ORIGINAL ARTICLE

E n d o c r i n e C a r e

Comparative Effectiveness of Therapies for Graves’

Hyperthyroidism: A Systematic Review and Network
Meta-Analysis

Vishnu Sundaresh,* Juan P. Brito,* Zhen Wang, Larry J. Prokop, Marius N. Stan,
Mohammad H. Murad, and Rebecca S. Bahn
Divisions of Geriatrics and Primary Care Internal Medicine (V.S.); Endocrinology, Diabetes, Metabolism,

Downloaded from https://academic.oup.com/jcem/article/98/9/3671/2833150 by guest on 29 April 2022

and Nutrition (J.P.B., M.N.S., R.S.B.); Preventive Medicine (Z.W., M.H.M.); and Library Public Services
(L.J.P.), Mayo Clinic, Rochester, Minnesota 55905

Context: Several treatment options are available for Graves’ disease (GD), including antithyroid
drugs (ATDs), radioactive iodine (RAI), and thyroidectomy.

Objective: The primary outcome was to determine the relapse rates of various treatment options.
The secondary outcome was to present data regarding adverse effects of ATDs.

Data Sources: We searched multiple databases through March 2012.

Study Selection: Eligible studies were randomized clinical trials and comparative cohort studies in
adults that included 2 or more treatment options for GD.

Data Extraction: Two reviewers independently selected studies, appraised study quality, extracted
outcome data, and determined adverse effect profiles.

Data Synthesis: We found 8 studies with 1402 patients from 5 continents. Mean follow-up duration
in months was: ATDs, 57; RAI, 64; and surgery, 59. Studies were at moderate to high risk of bias. Network
meta-analysis suggested higher relapse rates with ATDs (52.7%; 352 of 667) than RAI (15%, 46 of 304)
(odds ratio ⫽ 6.25; 95% confidence interval, 2.40 –16.67) and with ATDs than surgery (10%; 39 of 387)
(odds ratio ⫽ 9.09; 95% confidence interval, 4.65–19.23). There was no significant difference in relapse
between RAI and surgery. Examination of 31 cohort studies identified adverse effects of ATDs in 692
of 5136 (13%) patients. These were more common with methimazole, mainly owing to dermatological
complications, whereas hepatic effects were more common with propylthiouracil use.

Conclusion: We confirm the relatively high relapse rate of ATD therapy in comparison with RAI or
surgery, along with a significant side effect profile for these drugs. These data can inform discussion
between physicians and patients regarding the choice of therapy for GD. The limited quality of the
evidence in the literature underlines the need for future randomized clinical trials in this area.
(J Clin Endocrinol Metab 98: 3671–3677, 2013)

raves’ disease (GD) is an autoimmune condition de-
G fined by overproduction of thyroid hormones due to
unregulated stimulation of the thyroid by circulating TSH
receptor antibodies (1, 2). It is the most common form of
hyperthyroidism in the United States (3), and if left untreated
results in increased morbidity and mortality (4) mainly due to
cardiovascular (atrial fibrillation, heart failure, pulmonary
hypertension, angina pectoris, and stroke) (5) and skeletal
(osteoporosis)complications.Therefore,timelymanagementof
overthyperthyroidismisofutmostimportance.Inaddition,GD
has a negative long-term influence on the quality of life, due to
either the disease process itself or its treatment (4).
Treatment options for GD are aimed at inducing per-
manent hypothyroidism (radioactive iodine [RAI] therapy

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
Received April 12, 2013. Accepted June 25, 2013.
First Published Online July 3, 2013
* V.S. and J.P.B. have contributed equally to the manuscript.
Abbreviations: ATD, antithyroid drug; CBZ, carbimazole; CI, confidence interval; GD,
Graves’ disease; MMI, methimazole; OR, odds ratio; PTU, propylthiouracil; RAI, radioactive
iodine; RCT, randomized clinical trial.

doi: 10.1210/jc.2013-1954 J Clin Endocrinol Metab, September 2013, 98(9):3671–3677 jcem.endojournals.org 3671
3672 Sundaresh et al Effectiveness of Graves’ Disease Therapies J Clin Endocrinol Metab, September 2013, 98(9):3671–3677

and thyroidectomy) followed by thyroid hormone re- Study selection

placement or restoring euthyroidism while awaiting res-
olution of the autoimmune process and disease remission
(antithyroid drugs [ATDs]—methimazole [MMI], propy-
lthiouracil [PTU], carbimazole [CBZ]). Beta blockers are
used in combination with any of the above therapies to
ameliorate the symptoms of hyperthyroidism. Selection of
therapy is challenging for both patient and physician be-
cause each of the 3 modalities has been established as an
effective treatment strategy with unique individual fea-
tures. The recently published guidelines for the manage-
ment of hyperthyroidism stress the importance of active
Two reviewers (J.P.B., V.S.) working independently screened
titles and abstracts. Full-text articles obtained from initial screen-
ing were retrieved for second-stage screening. Chance-adjusted
inter-reviewer agreement was substantial (␬ statistic ⫽ 0.9), and
discrepancies were resolved through discussion with R.S.B. and
M.N.S.
Data extraction
The main outcome of interest was relapse of GD, which was
defined as the recurrence of hyperthyroidism after at least 12
months of treatment with ATDs, one dose of RAI, or first thy-
roidectomy. Disease recurrence was chosen as the main outcome
because its avoidance would represent to the physician effective

Downloaded from https://academic.oup.com/jcem/article/98/9/3671/2833150 by guest on 29 April 2022

discussion between patient and physician regarding the
risks, benefits, and logistics of the various treatment op-
tions, taking into consideration the values and preferences
of the patient (6). A better understanding of the favorable
and unfavorable characteristics of each option will facil-
itate this discussion and lead to high-quality shared deci-
sion-making. We therefore performed the first systematic
review and network analysis of randomized and observa-
tional studies to summarize the available evidence in
adults with GD undergoing treatment and to determine
the quality of evidence available in the literature support-
ing the efficacy of the available therapies. In addition, we
report the adverse effect profile of ATDs extracted from
cohort studies evaluating the use of ATDs alone.
therapy and “cured” disease. The two reviewers (J.P.B., V.S.)
independently reviewed each eligible study (each study included
in the analysis was reviewed in duplicate). A pilot-tested form
was used to extract the following information: demographic in-
formation, goiter size, type of treatment, treatment duration for
ATD, follow-up duration, type of surgery (total, subtotal, or
near-total thyroidectomy), number and dose of RAI treatment,
and number of patients with relapse. In addition, we reviewed all
cohort studies of ATD therapy identified in our initial search of
the literature to identify those listing adverse effects.
Quality assessment
Two reviewers (J.P.B., V.S.) working in duplicate assessed the
methodological quality of studies selected for the meta-analyses.
The Newcastle-Ottawa scale (8) was used for observational stud-
ies, and elements from the Cochrane risk of bias tool (9), includ-
ing allocation concealment, blinding, and loss of follow-up, were
utilized for RCTs.

Materials and Methods Data synthesis

This systematic review complies with the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-analyses)
statement (7).
Study eligibility
Studies eligible for this review were randomized clinical trials
(RCTs) and observational cohort studies. There was no language
restriction. We searched publications that involved adult pa-
tients (18 y and older) with the diagnosis of GD and compared
treatments with at least two of the following interventions: 1)
ATDs (MMI, CBZ, or PTU); 2) RAI; and 3) thyroidectomy.
Random effects meta-analysis models were constructed to
pool odds ratios (ORs) from direct comparisons using the
method of DerSimonian and Laird (10), with the estimate of
heterogeneity being taken from the Mantel-Haenszel model. We
used the I2 statistic and Cochran’s Q test to assess heterogeneity
across individual studies. We then conducted network meta-
analyses to combine direct and indirect evidence, using Lumley’s
generalized linear mixed models (11). A network meta-analysis
Records identified through Additional records identified
database searching through reference listst from
(n=3,274) retrieved articles (n=11)

Data sources and search strategies Records screened Records excluded by title and
We conducted a comprehensive search of databases from da- (n=3,285) abstracts (n=3,116)

tabase inception to March 2012. The following databases were

included: Ovid Medline In-Process & Other Non-Indexed Cita- Studies excluded (n=130)
tions, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Data- • Not RCTs or observational
studies (n=17)
base of Systematic Reviews, Ovid Cochrane Central Register of Studies used to
Full-text articles • Did not include selected
Controlled Trials, and Scopus. The search strategy was jointly extract adverse
assessed for interventions (n=108)
effects only
li ibilit (n=169)
eligibility ( 169)
designed by an experienced librarian (L.J.P.) and two of the in- (n=31) • Did not report the selected
outcomes (n=4)
vestigators (J.P.B., V.S.). Controlled vocabulary supplemented • Did not included selected
with keywords was used to search for the concepts GD, thyro- age group (n=1)

toxicosis, RAI, thyroidectomy, MMI, CBZ, PTU, and ATD ef- Studies included in the
fectiveness and adverse effects, limited to controlled trials and meta analyses
meta-analyses
(n=8) 7 English, 1 Spanish
cohort studies. The detailed research strategy is available upon
request. Figure 1. Study selection process.
doi: 10.1210/jc.2013-1954 jcem.endojournals.org 3673

Table 1. Detailed Description of Included Studies

ATDs RAI Surgery

Duration of Follow-Up Follow-Up Follow- Up

Total, Relapse, Therapy, Duration, Total, Relapse, Mean Dose Duration, Total, Relapse, Duration, Type of
Study Country n n (%) mo mo n n (%) of RAI, mCi mo n n (%) mo Surgery

Alizadeh, 1979 (21) United NR NR NR NR 11 0 (0) 8.56 36.6 11 4 (36) 43 NR

States
Sugrue, 1980 (22) Ireland 272 153 (56) 24 60 43 1 (2) 7.45 60 266 16 (6) 60 NR
Berglund, 1991 (23) Sweden 83 36 (43) 20 21 106 5 (5) NR 36 23 2 (9) 17 Subtotal
thyroidectomy
Mengistu, 1992 (24) Ethiopia 47 3 (6) 24 11 NR NR NR NR 6 1 (17) 36 NR
Torring, (old cohort) Sweden 35 12 (34) 18 30 39 15 (38) 6.8 48 37 3 (37) 42 Subtotal
1996 (13) thyroidectomy
Torring (young cohort) Sweden 25 10 (40) 18 30 NA NA NA NA 28 1 (4) 48 Subtotal

Downloaded from https://academic.oup.com/jcem/article/98/9/3671/2833150 by guest on 29 April 2022

1996 (13) thyroidectomy
Pineda, 1998 (25) Chile 88 58 (66) 6 – 48 NR 70 6 (9) 12.6 NR 37 2 (5) NR NR
Leary, 1999 (26) Ireland 74 50 (68) 18 –24 NR 38 10 (26) 7.5 NR 5 1 (20) NR Subtotal
thyroidectomy
Tutuncu, 2006 (27) Turkey 43 15 (35) 18 52 7 0 (0) 8.1 75 6 0 (0) 40 Subtotal
thyroidectomy

Abbreviations: NR, not reported; NA, not applicable.

approach provides estimates of effects sizes for all possible pair-
wise comparisons, whether or not they have been compared in
previous trials (12). We evaluated the agreements of indirect
comparisons, also called “incoherence,” and incorporated inco-
herence in the calculation of confidence interval (CI) of the
pooled OR. Data from direct evidence and network meta-anal-
yses were presented together and compared for consistency. Sta-
tistical analyses were completed using STATA version 12 (Stata-
Corp) and R version 2.15.0 (R Foundation for Statistical
Computing).
Results
Eight studies were eligible for the main outcome analysis:
1 RCT, and 7 comparative cohort studies (Figure 1). These
studies involved a total of 1402 patients (667 in the ATD
group, 314 patients in the RAI group, and 419 patients in
the surgical group). The dose of RAI used was included in
6 of 8 studies and was a mean of 8.5 mCi (range, 6.8 to
12.6). Mean follow-up duration was 57, 64, and 59
months for ATDs, RAI, and surgery, respectively. The
overall relapse rate was 52.7% (352 of 667) for ATD,
15% (46 of 304) for RAI, and 10% (39 of 387) for surgery.
The studies were conducted in the following countries:
United States, 1; Chile, 1; Ethiopia, 1; Ireland, 2; Sweden,
2; and Turkey, 1 (Table 1).
Methodological quality
The 7 observational studies included in our analysis
were of low quality and subject to high risk of bias (Table 2).
The primary limitation of these studies was a lack of com-
parability of cohorts regarding goiter size, gender, age,
and degree of hyperthyroidism. In the only RCT (13), in-
tention to treat analysis was not performed but allocation
concealment was properly described. Due to the limited
number of studies included, we were unable to test pub-
lication bias (14).
Network analysis
Eight studies were included in the analysis (Table 2).
For the primary outcome, both direct and indirect esti-

Table 2. Quality Assessment of Included Studies

Comparability of
the Cohorts Sufficient
Follow-Up for
Representative Goiter Degree of Assessment Outcomes
First Author, Year (Ref) Study Design of Cohorts Size Gender Age Hyperthyroidism of Outcome to Occur
Alizadeh, 1979 (21) Historical cohort No Unclear Unclear Unclear Yes Records linkage Yes
Sugrue, 1980 (22) Historical cohort No Unclear Unclear Unclear Unclear Records linkage Yes
Berglund, 1991 (23) Historical cohort No Unclear No No Unclear Records linkage Yes
Mengistu, 1992 (24) Concurrent cohort Yes Unclear Unclear Unclear Unclear Records linkage Yes
Pineda, 1998 (25) Historical cohort Yes No Yes No Yes Records linkage Yes
Leary, 1999 (26) Historical cohort Yes Unclear Unclear Unclear Unclear Records linkage Yes
Tutuncu, 2006 (27) Concurrent cohort No Unclear Unclear Unclear Unclear Records linkage Yes
Torring, 1996 (13) Randomized clinical trial NA Blinding Intention to treat analysis Allocation Funding
concealment
No No Yes Nonprofit

Abbreviation: NA, not available.

3674 Sundaresh et al Effectiveness of Graves’ Disease Therapies J Clin Endocrinol Metab, September 2013, 98(9):3671–3677

Table 3. Estimates of Direct and Indirect Comparisons

Direct Network

Comparisons OR 95% CI P Value OR 95% CI P Value

ATD:RAI 6.33 2.40, 16.67 ⬍.01 6.13 3.27, 11.49 .01
ATD:surgery 9.43 4.65, 19.23 ⬍.01 9.80 5.13, 20.00 .01
RAI:surgery 1.53 0.64, 3.65 .34 1.60 0.81, 3.18 .27

mates suggested higher relapse rates with ATDs than RAI adverse effect of MMI was rash (6%; 239 of 3969). He-
(OR ⫽ 6.25; 95% CI, 2.40 –16.67; I2 ⫽ 81%) and with patic involvement was more common with PTU (2.7%; 27
ATDs than surgery (OR ⫽ 9.09; 95% CI, 4.65–19.23; I2 of 983) (Figure 3). Twelve events among 184 patients were
⫽ 42%) (Table 3). There was no significant difference in not specified as to the type of ATD used.

Downloaded from https://academic.oup.com/jcem/article/98/9/3671/2833150 by guest on 29 April 2022

relapse between RAI and surgery. We did not find large
incoherence in the network (␻ ⬍ 0.001). Forest plots de-
picting the results of random effects meta-analysis are pre- Discussion
sented in Figure 2.
We conducted a systemic review and network analysis of
A search of observational studies describing adverse
the three therapeutic options for the treatment of Graves’
effects of ATD therapy yielded 31 reports in which 660 of
hyperthyroidism to inform the patient-physician discus-
5136 (13%) patients experienced events (MMI, 505 of
sion regarding choice of therapy and to determine the
3969 patients [14.9%]; and PTU, 68 of 983 patients
quality of evidence available in the literature supporting
[6.9%]; OR ⫽ 2.3; 95% CI, 1.8- 3.06). The predominant
the efficacy of these therapies. Clin-
ATDs vs surgery
ical experience demonstrates that all
Author, year OR (95% CI) Weight (%)
Sugrue, 1980 13.73 (8.65, 21.79) 30.22 two modalities successfully elimi-
Berglund, 1991 8.04 (1.77, 36.55) 13.40 nate hyperthyroidism. However, the
Mengistu, 1992 0.34 (0.03, 3.93) 6.75
Torring 1996
Torring, 5 91 (0.50,
5.91 (0 50 23.30)
23 30) 15 06
15.06 comparative effectiveness of these
Torring, 1996 18.00 (2.10, 154.58) 8.25 treatments, as characterized by re-
Pineda, 1998 33.83 (7.61, 150.36) 13.65
Leary, 1999 8.33 (0.88, 78.65) 7.72 lapse rates, is demonstrated in the lit-
Tutuncu, 2006 7.07 (0.37, 134.03) 4.96 erature only by low-quality evi-
q
Overall ((I-squared = 41.6%, P=0.101)) 9.45 ((4.66, 19.17)) 100.0
Note: Weights are from random effects analysis dence. As expected, we found ATDs
to have a higher relapse rate than ei-
0.01 0.1 1 10
ATD is better Surgery is better ther RAI therapy or thyroidectomy,
ATD vs RAI
ATDs
with the latter two therapies having
Author, year OR (95% CI) Weight (%)
Sugrue, 1980 6.10 (2.81, 13.24) 19.39 no significant difference in relapse
Berglund, 1991 15.47 (5.71, 41.95) 17.94 rates. It is important to note that the
Torring, 1996 0.93 (0.32, 2.16) 18.2
Pineda, 1998 20.62 (8.01, 53.10) 18.29 most “effective” therapy from the
Leary 1999
Leary, 5 83 (2.44,
5.83 (2 44 13.93)
13 93) 18 78
18.78 physician’s perspective both elimi-
Tutuncu, 2006 8.16 (0.44, 152.59) 7.35
Overall (I-squared = 81.2%, P=0.000) 6.35 (2.40, 16.77) 100.00 nates hyperthyroidism and prevents
Note: Weights are from random effects analysis its recurrence. In fact, the goal of
0.01
0 0 0.1
0 1 10
0 both RAI and thyroidectomy is to
ATD is better RAI is better
render the patient hypothyroid such
RAI vs surgery that lifelong thyroid hormone re-
Author, year OR (95% CI) Weight (%)
Alizadeh, 1979 0.07 (0.00, 1.55) 6.58 placement is necessary. In contrast,
Sugrue 1980
Sugrue, 19 2 25 (0
2.25 (0.98,
98 55.17)
17) 26 69
26.69 patients may well desire a treatment
Berglund, 1991 0.52 (0.09, 2.86) 14.99
Torring, 1996 7.08 (1.85, 27.19) 19.16 that has the potential to allow their
Pineda, 1998 1.64 (0.31, 8.56) 15.54 thyroid to resume normal function-
Leary, 1999 1.43 (0.14, 14.35) 10.15
Tutuncu, 2006 0.86 ((0.04, 16.85)) 6.88 ing. In this sense, ATDs carry an ad-
Overall (I-squared = 44.6%, P=0.094) 1.53 (0.64, 3.65) 100.00 vantage over surgery and RAI that
Note: Weights are from random effects analysis
was not captured in our comparative
0.01 0.1 1 10
effectiveness data.
RAI is better Surgery is better
The mean dose of RAI was 8.5
Figure 2. Random effect meta-analysis of the included studies comparing risk relapse rates
among the 3 interventions. Vertical lines indicate no risk difference; squares and horizontal lines mCi (range, 6.8 to 12.6). Dosing was
indicate OR and associated 95% CI for each study; diamonds indicate pooled OR. mainly based on goiter size and RAI
doi: 10.1210/jc.2013-1954
Metallic taste
Elevated liver
enzyme
Leucopenia
Nausea
Arthralgia
Pruritus
PTU
MMI
Rash
Any
15.0
% ing the increased risk of bias inherent in the included co-
Figure 3. Adverse effects documented in studies reviewed, with
percentage of total attributed to individual adverse effects.
uptake. In addition, 1 study incorporated age, gender, and
clinical severity in dose determinations, whereas in an-
other, dosing was empirical. The relatively low doses of
RAI used in these studies may be explained by the inclu-
sion of patients from iodine-deficient countries that tend
to have higher RAI uptake, by advice given to some pa-
tients to follow a low-iodine diet before RAI therapy or by
the goal of RAI in some practices being to achieve euthy-
roidism rather than to render the patient hypothyroid as
recommended in recent guidelines (6).
Full understanding of the consequences of the two
treatments includes a discussion between physician and
patient regarding the adverse effects of each modality. Un-
fortunately, adverse effects were not reported consistently
across the included studies. Therefore, we selected other
observational studies of ATDs to estimate the adverse ef-
fects of these agents and used landmark studies to discuss
the adverse effects of RAI therapy and thyroidectomy. We
found a significant rate of adverse effects for ATDs (13%)
reported in 31 observational studies involving medical
therapy alone. The predominant adverse effect of MMI
was rash (6%), and that of PTU was hepatic involvement
(2.7%) (Figure 3). Individual studies in the literature sug-
gest that the most common adverse effect of RAI therapy
is new or worsened Graves’ ophthalmopathy, which may
develop in 15–33% of patients, particularly smokers (15,
16). Another complication of RAI therapy is radiation
thyroiditis, occurring in about 1% of the patients (17).
Potential complications of thyroidectomy (either total
or subtotal) include hypoparathyroidism (temporary,
22.5%; permanent, 1.8%), recurrent laryngeal nerve in-
jury (temporary, 3.3%; permanent, 1.24%), and imme-
diate postoperative bleeding (1%) (18). Four among the 8
studies in our analysis specified the type of surgery per-
formed, which was subtotal thyroidectomy in every in-
stance. Because total thyroidectomy has become the stan-
dard of care in the last decade (6), it would be most
meaningful to discuss with the patient the potential
complications of total thyroidectomy alone. The same
jcem.endojournals.org 3675
meta-analysis (18) also reported the complications of
total thyroidectomy to be hypoparathyroidism (tempo-
rary, 32.5%; and permanent, 2.6%), recurrent laryngeal
nerve injury (temporary, 3.43%; and permanent, 1.46%),
and immediate postoperative bleeding (⬍1%). Because
these complications are operator dependent, individual
surgeons should discuss their own complication rates
while counseling their patients.
Our study has limitations, perhaps the primary one be-
hort studies. We identified only a single RCT; the remain-
ing studies were observational. In addition, the number of
Downloaded from https://academic.oup.com/jcem/article/98/9/3671/2833150 by guest on 29 April 2022
included studies and enrolled patients was small, affecting
the precision of our estimates. We also had limited infor-
mation concerning the size of thyroid gland, severity of
hyperthyroidism, or other predefined factors (dose of
ATD and extent of thyroid surgery) needed to conduct
subgroup analysis and explore the effect of important co-
variates. Our strengths stem from the clinical relevancy of
the question at hand, preplanned analysis, extensive lit-
erature search, reproducible duplicate data extraction and
collection, and greater generalizability of the results be-
cause our studies originated from five different countries
and six continents reflecting various races and ethnic pop-
ulation groups. Our network model also had low hetero-
geneity and appeared consistent.
Our search of the literature did not identify other ex-
isting network meta-analyses evaluating the comparative
effectiveness of the three treatment options for Graves’
hyperthyroidism in adults. The most recent systematic re-
view focusing on the best definitive treatment for GD re-
ported surgery to be 3.44 times more likely to be successful
than RAI (P ⬍ .001) (19). In that review, total thyroidec-
tomy was 95.45 times more successful than RAI, whereas
subtotal thyroidectomy was only 2.33 times more success-
ful than RAI (P ⬍ .001). The search strategy differed from
our own in that it was limited to studies published between
2001 and 2011, it did not compare ATDs, and a network
analysis was not performed.
The recently published guidelines for management of
hyperthyroidism by the American Thyroid Association
and the American Association of Clinical Endocrinolo-
gists have simplified the clinical decision-making process
(6). Factors that favor a particular modality as treatment
in the presence of limitations to the other therapies have
been well detailed. For example, a 44-year-old executive
concerned about insomnia with limited time for future
visits will value a treatment that offers the fastest resolu-
tion of symptoms and might opt for thyroid surgery per-
formed by a high-volume surgeon. A 35-year-old opera
singer concerned about the possible postoperative damage
to her voice and the need for lifelong thyroid replacement
3676 Sundaresh et al Effectiveness of Graves’ Disease Therapies
may opt for ATD therapy. Finally, the guidelines weave in
2 essential concepts: 1) the importance of careful discus-
sion between patient and physician; and 2) the need to
include the values and preferences of the patient in shared
decision-making. The treating physician is advised to dis-
cuss the available treatment options in light of the indi-
vidual patient’s medical status and preferences. Issues to
be discussed include advantages, drawbacks, potential ad-
verse effects, expected time to recovery, local availability
of expertise, financial implications, time away from work,
impact on social life in the immediate post-treatment pe-
riod, and longer-term quality of life issues. Once the pa-
tient understands the information and is able to partici-
pate in the decision-making process, the physician’s best
clinical judgment, coupled with the values and preferences
of the patient, will allow for optimum treatment selection.
In some instances, patients’ hyperthyroid state will impair
rational decision-making (20). In these cases, a good ap-
proach might be to treat the patient with ATDs until eu-
thyroid and discuss the option of long-term ATD therapy
or to pursue 1 of the definitive treatment strategies.
Decisions made by patients reflect information pre-
sented to them by their treating physician and perhaps also
information obtained from the internet and family/
friends. In a recent international survey of endocrinolo-
gists, the preferred treatment for an illustrative case of
uncomplicated GD was ATDs (53.9%), RAI therapy
(45%), and thyroidectomy (0.7%) (28).
These data suggest that individual physicians carry their
own biases concerning optimum therapy and that there is no
general consensus among physicians. Given this, it is partic-
ularly important for the physician to present the treatment
options fairly and involve the patient in the decision-making
process. An opportunity lies in the development of a state-
of-the-art risk communication tool for GD that could be used
by the physician to elicit the patient’s values and preferences
and by the patient for clarification of the risks and benefits of
each option.
In conclusion, high-quality evidence quantifying and
comparing the relapse rates and adverse effects of the var-
ious treatment options for GD is unavailable in the liter-
ature and warrants study in the setting of RCTs. The ob-
jective information gained from this meta-analysis can be
used to facilitate discussions between physician and pa-
tient concerning optimum choice of therapy for Graves’
hyperthyroidism.
Acknowledgments
Address all correspondence and requests for reprints to: Rebecca
S. Bahn, MD, Division of Endocrinology, Diabetes, Metabolism,
J Clin Endocrinol Metab, September 2013, 98(9):3671–3677
and Nutrition, Mayo Clinic, 200 First Street SW, Rochester,
Minnesota 55902. E-mail: bahn.rebecca@mayo.edu.
This publication was made possible by CTSA Grant UL1
TR000135 from the National Center for Advancing Transla-
tional Sciences, a component of the National Institutes of Health
(NIH). Its contents are solely the responsibility of the authors and
do not necessarily represent the official view of NIH.
Disclosure Summary: The authors have nothing to disclose.
References
1. Davies TF, Ando TA, Lin R-Y, et al. Thyrotropin-receptor-associ-
Downloaded from https://academic.oup.com/jcem/article/98/9/3671/2833150 by guest on 29 April 2022
ated diseases: from adenomata to Graves’ disease. J Clin Invest.
2005;115:1972–1983.
2. Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the patho-
genesis of Graves’ disease and ophthalmopathy. Endocr Rev. 2003;
24:802– 835.
3. Brent GA. Clinical practice. Graves’ disease. N Engl J Med. 2008;
358:2594 –2605.
4. Abraham-Nordling M, Torring O, Hamberger B, et al. Graves’ dis-
ease: a long-term quality-of-life follow up of patients randomized to
treatment with antithyroid drugs, radioiodine, or surgery. Thyroid.
2005;15:1279 –1286.
5. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system.
N Engl J Med. 2001;344:501–509.
6. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other
causes of thyrotoxicosis: management guidelines of the American
Thyroid Association and American Association of Clinical Endo-
crinologists. Endocr Pract. 2011;17:456 –520.
7. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA state-
ment. PLoS Med. 2009;6:e1000097.
8. Wells GA, Shea B, O’Connell D, et al. The Newcastle–Ottawa Scale
(NOS)forassessingthequalityofnonrandomisedstudiesinmeta-analyses.
http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. (Ac-
cessed July 9, 2013).
9. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Col-
laboration’s tool for assessing risk of bias in randomised trials. BMJ.
2011;343:d5928.
10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control
Clin Trials. 1986;7:177–188.
11. Lumley T. Network meta-analysis for indirect treatment compari-
sons. Stat Med. 2002;21:2313–2324.
12. Mills EJ, Ioannidis JP, Thorlund K, Schunemann HJ, Puhan MA,
Guyatt GH. How to use an article reporting a multiple treatment
comparison meta-analysis. JAMA. 2012;308:1246 –1253.
13. Torring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism:
treatment with antithyroid drugs, surgery, or radioiodine—a pro-
spective, randomized study. Thyroid Study Group. J Clin Endocri-
nol Metab. 1996;81:2986 –2993.
14. Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR. Empirical
assessment of effect of publication bias on meta-analyses. BMJ.
2000;320:1574 –1577.
15. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy
for hyperthyroidism and the course of Graves’ ophthalmopathy.
N Engl J Med. 1998;338:73–78.
16. Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthal-
mopathy after treatment for Graves’ hyperthyroidism. The Thyroid
Study Group. N Engl J Med. 1992;326:1733–1738.
17. Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med.
2011;364:542–550.
18. Guo Z, Yu P, Liu Z, Si Y, Jin M. Total thyroidectomy vs bilateral
subtotal thyroidectomy in patients with Graves’ diseases: a meta-
analysis of randomized clinical trials [published online ahead of
doi: 10.1210/jc.2013-1954
print April 19, 2013]. Clin Endocrinol (Oxf). doi:10.1111/
cen.12209.
19. Genovese BM, Noureldine SI, Gleeson EM, Tufano RP, Kandil E.
What is the best definitive treatment for Graves’ disease? A system-
atic review of the existing literature. Ann Surg Oncol. 2013;20:660 –
667.
20. Stern RA, Robinson B, Thorner AR, Arruda JE, Prohaska ML,
Prange AJ Jr. A survey study of neuropsychiatric complaints in pa-
tients with Graves’ disease. J Neuropsychiatry Clin Neurosci. 1996;
8:181–185.
21. Alizadeh J, Ward JA. Comparative follow-up of patients with hy-
perthyroidism treated with 131 or surgery. J Med Assoc Ga. 1979;
68:101–104.
22. Sugrue D, McEvoy M, Feely J, Drury MI. Hyperthyroidism in the
land of Graves: results of treatment by surgery, radio-iodine and
carbimazole in 837 cases. Q J Med. 1980;49:51– 61.
23. Berglund J, Christensen SB, Dymling JF, Hallengren B. The inci-
dence of recurrence and hypothyroidism following treatment with
All members have access to The Endocrine Legacy –
an online journal archive of all articles
from Volume 1, issue 1, to the 2011.
www.endo-society.org/legacy
jcem.endojournals.org 3677
antithyroid drugs, surgery or radioiodine in all patients with thy-
rotoxicosis in Malmo during the period 1970 –1974. J Intern Med.
1991;229:435– 442.
24. Mengistu M. A prospective study of 110 Ethiopians with thyrotox-
icosis. East Afr Med J. 1992;69:515–519.
25. Pineda G, Arancibia P, Mejia G. Treatment of Basedow-Graves’
hyperthyroidism: retrospective analysis after 30 years [in Spanish].
Rev Med Chil. 1998;126:953–962.
26. Leary AC, Grealy G, Higgins TM, et al. Long-term outcomes of
treatment of hyperthyroidism in Ireland. Ir J Med Sci. 1999;168:
47–52.
27. Tutuncu NB, Tutuncu T, Ozgen A, Erbas T. Long-term outcome of
Graves’ disease patients treated in a region with iodine deficiency:
relapse rate increases in years with thionamides. J Natl Med Assoc.
2006;98:926 –930.
Downloaded from https://academic.oup.com/jcem/article/98/9/3671/2833150 by guest on 29 April 2022
28. Burch HB, Burman KD, Cooper DS. A 2011 survey of clinical prac-
tice patterns in the management of Graves’ disease. J Clin Endocri-
nol Metab. 2012;97:4549 – 4558.