Cardiovascular Mortality in 6900 Patients with
Differentiated Thyroid Cancer: A Swedish Populationbased
Study
Maximilian Zoltek1, Therese ML Andersson2, Christel Hedman1, Anders Ekbom3, Caroline Nordenvall1 and Catharina Ihre-Lundgren1* 1Department of Molecular Medicine and Surgery, Karolinska Institute, Sweden 2Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden 3Department of Medicine, Karolinska Institute, Sweden
*Corresponding author: Catharina Ihre- Lundgren, Department
of Molecular Medicine and Surgery,
Karolinska Institute, Stockholm,
Sweden
Published: 20 Jun, 2017 Cite this article as: Zoltek M, Andersson TML, Hedman C,
Ekbom A, Nordenvall C, Ihre-Lundgren
C. Cardiovascular Mortality in 6900
Patients with Differentiated Thyroid
Cancer: A Swedish Population-based
Study. Clin Surg. 2017; 2: 1519.
Abstract
Background: Patients with differentiated thyroid cancer (DTC) are usually administered lifelong TSH suppression treatment to reduce the recurrence risk, but however concomitantly risk
hyperthyroidism and consequently cardiovascular (CV) mortality as an adverse effect. This study’s
objective was to assess the risk of CV mortality in Swedish DTC patients relative to the general
Swedish population. Methods: In this nationwide cohort-study, each patient was followed from one year post DTC
diagnosis to the date of death, migration or 31 of December 2014. CV mortality in DTC patients
was compared with the general population through standardized mortality ratios (SMRs). All
patients diagnosed with DTC in Sweden in 1987-2013 were at baseline included in the study, and
the vast majority of patients were assumed to have received life-long TSH suppression treatment in
compliance with the prevalent national guidelines. Results: Out of 6900 DTC patients included, 550 (7.97%) died with an underlying CV diagnosis. On
an aggregate level, the cohort did not experience a higher risk of CV mortality, although men ran an
increased risk of CV mortality (SMR 1.16 CI 95% 1.02-1.31). The cohort overall also had an elevated
risk of mortality in atrial fibrillation (SMR 1.36 CI 95% 1.12-1.64). We found that the age category
of < 45 years at diagnosis that lived 20 years after diagnosis experienced higher CV mortality (SMR
3.80 95% CI 1.71-8.46) than expected in the general population. Conclusion: We found no increased rate of CV mortality on an aggregate level in patients diagnosed
with DTC, compared with CV mortality in the general Swedish population. However, following a
DTC diagnosis, the data suggests that young patients with long follow-up duration were observed to
face an elevated risk of CV mortality. We also noted that patients encountered elevated risks of AF
mortality, and that male DTC patients faced elevated risk of CV mortality in general.
Keywords: Thyroid stimulating hormone; Cardiovascular; Mortality; Differentiated thyroid
cancer
Papillary and follicular cancers all fall into the category of differentiated thyroid cancer (DTC), which is by far the most common thyroid carcinoma, accounting for more than 95% of the cases [1].
Although a subject of recent debate [1], the general cornerstones of the initial curative treatment
traditionally consist of total thyroidectomy and radioactive iodine treatment [2]. After these
procedures, thyrotropin levels (TSH) are often suppressed with levothyroxine usually in a life-long
manner, since clinical data demonstrate that TSH stimulates cancer cells [1-3], where the cancer
stage determines the level of TSH suppression [1]. The prognosis of DTC is good, where the 10 year
relative survival surpasses 90% [4]. As a consequence of the good prognosis, the majority of patients do not die from the thyroid cancer itself, but instead risks dying from
the postoperative cancer treatment and or other illnesses [5]. A natural
consequence of TSH suppression is subclinical hyperthyroidism,
which several previous studies have examined in relation to
cardiovascular (CV) diseases and mortality. In patients without DTC,
subclinical hyperthyroidism has been shown to increase the heart rate
and left ventricular size [6,7], and is comorbid with atrial fibrillation
(AF) and heart failure (HF) [8,9]. A recent study also indicates that
patients with DTC have a higher incidence of AF compared to healthy
individuals [10]. The literature is however inconclusive whether
subclinical hyperthyroidism primarily generates HF, which in turn
gives rise to AF, or whether subclinical hyperthyroidism creates
AF through a direct pathway mechanism [11]. In the case of DTC
patients with TSH suppression, studies report increased incidence
of AF, HF, decreased arterial elasticity and negative prothrombotic
effects [12-16]. Furthermore, in patients without DTC, subclinical
hyperthyroidism is also associated with increased CV mortality
[17,18]. However, most studies conducted on patients with DTC do
not indicate increased CV mortality [19-21], with the exception of
one recent study [22] that suggests an increased risk of CV-mortality
thus giving clinicians reason to question the main body of evidence.
This study examines a nationwide population-based cohort during
an extensive duration of follow-up, and aims at assessing the risk of
CV mortality in DTC patients relative to the general population. We
hypothesized that DTC patients run a higher risk of CV mortality
relative to the general population.
Table 1
Entire Cohort
Cardiovascular Deaths
N
%
N
%
All
6900
100
550
7.97
Sex
Male
1812
26.26
203
11.20
Female
5088
73.74
347
6.82
Age at inclusion
<45
2523
36.57
14
0.55
45-54
1338
19.39
28
2.09
55-64
1161
16.83
79
6.80
65-74
1062
15.39
207
19.49
>=75
816
11.83
222
27.21
Year of inclusion
1987-1995
1941
28.12
334
17.21
1996-2004
1992
28.87
166
8.33
2005-2013
2967
43.00
50
1.69
TNM1
T-stage
Missing
668
22.51
7
1.05
0
28
0.94
0
0.00
I
1085
36.57
12
1.11
II
634
21.37
15
2.37
III
408
13.75
5
1.23
IV
144
4.85
11
7.64
N-stage
Missing
1118
37.68
12
1.07
0
1262
42.53
28
2.22
I
587
19.78
10
1.70
Table 1: Descriptive characteristics of patients diagnosed with differentiated
thyroid cancer in Sweden during 1987 to 2013 (follow up to 2014). 1Restricted to patients diagnosed in 2005 or later
Table 1
Descriptive characteristics of patients diagnosed with differentiated
thyroid cancer in Sweden during 1987 to 2013 (follow up to 2014).
Table 2
Cardiovascular Mortality
Endpoint
N
%
Overall SMR
Male SMR
Female SMR
Cardiovascular Mortality
550
100
1.02
1.16
0.95
95% CI
0.94-1.10
1.02-1.31
0.86-1.05
Ischemic Heart Disease
261
47.25
0.95
1.07
0.88
95% CI
0.84-1.07
0.88-1.28
0.75-1.03
Ischemic Heart Attack
127
23.10
0.95
1.00
0.92
95% CI
0.80-1.14
0.76-1.32
0.73-1.16
Heart Failure
237
43.10
0.97
1.11
0.91
95% CI
0.86-1.11
0.89-1.37
0.78-1.07
Atrial Fibrillation
108
19.64
1.36
1.25
1.40
95% CI
1.12-1.64
0.97-1.80
1.12-1.75
Cerebrovascular Disease
169
30.73
0.93
0.98
0.90
95% CI
0.80-1.08
0.75-1.30
0.75-1.08
Cerebral Infarction
109
19.82
0.98
1.11
0.93
95% CI
0.82-1.19
0.80-1.56
0.75-1.17
Table 2: Number of cardiovascular deaths and corresponding standardized
mortality ratios (SMRs) following a diagnosis of differentiated thyroid cancer in
Sweden 1987-2013.
Table 2
Number of cardiovascular deaths and corresponding standardized
mortality ratios (SMRs) following a diagnosis of differentiated thyroid cancer in
Sweden 1987-2013.
Materials and Methods
The publicly funded Swedish health-care system, in combination
with a unique personal identity number assigned to all residents
[23], enables high standard nationwide registers containing all
hospital admissions and discharges, cancer diagnoses, causes of
death and migration [24]. We identified individuals diagnosed with
DTC International Classification of Disease (ICD) 7 194, pathologyanatomy
diagnosis 096 (medullar and anaplastic thyroid cancer are
excluded), during 1987-2013 from the Swedish Cancer Registry.
Only the first diagnosis of thyroid cancer during the study period was
considered for individuals with more than one diagnosis. Information
on date and cause of death was collected from the Cause of death
registry. Only individuals that stayed in the cohort at least one year
post diagnosis were included in the final study cohort. End-points
To strengthen a potential causal relationship between TSH
suppression and CV mortality, each patient was followed from one
year post DTC diagnosis to the date of death, migration or 31 of
December 2014, whichever came first. The end-point of interest was
CV death, while migration, other mortalities and end of follow-up
were considered censoring events. We investigated 7 different endpoints
of CV death: Ischemic Heart Disease (ICD-9:410-414, ICD-
10:I20-25), Ischemic Heart Attack (ICD-9:410. ICD-101:I21, I22),
Heart Failure (ICD-9:428 ICD-10:I50), Cerebral Infarction (ICD-
9:431,434,436. ICD-10:I61, I63, I64), Cerebrovascular Disease (ICD-
9:430-434,436-438. ICD-10:I60-69) and Atrial Fibrillation (ICD-
9:427D, 427A. ICD-10:I48), and CV death overall (any of the listed
ICD-codes above). The seven different end-points were all categorized
by considering both primary and contributing causes of death. Covariates
The cohort was categorized with respect to age at diagnosis (under
45, 45-54, 55-64, 65-75 and 75+ years), calendar year at diagnosis
(1987-1995, 1996-2004, 2005-2013) and sex. TNM classification was
reported for patients included 2005 or later. Statistical analyses
The cohort’s relative risk of CV death, as compared to the general
population, was calculated through standardized mortality ratios
(SMRs), by comparing the rate in the study cohort to rates in the
general population taking sex, age (one year strata) and calendar year
(one year strata) into consideration. SMRs were calculated for the
aggregate cohort, as well as for subgroups of sex, age at diagnosis (in
categories given above), year of diagnosis (in periods given above) and
follow up time since diagnosis (measured in years). Complementary
calculations for TNM classification were also performed for
robustness validation. All aforementioned SMRs were computed
for all CV mortalities combined as well as for CV subcategories
(according to ICD-9 and ICD-10 as described in the “end-points”
section). STATA 12, StataCorp LP Lakeway Drive, Texas USA, was
used for statistical analyses. Ethical approval was acquired from the
Regional Ethical Board at Karolinska Institute (Stockholm, Sweden),
Dnr:2014/714-31.
Table 3
Cardiovascular Mortality
N=550
SMR
95% CI
Overall
1.02
0.94-1.10
Male
1.16
1.02-1.31
Female
0.95
0.86-1.05
Age <45
1.58
0.94-2.67
Age 45-54
1.21
0.85-1.76
Age 55-64
1.19
0.96-1.47
Age 65-74
1.16
1.02-1.32
Age 75+
0.87
0.77-0.98
Years 1987-1995
0.98
0.89-1.09
Years 1996-2004
1.06
0.92-1.22
Years 2005-2013
1.10
0.89-1.38
Follow Up (Years)
0-10
0.79
0.68-0.91
10-20
0.91
0.75-1.11
20-27
1.14
0.82-1.57
Table 3:The standard mortality ratios (SMRs) of 550 cardiovascular deaths in
6900 patients diagnosed with differentiated thyroid cancer in Sweden.
Table 3
The standard mortality ratios (SMRs) of 550 cardiovascular deaths in
6900 patients diagnosed with differentiated thyroid cancer in Sweden.
Table 4
Atrial Fibrillation Mortality
SMR
N=108
SMR
95% CI
Overall
1.36
1.12-1.64
Male
1.25
0.87-1.80
Female
1.40
1.12-1.75
Age 45-54
3.96
1.78-8.81
Age 55-64
2.40
1.57-3.69
Age 65-74
1.68
1.26-2.24
Age 75+
0.84
0.67-1.23
Years
1987-1995
1.60
1.26-2.04
1996-2004
1.20
0.85-1.67
2005-2013
0.88
0.47-1.63
Follow Up (Years)
0-10
1.11
0.74-1.67
10-20
1.35
0.90-2.01
20-27
1.43
0.77-2.66
Table 4:The standardized mortality ratios (SMRs) of atrial fibrillation mortality
(n=108) in patients diagnosed with differentiated thyroid cancer in Sweden
Table 4
The standardized mortality ratios (SMRs) of atrial fibrillation mortality
(n=108) in patients diagnosed with differentiated thyroid cancer in Sweden
Results and Discussion
Results
Table 1 displays basic characteristics of the cohort. Between 1987
and 2013, 6900 patients were diagnosed with DTC, survived and
did not emigrate, at least one year post diagnosis. The mean followup
time for the whole cohort was 9.66 years and the median was
8.01years (max 26.99 years, min 0.00 years). In the cohort, there were
550 (7.97%) cases of CV deaths, which constituted 26.47% of total
mortalities (n=2078). The cohort predominantly consisted out of
women (73.74%), however the number of events was relatively higher
among men (11.20% in men vs. 6.82% in women). The proportion
experiencing an event increased with the age at inclusion, as well as
for more advanced TNM stages.
Table 2 describes SMRs for all CV mortalities as well as for CV
mortalities categorized by ICD sub-diagnoses and sex. Among CV
mortalities, ischemic heart disease, HF and Cerebrovascular disease
were the most common death causes, accounting for 47.45%, 43.10%
and 30.73% of the cases respectively. Ischemic heart attack (23.10%),
cerebral infarction (19.82%), and AF (19.64%) were also common
death causes, but were represented to a lesser extent. It is important to
note that since ICD codes for the individual end-points overlap (e.g.
ischemic heart disease and myocardial infarction), and there are cases
of co-mortalities (e.g. AF and cerebral infarction), the individual endpoints
will sum up to more than 100% of the total CV mortalities.
When accounting for all CV mortalities, only men ran a significantly
elevated morality rate than expected (SMR 1.16 CI 95% 1.02-1.31).
The cohort did in general not run an increased hazard of death in
any particular CV death cause except for AF (SMR 1.36 CI 95% 1.12-
1.64).
Table 3 displays detailed SMRs for CV mortality overall. The age
group 65-74 was prone to a somewhat higher rate of CV death than
expected (SMR 1.16 CI 95% 1.02-1.32), which also turned out to be the
case for men (SMR 1.16 CI 95% 1.02-1.31) in general. Further analysis
displayed that men’s elevated rate was primarily attributable to the
age group 45-54 years’ olds (SMR 1.84 95% CI1.16-2.93). Moreover,
the SMR for overall CV mortality was not statistically significant for
any of the calendar periods of diagnosis. In complementary analyses
restricted to patients diagnosed in 2005 or later, stage T4 exhibit
edan increased mortality rate (SMR 1.87 CI 95% 1.19-2.94), whereas
variations with the N or M stage were uninformative on CV mortality. Atrial fibrillation Table 4 exhibits mortality in AF. Unlike the general case of CV
mortalities, the cohort experienced an increased rate of death due
to AF (SMR 1.36 1.12-1.64). This increased rate primarily pertained
to women (SMR 1.40 CI 95% 1.12-1.75) where as the SMR in men
was in general not statistically significant. Furthermore, young age
at diagnosis did increase the rate of death in AF compared to the general population, where the highest SMR was to be found in the
group 45-54 year olds (SMR 3.96 CI 95% 1.78-8.81). The SMR of AF
mortality was higher for those diagnosed in earlier calendar years,
where patients included 1987-1995 displayed an SMR of 1.60 (CI 95%
1.26-2.04). Complementary calculations regarding AF mortality did
not prove variations within the TNM classification to be significant.
The aforementioned results of AF mortality did not change notably
when including patients at diagnosis date, instead of one year post
diagnosis as conducted in this study. Age at diagnosis and follow-up duration
Table 5 portraits the relationship between age at diagnosis,
follow-up duration and the SMR of CV mortality. Patients diagnosed
at ages below 45 years had an SMR of 3.80 (CI 95% 1.71-8.46) 20 years
after diagnosis. Shorter follow-up duration than 20 years in the age
category < 45 did not incur an increased rate of CV mortality. Further,
there was no elevated rate of CV mortality for the group diagnosed at
ages 45-54 during any follow-up duration, where all SMRs were not
statistically significant. The oldest age category, 75 years or older at
diagnosis, displayed SMRs less than 1.00 for all follow-up durations,
where the data suggests a decreased rate of CV mortality the first
years post inclusion (SMR 0.68 95% CI 0.59-0.79). Discussion
The aim of this nationwide study was to evaluate CV mortality
in patients with DTC in comparison to the general population,
where we hypothesized that DTC patients run an elevated risk of CV
mortality. On an aggregate level, we did not find this patient group
to run a higher risk of CV mortality relative to the general Swedish
population, and thus cannot fully support our hypothesis. However,
we did identify certain clinically significant risk factors associated with
an elevated rate of CV mortality in this patient group. The first finding
was that young longtime survivors run a nearly 4-fold increased rate
of CV mortality compared the general population’s, which could
potentially be explained by long-term TSH suppression therapy.
Secondly, we found that DTC patients run an elevated rate of dying
in AF. Thirdly, DTC patients’ CV mortality rate was more elevated in
men compared with women. In general, the results of this study are
in line with the main body of previous literature demonstrating that
TSH suppression treatment on an aggregate population level does
not significantly increase CV mortality [19-21], where only one study
provides conflicting results [22].
Alternative study designs and patient materials potentially
explain why Hesselink et al. [22] found CV mortality to be
substantially increased in DTC patients, whereas this study did
not. Strengths with Hesselink’s study include available clinical data,
where they found a relationship between low TSH levels and the
risk of CV mortality [22]. A limitation with this study is the lack of
information on TSH levels. The National Swedish Clinical Guidelines
under the study period stipulate TSH suppression therapy to all DTC
patients, which makes it highly probable that suppression treatment
was administered to the vast majority of patients in this study. This
assumption is strengthened by the fact that the CV mortality rate
was elevated in young patients with longer duration of disease, as
well as in patients with advanced disease which were according to
the national guidelines suppressed to a greater extent. Furthermore,
complementary research suggests that the national guidelines have
been static over the study period. Although new national guidelines
were introduced in 2012, recommending suppression therapy for
only one year in patients with low risk DTC (Sköldkörtelcancer,
Nationellt Vårdprogram 2012), a change of praxis was not evident in
a review of 50 case-records from patients diagnosed in 2006-2008, and
50 diagnosed in 2011-2013, respectively (M Johansson, unpublished
data). Moreover, while Hesselink et al. [22] employed a case-control
study design, comparing 524 DTC patients with a selected cohort
of healthy individuals, we conducted a nationwide cohort study by
relating 6900 DTC patients to the general population.
Although this paper is not first to provide evidence that DTC
patients do not in general run a substantially elevated rate of CV
mortality, it still offers significant contribution to the literature by
being first to present a nationwide approach. Previous studies that
share this insight have not investigated CV mortality in particular,
but instead focused on overall mortality causes in patients with
DTC as well as thyroid cancer in general. Eustatia-Rutten et al. [19]
included 366 cases of DTC, out of which 5 were CV mortalities.
Likewise, Links et al. [20] investigated survival in 504 DTC patients,
and identified 9 cases of CV mortalities. Akslen et al. [21] studied
2479 cases of thyroid cancer, out of which 94 patients died due to
a CV disease. Hesselink et al. [22] studied 524 DTC patients and
identified 100 CV mortalities. Since the aforementioned studies and
Hesselink had altering objectives, more weight was naturally assigned
to the latter study since it was the first study whose sole purpose
was to investigate CV mortality in DTC patients. To the best of our
knowledge, this study alongside Hesselink et al. [22] are the only
publications examining CV mortality in DTC patients, where our
paper offers advantages regarding its nationwide approach.
The major strength of this study is the vast patient material
collected from a high quality population register, which included all
cases of DTC incidence in Sweden over 26 years, thus allowing us
to follow patients on average 9.66 years, making it the largest DTC
cohort study that has investigated CV mortality so far. The registers
cover the entire population, and given the national approach,
the risk of selection bias should be negligible. Further, actions of
precautions have been exercised in order not to overestimate results
and to highlight potential risks of CV mortality in DTC patients.
These include exclusion of mortalities up to one year post DTC diagnosis, only inclusion of first thyroid cancer diagnosis, and also
complementary calculations that verified significant results. As
already discussed, the major limitation in this study was the lack of
information on TSH levels. Other shortcomings include the inability
to control for smoking and previous CV disease history, which are
two major risk factors for CV mortality. Regarding history of CV
disease, no previous study has found elevated prevalence of CV
disease at DTC diagnosis. Smoking on the other hand has somewhat
surprisingly been negatively associated with DTC incidence [25].
One could thus argue that the SMR of CV mortality in DTC patients,
if anything, would be increased, were smoking to be considered.
However, to stress the objective of this study, we did not aim at
establishing an exact causal relationship between TSH levels and CV
mortality in DTC patients. Our aim was to use the vast population
registers, and study whether CV mortality in DTC patients differed
from the remainder of the Swedish population. We are fully aware of
the shortcomings of the register approach with respect to inference
on causality, but simultaneously acknowledge the vast possibilities of
studying a large cohort over time.
The pathophysiology mechanisms for elevated mortality in CV
diseases remain not fully established. The literature is congruent in
that subclinical hyperthyroidism increases left ventricular size [6,7]
and is comorbid with AF [8,9]; a relationship that has also been
proven in patients with DTC [12-16]. A recent study has however
not succeeded in establishing a dose-response relationship between
AF incidence in DTC patients and the level of TSH suppression,
thus raising questions whether plasma TSH levels are adequate
measures for tissue hyperthyroidism [10]. Furthermore, subclinical
hyperthyroidism is associated with CV mortality in patients without
DTC [17,18], where only one study [22] has been able to show
increased mortality in DTC patients. Our study suggests a chronic
process between TSH suppression and CV mortality in DTC patients,
by providing evidence of increased CV mortality risk in patients
diagnosed below 45 years of age, who probably have received
TSH suppression treatment for 20 years or more. We have made
complementary calculations, ensuring that these patients are not at a
higher risk of CV mortality due to more advanced TNM stages, and
thus more aggressive TSH suppression which consequently could
explain the higher CV mortality risk.
We believe there is evidence to suggest that the risk of CV
mortality increases with lower TSH levels among DTC patients. This
was displayed in Hesselink’s study [22], as well as suggested in this
study by the increased risk ratios of young patients with long duration
of disease, as well as in patients with advanced cancer stages. We
further suggest an increased risk of CV mortality in certain groups of
DTC patients, but however find the risk on an aggregate level not to
differ from that of the Swedish population, thus being negligible. We
identified the age at diagnosis together with the duration of disease
and, -sex of the patient to potentially be predictors of increased rates
of CV mortality, in particular increased rates of death due to AF, and
hence suggest these factors to be of further discussion and concern
in relation to TSH suppression in DTC patients. Nevertheless, due
to the lack of TSH levels, this study does not provide ultimate causal
evidence that low TSH levels solely explain the adversely elevated CV
mortality risk rates discussed above. To include exact TSH levels over
decades for 6900 patients is however obviously out of scope. We have
therefore chosen to focus on the CV outcome of this patient group
given the national guidelines’ TSH suppression program, rather than
attempting to provide definitive causal relationships, when not being
able to perform a randomized controlled trial.
To summarize, this nationwide study showed no generally
increased rate of CV mortality in patients diagnosed with DTC
compared with CV mortality in the general Swedish population.
However, following a DTC diagnosis, the data suggests that young
patients with long follow-up duration were observed to face an
elevated risk of CV mortality. We also noted that patients encountered
elevated risks of AF mortality, and that male DTC patients faced
higher relative risks of CV mortality in general.
Table 5
Age at diagnosis
Follow-up (years)
SMR
95% CI
<45
0-10
0.99
0.32-3.07
<45
10-20
1.18
0.49-2.83
<45
20-27
3.80
1.71-8.46
45-54
0-10
1.29
0.75-2.22
45-54
10-20
0.94
0.51-1.74
45-54
20-27
1.65
0.69-3.97
55-64
0-10
1.12
0.80-1.58
55-64
10-20
1.07
0.76-1.50
55-64
20-27
1.08
0.63-1.87
65-74
0-10
1.12
0.93-1.34
65-74
10-20
1.03
0.83-1.28
65-74
20-27
0.80
0.45-1.40
>=75
0-10
0.68
0.59-0.79
>=75
10-20
0.77
0.57-1.04
Table 5:The standardized mortality ratios (SMRs) of cardiovascular deaths in
patients diagnosed with differentiated thyroid cancer in Sweden, stratified by ageclusters
and follow-up time.
Table 5
The standardized mortality ratios (SMRs) of cardiovascular deaths in
patients diagnosed with differentiated thyroid cancer in Sweden, stratified by ageclusters
and follow-up time.