to 3150 µg/L on a mean
daily dose of 80 mg/kg of DFO at the onset of visual symptoms. Full
resolution of visual field and visual acuity defects occurred over a
period of 9 months after reduction in the dose of DFO. No
audiometric abnormalities developed in any of the patients.
Catheter-related complications
The catheter-related complications are itemized in Table
3. The median life span of the Port-A-Caths
(n = 22) was 623 days (range: 71-1851 days) with a median
complication-free survival of 516 days (range: 43-1659 days). The
Hickman catheters (n = 3) had a shorter survival (median: 285 days;
range: 68-536 days), with a median time to first complication of 285 days (range: 68-452 days). For both types of catheters, no
significant difference was seen between the time to first complication
and the overall life span (P = .516 and .881, respectively),
the onset of a complication leading to a greatly shortened catheter
survival; median 39 days (range: 0-638 days) for Port-A-Caths and 42 days (range: 0-84 days) for Hickman catheters. The principle
Port-A-Cath complications were infection (1.15 per 1000 days of
catheter use) and thromboembolism (0.48 per 1000 days of catheter use).
Rarer complications included catheter disconnection and migration
presenting as ventricular tachycardia (0.06 per 1000 catheter days),
perforation of the superior vena cava [previously reported by Russell
et al16 (0.06 per 1000 catheter days)], and nonthrombotic
catheter occlusion (0.12 per 1000 catheter days). The Port-A-Cath
removal rate because of complications was 0.91 per 1000 catheter days.
There were no catheter-related deaths.
Infection incidence.
Staphylococci were the predominant cause of Port-A-Cath infections,
with coagulase-negative strains accounting for 10 of 19 episodes,
methicillin-sensitive Staphylococcus aureus for 4 of 19 episodes, and endogenous infection with methicillin-resistant S
aureus for 3 of 19 episodes. Infections with gram-negative
organisms were much less common; Escherichia coli and
Achromobacter spp were each responsible for 1 of 19 infective
episodes. The methicillin-resistant S aureus infections in both
patients were believed to have arisen as a result of repeated courses
of antibiotic treatment for intra-abdominal conditions not directly
related to thalassemia. No significant preponderance was seen of
localized infections of the sc pocket over bacteremias (10 of 19 vs 9 of 19 episodes), but coagulase-negative staphylococci were involved in
a much higher proportion of the former (8 of 10 vs 2 of 9 episodes).
Eradication of infection from the lines with antibiotics was achieved
in 2 of 2 of the gram-negative infections, in 6 of 10 of
coagulase-negative staphylococcal infections, but in only 1 of 7 of
S aureus infections, giving an overall success rate of 9 of 19 (47%). Two Hickman lines were removed on account of infection. The
first infection was an exit-site abscess for which microbiology results
are unavailable, and the second was a bacteremic episode because of a
coagulase-negative staphylococcus. The overall rate of infection of the
Hickman catheters was 2.8 per 1000 days of catheter use. No cases of
localized or systemic fungal infections were seen during this study.
Thrombosis incidence.
Thromboembolic events included catheter thrombosis in 3 of 8 episodes,
pulmonary embolism in 2 of 8, superior vena cava thrombosis in 2 of 8, and thrombosis of the left internal jugular in 1 of 8, respectively.
The caval thrombus was complicated by a persistent postphlebitic
obstruction syndrome that necessitated a right internal jugular-right
atrial bypass operation 14 months after the initial thrombotic event.
One patient was found to have a small organized right atrial thrombus 3 years after removal of an infected Port-A-Cath. With the exception of
patient 8's second catheter, all catheters complicated by thrombus
formation were managed by catheter removal ab initio followed by oral
anticoagulation for 3 months. The tip of this catheter, which was
located in the right atrium, had a large (4.56 cm × 3.23 cm)
thrombus demonstrated by echocardiography and was treated for 3 months
with warfarin, following which complete dissolution of the thrombus was
documented by echocardiography. The catheter has subsequently been
repositioned without complication and remains in use 21 months later.
| |
Discussion |
This study shows that continuous IV DFO, administered through
indwelling catheters with dose adjustment for serum ferritin levels,
can correct left ventricular dysfunction and reverse serious cardiac
arrhythmias with acceptable degrees of catheter- and DFO-related complications. Furthermore, provided patients comply with IV therapy until the clinical objectives have been achieved and subsequently comply with conventional sc DFO, long-term survival is good, the actuarial survival being 61% at 13 years even in this high-risk group
of adult homozygous -thalassemia patients. The short-term benefits
of continuous IV DFO therapy for patients with cardiac decompensation
have been documented previously,10,11 but the effects of
such intervention on long-term survival have not been described. Direct
comparison of survival in this series with other high-risk groups is
not possible because of the limited follow-up data in other studies and
because of the heterogeneity of the high-risk patients in this study.
However, an indication of the effectiveness of this regimen may be
gleaned by comparing survival with other groups having persistently
high ferritin values or in groups with demonstrable cardiac disease.
All but 2 patients in our study had serum ferritin values consistently
above 2500 µg/L before IV therapy, levels which were previously
reported to be associated with 13-year cardiac survival of only
25%,2 and these 2 patients (patients 3 and 12) both had
demonstrable heart disease. Survival in patients with demonstrable
cardiac disease, before DFO was generally available, was only 50% at 1 year.17 More recently, survival in 39 patients with
demonstrable cardiac disease was only 29% at 3.6 years.18
If we examine only those patients with demonstrable cardiac disease in
our study (Table 1), actuarial survival is 62% at 13 years. Thus,
while precise comparisons are not possible, examination of the nearest clinically comparable data in patients not receiving this continuous DFO regimen strongly suggests that this regimen has beneficial effects
on survival of high-risk patients.
The 3 deaths occurred in patients who either did not comply with IV
therapy or who, after showing initial benefit with IV therapy,
subsequently failed to comply with regular sc treatment once the
catheter was removed. The common factor associated with improved
survival has been good compliance with treatment and is consistent with
previous findings that the long-term outcome ultimately depends on
compliance with DFO and on liver iron concentrations.3 It
is clear from inspection of the results that, although nearly all the
patients had poor compliance as an associated or primary factor for
commencing IV therapy, once the IV therapy ceased, all but 2 patients
complied well with regular sc DFO on its re-introduction. Thus, it
appears that most patients undertaking IV therapy are motivated
subsequently to comply better with regular therapy. The reasons for
improved compliance are likely to be complex but may in
part result from the demonstration of a measurable benefit from the
therapy (eg, reversal of cardiac dysfunction, suitable rate of fall in
serum ferritin) providing longer term motivation. In those that fail,
there may be unresolved psychosocial difficulties underlying continued
poor compliance.
This is the first study in which sustained reversal of life-threatening
arrhythmias with the use of continuous IV therapy has been demonstrated
in more than the occasional patient. Successful reversal of cardiac
arrhythmias has previously been reported with the use of discontinuous
IV therapy in 1 patient8 and continuous therapy in
another.11 However, it has not been possible until now to
establish whether arrhythmia reversal is consistently
achievable and to what extent the long-term prognosis is improved
thereby. In all 6 cases commenced on IV DFO on account of arrhythmias, a sustained reversal to sinus rhythm was documented. The observation that conventional anti-arrhythmic agents on their own appeared to
provide inadequate prophylaxis against the recurrence of arrhythmias in
several of these individuals suggests that DFO is an anti-arrhythmic sine qua non in this group of patients. The response of arrhythmias to
continuous DFO provides supportive evidence to experimental models on
the pathophysiological basis of cardiac dysfunction in iron-overloaded
patients. It is known that low molecular forms of NTBI are taken up
rapidly by heart cells in culture, at more than 200 times the rate of
iron uptake from transferrin iron,19 and induce abnormal
rhythmicity and poor contractile function through their ability to
generate highly toxic free hydroxyl radicals.20,21 These
effects are both preventable and reversible in vitro by DFO.21 The clinical implication is that removal of NTBI by
DFO22 may abrogate the arrhythmogenic effects of NTBI
independently of the effects of DFO on storage iron pools that are
accessed relatively slowly by DFO.23 This hypothesis is
consistent with the clinical observations in this study, namely that
objective improvements in arrhythmias often occurred relatively
quickly, before iron excretion by DFO could have reduced tissue iron to levels regarded as safe.3 Indeed, rapid and sustained
return to sinus rhythm from atrial fibrillation was documented in 1 patient within 5 days of treatment (when the effect of DFO on total
body iron would have been minimal), without the need for conventional anti-arrhythmic agents. We suggest that it is, thus, more likely that
the beneficial effect of continuous infusion of DFO on
cardiac arrhythmias is exerted by continuous removal of a toxic
labile iron pool than on reduction of absolute levels of total
tissue iron.
The optimal regimen for IV DFO in high-risk patients has not been
evaluated prospectively in controlled trials. However, continuous treatment has theoretical advantages over discontinuous treatment for
several reasons. First, in view of the rapid return of NTBI after
cessation of IV DFO infusions,22 24-hour continuous DFO therapy is likely to be preferable. Second, the evidence for benefit of
discontinuous therapy in high-risk patients is limited. In a previous
study using discontinuous DFO intravenously at 100 mg/kg for 8 h/d,9 no improvement in cardiac status was seen in 2 patients with proven cardiac disease after 41-43 months, despite the
falling ferritin levels. Although the numbers are small in
the latter study, the lack of improvement contrasts with the reversal
of arrhythmias and improvement in LVEF with the use of continuous
treatment in our study. In a further report,8 using
discontinuous treatment in 16 iron-overloaded patients, only 1 patient
had abnormal LVEF that demonstrably improved with treatment. The
optimum dose of DFO has not been prospectively tested in our study,
but, during the 16 years, progressively lower maximum doses were used
on new patients with cardiac disease and excellent outcomes were still
achieved, using maximum doses of 50 mg/kg (Patients 3, 6, 10, 12, and
17; Tables 1 and 2). Indeed, we have no evidence that NTBI is removed
more rapidly or that outcome is improved at higher doses.22
The data on serum ferritin kinetics in response to continuous DFO
infusions show that the rate and pattern of decline depend on the
pretreatment ferritin value. In patients with transfusional iron
overload, serum ferritin reflects both increased intracellular synthesis as well as release from damaged cells. A direct relationship with body iron stores cannot be assumed when ferritin levels exceed 4000 µg/L, and above this value there is an increasing contribution from damaged cells to the ferritinemia.24 The biphasic
response to DFO observed in grossly iron-overloaded individuals,
therefore, may represent effects both on leakage from damaged cells and
on ferritin synthesis in response to lowering of intracellular iron levels (Figure 2A). We suggest that the initial rapid phase of decline
(K1) in serum ferritin (Figure 2B) indicates the effect of
DFO on leaked ferritin, possibly mediated by a restoration of cell
membrane or organelle integrity as low molecular weight chelatable iron
pools are cleared rapidly. Thus, the greater the initial leakage, the
greater the rate of fall as damaged cells recover in response to
chelation therapy. We further suggest that the second slower phase
(K2) reflects the removal of iron from tissue stores that
is known to be a slow process, being only a limited amount of iron from
this pool available for chelation at any one time. Of interest, the
point of convergence of K1 and K2 in this study
is approximately 3000 µg/L (Figure 2B), which is close to the level
at which the maximum rate of ferritin synthesis is thought to be
reached.24 We have found it helpful to be able to estimate
for patients the likely rate of fall in the serum ferritin based on
these observations. Figure 2B can be used to predict the approximate
rate of fall for each ferritin value above 3000 µg/L. For ferritin
values below 3000 µg/L, a fall of 133 µg/L/mo can be used to
estimate the likely decrements, as the rate of decline below this value
appears to be relatively independent of the serum ferritin. This
prediction may help to avoid overoptimistic expectation of
the rate of ferritin fall and also allows patients to check their
progress against a predicted range of response.
The benefits of IV therapy described above must inevitably be weighed
against the additional potential risks of the indwelling lines.
However, this study shows that the incidence of infection and
thrombosis of the Port-A-Caths compare favorably with those seen in
other patient groups and should not act as a deterrent to this
treatment in those at high risk from the complications of iron
overload. In a review of 8 studies on the use of similar venous access
devices in adult and pediatric oncology patients (306 patients, 314 catheters, 4700-12 797 catheter days), the infection rate ranged
between 0.00 and 2.35 per 1000 days of catheter use.25
Similarly, coagulase-negative staphylococci and S aureus have
been the organisms most frequently implicated in catheter infections in
other patient groups.26 Of note, no cases of fungal infections were documented in the present study, in particular mucormycosis that has been described in immunosuppressed thalassemia patients27,28 and in dialysis patients receiving
DFO.29 The higher infection rate in the Hickman catheters
in our study must be interpreted with caution in view of the very small
sample size, but it is of interest to note that the incidence of
Hickman infections were also higher than in Port-A-Caths in a previous
study of thalassemia patients.8 Novel developments in
catheter design, including polymer improvements30 and the
incorporation of antiseptics and antimicrobials,31-33 may
in the future offer additional strategies to scrupulous aseptic
technique in the prevention of catheter sepsis, but their efficacy in
patients requiring indwelling catheters for longer than a few weeks is
at present unknown.
The rate of thrombotic complications in this study is comparable to the
rates in other patient groups. Three studies34-36 in oncology patients reported thrombotic rates of 1.2, 0.97, and 0.53 per
1000 days of catheter use. Although regularly transfused thalassemia
patients do not, therefore, appear to be at increased risk of
thrombotic complications from indwelling lines, we have recently
introduced prophylactic anticoagulation for patients having new lines
inserted. The reasons for introducing prophylactic anticoagulation are: first, some of the thrombotic
complications have been troublesome, such as superior vena cava and
right atrial thrombosis; second, it has been suggested that
anticoagulation may also reduce the incidence of catheter infection in
other patient groups, as thrombus formation is a well-known etiological
factor in catheter infections;37-40 and third, as this
study has shown, the onset of infective and thrombotic complications
greatly shortens catheter survival on which the success of IV therapy
depends. As the effectiveness of fixed mini-dose warfarin at 1 mg daily for the purpose of reducing the risk of central venous catheter-related thrombosis remains unproven,41 our policy is to
anticoagulate with adjusted-dose warfarin to a target international
normalized ratio of 2.0:3.0 for as long as the lines remain in situ,
unless there is a patient-specific contraindication. Insufficient
follow-up at this point is available to comment on the effectiveness of this strategy in reducing thrombosis and infection significantly.
The low frequency of catheter-related complications, together with only
1 case of reversible DFO-related complications, shows that, with
careful monitoring and use of appropriate dose adjustment as serum
ferritin levels decline, continuous DFO infusions are a safe
therapeutic option in patients at high risk of cardiac toxicity. The
findings of consistent reversal of arrhythmias and left ventricular
dysfunction should stimulate further investigation into the mechanisms
that underlie these benefits and should argue in favor of continuous
therapy in patients with cardiac disease. Finally, the long-term
survival and compliance data show that in most patients a secondary
benefit is observed following cessation of IV therapy; namely, improved
long-term compliance with conventional sc therapy that, in turn,
contributes to the long-term survival of these high-risk patients.
| |
Acknowledgments |
We wish to thank Sarah Benn-Hirsch and Barbara Bull for their kind
assistance with data collection and Goli Taghipour for help with
analysis of the survival data. Special thanks goes to Catherine Jarrold
for helpful advice regarding the chelation protocol used in this study.
| |
Footnotes |
Submitted August 19, 1999; accepted October 18, 1999.
Supported in part by a grant from Cooley's Anemia Foundation, USA.
Reprints: John B. Porter, Department of Hematology,
University College London Medical School, 98 Chenies Mews, London WC1E
6HX, UK; e-mail: j.porter{at}ucl.ac.uk.
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.
| |
References |
1.
Zurlo MF, De Stefano P, Borgna-Pignatti C, et al.
Survival and causes of death in thalassaemia major.
Lancet.
1989;2:27[Medline]
[Order article via Infotrieve].
2.
Olivieri NF, Nathan DG, MacMillan JH, et al.
Survival in medically treated patients with homozygous -thalassemia.
N Engl J Med.
1994;331:574[Abstract/Free Full Text].
3.
Brittenham GM, Griffith PM, Nienhuis AW, et al.
Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.
N Eng J Med.
1994;331:567[Abstract/Free Full Text].
4.
Gabutti V, Piga A.
Results of long term iron chelating therapy.
Acta Haematol.
1996;95:26[Medline]
[Order article via Infotrieve].
5.
Porter JB, Jaswon MS, Huehns ER, East CA, Hazell JWP.
Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage.
Br J Haematol.
1989;73:403[Medline]
[Order article via Infotrieve].
6.
Olivieri NF, Brittenham GM.
Iron-chelating therapy and the treatment of thalassemia.
Blood.
1997;89:739[Free Full Text].
7.
Porter JB.
A risk-benefit assessment of iron chelation therapy.
Drug Saf.
1997;17:407[Medline]
[Order article via Infotrieve].
8.
Cohen AR, Martin M, Schwartz E.
Current treatment of Cooley's anemia.
Ann N Y Acad Sci.
1990;612:286[Medline]
[Order article via Infotrieve].
9.
Tamary H, Goshen J, Carmi D, et al.
Long-term intravenous deferoxamine treatment for non-compliant transfusion dependent beta-thalassemia patients.
Isr J Med Sci.
1994;30:658[Medline]
[Order article via Infotrieve].
10.
Marcus RE, Davies SC, Bantock HM, Underwood SR, Walton S, Huehns ER.
Desferrioxamine to improve cardiac function in iron-overloaded patients with thalassaemia major.
Lancet.
1984;1:392[Medline]
[Order article via Infotrieve].
11.
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[Medline]
[Order article via Infotrieve].
12.
Olivieri NF, Berriman AM, Tyler BJ, Davis SA, Francombe WH, Liu PP.
Reduction in tissue iron stores with a new regimen of continuous ambulatory intravenous deferoxamine.
Am J Hematol.
1992;41:61[Medline]
[Order article via Infotrieve].
13.
Walton S.
Radionuclide ventriculography. In:
Murray IPC,Ell PJ, eds.
Nuclear Medicine in Clinical Diagnosis and Treatment. Vol 1. London, England: Churchill Livingstone; 1994:1069.
14.
Arden GB, Wonke B, Kennedy C, Huehns ER.
Ocular changes in patients undergoing long-term desferrioxamine treatment.
Br J Ophthalmol.
1984;68:873[Abstract/Free Full Text].
15.
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[Medline]
[Order article via Infotrieve].
16.
Russell SJ, Giles FJ, Edwards D, Porter JB, Hardmann S, Harrison R.
Perforation of superior vena cava by indwelling central venous catheters.
Lancet.
1987;1:568[Medline]
[Order article via Infotrieve].
17.
Engle MA, Erlandson M, Smith CH.
Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis.
Circulation.
1964;30:698[Abstract/Free Full Text].
18.
Olivieri NF, Snider MA, Nathan DG, et al.
Survival following the onset of iron-induced cardiac disease in thalassemia major.
Blood.
1995;86:250a.
19.
Link G, Pinson A, Hershko C.
Heart cells in culture: a model of myocardial iron overload and chelation.
J Lab Clin Med.
1985;106:147[Medline]
[Order article via Infotrieve].
20.
Gutteridge JMC, Rowley DA, Griffiths E, Halliwell B.
Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis.
Clin Sci (Colch).
1985;68:463[Medline]
[Order article via Infotrieve].
21.
Link G, Athias P, Grynberg A, Pinson A, Hershko C.
Effect of iron loading on transmembrane potential, contraction, and automaticity of rat ventricular muscle cells in culture.
J Lab Clin Med.
1989;113:103[Medline]
[Order article via Infotrieve].
22.
Porter JB, Abeysinghe RD, Marshall L, Hider RC, Singh S.
Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy.
Blood.
1996;88:705[Abstract/Free Full Text].
23.
Crichton RR, Roman F, Roland F.
Iron mobilisation from ferritin by chelating agents.
J Inorg Biochem.
1980;13:305[Medline]
[Order article via Infotrieve].
24.
Worwood M, Cragg SJ, Jacobs A, McLaren C, Ricketts C, Economidou J.
Binding of serum ferritin to concanavalin A: patients with homozygous thalassaemia and transfusional iron overload.
Br J Haematol.
1980;46:409[Medline]
[Order article via Infotrieve].
25.
Decker MD, Edwards KM.
Central venous catheter infections.
Pediatr Clin North Am.
1988;35:579[Medline]
[Order article via Infotrieve].
26.
Elliot TSJ, Faroqui MH.
Infections and intravascular devices.
Br J Hosp Med.
1992;48:498.
27.
Gaziev D, Baronciani D, Galimberti M, et al.
Mucormycosis after bone marrow transplantation: report of four cases in thalassemia and review of the literature.
Bone Marrow Transplant.
1996;17:409[Medline]
[Order article via Infotrieve].
28.
Sands JM, Macher AM, Ley TJ, Nienhuis AW.
Disseminated infection caused by Cunninghamella bertholletiae in a patient with beta-thalassemia.
Ann Intern Med.
1985;102:59.
29.
Boelaert JR, Fenves AZ, Coburn JW.
Deferoxamine therapy and mucormycosis in dialysis patients: report of an international registry.
Am J Kidney Dis.
1991;18:660[Medline]
[Order article via Infotrieve].
30.
Tebbs SE, Elliott TSJ.
Modification of central venous catheter polymers to prevent in vitro microbial colonisation.
Eur J Clin Microbiol Infect Dis.
1994;13:111[Medline]
[Order article via Infotrieve].
31.
Tebbs SE, Elliott TSJ.
A novel antimicrobial central venous catheter impregnated with benzalkonium chloride.
J Antimicrob Chemother.
1993;31:261[Abstract/Free Full Text].
32.
Maki DG, Stolz SM, Wheeler S, Mermel LA.
Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter: a randomized, controlled trial.
Ann Intern Med.
1997;127:257[Abstract/Free Full Text].
33.
Raad I, Darouiche R, Dupuis J, et al.
and the Texas Medical Center Catheter Study Group. Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections. A randomized, double-blind trial.
Ann Intern Med.
1997;127:267[Abstract/Free Full Text].
34.
Lokich JJ, Bothe A, Benotti P, Moore C.
Complications and management of implanted venous access catheters.
J Clin Oncol.
1985;3:710[Abstract].
35.
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Abstract
Introduction