Original paper

Submitted: 26.02.2024 Endokrynologia Polska

Accepted: 13.04.2024 DOI: 10.5603/ep.99555
Early publication date: 06.06.2024 ISSN 0423–104X, e-ISSN 2299–8306
Volume/Tom 75; Number/Numer 3/2024

Block-and-replace regimen versus titration of antithyroid

drugs: a recent meta-analysis
Ana-Maria Stancu 1, 2
, Corin Badiu 1, 2

Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

1

ORIGINAL PAPER
C. I. Parhon National Institute of Endocrinology, Bucharest, Romania
2

Abstract
Introduction: Drug therapy for Graves’ disease (GD) is the first-line treatment in Europe. The use of a specific regimen for the adminis-
tration of anti-thyroid drugs (ATDs) is still controversial. The objective was to compare block-and-replace therapy (BRT) with a titration
(T) regimen in terms of incidence of overt hypothyroidism and development of Graves’ orbitopathy (GO) over 18 months of treatment.
Material and methods: Two databases (PubMed, Cochrane Library) and reference lists were searched. Prospective and retrospective
observational cohort studies were included. Data collection and analysis were performed independently by 2 authors.
Results: Two studies with 716 GD patients (40.36% treated with BRT, 59.64% with T regimen) were included. No statistically significant
differences were observed between the ATDs regimens used in terms of incidence of overt hypothyroidism during 18 months of treat-
ment [Mantel-Haenszel (M-H) odds ratio (OR): 1.54, 95% confidence interval (CI): 0.75–3.16, p-value = 0.24]. GD patients who followed
BRT were less likely to achieve control of thyroid function than patients on T regimen (M-H OR: 0.55, 95% CI: 0.34–0.88, p = 0.01). One
study reported fewer thyroid function tests (TFT) during BRT than during the T regimen. The other study included patients without GO
at baseline and reported a lower incidence of GO during BRT than in the T regimen (9.1% versus 17.8%), with no statistical difference
between the 2 regimens (M-H OR: 0.47, 95% CI: 0.19–1.14, p = 0.10).
Conclusion: BRT may be more useful than the T regimen for patients with complicated GD or for those who required fewer TFTs.
(Endokrynol Pol 2024; 75 (3): 317–327)
Key words: thyroid; Graves; block-replace; titration

Introduction surgery, but it is worsened by RAI treatment [7]. RAI

and total thyroidectomy (TTx) have a low risk for hy-
Graves’ disease (GD) is the most common cause perthyroidism recurrence, but patients require lifelong
of hyperthyroidism in iodine-replete regions, usu- treatment with levothyroxine (LT4) [8]. Using ATDs,
ally affecting women aged 40 to 60 years old [1]. It is the risk of GD recurrence is ~50% [9].
an autoimmune disorder characterized by the presence The main ATDs used are carbimazole (CBZ), with
of thyroid-stimulating hormone receptor antibodies its active metabolite methimazole (MMI) and propyl-
(TRAb) that stimulate follicular thyroid cells to synthe- thiouracil (PTU). They control hyperthyroidism by
size and secrete thyroxine (T4) and triiodothyronine inhibiting thyroid hormone synthesis and by their
(T3) [2]. Consequently, the thyroid gland increases its immunosuppressive effect. In addition, PTU inhibits
volume and vascularity. The main extra-thyroidal mani- the peripheral conversion of T4 to T3 [10]. The most
festation is Graves’ orbitopathy (GO), which affects 20% common adverse reactions are skin rash, arthralgia,
of patients with Graves’ hyperthyroidism (GH) [3]. GD and transient mild leukopenia, which develop in
is easily recognized by the triad: thyrotoxicosis, diffuse 1% to 5% of patients. Very rarely (< 0.1% of cases)
goiter, and ophthalmopathy [4]. agranulocytosis may occur with MMI or CBZ therapy
Management of GD implies drug treatment us- and liver failure during PTU therapy [11]. The optimal
ing anti-thyroid drugs (ATDs) in different regimens, duration of ATDs administration is considered to be
radioactive iodine (RAI), or thyroidectomy (Tx) [5]. 12–18 months [12].
The first-line treatment in Europe is anti-thyroid medi- ATDs can be administrated in a titration (T) regimen
cation, while in the United States RAI is preferred [6]. or using a block-and-replace regimen, as first described
The course of GO is not influenced by thionamides or by Hashizume [13]. No difference was observed be-

 Ana-Maria Stancu, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; C. I. Parhon National Institute
of Endocrinology, Bucharest, Romania; Address: Street Bd. Aviatorilor, no. 34–36, sector 1, Bucharest 011863, Romania,
tel: +40 729 024 921; e-mail: ana.maria.stancu@drd.umfcd.ro; drd.ana.maria.stancu@gmail.com

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 Block-and-replace therapy versus titration Ana-Maria Stancu et al.

tween the risk of GD relapse between the 2 treatment Types of outcome measures
regimens or in the duration of therapy [12]. However,
no systematic review has described the control of thy- Primary outcomes
roid function during block and replace therapy (BRT) Primary outcomes included:
versus T of ATDs and how these therapies would influ- —— incidence of overt hypothyroidism during 18 months
ence the onset of GO. of treatment (the recommended duration of medical
We want to assess the control of GH during ATDs treatment for GD);
therapy. We compared ATDs used in a block-and-replace —— prevalence of euthyroid patients over 18 months of
regimen versus a T regimen to evaluate the incidence ATDs treatment for GD;
of overt hypothyroidism during therapies, the number —— number of TFT during medical therapy of GD.
of euthyroid patients during 18 months of treatment,
ORIGINAL PAPER

and the number of thyroid function tests (TFT) during Secondary outcomes
therapies. Secondary outcomes are assessment of GO Secondary outcomes included:
development, body weight changes, and lipid profile —— incidence of GO development during ATDs treat-
evolution in the BRT group versus the T group. ment for GD;
—— changes in weight during medical treatment for GD;
Material and methods —— lipid profile changes during GD drug therapy.

Criteria for considering studies for this review Search methods for identification of studies

Types of studies Electronic searches

Prospective and retrospective cohort studies that met The following sources were used to identify cohort
the inclusion criteria were included in this systematic studies:
review and meta-analysis. The minimum duration of —— PubMed database (MEDLINE) — until July 2023;
therapy should be 18 months, and thyroid function —— Cochrane Library (CENTRAL) — until July 2023.
should be assessed during this period. The terms used to identify potential articles were:
“block replace”, “thyroid”, and “Graves”. The search
Types of participants was restricted to articles written in English with full
Patients with a first episode of GD following medical text available.
treatment were included. Diagnosis of GD was made
on documentation of thyrotoxicosis [suppressed Searching other resources
thyroid-stimulating hormone (TSH), increased free T4 The reference lists of retrieved papers were searched
(fT4) and/or free T3 (fT3)], positive TRAb, enlarged goiter, for additional cohort studies.
with increased vascularity or diffuse increased radioio-
dine uptake on thyroid scans. Patients aged < 18 years, Data collection and analysis
pregnant women, or patients with a positive history of
RAI or TTx were excluded. Selection of studies
Two authors independently searched the literature
Types of interventions and evaluated each record by the title and abstract of
The intervention consists of using medical therapy with the article. Articles containing patients diagnosed with
ATDs in patients with GD. We compared the number of GD on ATD treatment for a period of 18 months were
patients with overt hypothyroidism during BRT versus read in full text. Any queries regarding the criteria for
T regimen. After 18 months of therapy, we compared inclusion of certain articles in the meta-analysis were
the number of patients with stable thyroid function discussed between the authors.
in each group. We defined stable thyroid function
as: euthyroidism (TSH and fT4 in reference range), Data extraction and management
subclinical hypothyroidism (TSH > 4.5 mIU/L, fT4 in The extraction of data related to the first author, name
reference range), and subclinical hyperthyroidism of the journal, year of publication, title, and abstract
(TSH < 0.4 mIU/L, fT4 in reference range). The ATDs of the article was done automatically in Reference
used were CBZ, MMI, or PTU. BRT consisted of the ad- Manager. Two authors independently extracted the data
dition of LT4 to a high dose of thionamide. In addition, on sample size, age and sex of patients, accuracy of GD
we compared the number of GD patients who devel- diagnosis, type of intervention, duration of treatment,
oped GO during BRT versus T and the number of TFT and outcomes (number of euthyroid patients at the end
performed. of therapy, incidence of hypothyroidism during ther-

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 Endokrynologia Polska 2024; 75 (3)

apy, presence of GO among the patients, and number design or the risk of bias of each study were taken into
of TFT during therapy). Statistical analysis was done in account.
Review Manager 5.4.
Subgroup analysis and investigation
Assessment of risk of bias in the included studies of heterogeneity
Two authors independently assessed the risk of bias Subgroup analysis was not performed.
in the studies using the Newcastle-Ottawa scale
(NOS). For each answer marked with asterisk one Sensitivity analysis
point is added. The maximum score for each sec- We only included published articles written in English
tion is as follows: 4 points for Selection, 2 points that met the inclusion criteria and that we assessed for
for Comparability, and 3 points for Outcomes. risk of bias. For each outcome we statistically processed

ORIGINAL PAPER
A score higher than 7 points indicates a high qual- using both fixed-effect and random effect-models
ity of the study. Any disagreements were discussed and expressed the results in risk ratio (RR), OR, and risk
between the authors. difference.

Measures of treatment effect Results

We expressed dichotomous data as Mantel-Haenszel
(M-H) odds ratio (OR) with 95% confidence intervals Description of studies
(CI) using a random-effects model. We expressed con- The publication dates of the articles included in
tinuous variables as mean difference or adjusted mean the meta-analysis are from 2014 to the present day.
difference. One study included patients from a single center [15],
and the other study is a multicenter study, including
Dealing with missing data 10 centers from Europe [16]. Both articles included
To have complete data we chose the original studies observational cohort studies.
of each author and avoided duplicate publications.
We checked the guidelines for appropriate medi- Results of the search
cal management of GD (doses of drugs used, addition Two databases were searched, including a total
to LT4). We calculated the proportion of patients lost to of 115 studies: PubMed (MEDLINE) — 62 studies
follow-up. We estimated the number of patients with and Cochrane Library (CENTRAL) — 53 studies. An ad-
stable thyroid function during therapy using values at ditional search was done using reference lists of re-
different treatment endpoints. trieved articles. Three more studies were subsequently
added. Duplicate papers and those without full-text
Assessment of heterogeneity available or not written in English were excluded. Also,
Heterogeneity was assessed by visual inspection of articles that were not in accordance with the terms:
the forest plot and I2 calculation. An I2 value greater “block replace”, “thyroid”, or “Graves” were excluded.
than 75% indicates high heterogeneity, while a value Twenty-seven articles were sought for retrieval, and 17
less than 25% indicates low heterogeneity. For this me- of them were screened for eligibility (Fig. 1). Twelve
ta-analysis a random-effects model was used. articles [17–28], one conference paper [29], and 2 clinical
trials were excluded.
Assessment of reporting biases
Each publication was assessed for risk of bias. In addi- Included studies
tion, forest plots were inspected for their asymmetry. Only 2 articles were included in this meta-analysis
and used for data abstraction (Tab. 1). Each study had
Data synthesis 2 subgroups of patients: those who underwent BRT
We used a random-effects model to statistically process and those who underwent a T regimen of ATDs.
data from heterogeneous studies. For each outcome
the data were combined using dichotomous variables, Overview of study population
expressed as OR, with 95% CI. The two studies included 794 GD patients who com-
pleted 18 months of treatment, but only 716 patients
Quality of the evidence were included in the statistical analysis. We excluded
Two authors independently assessed the quality of 78 patients treated using both BRT and T [15]. In total,
evidence on main outcomes according to Grading 289 (40.36%) GD patients were on BRT and 427 (59.64%)
of Recommendation, Assessment, Development, GD patients were on T. Approximately 8.75% (33/377)
and Evaluations (GRADE) [14]. Factors such as study of patients were lost at follow-up [16].

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 Block-and-replace therapy versus titration Ana-Maria Stancu et al.

Identification of studies via databases and registers

Records removed before screening: Postpartum thyroiditis (n = 1)

Duplicate record removed (n = 8) Autoimmune Endocrine Disease
(n = 2)
Identification

Records identified from: Records marked as ineligible by Primary myxedema/

PubMed database (n = 62) automation tools (n = 35): /thyroidectomy (n = 2)
Cochrane Library (n = 53) PubMed database (5) + Cochrane LT4 therapy and skeletal
Total: 115 articles Library (n = 30) integrity in women (n = 1)
Beta-adrenergic blockade in
ORIGINAL PAPER

No abstract or full text available: hyperthyroidism (n = 2)

Cochrane library (n = 3) Other pathologies (n = 27)

Pregnant GD patients (n = 6)
Pediatric GD patients (n = 5)
Records excluded by title and Infants with GD (n = 2)
Records screened (n = 69):
abstract (n = 45): GD secondary to therapies (n = 2)
PubMed database (57)
PubMed database (36) + Reviews and meta-analysis (n = 14)
Cochrane Library (12)
Cochrane Library (9) Case reports (n = 9)
Survey (n = 1)
Lab tests/animal studies (n = 6)

Pediatric GD patients (n = 4)
Reports sought for retrieval Reviews (n = 3)
Screening

(n = 27): Consensus guideline (n = 1)

Reports not retrieved Full text article in Italian
PubMed database (n = 21)
(n = 10) language (n = 1)
Cochrane Library (n = 3)
Reference lists (n = 3) GD patients with block-replace
therapy excluded (n = 1)

Reports excluded:
Reports assessed for Carbimazole + T3 (n = 2)
eligibility (n = 17): Radioactive iodine/partial thyroidectomy (n = 5)
PubMed database (11) GD remission/recurrence (n = 5)
Cochrane Library (3) Inflammatory response (n = 1)
References list (3) Other causes of hyperthyroidism (n = 1)
No group control in titration regimen (n = 1)

Studies included in review (n = 2):

Included

Retrospective observational (n = 1)
Prospective observational (n = 1)

Figure 1. PRISMA chart

Study design and settings design [15], while the other had a prospective design
The 2 cohort studies included were performed between [16]. Consecutive hospitalized patients who followed
1997 and 2015. One was conducted in a retrospective ATD therapy for GD were included. Each main group

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Table 1. Characteristics of included studies

Vaidya, 2014
Study design Retrospective observational cohort study
Location: single center, Royal Devon & Exeter Hospital, United Kingdom
Period of study: 1 January 1997–31 January 2012
Inclusion criteria: Patients with GD
Diagnostic criteria: thyrotoxicosis with presence of a diffuse goiter, thyroid eye disease, positive TSH receptor
antibodies (TRAb), thyroid peroxidase antibodies (TPO-Ab) or diffuse uptake on radionuclide uptake scan
Exclusion criteria: Patients with thyrotoxicosis due to causes other than GD, GD treated with ATD < 6 months, GD

ORIGINAL PAPER
Patients treated with radioactive iodine or thyroidectomy and pregnancy
Data collection: electronic database; data from the first episode of GD; data from the first 2 years of treatment with
ATDs
No. patients: Total: 450; BRT: 223; T: 149; Both regimens: 78
Sex F/M: BRT: 178/45; T: 129/20
Age [years] (mean (SD)): BRT: 49 (15); T:49 (18)
Baseline characteristics: No statistically significant differences
BRT: CBZ + LT4
Intervention
T: CBZ/PTU
Main outcomes:
1. Stability of thyroid function during BRT versus T regimen
Outcome 2. Number of thyroid function test during BRT versus T regimen
Secondary outcome:
Changes in weight during medical treatment for GD
Study details Duration of therapy (months): BRT: 20; T: 19
Publication details Language of publication: English
Risk of bias Newcastle-Ottawa Quality Assessment Scale (NOS): 7/9
Žarković, 2020
Study design Prospective observational cohort study
Location: multicenter [10 centers of the European Group of Graves’ Orbitopathy (EUGOGO)]
Period of study: May 2009–May 2015
Inclusion criteria: Patients with untreated GH, absence of overt GO, and planned treatment with ATD for 18 months
Diagnostic criteria: GH: (1) decreased TSH, elevated fT4 and/or fT3, and (2) a diffuse thyroid gland (either by palpation or
ultrasonography) and/or homogeneous thyroid uptake at scintigraphy
GO: (1) soft tissue changes (moderate or severe eyelid/conjunctival redness, moderate or severe eyelid/periorbital
swelling); (2) proptosis above the upper normal limit (Asians 18 mm, Caucasian 20 mm, Black 22 mm); (3) diplopia
(intermittent, inconstant, or constant), (4) decreased visual acuity attributable to GO
Exclusion criteria: (A) previous or planned treatment with 131-I or thyroidectomy; (B) presence of GO; (C) drugs
Patients
interfering with the natural course of GO (e.g., glucocorticoids, cytokines, anticytokines, thiazolidinediones, selenium);
(D) drugs interfering with thyroid function (amiodarone, lithium, iodine supplements); (E) drug or alcohol abuse; (F) lack
of informed consent
Data collection: no description
No. patients: Total: 344; BRT: 66; T:278
Sex F/M: BRT: 53/13; T: 231/47
Age [years] (mean (SD)): BRT: 41.6 (14.5); T: 43.1 (12.8)
Baseline characteristics: No statistically significant differences except for overrepresentation of non-Caucasians in
the BRT group
BRT: ATD + LT4
Intervention
T: ATD

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 Block-and-replace therapy versus titration Ana-Maria Stancu et al.

Table 1. Characteristics of included studies

Main outcome:
Frequency of euthyroidism during BRT versus T regimen
Outcome
Secondary outcomes:
Development of GO during BRT versus T regimen
Duration of therapy (months): BRT: 18; T: 18
Allocated: BRT: 83; T: 305
Study details
Completed: BRT: 66; T: 278
Assessed: BRT: 66; T: 278
ORIGINAL PAPER

Publication details Language of publication: English

Risk of bias Newcastle-Ottawa Quality Assessment Scale (NOS): 7/9
GD — Graves’ disease; TSH — thyroid-stimulating hormone; ATD — anti-thyroid drug; BRT — block-and-replace therapy; T — titration; SD — standard deviation;
CBZ — carbimazole; LT4 — levothyroxine; PTU — propylthiouracil

was divided into 2 subgroups according to the ATD provided information on the number of thyroid func-
regimen used. tion tests [15], and the other on the number of patients
who developed GO during therapy [16].
Participants
Patients included in both studies had a mean age of Excluded studies
40 years. Female patients were more prevalent in both The main reasons for exclusion of studies initially con-
studies: 82.52% (307/372) [15] and 82.55% (284/344) [16]. sidered as eligible were as follows: block-and-replace
The number of current smokers was 29.36 % (101/344) in therapy consisting of the addition of T3 to ATDs [27,28],
the first study and 21.5% (80/372) in the second one. Only absence of a control group [22], assessment of risk of
one study [16] reported a higher prevalence of non-Cau- relapse of GD (short duration of therapy or no assess-
casian patients in the block-and-replace subgroup. ment of thyroid function during therapy) [18, 19, 24,
26, 30], inclusion of patients with RAI and/or TTx [20,
Diagnosis 21, 23], and hyperthyroidism of other causes or other
In both studies, the diagnosis of GD was based on primary outcomes [17, 29] (Tab. 2).
the association of hyperthyroidism (suppressed TSH,
increased fT4 and/or fT3), diffuse goiter (ultrasound/scin- Risk of bias in the included studies
tigraphy), and positive TRAb. The presence of extra-thy- The risk of bias was assessed using the Newcastle-Ottawa
roidal manifestations of GD (e.g., GO, dermopathy) at scale (NOS). Both studies scored 7/9 points, indicat-
baseline as a diagnostic criterion was included in only ing high study quality (Tab. 3).
one study [15].
Allocation
Intervention The allocation of GD patients to a particular type of
All patients included in the 2 studies were at their first epi- ATDs regimen was not mentioned in any of the studies.
sode of GD and were treated with ATDs ± LT4. Duration
of treatment was 18 months regardless of the regimen Blinding
used. One study [15] reported the use of CBZ and PTU This criterion was not applied for the type of studies
as ATDs. None of the studies described the drug doses included in the meta-analysis.
used or the method of administration. We assumed that
the doses of drugs used were in line with current guide- Incomplete outcome data
lines. Five centers used both ATDs regimens to treat GD The percentage of patients lost to follow-up dur-
patients and 6 centers used only the T regimen. ing therapy was low (8.75%) and was not taken into
consideration in the statistical analysis. In one study,
Outcomes the percentage of euthyroid patients or patients with
Both studies aimed to determine the maintenance of abnormal thyroid function during therapy was ex-
stable thyroid function during drug therapy and ex- pressed at different endpoints of treatment. We used
press the frequency of euthyroidism and overt hypo- these values to calculate an average number of patients
thyroidism over 18 months of treatment. One study with normal or abnormal thyroid function tests.

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 Endokrynologia Polska 2024; 75 (3)

Table 2. Characteristics of excluded studies ordered by reported data on lipid profile changes during medical
the name of the first author/identification name of the clinical therapy of GD.
trial
Other potential sources of bias
Study Reason for exclusion
Other potential sources of bias could be estimating
Other causes of hyperthyroidism the number of patients with stable thyroid function by
Bonnema 2011
(toxic nodular goiter)
including subclinical hypothyroidism and/or hyper-
Elbers 2011 Recurrence of GD
thyroidism. Also, the number of patients with stable
Grebe 1998 Recurrence of GD thyroid function during therapy in one study was
Kung 1994 RAI obtained by calculating an average of the number of
patients at different treatment endpoints.

ORIGINAL PAPER
Kung 1995 RAI
Lantz 2016 No group control
Effects of intervention
Laurberg 2011 RAI + partial thyroidectomy The main results of this meta-analysis are the propor-
McIver 1996 Recurrence of GD tion of patients with overt hypothyroidism and eu-
NCT02568085 thyroidism during 18 months of treatment with ATDs
Thyroidectomy
(clinical trial), 2018 using a block-and-replace regimen versus a T regimen.
Rittmaster 1996 Remission of GD
Stefanic 2014 Remission of GD
Baseline characteristics
No differences were observed between studies in terms
Rodionova 2015 Inflammatory response (level of cytokines)
of mean age of groups, proportion of female gender,
UMIN000022261 current smokers, or duration of therapy. At baseline in
RAI
(clinical trial), 2019
both studies, the mean TSH was less than 0.03 mIU/L
Wise 1973 CBZ + T3 and fT4 was 1.5 times the upper normal limit (UNL).
Wise 1979 CBZ + T3 Only one of the studies [16] included patients without
GD — Graves’ disease; RAI — radioactive iodine; CBZ — carbimazole;
GO at baseline.
T3 — triiodothyronine
Primary outcomes

Selective reporting Incidence of overt hypothyroidism

The 2 studies had a low risk of bias and reported data No statistically significant differences were observed
on thyroid function testing over 18 months of medical between the ATD regimens used in terms of incidence
treatment of GD. However, outcomes such as devel- of overt hypothyroidism during 18 months of treat-
opment of GO during therapy were not reported in ment (M-H OR: 1.54, 95% CI: 0.75–3.16, p-value = 0.24)
one study [15]. Weight gain during therapy was not (Fig. 2A). Only 8.3% (24/289) of patients treated with
reported in the other study [16]. None of the studies a block-and-replace regimen had clinical hypothyroid-

Table 3. Assessment of risk of bias. Newcastle-Ottawa scale (NOS) cohort studies used

Author, Year
NOS Vaidya, 2014 Zarkovic, 2020
Representativeness of the exposed cohort * *
Selection of the non-exposed cohort * *
Selection
Ascertainment of exposure *
Demonstration that outcome of interest was not present at start of study * *
Comparability Comparability of cohorts on the basis of the design or analysis * **
Assessment of outcome *
Outcome Was follow-up long enough for outcomes to occur * *
Adequacy of follow up of cohorts *
Total score 7/9 7/9

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 Block-and-replace therapy versus titration Ana-Maria Stancu et al.

B
ORIGINAL PAPER

Figure 2. A. Forest plot of comparison 1: Number of patients with overt hypothyroidism during 18 months of block-and-replace
therapy (BRT) versus titration (T). Main outcome: 1. Incidence of overt hypothyroidism during 18 months of medical treatment
of Graves’ disease (GD). B. Forest plot of comparison 2: Prevalence of euthyroid patients over 18 months of BRT versus T.
Main outcome: 2. Prevalence of euthyroid patients over 18 months of anti-thyroid drugs (ATDs) treatment for GD. C. Forest
plot of comparison 3: Incidence of GO development during medical treatment. Secondary outcome: 1. Incidence of GO
development during ATDs treatment for GD. D. Forest plot of comparison 4: Incidence of GO development during medical
treatment. Secondary outcome: 1. Incidence of GO development during ATDs treatment for GD. BRT — block-and-replace
therapy; CI — confidence interval; M-H — Mantel-Haenszel odds ratio

ism, compared to 3.98% (17/427) of patients on the titra- formed on average 3.2 ± 1.2 thyroid function tests per
tion (T) regimen. year, while patients on the T regimen required 3.4 ± 1.5
tests per year (adjusted mean difference –0.4, 95% CI:
Prevalence of euthyroidism –0.7; –01, p = 0.008) [15].
GD patients who followed a block-and-replace therapy
were less likely to achieve control of thyroid function Secondary outcomes
than patients on a titration regimen (M-H OR: 0.55,
95% CI: 0.34–0.88, p = 0.01) (Fig. 2B). In this statistical Incidence of GO development during ATD
analysis, all patients who achieved euthyroidism, or treatment
subclinical hypo- or hyperthyroidism were considered We assumed that both studies included at baseline GD
to have obtained control of overt hyperthyroidism due patients without GO. No statistically significant differ-
to GD. ence in terms of incidence of GO development during
BRT versus T regimen was observed (M-H OR: 1.18,
Number of TFT during medical therapy 95% CI: 0.20–7.06, p = 0.86) (Fig. 2C).
The number of TFT was assessed in one study dur- If only the study that specified no GO at baseline
ing medical treatment of GD. Patients on BRT per- is included in the analysis, then the incidence of GO

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 Endokrynologia Polska 2024; 75 (3)

during BRT was lower than in the T regimen (9.1% erature, where BRT can be considered for patients
versus 17.8%), with no statistically significant differ- with fluctuating thyroid disease [32]. Lewandowski et
ence between the 2 regimens (M-H OR: 0.47, 95% CI: al. described an atypical onset of GD with myocardial
0.19–1.14, p = 0.10) (Fig. 2D). infarction in a 31-year-old woman. She achieved con-
trol of hyperthyroidism using BRT [33]. It may also be
Changes in weight during medical treatment suitable for patients with difficult access to healthcare
Only one study assessed weight gain during BRT versus due to the reduced number of thyroid function tests
T regimen, which was greater in the former group, but during therapy [15, 31].
not significantly. The adjusted mean difference between GO development during BRT compared to T regi-
the groups was 1.6 kg (95% CI: –0.3–3.5, p = 0.09) [15]. men was evaluated in a single study. The incidence of
GO was lower in the group treated with BRT than in

ORIGINAL PAPER
Lipid profile changes during GD therapy the T group, but the difference was not statistically
No data regarding the evolution of lipid profile significant [15]. No other studies were found to assess
during medical treatment of GD were included in the occurrence of GO during different ATD regimens.
the studies. The other study did not report on the proportion of pa-
tients with GO at baseline. However, more patients with
Subgroup analyses extra-thyroidal manifestations were treated with BRT. In
Subgroup analysis was not performed. the BRT group, 15.5% of patients had GO and 2.8% of
patients had dermopathy, compared to 6.3% and 1.4%
Sensitivity analyses in the T group [16]. The combined results of these stud-
Sensitivity analysis was performed only for one ies have a very low quality of evidence. Further research
outcome (development of GO) by excluding articles is needed to assess whether BRT could be a protective
not mentioning the absence of GO at baseline. factor in GO development.
We found no studies comparing the effects of differ-
Assessment of reporting bias ent ATDs regimens used in GD on metabolism.
Both studies were assessed as low risk of bias in terms
of primary outcomes. Summary of main results
BRT and T regimens have the same effectiveness in
Discussion avoiding overt hypothyroidism during treatment.
BRT could offer a stable thyroid function with fewer
Summary of outcomes and quality of evidence thyroid function tests during therapy than the T regi-
Two observational cohort studies were included in men.
this meta-analysis. Participants were following either BRT could be more suitable for complicated GD
a BRT or T regimen to treat GD hyperthyroidism. No than the T regimen.
differences in the incidence of overt hypothyroid- This meta-analysis is assessed overall as having a low
ism were observed between the 2 regimens. None to very low quality of evidence.
of the studies mentioned the doses of drug used.
In a systematic review by Abraham et al. CBZ was Potential bias in the review process
used in dose ranges between 30 and 60 mg per day One of the limitations of this study relates to the small
and only in one study up to 100 mg per day [10]. number of articles included. Unpublished data were
Current guidelines recommend CBZ 40 mg/day, not included. Articles written in languages other than
MMI 30 mg/day, or PTU 50–150 mg 3 times daily as English were also not included.
the starting dose [6, 31].
There was a lower probability of achieving stable Agreements and disagreements with other studies
thyroid function using BRT compared to the T regi- or reviews
men. This result has low GRADE quality evidence, To our knowledge there are no other publications
and further research is needed. One reason is that comparing the incidence of overt hypothyroidism
the number of patients considered to have stable and GO development in GD patients using different
thyroid function was estimated and included patients ATD regimens.
with euthyroidism and subclinical hypo- or hyperthy-
roidism. The second reason is that in the retrospective Conclusion
cohort study there were more patients at baseline with
complicated GD in the BRT group than in the T-reg- Although initially controversial, block-and-replace
imen group. This is consistent with studies in the lit- therapy is now more and more accepted as being in-

325
 Block-and-replace therapy versus titration Ana-Maria Stancu et al.

dicated for selective categories of patients diagnosed 12. Abraham P, Avenell A, McGeoch SC, et al. Antithyroid drug regimen
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Conflict of interest roxine in treated Graves’ disease. Effects on the level of antibodies
Authors declare no conflict of interest. to thyroid-stimulating hormone receptors and on the risk of recur-
rence of hyperthyroidism. N Engl J Med. 1991; 324(14): 947–953,
doi: 10.1056/NEJM199104043241403, indexed in Pubmed: 1900575.
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Publication of this paper was supported by the University of Medi- of evidence in environmental and occupational health. Environ Int.
2016; 92-93: 611–616, doi: 10.1016/j.envint.2016.01.004, indexed in
cine and Pharmacy Carol Davila through the institutional program
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610–613, doi: 10.1111/cen.12478, indexed in Pubmed: 24801484.

A.M.S. and C.B. independently searched the literature and evalu- 16. Žarković M, Wiersinga W, Perros P, et al. EUGOGO (European Group
ated each article. A.M.S. performed the statistical analysis and wrote on Graves’ Orbitopathy). Antithyroid drugs in Graves’ hyperthyroid-
the article. C.B. supervised the writing of the article. Both authors ism: differences between “block and replace” and “titration” regimes in
reviewed and approved the final draft. frequency of euthyroidism and Graves’ orbitopathy during treatment.
J Endocrinol Invest. 2021; 44(2): 371–378, doi: 10.1007/s40618-020-01320-7,
indexed in Pubmed: 32524368.
Funding 17. Bonnema SJ, Grupe P, Boel-Jørgensen H, et al. A randomized trial
evaluating a block-replacement regimen during radioiodine therapy.
This work was co-financed by the European Social Fund through Eur J Clin Invest. 2011; 41(7): 693–702, doi: 10.1111/j.1365-2362.2010.024
the Operational Program, project number POCU/993/6/13/154722. 52.x, indexed in Pubmed: 21175612.
18. Elbers L, Mourits M, Wiersinga W. Outcome of very long-term
treatment with antithyroid drugs in Graves’ hyperthyroidism as-
Disclosures sociated with Graves’ orbitopathy. Thyroid. 2011; 21(3): 279–283,
None declared. doi: 10.1089/thy.2010.0181, indexed in Pubmed: 21190446.
19. Grebe SK, Feek CM, Ford HC, et al. A randomized trial of short-term
treatment of Graves’ disease with high-dose carbimazole plus thyroxine
Data availability versus low-dose carbimazole. Clin Endocrinol (Oxf). 1998; 48(5): 585–592,
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20. Kung AW, Yau CC, Cheng A. The incidence of ophthalmopathy
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