Treatment - The Journal of Clinical Endocrinology & Metabolism

J Clin Endocrinol Metab, October 2009, 94(10):3700–3707 jcem.endojournals.org 3701
analysis did not show an association between TAO and
posttherapy hypothyroidism (9), a new study in a similar
population with early administration of L-thyroxine
was strongly called for.
The principal aim of this study was to compare radioiodine
treatment and medical therapy for long-term worsening
or development of TAO. Smoking and hypothyroidism
as confounding risk factors were controlled for, and
L-thyroxine supplementation was given early, i.e. at 2 wk
after the initiation of treatment for hyperthyroidism in
both arms.
Patients and Methods
Study design
The study was designed as an open, randomized, prospective
multicenter trial. Patients were randomized to radioiodine
(group I) and medical treatment (group M) within each center
(stratified randomization). Randomization was made in blocks
over time and was performed by the Oncological Centre at the
Karolinska University Hospital in Stockholm.
The primary endpoint was the difference in the proportion of
patients with worsening or development of TAO during a 4-yr
follow-up in the two groups (intention-to-treat analysis). A comparison
(� � 0.05, two-tailed test) of the binomial proportions
between two groups of 300 patients each would give more than
90% probability (power) to detect a true difference of 10%.
Power estimates were based on the results from the previous trial
by Tallstedt et al. (2).
Enrollment in the study (TT 96) started in May 1996. By
the second half of 2002, it was obvious, however, that the
inclusion rate was too slow to obtain the full number of patients
within a reasonable period of time, and the study was
closed in 2003. This meant that with the above specifications
and the number of observations obtained so far (333 enrolled
patients), the study had a power of about 70% at least. With
the 4-yr clinical follow up, the study was terminated by the end
of 2007.
The study was approved by the ethics committee of the Karolinska
Institute (Ref.: KI 96-096).
Patients
Inclusion criteria were as follows: age, 35–69 yr; symptomatic
Graves’ hyperthyroidism; confirmation of the diagnosis by serum
TSH (�0.1 mIU/liter) and T 3 and/or free T 4 (elevated), thyroid
uptake of iodine-131, and radionuclide scans compatible with
Graves’ disease, i.e. an even distribution of radionuclide. Furthermore,
the activity of an orally administered dose of iodine-131
(as calculated for the patient to give an absorbed radiation dose
of 120 Gy) should not exceed 600 MBq, enabling the therapy to
be given on an outpatient basis (see formula in Iodine-131
section). Patients with a previous history of treatment with
antithyroid drugs, iodine-131, or thyroid surgery were excluded
as well as patients with severe TAO requiring treatment
with corticosteroids at the time of inclusion. This was
done because concomitant steroid treatment would limit the
possibility to evaluate the effect of the treatment for Graves’
disease on worsening or development of TAO. Additional
exclusion criteria were: incipient toxic crisis, coronary heart
disease, pregnancy, breast-feeding or pregnancy planned
within the following 2 yr.
The full number of patients that met the inclusion criteria is
not known, but the reported cases were 482. A total of 333
patients gave their informed consent to participate and were
enrolled in the study. For ethical reasons, clinical data were not
documented for the patients who did not wish to participate or
did not meet the inclusion criteria.
Of the 333 patients enrolled in the study, 313 were included
in the study group: 150 in the medical therapy group, and 163
in the radioiodine group (Table 1). The number of patients
belonging to each center was: Gothenburg, 58; Lund, 40; Malmoe,
73; and Stockholm, 142 patients, respectively. Twenty
patients were excluded: one patient had an incorrect diagnosis
(Hashimoto thyroiditis), 17 had no ophthalmological assessment
at randomization, and two had no follow-up visits.
These excluded patients had an average age of 50.1 yr, the
male/female ratio was 5/15, five of 18 were smokers, and two
were missing data.
The cumulative dropout (last observation carried forward)
from the ophthalmological follow-up in group I and group M,
respectively, was as follows: at 1 yr, 3 and 1%; at 2 yr, 6 and 3%;
and at 3 yr, 10 and 9%, respectively. At 4 yr (i.e. after protocol
for ophthalmological follow-up), 20% of the patients in both
groups were still followed by ophthalmologists.
Treatment for Graves’ hyperthyroidism
Medical
Methimazole was given 15 mg twice daily; at d 14, 50 �g of
L-thyroxine was added, and it was increased to 100 �g 2 wk later.
At 6 wk, the dose of L-thyroxine was adjusted to normalize the
levels of serum T 3 and free T 4 and to bring TSH to less than 0.4
mIU/liter. A slightly elevated serum free T 4 was accepted up to
20% above the upper normal limit.
Beta-blockers were used for symptomatic treatment. Patients
showing serious adverse reactions to methimazole received alternative
treatment. Methimazole was replaced by 150 mg propylthiouracil
three times daily in patients with minor adverse
reactions.
Antithyroid drug therapy was discontinued after 18 months
with an additional month of L-thyroxine substitution of 100 �g
daily, which thereafter was discontinued.
Departments of Endocrinology (E.N.), Oncology (G.B.), and Ophthalmology (T.A.), Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden; Departments of Endocrinology (P.H.)
and Ophthalmology (V.P.), Lund University Hospital, SE-221 85 Lund, Sweden; Departments of Endocrinology (B.H., M.L.) and Ophthalmology (P.Å.), Malmoe University Hospital, SE-205
02 Malmoe, Sweden; Department of Oncology, Radiumhemmet (G.L.), Department of Molecular Medicine and Surgery, Division of Surgery (G.W.), and Department of Endocrinology
(J.C.), Karolinska University Hospital, Karolinska Institute, SE-141 86 Stockholm, Sweden; Department of Clinical Neurosciences (L.T., F.T.), St. Erik Eye Hospital, Karolinska Institute, SE-112
82 Stockholm, Sweden; Department of Clinical Research and Education, Karolinska Institute and Department of Internal Medicine, Division of Endocrinology, (O.T.), Södersjukhuset, SE-118
83 77 Stockholm, Sweden; Department of Clinical Sciences, Division of Surgery (M.A.-N.), Danderyd Hospital, Karolinska Institute, SE-171 77 Stockholm, Sweden; and Department of
Information Science (A.T.), University of Uppsala, SE-751 20 Uppsala, Sweden