A raised thyroid stimulating hormone result is associated with an increased rate of cardiovascular events and would benefit from treatment Gibbons V, Conaglen JV, Lawrenson RA. University of Auckland – Waikato Clinical School.

Introduction Hypothyroidism is common in women The prevalence of hypothyroidism increases with age Laboratory testing for thyroid function is routinely investigated in General Practice Best Practice guidelines recommend a change in behaviour for investigating thyroid dysfunction There remains much controversy and debate regarding testing, treatment and long-term outcomes for subclinical and clinical hypothyroidism

Background Hamilton Study 2007, C-S study, ~21,000 patients, note review, lab and prescribing data, OH 2.5% SCH 6.8% Laboratory data – TSH testing is common, av. 92% are normal, range from 96% <30 to 79% 80+ yrs Decision-making for testing: much variability relating to patient factors, protection, diagnosis, management Treatment: variability, cut-off, outcomes, benefits vs. harm Despite guidelines for investigation and management, recommendations are based on expert opinion.

GOBSAT

Long-term outcomes of patients with hypothyroidism To examine survival in individuals ≥20 years of age with varying degrees of hypothyroidism in relation to CVD events over a decade ( ) by age, gender, and ethnicity and compare them with euthyroid individuals (normal thyroid function)

Methods Laboratory Data Set - all thyroid function tests with a valid NHI from one laboratory in Waikato National Minimum Data Set (NMDS) – hospital events data based on provided NHI numbers Mortality Data Set – death data based on NHI numbers from lab data Demographic Data Set – captures individuals not in the other NMDS or mortality Data Sets

Study population NormalSCHOH Total sample n=63,462 (90.0) n=4,048 (5.8) n=2,970 (4.2) Mean age at entry, years 48.5 (17.6)60.7 (16.9)60.4 (16.9) Age 20-44y 28,333 (95.3)759 (2.6)568 (1.9) 45-64y 22,033 (89.7)1,436 (5.8)1,101 (4.5) 65-79y 10,109 (82.0)1,334 (10.8)886 (7.2) 80+ 2,987 (76.0)529 (7.2)415 (10.6) Gender Female, No (%) 39,996 (88.6)2,832 (6.3)2,308 (5.1) Male, No (%) 23,466 (92.6)1,226 (4.8)662 (2.6) Ethnicity European, No (%) 54,623 (89.6)3,701 (6.1)2,632 (4.3) Māori, No (%) 8,839 (92.3)357 (3.7)338 (3.5)

Incidence of cardiovascular disease by thyroid status Incidence Cardiovascular diseases Total (n=6,318) (%) Euthyroidism (n=5,245) (%) Subclinical Hypothyroidism (n=569) (%) Overt Hypothyroidism (n=504) (%) CHD2,656 (42.0)2,172 (41.4)251 (44.1)233 (46.2) PVD1,540 (24.4)1,332 (25.4)114 (20.0)94 (18.7) CVA1,198 (19.0)1,011 (19.3)108 (19.0)79 (15.7) HF924 (14.6)730 (13.9)96 (16.9)98 (19.4)

Number and crude rates of cardiovascular events per 1000 person-years by thyroid category Thyroid category Sample size No. Of cardio- vascular events Person-time (1000 yrs) Cardio- vascular events per (1000)/p-yLower CI*Upper CI* Normal60,4515, SCH3, OH2,

Association between TSH category and CVD events

Cox regression CVD events Thyroid category UnadjustedAdjusted* Normal1.00 (reference) SCH1.96 ( )1.22 ( ) OH2.33 ( )1.58 ( ) *After adjustment for age, gender, ethnicity and deprivation

<65 years v.s. ≥65 years CVD events

Conclusion for survival analysis Although absolute risk is higher, the excess risk of cardiovascular events in 65 year plus age group is 1.14 in patients with subclinical hypothyroidism compared with 1.26 in those under 65 years. This suggests that the expected benefit of treatment is likely to be greatest in those under 65 years.

What is the effectiveness of thyroxine in reducing cardiovascular risk factors in patients with subclinical hypothyroidism The aim of this systematic review is to examine the relationship between levo-thyroxine treatment and cardiovascular risk factors in individuals with SCH within the TSH range of mIU/L.

Search criteria and study selection Studies from Medline and EMBASE (1506) Reviewed by title and abstract (1081) Full-length articles reviewed (79) Further excluded (69) Excluded (425) Included (10) Excluded(1002)

Participants 669 SCH patients involved in 10 RCTs Majority were female (74.9%) Mean age range was 32 – 64 years Anti-thyroid antibodies positive in all or some Mean TSH ranged from 5.3 – 10.9 mIU/L

Total Cholesterol (mmol/L) improvement We found a reduction in total cholesterol of 0.13 mmol/L. A reduction in total cholesterol of 10% may reduce cardiovascular mortality by 20% 491.

LDL (mmol/L) improvement There was a modest reduction in low-density lipoprotein of 0.29 mmol/L, which equates to a 10-12% reduction in coronary heart disease 20.

Systolic BP (mm/Hg) improvement Systolic blood pressure was reduced by >3mm Hg. A 5% reduction in cardiovascular death over 10 years would result from a 3 mmHg reduction 15.

Adverse effects One study: anxiety, depression and general health questionnaires administered to 34 participants (20 on tx) 80% of participants on LT 4 thought they were on placebo and 7% on placebo thought they were on LT 4 Studies that showed changes in symptoms such as anxiety, depression, tiredness and libido did not reach statistical significance.

Conclusions Clinical evidence demonstrates that a raised TSH has adverse outcomes on cardiovascular event rates Treating patients who have SCH addresses one of the causes of abnormality and is likely to benefit cardiovascular risk Evidence is presented that supports the prescribing of levo-thyroxine treatment to individuals less than 65 years of age with subclinical hypothyroidism