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 (1997-2006) 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 populationNormal SCH OH

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) (%)

CHD 2,656 (42.0) 2,172 (41.4) 251 (44.1) 233 (46.2)

PVD 1,540 (24.4) 1,332 (25.4) 114 (20.0) 94 (18.7)

CVA 1,198 (19.0) 1,011 (19.3) 108 (19.0) 79 (15.7)

HF 924 (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-y Lower CI* Upper CI*

Normal 60,451 5,245 304.29 17.24 16.78 17.71

SCH 3,587 569 16.78 33.91 31.23 36.81

OH 2,594 504 12.51 40.29 36.92 43.97

Association between TSH category and CVD events

0.00

0.10

0.20

0.30

0.40

0 2yrs 4yrs 6yrs 8yrs 10yrs1997-2006

Normal SCHOH

Cox regression CVD events

Thyroid category Unadjusted Adjusted*

Normal 1.00 (reference) 1.00 (reference)

SCH 1.96 (1.80 - 2.14) 1.22 (1.12-1.33)

OH 2.33 (2.13-2.56) 1.58 (1.44-1.73)

*After adjustment for age, gender, ethnicity and deprivation

<65 years v.s. ≥65 years CVD events0.

000.

100.

20Pr

opor

tion

failin

g (C

VD e

vent

)

1593 1295 1008 676 342OH2109 1695 1253 857 415SCH49286 41589 30733 19721 9397Normal

Number at risk

0 2 4 6 8Years since entry

Normal SCHOH

0.00

0.20

0.40

0.60

Prop

ortio

n fa

iling

(CVD

eve

nt)

1001 708 502 326 142OH1478 1088 700 439 184SCH11165 8868 6132 3729 1584Normal

Number at risk

0 2 4 6 8Years since entry

Normal SCHOH

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 5-10 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

Study or Subgroup

Duman 2007Iqbal 2006Kong 2002Mikhail 2008Nagasaki 2009Razvi 2007

Total (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 3.04, df = 5 (P = 0.69); I² = 0%Test for overall effect: Z = 3.58 (P = 0.0003)

Mean [mmol/L]

5.23185.75.7

5.055.195.7

SD [mmol/L]

0.731.1

1.010.980.16

1

Total

2032166048

100

276

Mean [mmol/L]

5.23185.8

5.625.045.33

6

SD [mmol/L]

0.730.9

0.730.670.24

1

Total

1932116047

100

269

Weight

2.6%2.2%1.3%6.0%

80.7%7.1%

100.0%

IV, Random, 95% CI [mmol/L]

0.00 [-0.46, 0.46]-0.10 [-0.59, 0.39]0.08 [-0.58, 0.74]0.01 [-0.29, 0.31]

-0.14 [-0.22, -0.06]-0.30 [-0.58, -0.02]

-0.13 [-0.21, -0.06]

Treatment Control Mean Difference Mean DifferenceIV, Random, 95% CI [mmol/L]

-1 -0.5 0 0.5 1Favours treatment Favours control

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

Study or Subgroup

Duman 2007Iqbal 2006Kong 2002Mikhail 2008Nagasaki 2009Razvi 2007

Total (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 2.37, df = 5 (P = 0.80); I² = 0%Test for overall effect: Z = 5.12 (P < 0.00001)

Mean [mmol/L]

3.3673.6

3.49652.893.143.4

SD [mmol/L]

0.830.9

1.50220.590.290.8

Total

2032166048

100

276

Mean [mmol/L]

3.31523.6

3.60013.113.363.7

SD [mmol/L]

0.831

1.60580.770.190.9

Total

1932116047

100

269

Weight

2.5%3.1%0.5%

11.3%70.4%12.2%

100.0%

IV, Random, 95% CI [mmol/L]

0.05 [-0.47, 0.57]0.00 [-0.47, 0.47]

-0.10 [-1.30, 1.10]-0.22 [-0.47, 0.03]

-0.22 [-0.32, -0.12]-0.30 [-0.54, -0.06]

-0.22 [-0.30, -0.13]

Treatment Control Mean Difference Mean DifferenceIV, Random, 95% CI [mmol/L]

-1 -0.5 0 0.5 1Favours treatment Favours control

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

Study or Subgroup

Mainenti 2009Monzani 2001Nagasaki 2009Razvi 2007

Total (95% CI)

Heterogeneity: Chi² = 4.31, df = 3 (P = 0.23); I² = 30%Test for overall effect: Z = 4.31 (P < 0.0001)

Mean [mm Hg]

154.6117.3128.8132.8

SD [mm Hg]

23.96.83.8

22.8

Total

121048

100

170

Mean [mm Hg]

142.3116.8132.2134.6

SD [mm Hg]

18.29.63.5

22.9

Total

111047

100

168

Weight

0.7%3.7%

90.8%4.9%

100.0%

IV, Fixed, 95% CI [mm Hg]

12.30 [-4.98, 29.58]0.50 [-6.79, 7.79]

-3.40 [-4.87, -1.93]-1.80 [-8.13, 4.53]

-3.08 [-4.47, -1.68]

Treatment Control Mean Difference Mean DifferenceIV, Fixed, 95% CI [mm Hg]

-10 -5 0 5 10Favours treatment Favours control

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 LT4 thought they were on placebo and 7% on placebo thought they were on LT4

• 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