1. 1 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

2. 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 2 1 USPTSF 2004, Helfand M. Ann Intern Med 2004, 2 Surks M, JAMA 2004

3. Background (2) Data on cardiovascular outcomes are conflicting among several prospective cohorts 1,2. 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 definitions 3-5 3 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

4. 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

5. Cardiovascular Health Study Health, Aging and Body Composition Study Pisa cohort -Leiden 85+ Study Birmingham Study Whickham Survey HUNT Study Nagasaki Adult Health Study Busselton Health Study Thyroid Studies Collaboration 5

6. 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

7. 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 -I 2 statistic (% of total variation across trials is attributable to heterogeneity rather than chance) 1 7 1 Higgins et al., BMJ, 2003

8. Risks Associated with Subclinical Hypothyroidism (n=41685) N events / Participants Adjusted for age and gender HR (95% CI) Multivariate model* HR (95% CI) I2I2 CHD events2791 / 133551.25 (0.98, 1.59)1.23 (0.97, 1.56)67% CHD mortality1715 / 41676 1.14 (0.98, 1.34)1.14 (0.96, 1.34) 0% Total mortality7770 / 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 8 Study sample: -41,685 adults comprising 2,621 (6.3%) with subclinical hypothyroidism Number of outcomes: -2791 CHD events, 1715 CHD deaths and 14449 total deaths

9. Hazard Ratios for CHD Events, CHD Mortality and Total Mortality Panel A: Elevated TSH Categories vs. Euthyroid HR adjusted for age and gender Sizes of data markers are proportional to the inverse of the variance of the hazard ratios. 9

10. Hazard Ratios for Coronary Heart Disease (CHD) Events, CHD Mortality and Total Mortality Panel B: Subclinical Hypothyroidism vs. Euthyroid Stratified by Age 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. 10

11. 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 All eligible studies : Random-effects2.00 (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 procedures 1-4 2.05 (1.14, 3.68) 1.77 (1.08, 2.89) Further adjustment for lipid lowering and anti- hypertensive medications in addition to cardiovascular risk factors 1.96 (1.14, 3.35)1.60 (1.06, 2.42) 11 * 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

12. Limitations Our IPD analysis included predominantly white populations, except for a study in Japan 1 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 12 1 Imaizumi M, et al. J Clin Endocrinol Metab 2004

13. 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 treated 1 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. 13 1 Fatourechi V et al. Mayo Clin Proc 2003

14. 14 Thank you for your attention