Subclinical Hypothyroidism and the Risk of
Coronary Disease and Mortality:
An Individual Participant Data Analysis
from Nine Prospective Cohorts
N. Rodondi, W. P. J. den Elzen, D. C. Bauer, A. R. Cappola, S. Razvi,
J. P. Walsh, B. O. Åsvold, G. Iervasi, M. Imaizumi, A. Bremner,
P. Maisonneuve, M. Vanderpump, A. B. Newman, J. Cornuz,
J. A. Franklyn, R.G.J. Westendorp, E. Vittinghoff,
J. Gussekloo for the Thyroid Studies Collaboration
Switzerland, The Netherlands, United States, United Kingdom, Western
Australia, Norway, Italy, Japan
Conflict of interest: none
Minneapolis, SGIM, April 2010
1
Background (1)
• Subclinical hypothyroidism =
– elevated thyroid-stimulating hormone (TSH)
– normal levels of free thyroxine (T4)
• Prevalence:
– US adult population: 4.3% (NHANES III)
– increases with age: ~ 10% in women > 60 years
• Controversy about screening and treatment of
subclinical hypothyroidism
• Current evidence about the risks is limited 1,2
1 USPTSF 2004, Helfand M. Ann Intern Med 2004, 2 Surks M, JAMA 2004
2
Background (2)
• Data on cardiovascular outcomes are
conflicting among several prospective
cohorts1,2.
• 3 recent study-level meta-analyses 3,4,5:
– Modestly increased risks for CHD and mortality
– Limitations: clinical heterogeneity, with different
TSH cutoffs, confounding factors for
adjustment and varying CHD definitions3-5
1
Cappola AR. JAMA 2006, 2 Walsh JP. Arch Int Med 2005, 3 Rodondi N. Ann Intern Med 2008,
4 Razvi S. J Clin Endocrinol Metab 2008. 5 Volzke H. J Clin Endocrinol Metab 2007
3
Objectives
• To perform an analysis of individual participant
data (IPD) from large cohort studies to define the
influence of age, TSH levels, and preexisting CVD
on the association between subclinical
hypothyroidism and:
- CHD events, CHD mortality, Total mortality
• IPD analysis
- Gold standard for synthesizing evidence across
several studies
- Subgroup analyses: not subject to potential bias from
study level meta-analyses (ecological fallacy)
4
Thyroid Studies Collaboration
HUNT Study
• Birmingham Study
• Whickham Survey
• Cardiovascular
Health Study
• Health, Aging and
Body Composition
Study
- Leiden 85+ Study
Pisa cohort
Nagasaki Adult
Health Study
Busselton
Health Study
5
Standardized Definitions
• Difference with study-level meta-analyses
• Thyroid function:
- Euthyroidism:
• TSH 0.50-4.49 mU/L
- Subclinical hypothyroidism:
• TSH 4.5 mU/L & TSH <20 mU/L
• Normal free T4 (site and study specific)
• CHD mortality
• CHD events:
-
nonfatal myocardial infarction
CHD death
hospitalization for angina or coronary
revascularization
6
Statistical Analyses
• Summary estimates and 95%CI
- Two stage method:
• Cox proportional hazard models for each cohort
separately (SAS Version 9.2)
• Combine estimates (generic reverse variance,
random effects model, RevMan 5)
• Heterogeneity
- I2 statistic (% of total variation across trials is
attributable to heterogeneity rather than
chance)1
1
Higgins et al., BMJ, 2003
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Risks Associated with Subclinical
Hypothyroidism (n=41’685)
Study sample:
- 41,685 adults comprising 2,621 (6.3%) with subclinical hypothyroidism
Number of outcomes:
- 2791 CHD events, 1715 CHD deaths and 14’449 total deaths
N events /
Participants
Adjusted for
age and gender
HR (95% CI)
Multivariate
model*
HR (95% CI)
I2
CHD events
2791 / 13355
1.25 (0.98, 1.59)
1.23 (0.97, 1.56)
67%
CHD mortality
1715 / 41676
1.14 (0.98, 1.34)
1.14 (0.96, 1.34)
0%
Total mortality
7770 / 41685
1.09 (0.94, 1.25)
1.12 (0.95, 1.31)
67%
* Adjusted for gender, age, systolic blood pressure, current and former smoking,
total cholesterol, and prevalent diabetes at baseline
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Hazard Ratios for CHD Events, CHD Mortality
and Total Mortality
Panel A: Elevated TSH Categories vs. Euthyroid
Subclinical hypothyroidism
Euthyroidism
Events / Participants
Events / Participants
Hazard Ratio (95% CI) *
Panel A: TSH
CHD events †
TSH 4.5-6.9 mU/L
TSH 7.0-9.9 mU/L
TSH 10-20 mU/L
202 / 854
69 / 285
55 / 153
2465 / 12063
2465 / 12063
2465 / 12063
1.07 (0.84, 1.35)
1.12 (0.88, 1.44)
2.00 (1.25, 3.20)
Ptrend=0.004
CHD mortality ‡
TSH 4.5-6.9 mU/L
TSH 7.0-9.9 mU/L
TSH 10-20 mU/L
114 / 1873
41 / 496
24 / 251
1536 / 39056
1536 / 39056
1536 / 39056
1.11 (0.91, 1.34)
1.40 (0.96, 2.04)
1.64 (1.11, 2.42)
Ptrend=0.007
Total mortality §
TSH 4.5-6.9 mU/L
TSH 7.0-9.9 mU/L
TSH 10-20 mU/L
559 / 1873
145 / 496
88 / 252
6978 / 39064
6978 / 39064
6978 / 39064
1.06 (0.97, 1.17)
1.04 (0.82, 1.32)
1.13 (0.69, 1.86)
Ptrend=0.65
HR adjusted for age and gender
Sizes of data markers are proportional to the inverse of the variance of the hazard ratios.
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Hazard Ratios for Coronary Heart Disease (CHD)
Events, CHD Mortality and Total Mortality
Panel B: Subclinical Hypothyroidism vs. Euthyroid Stratified by Age
Panel B: Age ||
CHD events
Age 18-49 years
Age 50-64 years
Age 65-79 years
Age 80 years
10 / 111
25 / 150
249 / 907
42 / 124
197 / 2687
359 / 2220
1649 / 6148
260 / 1008
1.95 (1.02, 3.70)
1.45 (0.97, 2.19)
1.21 (0.90, 1.61)
1.30 (0.93, 1.82)
Ptrend=0.22
CHD mortality
Age 18-49 years
Age 50-64 years
Age 65-79 years
Age 80 years
2 / 334
13 / 705
135 / 1357
29 / 224
44 / 10841
213 / 12855
979 / 13047
300 / 2313
2.45 (0.79, 7.60)
1.61 (0.95, 2.73)
1.33 (1.04, 1.70)
1.01 (0.62, 1.63)
Ptrend=0.14
Total mortality
Age 18-49 years
Age 50-64 years
Age 65-79 years
Age 80 years
13 / 334
70 / 705
539 / 1358
170 / 224
268 / 10841
984 / 12857
4134 / 13048
1592 / 2318
1.50 (0.85, 2.67)
1.13 (0.84, 1.51)
1.18 (0.98, 1.42)
0.96 (0.81, 1.14)
Ptrend=0.16
0.2
0.5
1
2
5
Risks did not significantly differ by gender or preexisting CVD
HR adjusted for age and gender as a continuous variable to avoid residual confounding within age
strata, Sizes of data markers are proportional to the inverse of the variance of the hazard ratios.
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Sensitivity Analysis on the Risks of
CHD Events and CHD Mortality
CHD Events
TSH 10-20 mU/L
CHD Mortality
TSH 10-20 mU/L
2.00 (1.25, 3.20)
1.64 (1.11, 2.42)
Excluding those treated by thyroid medication at
baseline
1.84 (1.07, 3.16)
1.58 (1.04, 2.39)
Excluding those treated by thyroid medication at
baseline and during follow-up
2.26 (1.39, 3.68)
2.02 (1.26, 3.26)
Excluding “soft” CHD outcomes *
1.88 (1.00, 3.53)
NA
4 Studies with formal adjudication procedures1-4
2.05 (1.14, 3.68)
1.77 (1.08, 2.89)
Further adjustment for lipid lowering and antihypertensive medications in addition to
cardiovascular risk factors
1.96 (1.14, 3.35)
1.60 (1.06, 2.42)
All eligible studies :
Random-effects
*
Possible in 4 studies 1-4
1
Cappola AR et al, JAMA 2006; 2 Rodondi N et al. Arch Intern Med 2005
3 Iervasi G, et al. Arch Intern Med 2007, 4 Gussekloo J, et al. JAMA 2004
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Limitations
• Our IPD analysis included predominantly white
populations, except for a study in Japan1
• Thyroid function testing performed only at
baseline:
- limitation of all published large cohorts
• Commencement of thyroid medication during
follow-up (by 0-12.6%) might have attenuated
any true effects of subclinical hypothyroidism:
- higher estimators in the sensitivity analysis excluding
such participants
1 Imaizumi
M, et al. J Clin Endocrinol Metab 2004
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Conclusions
• Subclinical hypothyroidism is associated with an
increased risk of CHD in those with higher TSH levels
among 41,685 participants.
• Our results might help refine a TSH threshold at
which larger benefits of thyroxine replacement would
be expected:
- Many adults with minimal TSH elevation currently treated1
despite no significant increased risk of CHD (or other risks)
• An appropriately powered RCT is needed to examine
the efficacy of screening for and treating subclinical
hypothyroidism.
1 Fatourechi
V et al. Mayo Clin Proc 2003
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Thank you for
your attention
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