Quality
assessment
The details of the methodological quality assessment of the studies are
tabulated and summarised in Table 2 and Table 3. To sum up, more than
half of the studies (N=12, 60%) were considered high-quality studies,
while the remaining studies (N=8, 40%) were considered medium-quality
studies.
Newcastle-Ottawa Scale for
cross-sectional study
(N=16)
Overall, most of the
cross-sectional studies (N=11) clearly defined the representative sample
of the thalassaemia population, but there were no descriptions of the
population in 5 of the studies [11, 12, 20, 23, 26]. Only 5 studies
reported having a sufficient sample size following an appropriate
formula of sample size estimation [12-14, 19, 24].
One study had an unsatisfactory response rate (less than 80%) [25]
while there were no descriptions of the response rate nor the
characteristics of the respondents and the non-respondents in 4 studies
[14, 16, 22, 26].
All of the studies measured compliance rates using validated measurement
tools or were able to describe the measurement tool except in the study
by Haghpanah et al. (2013) [15].
Aside from that, 6 studies were not adequately designed or analysed to
control confounders with regard to demographic factors such as education
level, age, income, and treatment type[11, 13, 19-22]. For the
remaining 10 studies, the comparability among the different outcome
groups was shown and the confounding factors were controlled. In these
studies, recruited samples were matched in age, gender or other
significant factors [12, 16, 17, 19]; data analysed in multiple
logistic regression while controlling multiple factors such as income
levels, and family history that would affect compliance [14, 15, 23,
24]; or the outcome stratified based on gender [26],
sociodemographic and clinical factors [25]. The data in all the 16
cross-sectional studies were assessed from reliable resources such as
medical records, laboratory investigation, and validated questionnaires.
They also used appropriate statistical tests and described the
measurement of the relationship among outcomes of interest.
Newcastle-Ottawa Scale for cohort
study
(N=3)
All the cohort studies [27-29] had representative samples of the
thalassaemia population and their non-exposed cohort were drawn from the
same population as the exposed cohort. During the selection of the
cohort study, only Wolfe et al. (1985) [27] reported that all the
patients did not have a cardiac disease (outcome of interest). The
comparability of cohorts on the basis of the design or analysis was
appropriate and justifiable. Two studies recruited both arms from a
similar sociodemographic background, while the other study [28] used
logistic regression to explain the relationship between multiple
variables and the outcome of interest. All the studies assessed the
outcome through independent blind assessment. All studies had an
adequate period for assessing the outcome ranging between 6 years to 12
years and complete follow-up of the subjects. Wolfe et al. (1985)
[27] prospectively followed up the patients for 6 years without any
dropouts, while the other studies retrospectively review patients
attended the clinic for 12 years [28] and 10 years [29].
Newcastle-Ottawa Scale for
randomized controlled trial
(N=1)
The sole randomized controlled trial in this study is considered to have
high quality. [30] The participants of the study were regular
thalassaemia attendees of the Thalassaemia Centers, Ain Shams
University, Egypt and Sultan Qaboos University Hospital Oman who had
severe iron overload defined as serum ferritin >2500ng/mL,
liver iron concentration >7mg/g and cardiac T2*
<20 and >6 ms without heart dysfunction. The case
and control groups were adequately defined and appropriately represented
the targeted population.. The cases and controls were age and gender
matched. The data were then assessed through laboratory test and SF-36
health survey for both groups without dropouts.
Compliance towards
ICT
The included studies that reported the rate of ICT compliance are
summarised in Table 3. Among these studies, 8 evaluated the compliance
rate toward DFO monotherapy [11-15, 20, 27, 28], one compared DFO,
DFP and DFX [29], and another compared DFO and DFX [16]. The
compliance rates were compared between the groups of DFO & DFP and DFO
& DFX in one study [30], while a different study compared DFO, DFP
and DFX, and measured overall compliance [21]. Two studies [17,
23] measured but did not report the compliance rate while the
remaining studies examined compliance toward ICT as a whole.
Generally, the rate of ICT
compliance ranged from 20.93% to 75.3%. Specifically, the ICT
compliance rate of the different agents ranged from 48.84 - 85.1% for
DFO, 87.2- 92.2% for DFP, and 90 -100% for DFX. Based on the frequency
of ICT administration, the rates of compliance ranged from 27.5% to
85.1%. There were a variety of ways to define compliance in the
included studies with compliance defined as at least 4-7 days per week
on DFO [11, 16], the number of DFO infusions >50% of
the calculated doses per month [23] or >80% of the
prescribed doses per year [12], percentage of the day in a month
administering DFO >90% [14], using the drugs at least
27 out of 36 months [18], and >50mg/kg/day of DFO or
>30mg/kg/day of DFX [19]. The average compliance rates
based on the vial or pill count were reported to range from 20.93% to
100% [13, 27-30]. In comparison, the average compliance rate was
reported to be 54.9% in the study using MPR [20].
Meanwhile, six articles evaluated compliance using self-reported
measurements. Among these studies, four reported a range between 75.3%
to 91.4% of patients being compliant to ICT [21, 24-26] with the
study by Theppornpitak et al. (2021) [22] reporting 22.9% of
patients had high compliance levels. Haghpanah et al. (2013) [15]
also reported that 85.1% of patients had good compliance levels
although the authors did not mention how they defined compliance in the
study.
Studies’ findings based on
outcomes
Overall, our review revealed a trend toward the advantages of ICT
compliance in reducing serum ferritin, risk of cardiac and liver
complications, and increasing patients’ HRQoL. For studies that reported
these outcomes, the majority of the studies (N=10/11, 90.9%) found a
significant association between patients’ compliance and serum ferritin
levels while most of the studies revealed that ICT compliance was linked
to a lower risk of liver disease (N=4/7, 57.14%) and cardiac disease
(N=6/8, 75%), endocrinologic morbidity (N=4/5, 90%), and lower HRQoL
(N=4/6, 66.67%).
In total, 11 studies [11, 13, 14, 16, 20-22, 24, 27, 28, 30]
examined the relationship between compliance rate and serum ferritin
levels. Nine studies found a significant negative correlation between
patients’ compliance, the average serum ferritin [11, 13, 16, 20, 21,
24, 28], and the mean decrease in serum ferritin prior enrolment to
end of study [22, 27]. Concurrently, a study [30] showed better
result (trend) in mean reduction in serum ferritin from baseline to the
end of therapy in compliant group although there is no significance
difference among the groups while the remaining one study [14]
showed no significant relationship between compliance and serum ferritin
levels despite most of the non-compliant patients having high serum
ferritin levels (>6000μg/L). Furthermore, serum ferritin is
proven as an important predictor of liver and cardiac iron load [19,
25], and endocrine complications [23, 25].
Seven studies in the review evaluated the relationship between the
degree of ICT compliance and liver iron overload or complications.
Compliance was shown to have a significant inverse association with
liver iron overload or complication in 3 of the studies [21, 24, 28]
Meanwhile, it showed the trend of higher compliance with higher mean
decrease in mean liver iron concentration (LIC) level from baseline to
end of treatment [30] while the remaining 3 studies revealed
opposite results in liver iron load in MRI finding [19, 25] and
prevalence of liver morbidities [29]
In addition, six studies revealed that compliance significantly reduces
cardiac iron overload [19, 21], cardiac complications [13, 29],
and the risk of developing the cardiac disease [27, 28] and a study
revealed the better effectiveness in increasing the mean cardiac T2*
value from the baseline.[30] In contrast, two articles reported no
significant relationship between cardiac iron overload and compliance
status [24, 25]. Mokhtar et al. (2013) [29] reported a
significantly higher incidence rate of impaired left ventricular
contractility in the non-compliant group (p<0.001). The MRI
finding reported in the study by Sukhmani et al. (2020) [21]
revealed that non-compliant patients tend to have cardiac and severe
hepatic overload, but there were no significant differences in the
incidence of complications due to these findings between compliant and
non-compliant groups.
Furthermore, endocrinologic complications or morbidities were shown to
be significantly associated with poor ICT compliance (N=4/5, 90%)
[20, 21, 23, 25, 29] except in the study of Sukhmani et al. (2021)
[21]. The endocrinologic morbidities in the studies including
hypothyroidism, subclinical hypothyroidism, impaired glucose tolerance,
impaired fasting glucose, diabetes mellitus, osteoporosis, and others.
The number of non-compliant patients with hypothyroidism, overt and
subclinical hypothyroidism were found significant higher [20] while
the remaining studies examined the relationship using the number of
patients with endocrinopathy (without specify) among the groups. The
thyroid function tests such as thyroid stimulating hormone (TSH), free
tri-iodothyronine (FT3), free thyroxine (FT4) and parathyroid hormone
test (PHT) were used as parameter for the diagnosis of endocrine
disorders in the studies [20, 21, 23], however, only the study by
Yassouf et al. (2019) [20] evaluated the readings of TSH and FT4
among the groups and concluded non-compliance with DFO therapy raised
the risk of thyroid dysfunction by 6.38 times. Meanwhile, the studies by
Mokthar et al. (2013) [29] and Lam et al. (2021) [25] did not
mention or evaluate the thyroid function.
In this review, only six studies
evaluated the association between compliance and quality of life. The
tools to measure HRQoL were Quality of Care (QoC) and Quality of Life
(QoL) questionnaires [12]; Pediatric Quality of Life Inventory
(PedsQL) [18]; Short Form-36 (SF-36) [15, 17, 30] and
Transfusion-dependent QoL (TranQoL) [25] Four of the studies
concluded the positive relationship between HRQoL and compliance, i.e.,
patients with higher compliance had better HRQoL [12, 15, 18, 30].
However, the remaining two studies demonstrated no association between
compliance and HRQOL for patients [17, 25]
Discussion
Clinically, good compliance to chelation therapy has a great impact on
disease control and the quality of life in thalassaemia patients. A high
level of compliance is associated with significantly lower serum
ferritin levels which tend to produce lower risk of iron overload
complications, as well as a better quality of life. However, inadequate
compliance to ICT therapy is common and patients are generally
considered to have the lowest level of compliance to DFO and the highest
level of compliance to DFX. Indeed, many studies measured the patients’
compliance or the clinical burden of thalassaemia itself, but not many
studies measured the association among them. This systematic review
identified and evaluated 20 medium to high quality articles that
measured and compared the impact of chelation compliance on health
outcomes or health-related quality of life. This would provide a clearer
and a more comprehensive picture of the importance of compliance on
various clinical outcomes for optimal management of thalassemia
patients.
Almost all of the included studies (10 out of 11) that evaluated the
association between compliance and serum ferritin levels reported
significant negative correlations or trend among them, except the study
by Lee et al. (2011) conducted in paediatric patients in Malaysia. This
might be due to the markedly high average serum ferritin levels (6156 ±
4296 mg/L) of the patients in the study. Generally, iron chelator
correlates better with a lower level of total body iron and leads to
better therapy results [31]. However, it should be noted that the
patients in the study by Lee et al. (2011) had only received DFO therapy
for 2 years even though they had an average of 9 years of regular blood
transfusions. A longer period of iron-chelation therapy will be needed
to observe a significant decline in serum ferritin. This is further
supported by the findings of Richardson and his colleagues which showed
a prolonged administration of ICTs (early commencement) was associated
with a greater reduction of serum ferritin [28].
Besides, the relationship between compliance levels and the risk of
complications associated with ICT is still inconclusive. Several studies
in our current review measured the risk of liver or cardiac iron
overload complications through MRI [16, 19, 24] or cardiac
evaluation such as clinical examination, echocardiography and,
electrocardiography [27-29]. MRI T2* is an accurate and reliable
tool to assess iron status in patients but it is sometimes not feasible
due to high cost, and patients’ uncooperativeness to hold their breath
throughout the process. Furthermore, MRI T2* is only applicable for
patients aged 10 and above [32]. As a result, only a few articles
reported the findings of MRIs involving a small sample size of patients
explaining the unequivocal findings. Furthermore, previous literature
showed that cardiac iron overload was discovered in cases of severe iron
accumulation in the myocardium only [17]. Moreover, the age of the
participants of these studies was relatively young. A large clinical
study revealed that thalassaemia patients over 40 years old tend to
develop and have a higher incidence of cardiac complications such as
atrial fibrillation as well as a higher risk of stroke even without any
evidence of iron overload [33]. This would suggest that further
studies requiring a longer follow-up of participants are important to
identify patients with iron overload complications.
Another interesting point to discuss regarding the association between
medication compliance and HRQoL is that thalassaemia is a progressive
disease. Symptoms of hyperferritinemia are often ambiguous and
non-specific, and commonly present without causing any early real
clinical manifestations. Hence, a high level of serum ferritin may not
affect thalassaemia patients in their daily life, but the accumulation
of excess iron may result in the occurrence of life-threatening
complications in later life. Some thalassaemia patients receiving DFO
therapy have lower chelation compliance due to the inconvenient
administration procedure and pain at the injection site. Avoiding such
an inconvenient procedure may temporarily improve their current quality
of life, however, the long-term consequences of increased iron loading
will be more likely to result in reduced quality of life in the future
[34]. Additionally, generalising and comparing patients’
health-related quality among these studies is challenging due to
thevariations in the tools used for measuring HRQoL.
Anyway, the objective of our systematic review is very similar to the
review by Delea et al in 2007 [5]. In terms of compliance rate,
Delea et al. found a slightly lower range of mean scores towards DFO
(59%-78%) and DFP (79%-98%) in comparison to our study. However,
they were unable to include any studies that looked into DFX (not
available during the conduct of the review by Delea et al. 2007).
Although Delea et al. systematically reviewed 18 studies on compliance
rates with ICT, they only managed to include 5 articles to discuss the
association between compliance and the incidence of iron overload
complications. The review demonstrated a higher incidence of cardiac and
endocrinopathies complications in poor compliant patients. The five
articles included in the previous review represented studies conducted
in Western and developed countries only (the United States, Australia,
and Italy) and all were performed before 2000, making it difficult to
generalise the findings for developing countries such as Malaysia.
Moreover, after two decades, the clinical management of thalassaemia
population has improved due to more options of ICT and improved
healthcare technologies in recent years. Our review also included two
articles from the previous review since they fulfilled our inclusion
criteria. As a result, our review provided updated information on the
impact of compliance on thalassaemia patients.
Based on the findings from our study, several recommendations for future
studies could be suggested in regard to the impact of chelation
compliance on iron overload complications. In the included studies in
our current review, the sample sizes used to assess the relationship
between compliance and iron overload complications were relatively
small, ranging from 36 to 90, except for the study by Mokhtar et al.
(2013) which had a sufficient sample size (n=447). For any study, an
adequate sample size always allows statistically more reliable
conclusion to be derived from the results. Secondly, researchers should
consider and recruit patients of older age in the study as higher risk
and incidence of iron overload complications were found in older
thalassaemia patients (>40 years old) [33]. In the
studies included in our review, the median age of the samples ranged
from 11.34 to 22.7 years old.
Researchers may also design studies with different age groups and
compare the impact of poor compliance. Besides, to appropriately
identify patients with incidence of iron overload complications, a
longer period of study is needed.
Lastly, our review does contain some limitations. We did not include
non-English language studies in this review. In addition, grey
literature was also not included due to its diversity and challenges to
assess the quality of the literature. The exclusion of these articles
may cause the exclusion of potentially valuable data. However, the
available evidence in our review is considerably more appropriate and
robust to fill the gaps in the topic.
To our best knowledge, this is the first review with worldwide data from
developed and developing countries that demonstrated the positive impact
of compliance in improving health outcomes (especially serum ferritin,
cardiac, liver, and endocrinologic complications), and patients’ HRQoL.
The conclusion of the current review was drawn and supported by more
than 50% of the studies reviewed. Nevertheless, we were unable to
perform a meta-analysis to provide a more precise estimate of the
association between compliance and the various outcomes due to the
limited number and heterogeneity of studies reporting the different
outcomes of interest.