Costs, quality of life, treatment satisfaction and compliance in patients with β-thalassemia major...

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CURRENT MEDICAL RESEARCH AND OPINION�

VOL. 24, NO. 7, 2008, 1905–1917

0300-7995

doi:10.1185/03007990802160834

� 2008 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

ORIGINAL ARTICLE

Costs, quality of life, treatmentsatisfaction and compliance inpatients with �-thalassemiamajor undergoing iron chelationtherapy: the ITHACA studyLuciana Scalonea, Lorenzo G. Mantovania,Marieke Krolb, Diana Rofailc, Simona Raverad,Maria Grazia Biscontee, Caterina Borgna-Pignattif,Zelia Borsellinog, Paolo Cianciullih, Domenico Gallisaii,Luciano Prossomaritij, Ippazio Stefanok andMaria D. Cappellinil*a CIRFF – Centre of Pharmacoeconomics, University of Naples Federico II,

Naples, Italy; CHARTA Foundation (member of COPERA), Milan, Italyb Institute for Medical Technology Assessment, Erasmus Medical Centre,

Rotterdam, The Netherlandsc MAPI Values, Questionnaire Development and Validation Unit, Bollington, UKd Centre of Pharmacoeconomics, University of Milan, Milan, Italye Centro Microcitemie, Presidio Ospedaliero dell’Annunziata, Azienda

Ospedaliera Cosenza, Italyf Arcispedale S. Anna Dipartimento di Medicina Clinica Sperimentale – Clinica

Pediatrica Ferrara, Italyg UOC Ematologia - Emoglobinopatie, ARNAS Civico, Palermo, Italyh Ospedale S. Eugenio – Centro Microcitemie DH talassemia Roma, Rome, Italyi Istituto di Clinica Pediatrica – Universita degli Studi di Sassari, Sassari, Italyj Azienda Ospedaliera ‘A. Cardarelli’ UOC Microcitemie Padiglione C Centro

Talassemici, Naples, Italyk Azienda Ospedaliera SS. Annunziata, Taranto, Italyl Congenital Anemia Center, IRCCS Foundation Policlinico, Mangiagalli,

Regina Elena Hospitals and University of Milan, Italy

Key words: Compliance – Cost analysis – HRQoL – Iron chelation therapy – Satisfaction –�-Thalassemia

Address for correspondence: Lorenzo G. Mantovani, CIRFF – Center of Pharmacoeconomics,Federico II University of Naples, Via Domenico Montesano 49, I-80131 Naples, Italy.Tel.: þ39 081 678657; [email protected]

*For the ITHACA Study Group

Paper 4215 1905

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ABSTRACT

Objectives: Iron chelation treatment (ICT) in �-thalassemia

major (�-TM) patients undergoing blood transfusions can

cause low satisfaction, low compliance, with possible

negative consequences on treatment success, patients’

wellbeing, and costs. The purpose was to estimate the

societal burden attributable to �-TM in terms of direct and

indirect costs, health-related quality-of-life (HRQoL),

satisfaction and compliance with ICT in patients undergoing

transfusions and ICT.

Research design and methods: The naturalistic,

multicenter, longitudinal Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) cost-of-illness study was

conducted involving patients of any age, on ICT for at least

3 years, who were enrolled at 8 Italian Thalassemia Care

Centers. Costs were estimated from the societal perspec-

tive, quantified with tariffs, prices, or net earnings valid in

2006.

Results: One-hundred and thirty-seven patients were

enrolled (median age¼ 28.3, 3–48 years, 49.6% male) and

retrospectively observed for a median of 11.6 months.

Mean direct costs were E1242/patient/month, 55.5%

attributable to ICT, 33.2% attributable to transfusions.

Relevant quantity and quality of productivity was lost.

Both physical and mental components of HRQoL were

compromised. Little difficulties remembering to take ICT

and positive satisfaction with the perceived effectiveness

of therapy were declared, but not good levels of satisfac-

tion with acceptance, perception of side effects and

burden of ICT.

Conclusions: The management of �-TM patients

undergoing transfusions and ICT is efficacious, although

costly, but overall benefits were not always perceived as

optimal by patients. Efforts must be focused to improve

patients’ acceptance and satisfaction with their therapy;

this would contribute to a better compliance and hence an

increase in treatment effectiveness and patients’ overall

wellbeing, with expected improved allocation of human and

economic resources.

Introduction

People with hematological disorders like �-Thalassemia

Major (TM) require life-long blood transfusions as a

supportive therapy. The implementation of regular

blood transfusions in the 1960s radically changed

these patients’ life expectancy, although an important

consequence of this progress has been the increase of

the iron overload morbidity1,2: if the excess of iron is

not removed, it may damage vital organs, particularly

the liver, the heart, endocrine glands, and may lead to

death. Further progress was then made with the regular

use of iron chelation therapy (ICT), which in Italy

started with intramuscular deferoxamine in the late

1970s (the first iron chelator agent, deferoxamine,

was licensed by the FDA in 1968), then with continu-

ous intravenous and finally with subcutaneous infu-

sions to remove the excess of iron in transfused

patients3–5. Regular blood transfusion in combination

with ICT using subcutaneous deferoxamine infusions

have sensitively reduced patients’ morbidity and

increased their survival6–9. According to Zurlo et al.6

the overall survival from birth of patients born

in 1970–1974 was 97.4% at 10 years and 94.4% at

15 years. Borgna-Pignatti et al.7 recently reported data

on survival and causes of death in 977 Italian patients

with TM born since 1960, grouped according to their

year of birth: it was shown that patients born in more

recent years, treated with regular blood transfusions

and ICT, had a higher survival and a higher complica-

tions free survival.

Currently, the drug most frequently given is

deferoxamine, administered in an 8–12 h continuous

infusion, 5–7 times per week. An alternative drug to

be used is deferiprone, orally administered 3 times

per day and indicated for the treatment of iron overload

in patients with TM when deferoxamine therapy is

contraindicated or inadequate10. Recently it has been

shown that deferiprone has a better activity on removal

of iron from the heart11,12. An observed therapeutic

trend is to administer a combination of deferoxamine

and deferiprone for intensive chelation, as promising

results are attributed to a possible synergistic effect

of the two drugs13. New iron chelators seem to have

interesting properties and activities: in particular,

Deferasirox is a new oral iron chelator recently

approved by FDA and EMEA for the treatment of

transfusional iron overload14. In order to understand

the overall impact of transfusions and chelation treat-

ment in TM patients not only it is necessary to evaluate

the consequences on their morbidity and mortality, but

also on their overall wellbeing and on the health care

resources consumption necessary to treat them: in par-

ticular the treatment regimen can sensitively influence

patients’ satisfaction and compliance and their health

state perception, with possible consequences on the

effectiveness of the therapy and on health care costs.

So far little is known about the socio-economic

burden in patients affected by �-TM and undergoing

blood transfusions and ICT. The few studies available,

indicating that the costs of iron chelating therapy are

considerable, suffer from some drawbacks, as that they

do not include all relevant cost items, but only analyze

some aspects influencing the overall burden attributa-

ble to this condition and its treatment15–22. To be able

to understand the real overall burden of the phenom-

enon a number of factors should actually be taken into

account: both medical costs (such as treatment and

1906 Costs and outcomes in �-TM patients undergoing ICT � 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(07)

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monitoring costs), non-medical costs (such as costs of

transportation), indirect costs, i.e. the cost attributable

to the loss of productivity by the patients and their

caregivers, the impairment of wellbeing (known as

intangible costs) and all other relevant aspects, rather

than just the cost of therapy, are important issues to be

considered to understand the overall impact of a disease

and to identify how to make efforts to reduce the

burden attributable to the disease, from both patients’,

their families’, healthcare providers’ and payer’s point

of view.

Accordingly, we conducted the Italian THAlassemiaCost & Outcomes Assessment (ITHACA) study

reported here, with the aim of estimating the societal

burden of �-thalassemia major (�-TM) managed with

blood transfusions and ICT. In particular direct costs

(e.g., cost of treatment), indirect costs (productivity

loss), intangible costs (health related quality of life),

attitude toward ICT (in terms of patients’ reported

compliance), and treatment satisfaction were estimated

in a cohort of pediatric and adult �-TM patients under-

going transfusions and ICT.

Patients and methods

Study design

A naturalistic, multicenter, retrospective, prevalence-

based cost of illness study was conducted. The techni-

que of cost of illness was chosen as appropriate to

estimate the societal burden attributable to �-TM and

its management with transfusions and ICT, according

to current clinical practice23.

Study sample

Adult and pediatric subjects of any age with �-TM

were enrolled in the ITHACA study between

November 2005 and March 2006. The patients had

to be on a transfusional regimen and ICT for at least

3 years and attending a thalassemia treatment center.

The patients who agreed to take part in the study

signed an informed consent. In the case of patients

aged less than 18 years, both they and their caregivers

were asked to sign the informed consent. The partici-

pating patients agreed that their data from hospital

charts could be stored into a database, in an anonymous

way, and that they (or their caregiver, in the case

of children) completed a one-time questionnaire to

provide the required data.

Data

To reach the objective of the ITHACA study

the following data were collected: demographic

characteristics and clinical status, direct (medical and

non-medical), indirect (i.e., loss of productivity), and

intangible costs (i.e., Health Related Quality of Life,

HRQoL), satisfaction and compliance with treatment,

as reported by the patients. A questionnaire asking

information on patients’ demographic and clinical

data and on direct medical resources consumption

occurring from January 1, 2005 was completed by

the physicians. To complete these questionnaires the

physicians used the patients’ medical charts. The

patients (or one caregiver if children) completed a

further questionnaire with questions on non-medical

resources consumption (e.g., cost of transportation to

the hospital or the physician), indirect resource con-

sumption, HRQoL, satisfaction and compliance with

their ICT.

Direct costs

The information required to estimate direct medical

costs was based on the occurrence and the amount of

medical resources absorbed during the observational

period: ICT administered, concomitant medications,

transfusions, hospitalizations, medical visits, laboratory

and instrumental tests. Costs were estimated by multi-

plying the amount of the resource consumed

(for instance the quantity of drugs used during the

observational period) by the corresponding unit cost

(price or tariff, as appropriate) applied in 2006.

In order to take into account the costs of infusion of

deferoxamine (pump, needles, syringes, and other

consumables) the physicians were further interviewed

and asked to specify which kind of device they used to

administer the deferoxamine to their patients, the aver-

age amount consumed in a month for patients treated

with deferoxamine, and the unit cost for each device.

The data collected with these interviews were used to

estimate a mean monthly cost of administration

in patients treated with deferoxamine. In order to

estimate the cost per infusion the obtained monthly

cost was divided by the average number of administra-

tions reported for the patients taking part in the study

and treated with deferoxamine. Hence, the estimated

mean cost per infusion was used to estimate the total

cost of infusions in the patients taking deferoxamine

alone or in combination with deferiprone. Direct non-

medical costs were estimated in terms of costs of travel

to reach the hospitals or the physicians’ offices for

a visit, or to reach the hospitals for transfusions or

for hospitalizations.

Indirect costs

For the estimation of indirect costs (i.e., costs due to

production losses, because patients were absent from

� 2008 Informa UK - Curr Med Res Opin 2008; 24(07) Costs and outcomes in �-TM patients undergoing ICT Scalone et al. 1907

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work or less productive at work as a result of their

disease), a short version of the ‘Health and Labour

Questionnaire’ (SF-HLQ) was administered in subjects

aged �16 years24. It consisted of 4 modules to collect

data on absence from work, reduced productivity,

unpaid labor production, labor-related problems.

Questions referred to the previous 2 weeks.

Patients aged 12–15 years self-completed the

‘children-part’ of the HLQ. It consisted of two mod-

ules: one on absence from school, the other on times of

inability to do usual activities. Questions referred to the

previous 3 months. For patients younger than 12 years,

their caregivers completed the parent-version of the

children-part of the HLQ.

A monetary value to the loss of productivity was

applied when patients had paid work, in terms of

income-effect and by taking into consideration the

patients net earning. When the productivity loss was

related to unpaid labor (i.e., when the patients loosing

their productivity did not actually have paid employ-

ment, like children or housewives), the indirect costs

were not expressed in monetary terms. In particular,

absence from work and/or being less productive at

work were reported in terms of days/patient-week

and E/patient-week. The costs of being less able to per-

form household activities are presented in received

hours of formal and informal household care.

Health related quality of life

Health related quality of life was assessed in patients

aged from 14 years, by using a battery of 2 generic

questionnaires, the SF-36 and the EQ-5D. These ques-

tionnaires were chosen for their capability to evaluate

both the physical and psychological components of

quality of life, and because they allow the comparison

of HRQoL within and between different clinical con-

ditions and with the general population. The SF-36

questionnaire assesses eight dimensions of HRQoL,

which relate to the physical and mental components

of the individual’s health perception. Specifically, the

domains ‘physical functioning’, ‘role-physical’, ‘bodily

pain’, and ‘general health’ are more related to the

physical component, whereas the domains ‘vitality/

energy’, ‘social functioning’, ‘role-emotional’, and

‘mental health’ are more related to the psychological

component. Possible scores for each domain range from

0 (corresponding to the worst possible state) to 100

(corresponding to the best possible state). These eight

domains can be grouped into two summary scores:

the ‘physical component summary’ (PCS) evaluates

the patients’ perception of limitations or disabilities

in self-care, physical, social and role activities, the

presence of bodily pain and fatigue. The ‘mental com-

ponent summary’ (MCS) score evaluates the feelings of

psychological distress, social and role disability because

of emotional problems.

In accordance with standard procedures and using

the US algorithm, the summary scores were computed

by multiplying each of the eight individual SF-36 scores

by their specific factor score coefficients25,26. The sum-

mary scores are norm-based to allow their comparison

to the US population in which a mean of 50 and

a standard deviation of 10 are achieved. The EQ-5D

questionnaire consists of two main parts: the first part

generates a health profile (EQ-5D profile) made of

5 domains, namely ‘mobility’, ‘self care’, ‘anxiety or

depression’, ‘usual activities’, and ‘pain or discomforts’,

each one with three levels of severity (‘no problem’,

‘some or moderate problems’, ‘extreme problems’).

The second part of the questionnaire consists of a

visual analogue scale (EQ-5D VAS), measuring overall

HRQoL ranging from 0 (worst imaginable health

status) to 100 (best imaginable health state)27.

HRQoL of �-TM patients enrolled in this study was

compared with HRQoL of the general Italian popula-

tion28 and with the one of another congenital, chronic,

disabling rare disease: data from two Italian studies

on patients with moderate to severe hemophilia

were used29,30.

Satisfaction with ICT and compliance

ICT satisfaction and compliance was assessed in

patients aged from �12 years old: they completed a

Satisfaction with ICT questionnaire31 of 28 questions

measured on a 5-Likert scale: 19 items are grouped in

4 satisfaction domains: (1) satisfaction with ICT

perceived effectiveness, pertaining to the patients’ per-

ceptions of benefits of ICT; (2) acceptance (i.e., con-

venience) of ICT, exploring positive orientations

towards ICT with regard to expectations and conveni-

ence of taking ICT; (3) burden of ICT, measuring nega-

tive impact incurred from ICT on activities of

daily living, sleep, time to take ICT and dependency;

(4) side effects of ICT, assessing potential side effects of

ICT and their impact on individual appearance. The

possible scores are from 1, meaning ‘low satisfaction’,

to 5, meaning ‘high satisfaction’. Three items are on

compliance to ICT, as reported by the patients, with

questions on how often the interviewee (1) had trouble

remembering to take ICT; (2) thought about stopping

ICT; (3) followed the ICT regimen exactly as recom-

mended by his/her doctor in the previous 4 weeks.

Possible scores are 1, meaning ‘always’, to 5, meaning

‘never’. Six additional items are on worries, overall con-

cerns, and treatment preference. While this question-

naire is in the process of finalization and validation, its

initial version has been used and its psychometric


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properties were checked in this study (internal consis-

tency, reliability, construct validity).

Perspective of the analysis

The society’s point of view was taken into considera-

tion in this study, in particular the Italian National

Health Service’s, the patients’ and their families’ per-

spectives were adopted as appropriate, according to

the type of data collected. In particular, direct costs

were estimated from the perspective of the Italian

NHS, patients’ and/or their caregivers. The patients’

perspective was adopted in the estimate of indirect

costs, HRQoL, treatment satisfaction and compliance.

Time horizon

Different time horizons were adopted, depending on

the type of data collected and on the instrument

adopted to collect each type of data. While the time

horizon for the clinical data and the consumption of

medical resources was around 1 year (i.e., from the

time of enrolment back to January 2005), the one

regarding the productivity loss was of 2 weeks or

3 months (depending on the age-specific version of

the labor questionnaire administered), while the time

horizon adopted to assess HRQoL, satisfaction and

compliance were referred to a period of up to

4 weeks before the interview. The results are reported

by taking into account the specific time horizons con-

sidered in each category of variables: for instance, the

direct costs will be expressed in terms of E per patient/

month, while the indirect costs as E or days per patient/

week. This approach was chosen to avoid possible

biases attributable to the adoption of different periods

to observe the occurrence of the events of interest.

Statistical analyses

A descriptive analysis was carried out using proportions

for categorical data, mean and/or median as central

tendency parameters for continuous data, with stan-

dard deviation (SD), minimum (min) and maximum

(max) values as dispersion parameters, as appropriate.

Cost were expressed in terms of mean cost per

patient-month (or per patient-week in case the time

horizon was lower than 1 month, as for the indirect

costs): this parameter can in fact be easily used to

make projections on different populations, allows the

calculations of total costs (e.g., by multiplying the mean

per patient cost by the prevalence of the disease) and is

of easy use for policy makers. Because of the highly

skewed distribution of cost variables, we report,

as a measure of variability, the distribution of costs

per patient per month, instead of standard deviations.

Stratification analyses were also conducted to investi-

gate a possible relationship between costs of transfu-

sions and of ICT and patients’ age. The internal

consistency of the SF-36 and the Satisfaction question-

naire was assessed through the calculation of

Cronbach’s alpha, for which values40.70 can be con-

sidered satisfactory32. All analyses were performed

using SPSS version 13.0 software (SPSS, Chicago, IL).

Ethical aspects

Approval for the study was granted by the Institutional

Review Board of the coordinating centre (i.e., the

Congenital Anemia Center of the IRCSS Foundation

Policlinico, Mangiagalli, Regina Elena Hospitals).

Each patient was asked to sign an informed consent

form. In the case of patients less than 18 years old,

both the patients and their parents/guide had to sign

the informed consent form.

Results

Socio-demographic and clinical data

A total of 137 patients were enrolled from eight tha-

lassemia care centers and were retrospectively observed

for 10–13 months (mean¼ 11.8, median¼ 11.6), for a

total of 1604 patient-months. Socio-demographic and

clinical data are reported in Tables 1 and 2. Details of

main characteristics are specified below. Fifty percent

of the patients were female, the median age was

28 years, with the youngest patient aged 3 years and

the oldest 48 years. The 21 patients aged not more than

15 years were attending kindergarten or school,

depending on their age. Among those aged �16 years

(116), 61 patients (52.6%) declared to have paid

employment, 55 (47.4%) did not have paid employ-

ment. It is worth noting that 6% of the patients declared

to be unable to work because of their health problems

and 18% declared that they did not have paid employ-

ment and were early retired or were receiving a pension

despite their young age, presumably for their disease.

The majority of the patients (121, 89% of the sample)

were diagnosed with �-TM by the age of 2 years

(median¼ 1 year). However 11% of the patients, who

were diagnosed later in their life (when they were 3–11

years of age), were transfusion dependent at the time of

the participation in the study. With reference to the last

detection of ferritin levels during the observational

period, almost 28% of the patients had less

than 500 ng/mL, one third had between 500 and

1000 ng/mL, and almost 40% had higher levels of fer-

ritin, in particular 34 patients, 25.4% of the study

sample, had levels higher than 1500 ng/mL.


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Eighty-two percent of patients had one or more

complication attributable to the disease or to the trans-

fusions received: in particular more than half of the

patients had an endocrine disease (58%) and/or a

blood-borne viral infection (55%); 42% had chronic

hepatitis or cirrhosis (note that 47 patients reported

both hepatic disease and blood-borne viral infection)

and 18% a cardiac disease.

Iron chelation therapy regimen

Data on ICT were available for 136 out of 137 patients

(data from 1 patient were missing). At enrolment 70

(51.5%) patients were treated with deferoxamine, 43

(31.6%) were treated with deferiprone, 23 (16.9%) trea-

ted with both deferoxamine and deferiprone. It is worth

noting that a number of patients experienced one or

more treatment change during the observational period:

in particular, 14 patients (10.2% of the sample), aged

from 3 to 48 years, changed, at least once, the dosage

of the drug used, while 19 (13.9% of the sample) chan-

ged at least once from deferoxamine to deferiprone or

vice versa (aged between 14 and 36 years), and/or from

monotherapy to combined therapy or vice versa (11

patients, aged between 25 and 34 years).

During treatment with deferoxamine alone the

patients were on average administered the treatment

5.3 days per week, with a minimum of 3 and a maximum

of 7 days per week and a mean of 11 h/infusion (from 6 to

24 h). When receiving deferiprone, patients were admin-

istered the treatment an average of 6.7 days per week,

with a minimum of 4 and a maximum of 7 days per

week. As regards treatment with both deferoxamine

and deferiprone, the patients received a mean of 4.7

infusions of deferoxamine (from a minimum of 2 to a

maximum of 7 infusions) and were administered with

deferiprone 6.7 days per week (from 2 to 7 days

per week).

Direct costs

Cost of iron chelation therapy

Regarding cost to administer deferoxamine (i.e., pump

plus consumables), on average E227/patient/month

was estimated. A cost of E9.7 per infusion was then

estimated by dividing the monthly cost by the mean

Table 1. Socio-demographic characteristics of enrolled

patients (N¼ 137)

Description of variables Values

Female patients: N (%) 69 (50.4)

Age

Mean (SD) 27.2 (9.6)

Median (min–max) 28.3 (2.7–48.5)

N (%) of patients with

510 years 7 (5.1)

10–15 years 14 (10.2)

16–25 years 32 (23.4)

26–35 years 60 (43.8)

�36 years 24 (17.5)

Working/school status at enrolment

N (%) of patients aged �15 years,

going to kindergarten or school

21

N (%) of patients aged �16 years 116

N (%) of patients with paid

employment

61 (52.6)

N (%) of patients without paid

employment*

55 (47.4)

N (%) having a daily task of running

a household

18 (36.7)

N (%) student 18 (36.7)

N (%) receiving a pension or early

retired

10 (18.2)

N (%) unable to perform paid work

due to health problems

3 (6.1)

*Six patients did not specify their activityPercentages according to the activity performed were computedon the remaining 49 patients

Table 2. Clinical characteristics of enrolled patients

(N¼137)

Age at first TM diagnosis: median

(min–max)

1.2 (0.0–11.1)

Ferritin levels according to the last

detection

Median ng/mL (min–max) 874 (82 – 7,119)

Patients (N, %) with5500 ng/mL* 37 (27.6)

500–1000 44 (32.8)

1001–1500 ng/mL 19 (14.2)

41500 ng/mL 34 (25.4)

Presence of disease or treatment

related complications: N (%)

112 (81.8)

Endocrine disease: N (%) 80 (58.4)

Blood-borne viral infections: N (%)y 76 (55.5)

Hepatic disease: N (%)y 58 (42.3)

Cardiac disease: N (%) 25 (18.2)

Frequency of patients according to

the no. of complications

No complication: N (%) 25 (18.2)

1–2 complications: N (%) 34 (24.8)

3–4 complications: N (%) 47 (34.3)

�5 complications: N (%) 31 (22.5)

* No data on Ferritin levels was reported for 3 patients.Percentages were computed on the basis of patients reportingthis data (134)yForty-seven patients had both hepatic complication and bloodborne viral infection


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number of infusions per month (23.5) estimated from

the data collected during the study.

The total cost of deferoxamine treatment, including

the drug, was estimated to be on average E793/patient/

month, of which E565/patient/month was attributable

to the drug (71.3% of the total treatment cost),

E227/patient/month was attributable to the adminis-

tration costs (28.7% of the total treatment cost), as

reported in Table 3.

The cost of treatment with only deferiprone was on

average E480/patient/month. When a treatment with

both the drugs in a different combination was applied,

an average of E963/patient/month were spent, including

the cost to administer the deferoxamine. The cost of the

drugs (deferoxamine and deferiprone) corresponded to

E779/patient/month (80.9% of total costs), while the

cost to administer deferoxamine corresponded to E184/

patient/month (19.1% of total ICT cost).

Total direct cost

Overall the total cost of ICT was estimated to be

E690/patient/month, corresponding to 55.5% of the

total direct societal costs (Table 4). Concerning other

medical costs E412/patient/month were spent for

transfusions, corresponding to 33% of the total direct

cost, and around E100 (8% of the total direct cost)

were spent for hospitalizations, mainly occurring for

surgery (e.g., splenectomy and colecistectomy), labora-

tory and instrumental tests, medical visits, and concom-

itant medications. The total societal direct cost,

both medical and non-medical, were estimated as

E1240/patient/month.

It must be noted that 32% of patients cost less than

E1000 per patient/month and 49% cost between

E1000 and E1500, while only 5% of patients cost

between E2000 and E3200 per patient/month.

Regarding transfusions, in 75% of patients these cost

were less than E500 per patient/month, in 20%

between E500 and E1000, while only 5% of patients

cost from E1000 to almost E1700 per patient/month.

Finally ICT costs less than E500 per patient/month in

35% of patients, between E500 and E1000 in 52%, and

from E1000 to E1500 in 13% of patients. Distribution

of costs are reported in Figure 1. It is reasonable to

expect that this distribution of costs can be attributed

to the high variability of the study sample in terms of

age (and weight): Table 5 shows means, minimum and

maximum costs of ICT, and transfusions (i.e., the main

cost factors) according to the patients’ age. According

to mean costs some relationships with the patients’ age

in fact appears. However, age seems not to be the sole

factor determining the skewed distribution of direct

costs: in fact, in every age range at least one patient

cost less than E500 per month as regards ICT and less

than E200 per month for transfusions, furthermore,

high differences do not exist as regards the maximum

costs between the different age ranges.

Indirect costs

Among the patients aged 16 years or more and in paid

employment, 21 (34%) were not able to work for one or

more days during the last 2 weeks before the interview,

with 5% of these declaring that they were absent from

work for a longer period than 2 weeks when completing

the questionnaire. An average of 0.7 days/week of

absenteeism was estimated among all the working

patients, corresponding to approximately 14% of the

working week lost. By taking into account only the

patients who declared absence from work, the average

number of working days/week lost was 3 per patient

(60% of the working week). Fifteen working patients

(26.4%) declared to be hindered by health problems

(for instance with concentration, having to work at a

slower pace at times, having to seclude themselves,

finding decision-making more difficult) at work over

the previous 2 weeks an average of 2.3 days/week and

42.5% of their working time. In patients with paid

employment the estimated total productivity loss cor-

responded to a mean of E37/patient-week. Thirty-two

patients (corresponding to 28% of patients aged

16 years or more) reported they were hindered while

doing household activities. These patients received

0.6 h/week of informal help (i.e., not paid, from

family members, or other people) and 1.5 h/week of

paid help. To note, 2 respondents made the remark

that they did not do any housework unrelated to

whether they experienced health problems or not.

As regards patients aged less than 16 years

(21 patients), 18 (85.7%) missed schooldays in the

Table 3. ICT costs according to the regimen of treatment

(N¼ 136; data on ICT was missing for 1 patient)

Description E per

patient-month

% within

regimen

Treatment with

deferoxamine only

792.69 100.0

Costs of deferoxamine 565.39 71.3

Costs of pump and

consumables

227.30 28.7

Treatment with

deferiprone only

480.47 –

Treatment with

deferoxamineþ deferiprone

963.05 100.0

Costs of deferoxamine 398.79 41.4

Costs of deferiprone 380.41 39.5

Costs of pump and

consumables

183.85 19.1


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3 months before the interview, with an average of 0.6

days/patient-week, which corresponds to 10–12% of

the school week. Six patients declared they missed reg-

ular activities, like performing sport, an average of

0.02 days/patient-week.

Health related quality of life

Patients reported compromised levels of wellbeing.

The results with the EQ-5D profile show (Table 6)

that 9% of the patients reported moderate problems,

while no patient declared to have severe problems

with this domain. Only 1 patient declared to have

some problems in washing or dressing (self-care

domain), but 23% declared to have some problems in

doing usual activities (i.e., going to school, to work,

doing housework, family, or leisure activities).

Patients reporting moderate levels of pain or discomfort

were 61%, while 1 patient declared extreme pain or

discomfort, finally 40% declared to be moderately and

2.5% to be extremely anxious or depressed. The

EQ-Visual Analogue Scale score had a mean value of

73 (median¼75, from 30 to 100). Similar trends

were observed with the SF-36: details are reported

in Table 6, in particular the mean (SD) Physical

Component Summary score, which summarizes the

physical related scores, was 47.0 (8.4); the mean (SD)

Mental Component Summary score, summarizing

the mental related scores, was 45.0 (8.8). The internal

consistency of the SF-36 was good, with Cronbach

values ranging from 0.71 to 0.86 in every dimension.

As shown in Figure 2, the physical component of

HRQoL in �-TM patients on ICT was on average

worse than in the general Italian population compar-

able for sex and age, the mental component of

HRQoL was also worse than the one of the Italian gen-

eral population28. As it can be expected, the mean

Physical Component Summary score in male �-TM

patients was higher than the one in moderate to

severe adult hemophilic patients, with or without

inhibitors towards replacement therapy with coagula-

tion factor concentrates, while the mean Mental

Component Summary score was comparable with

these two categories of patients29,30.

Treatment satisfaction with ICTand compliance

Before analyzing the Satisfaction scores, the psycho-

metric properties of the Satisfaction questionnaire

were checked. All scores showed good internal

1.5%

34.6%

75.2%

30.1%

52.2%

19.7%

49.3%

13.2%

4.4%

14.0%

0.0% 0.7%5.1%

0.0% 0.0%0%

15%

30%

45%

60%

75%

90%

Fre

quen

cy o

f pat

ient

s

<500 € 500–999 € 1000–1499 € 1500–1999 € ≥2000 €Monthly per patient/costs

Total costs

ICT

Transfusions

Figure 1. Frequency of patients according to monthly direct costs, with comparisons between total (light grey bars), ICT (dark

grey bars), and transfusions (white bars) specific costs

Table 4. Total direct costs

Description of variables E per

patient-month

% on total

direct cost

ICT, any regimen, including

administration

689.63 55.5

Transfusions 412.12 33.2

Hospitalizations with surgery 41.26 3.3

Laboratory and instrumental

tests, medical visits

39.20 3.2

Concomitant medication 19.49 1.6

Total medical costs 1201.77 96.7

Non-medical costs

(travel cost)

42.78 3.4

Total direct costs 1242.66 100.0


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consistency reliability: Cronbach’s alpha coefficients

were higher than 0.70 (from 0.73 to 0.83). The con-

struct validity of the scores were also good since all

items were more correlated to their own scale (as

opposed to the other scales), and correlation between

each item and its own scale, corrected for overlap, was

higher than 0.40 (except for 2 items). The Satisfaction

with ICT questionnaire was completed by all patients

�12 years of age (n¼126). As a score of 5 represents

‘Very Satisfied’ for all items in a domain, a mean of 3.5

or more suggests that most patients were rather satis-

fied with most or all of the items in the domain.

Satisfaction with ICT domains were highest for

Perceived Effectiveness with ICT (mean¼ 4.3),

followed by Burden of ICT (mean¼ 3.9), and then

Table 6. Health related quality of life results

Description of domains and levels Value

EQ-5D results

Mobility (N, %)

No problem in walking. 110 (90.9)

Some problems in walking 11 (9.1)

Confined to bed 0

Self-care (N, %)

No problem 120 (99.2)

Some problems in

washing or dressing

1 (0.8)

Unable to wash or dress 0

Usual activities (N, %)

No problem to perform

usual activities.

93 (76.9)

Some problems to perform

usual activities

28 (23.1)

Unable to perform usual activities 0

Pain/discomfort (N, %)

None 46 (38.0)

Moderate 74 (61.2)

Extreme 1 (0.8)

Anxiety/depression (N, %)

None 70 (57.9)

Moderate 48 (39.7)

Extreme 3 (2.5)

Visual Analogue Scale

Mean (SD) 73.1 (16.0)

Median (min, max) 75.0 (30–100)

SF-36 results

Physical functioning

Mean (SD) 82.8 (16.7)

Min–max (35.0–100.0)

Role–physical

Mean (SD) 68.2 (36.5)

Min–max (0–100)

Bodily pain

Mean (SD) 69.4 (24.3)

Min–max 72.0 (10–100)

(continued)

Table 6. Continued

Description of domains and levels Value

General health

Mean (SD) 52.6 (22.4)

Min–max (5–100)

Vitality/energy

Mean (SD) 64.5 (19.1)

Min–max (10–100)

Social functioning

Mean (SD) 74.1 (22.8)

Min–max (12.5–100)

Role–emotional

Mean (SD) 71.7 (39.7)

Min–max (0–100)

Mental health

Mean (SD) 70.0 (17.7)

Min–max (28–100)

Physical component summary

Mean (SD) 47.0 (8.3)

Min–max (23.2–59.3)

Mental component summary

Mean (SD) 45.0 (8.7)

Min–max (24.0–62.14)

Table 5. Costs of ICT and transfusions according to patients’ age

Patients’ age range E per patient-month

for ICT* mean (min–max)

E per patient-month for

transfusions mean (min–max)

510 years old 348.06 (194.45–497.52) 259.95 (185.25–353.92)

10–15 years old 583.64 (243.74–1400.71) 402.75 (199.38–743.87)

16–25 years old 677.85 (267.41–1472.64) 405.32 (140.40–806.55)

26–35 years old 771.64 (329.28–1331.79) 383.18 (174.04–1410.02)

435 years old 661.27 (280.63–1157.63) 543.38 (127.73–1696.80)

* Any regimen, including costs of administration


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Side Effects of ICT (mean¼ 3.6). Acceptance of ICT

was the lowest mean score (mean¼ 3.4) indicating

positive orientations towards ICT relating to expecta-

tions and convenience.

Concerning the items to measure compliance, the

mean score for ‘thinking about stopping ICT’ was 4.6

(with 1 meaning ‘always’, 5 meaning ‘never’), the mean

score for ‘following the ICT as directed by the doctor’

was 1.6, and the mean for ‘having troubles remember-

ing to take the ICT’ was 4.2.

Discussion

Although a number of studies have allowed the estima-

tion of direct costs, or more specifically ICT costs, or

compared costs and efficacy of alternative treatment

options, no information was available, to our knowl-

edge, on the overall impact attributable to �-TM and

its management from the societal perspective. The

ITHACA study was a naturalistic study conducted to

estimate the overall societal costs attributable to �-TM

and current medical strategies adopted for transfusions

and ICT. According to its objective, the technique

adopted for this study is in its nature not for making

comparisons between alternative options (as for

instance with cost-effective analyses), but for observing

the impact attributable to the disease and current

clinical practice adopted to manage the patients.

Total direct costs were estimated to correspond to an

average of E1242/patient/month from the societal

point of view. If multiplied by the number of patients

with transfusion dependent TM patients in Italy,

who are approximately 7000 persons, the total

societal direct costs corresponds to almost E107

million per year over the Italian society or, in other

terms corresponds to a cost of almost E2 per Italian

citizen per year. Fifty-six percent of direct costs is

attributable to ICT (E60 million per year) and 33%

to transfusions (E35 million per year). Treatment

with deferoxamine is 60–65% more expensive than

treatment with deferiprone, depending on the regimen

followed by the patients. The distribution of direct

costs is highly right skewed, showing that one third of

the sample cost less than E1000, almost 50% cost

between E1000 and E1500 per month, while 20%,

less than a quarter of the sample, cost E2000 per

month or more, this contributing to the high levels of

direct total costs attributable to the management of this

category of patients. Despite a slight relationship of

mean costs with age, the skewed distribution appears

to be mostly dependent on other factors, like the

patients’ clinical conditions or the treatment regimen

adopted, according to the physicians’ decisions or

patients’ requests.

Regarding indirect costs, one main point to be noted

is that one fourth of the sample declared to be

pensioned, early retired, or not able to work because

of their health status. Furthermore, patients reported a

high percentage of absenteeism and experienced sub-

stantial difficulties while working, participating at

school activities, or doing other usual activities.

Overall a percentage of 10–14% of productivity was

lost by the study sample. Among patients younger

than 16 years of age, while a high percentage of

youths missed a number of schooldays, an apparent

lower amount of time was lost in terms of regular activ-

ities. It is worth noting, in this regard, the possible

underestimate of the true loss of productivity in this

category of patients: children often go to medical

visits for their disease during school-time while other

Men

0

10

20

30

40

50

60

PCS MCS

ITHACA (aged 14–48 years; N = 60)

Italian population (aged 18–54 years; N = 621)

Moderate to severe hemophilia patients withoutinhibitors aged 18–49 years; N =178 (COCHE Study)

Moderate to severe hemophilia patients with inhibitors,aged 15–48 years; N = 42 (COCIS Study)

Women

0

10

20

30

40

50

60

PCS MCS

ITHACA (aged 14–48 years; N = 60)

Italian population (aged 18–54 years; N = 621)

(A) (B)

Figure 2. Comparison of physical and mental summary components of HRQoL from the SF-36, between �-TM, hemophilia

patients and general population comparable for age and sex


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activities (e.g., sport) take place outside the physicians’

normal working time.

For instance, although no information was available

on the specific reasons of loss of productivity, like going

to the hospital for transfusions or to the physician’s

office to monitor and manage complications, or receiv-

ing infusions for ICT, the participating physicians

suggested that most of this loss was attributable to the

necessity to reach hospitals or other places for visits,

transfusions, surgical interventions etc, which can also

require a lot of travel time, above all among patients

living in places far from the clinical centers (e.g., rural

areas). By contrast, infusions for chelation therapy are

mostly administered at home, when the patient is more

available, for instance during the night. As a conse-

quence, it is likely that the respondents did not consider

the time spent for infusions (on average 11 h per infu-

sion) as lost in terms of productivity. Another possible

interpretation is that not all children carry out, outside

their school-time, specific activities such as sport: they

probably did not consider missing activities for their

disease simply because they did not have to give up

any of them. Hence, this estimate should be considered

as conservative, although it does show that a high

amount of productivity was lost by both adult and

pediatric patients and, when present, by their care-

givers. This cost significantly contributes to the high

overall cost of this illness and is, therefore, an issue

that the health care system should take into considera-

tion to increase the efficiency of treatment strategies.

In general, the current health state perception among

�-TM patients undergoing transfusions and ICT was

impaired if compared to the one among the general

population, comparable for age and sex: reasons of

poor wellbeing can be attributed both to the disease

and to the treatment that patients receive and that can

be perceived cumbersome and not satisfactory. In fact

the patients reported, in general, non-optimal levels of

satisfaction with their ICT (with deferoxamine, defer-

iprone or combination of the 2 drugs): while on average

the patients were satisfied with the perceived effective-

ness of the therapy, lower levels of satisfaction were

reported as regards other aspects related to ICT, in par-

ticular they were on average poorly satisfied with the

convenience of ICT, the perception of side effects, and

of the burden attributable to the regimen treatment.

These results suggest that despite the clinical benefits

derived from the current medical interventions, which

have improved survival and reduced the risk and sever-

ity of complications, dealing with things like for

instance, way, duration and frequency of administra-

tions, perception of pain, consequent limitations

on doing daily activities and having a normal life, can

actually contribute to reduce patients’ wellbeing.

A consequence of this can be a poor compliance with

treatment, with a likely impairment of the overall real

benefits of the treatment. The patients participating in

this study declared, in general, to be adherent to the

prescribed ICT at enrolment. It should be remembered

in this regard that only patients undergoing ICT from at

least 3 years were eligible for this study: it is possible

that those who were more compliant and for this reason

were receiving the ICT for a relatively longer period,

actually participated in this study. This might be the

cause of an overestimate of the levels of satisfaction of

ICT among the overall target population. However, it

must be noted that 14% of patients actually changed

the regimen of treatment: this may correspond to a

result of poor compliance or, in the case of switching

to combined therapy, may correspond to a clinical need

of intensive chelation.

In fact, different reasons for changing the drug or the

dosage were reported by the physicians participating

in the study, like ferritin levels, but also the patients’

compliance, which caused the physicians’ decision or

even the patients’ request to change dosage or drug.

Physicians in general decided to switch from a mono-

therapy to a combined therapy when they recognized

that their patients needed intensive chelation therapy

due to severe iron overload, while switched to mono-

therapy when the iron overload was less severe.

According to the results of a recent literature review

of 18 studies on compliance with deferoxamine com-

pared with deferiprone therapy33, the compliance may

improve with an oral drug, which is easier and quicker

to be administered. Poor compliance with ICT results in

increased risk of cardiac disease and endocrinopathies,

as well as lower survival, with the additional

consequence of increased overall costs. One point that

is worth noting, however, is that what was observed in

our study could also be a consequence of the absence of

a standardized, homogeneous, agreed procedure and

the presence of different approaches decided by the

physicians, according to their personal experience and

opinions. In fact, the first recommendations on how to

optimally manage TM patients have only recently been

published, by the Italian Society of Hematology34.

The results of the ITHACA study show that the

current clinical practice allows, although at high costs,

transfusion dependent �-TM patients to receive effica-

cious treatment based on transfusions and iron chela-

tion therapy. However, optimal benefits have not been

reached yet, as shown by the results in terms of

HRQoL, satisfaction, and attitude toward ICT. This

picture of the current medical practice highlights the

necessity of further efforts aimed at improving patients’

acceptance and satisfaction with their therapy35, in

order to increase their compliance, hence to improve


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the effectiveness of treatment. As a result of a better

compliance with and acceptance of the prescribed ICT,

the treatment can be expected to be more successful in

reducing iron overload in these patients and improving

their clinical status and overall wellbeing. As a further

consequence, a likely reduction of both direct and

indirect costs, for instance, an optimization of resources

allocation, can be expected for the health care system

and overall society’s benefit.

One potential limitation of this study is

attributable to the fact that only a sample of Italian

patients were involved: however, we do not have ele-

ments suggesting that the results of the ITHACA

cannot be considered valid in other populations of

patients with similar characteristics as those participat-

ing in this study. It is worth noticing that possible

differences may be present in the values expressed in

monetary terms, depending on possible different payers

for the healthcare services (e.g., insurances rather

than the National Health Service) in the different

countries, and/or on the different prices or tariffs

applied. However, the amount of the resources

adsorbed are reported and could be used for compari-

sons or projections.

Conclusion

The ITHACA study shows that the modern strategies

applied to manage �-TM patients undergoing transfu-

sions and ICT generates high costs to society but are

efficacious in clinical terms, even though optimal levels

of benefits have still to be reached, in terms of treat-

ment satisfaction and overall wellbeing. Efforts must be

made to improve patients’ acceptance and satisfaction

with their therapies, in order to increase their compli-

ance, to improve the effectiveness of treatment, hence

the patients’ general wellbeing. This would allow a

more appropriate use of the resources. In particular,

a more flexible regimen for ICT, such as an oral treat-

ment, adhering to good levels of safety, can be consid-

ered an objective to be reached, in order to ensure that

patients can receive a therapy they can comply with.

This objective may well be reached by the introduction

of a new oral iron chelator agent, deferasirox, of which

promising results have been shown in a randomized

phase III trial35, although these still need to be con-

firmed with further research and real use in clinical

practice.

As a result of a better accepted therapy, higher clin-

ical and perceived benefits can be expected, with pos-

sible positive consequences on the perspective of both

the National Health Service (the main payer, in Italy,

for direct costs), patients and their families, who mostly

pay for loss of productivity (indirect costs) and

wellbeing (intangible costs).

Further research is now advocated to compare the

overall costs and consequences attributable to the avail-

able options, with the specific objective to identify and

to inform decision makers about the most efficient

strategy to adopt in this category of patients.

Acknowledgments

Declaration of interest: An unrestricted grant was

provided by Novartis Pharmaceutical Corporation,

East Hanover, NJ, USA, for this study.

L.G.M. and M.D.C. designed the study. S.R. mana-

ged the collection of the data from the participating

centers. S.R., L.S., M.K., and D.R. analyzed the data.

L.S., M.D.C., L.G.M. wrote the paper. M.B., C.B-P.,

C/B P.C., D.G., L. P., I.S, S.R., M.K., and D.R.

reviewed and integrated the paper by adding further

information that helped to interpret the results. The

other co-investigators, listed as ITHACA study group

members, contributed with the collection of the data.

The views expressed in the paper are those of the

authors.

We thank the patients and caregivers who took part

in this study. Thanks also to Dr. Jean-Francois Baladi.

Other ITHACA study group members were:

M. Capra, L. Cuccia, from U.O.C. Ematologia –

Emoglobinopatie, A.R.N.A.S. Civico, Di Cristina,

Ascoli – Palermo; F. Sorrentino, from Ospedale

S. Eugenio – Centro Microcitemie DH talassemia

Roma; M. Viala, from Mapi Valued Questionnaire

Design and Validation Unit – Bollington, Cheshire,

UK; C. Uyl-de Groot, from Institute for Medical

Technology Assessment, Erasmus Medical Centre,

Rotterdam, The Netherlands.

The results of this study have been presented

at a national and some international Congresses:

poster at The 11th EHA Congress, Amsterdam

(The Netherlands) June 15–18, 2006; posters at The

9th Annual European Congress of ISPOR,

Copenhagen (Denmark), October 29–31, 2006; oral

presentation at The IV National Congress of SOSTE

(Societa per lo Studio delle Talassemie ed

Emoglobinemie), Rome (Italy), November 18–19,

2006; posters at The ASH Congress, Orlando (USA),

December 9–12, 2006.

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CrossRef links are available in the online published version of this paper:

http://www.cmrojournal.com

Paper CMRO-4215_5, Accepted for publication: 25 April 2008

Published Online: 27 May 2008

doi:10.1185/03007990802160834


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