cardiovascular complications of thyroid dysfunction · cardiovascular complications of thyroid...

CardiovascularCardiovascular complicationscomplications of of thyroidthyroid dysfunctiondysfunction

Brigitte VelkeniersDepartment of Internal Medicine-EndocrinologyUZ-Brussel Free University of Brussels (VUB)

titel2 16-12-2007Klein I, Circulation, 2007

titel3 16-12-2007

Direct effects of T3

on the heart

titel4 16-12-2007

KleinN Engl J Med2001

titel5 16-12-2007

T3 and contractile events:

inotropic effects (related to contraction)

lusitropic effects (related to relaxation)T3 markedly shortens diastolic relaxation .

The hyperthyroid heart relaxes with a higher speed, whereas diastole is prolonged in hypothyroid states(lusitropic activity)

titel6 16-12-2007

Klein , N Engl J Med, 2001

titel7 16-12-2007

Effects of treatment of hyperthyroidism on cardiovascular morbidity and mortality

Subclinical thyroid dysfunction and the cardiovascular system

titel8 16-12-2007

Hyperthyroidism and the cardiovascular system

Cardiac arrhytmia and hyperthyroidism

Long term morbidity and mortality of treated

hyperthyroidism

Effects of subclinical hyperthyroidism on the

CV system (to treat or not to treat ?)

titel9 16-12-2007

Hyperthyroidism and the heart

Parry 1786

“ There is one malady which I have in five cases seen, coincident with what appeared enlargement of the heart , and which, so far as I know has not been noticed in that connection, by medical writers. The malady to which I allude is enlargement of the thyroidgland “

titel10 16-12-2007

Cardiac symptoms in hyperthyroid patients

chronotropic alterations: sinus tachycardiaatrial fibrillationshortened PR intervals

inotropic alterations: increased CIincreased stroke volumedecreased ejection perioddiastolic relaxation shortened

titel11 16-12-2007

Main symptoms: palpitations

increase in heart rate

maintained circadian rhythm of heart rate

increased heart rate variability

increased incidence of atrial fibrillation (AF)

ventricular arrhytmia = rare in patients without

cardiac disease

24 h ECG recordings

titel12 16-12-2007

Cellular mechanisms of AF and hyperthyroidism

Genomic and non genomic actions on atrialion channelsEnlargement of atrium as a result of the expanded blood volumeHigh prevalence of pulmonary hypertension ( no effect on pulmonary vasculature) and atrioventricular valve regurgitation(65 % of patients with Graves’ disease were found to have PAHT) Marvisi et al, Eur J Intern Med, 2006

titel13 16-12-2007

Prevalence of AF

10-15 % of hyperthyroid patients develop AF , risk increases with age

Prevalence of hyperthyroidism in newly diagnosed AF:< 1 – 15 %

(Nakazawa et al, 2000; Forfar et al , 1979)

Screening for TSH:American College of Cardiology and American Heart Association(ACC – AHA)Task ForceN Engl J Med, Page RL 2004

titel14 16-12-2007

Is the frequency of stroke and systemic embolismincreased in thyrotoxic AF? Very controversial

Thrombo-embolic risk in thyrotoxic AF increases with

age

men

o associated cardiomyopathy (ischemic or valvular disease,congestiveheart failure)

Danish National Registry

No controlled studies have evaluated the impact of anticoagulation onmorbidity and mortality

titel15 16-12-2007

Only one study included treated patients with hyperthyroidismAFASAK study Peterson, lancet 1989Thromboembolic events :16 in warfarin arm (5%)12 in aspirin arm (4%)13 in placebo group ( 4%)Insufficient to draw conclusions

titel16 16-12-2007

Antithrombotic therapy should be chosen based on associated risks and the risk of bleeding, as stated by international guidelines

titel17 16-12-2007

Objectives of treatment

Rhythm control (β-blockade)

treatment of hyperthyroidism (anti-thyroid drugs, I131)

titel18 16-12-2007

Shimizu et al, Thyroid, 2002

Timing of spontaneous restoration to sinus rhythmafter attainment of euthyroidism

titel19 16-12-2007

Shimizu et al, Thyroid, 2002

Proportion of patients remaining in sinus rythm with timeafter cardioversion

titel20 16-12-2007

Hyperthyroid-tachycardiomyopathyRate related left ventricular dysfunction and heart failure

Pre cardioversion Post cardioversion

With the courtesy of Prof Guy Van Camp

titel21 16-12-2007

Hyperthyroidism and left ventricularhypertrophy and mortality

Left VH = risk factor for:

ischemic heart disease

CVA

heart failure

ventricular arrhytmia

sudden death

titel22 16-12-2007

Dorr et al., JCEM, 2005Association of hyperthyroidism and Left Ventricular HypertrophyCross sectional survey in West-Pomerania , Germany1510 participants

1.5% 0.5%13.3%

titel23 16-12-2007

Dorr et al., JCEM, 2005Association of hyperthyroidism and Left Ventricular Hypertrophy OR and 95% CICross sectional survey in West-Pomerania , Germany1510 participants

titel24 16-12-2007

Follow-up after treatment of hyperthyroidism: morbidity en mortality

titel25 16-12-2007

Main studies on cardiovascular mortality in treated overt hyperthyroidism

Increase in all cause mortality (SMR, 1.3; 95% CI, 1.2-1.4), risk of fatal events due to circulatory system disease (SMR, 1.4; 95% CI, 1.3-1.6)

Mortality data and causes of death compared with data on age-specific mortality

1763 hyperthyroid subjects, treated with radioactive iodine

Retrospective cohort-studyPart of the Cooperative ThyrotoxicosisTherapy follow up Study17.2 years follow-up

Goldman et al 1988USA

Main outcomeMain measures

SubjectsDesignStudy

titel26 16-12-2007

Increased risks of cardiovascular diseases in toxic goiter (RR, 1.50; 95% CI, 1.11-2.02) and Graves’ disease (1.42; 95% CI, 1.20-1.67) despite restoration of euthyroidism

Number of hospitalizations for cardio or cerebrovascular disease or death compared to matched control patients

2230 patients with toxic multinodulargoiter or Graves’disease

Retrospective (medical records), case-control study; 20-year follow-up

Nyirenda et al 2005Scotland

Increased risk of death from cardiovascular disease (SMR 1.65; 95% CI, 1.59-1.71)

Causes of death matched with a cause of death register (matched)

10000 hyperthyroid patients after radioiodine treatment

Case-control study; 15-year follow-up

Hall et al 1993Sweden

Main outcomeMain measuresSubjectsDesignStudy


titel27 16-12-2007


Increase in all cause mortality (SMR, 1.1; 95% CI, 1.1-1.2), risk of fatal events due to cardiovascular disease (SMR, 1.2; 95% CI, 1.2-1.3), and cerebrovascular disease (SMR, 1.4; 95% CI, 1.2-1.5)

Mortality data and causes of death compared with data on sex –and age-specific mortality

7209 hyperthyroid subjects, treated with radioactive iodine

Retrospective Population-based cohort-study

At least 7 years and some patients 40 years105028 person years of follow-upMean follow-up 14.6 years

Franklyn et al 1998UK


titel28 16-12-2007

1. Increased all-cause (SMR, 1.14; 95 % CI, 1.04-1.24) and cardiovascular mortality (SMR 1.19; 95% DI 1.05-1.35) in hyperthyroid patients.

2. Decreased all-cause, mortality (HR, 0.65; 95% CI 0.54-0.79) and circulatory mortality (HR, 0.65; 95% CI, 0.48-0.87) during T4 therapy of post radioiodine hypothyroidism compared to periods without T4 substitution.

1. Causes of death compared with age- and period-specific mortality

2. Influence of T4 therapy and subclinical thyroid dysfunction on mortality

2668 individuals with overt hyperthyroidism, aged 40 years or older, treated with radioiodine

Population-based surveyUK

Mean follow-up 6 years

Franklyn et al 2005

UK



titel29 16-12-2007

No increase in all-cause mortality or cardiovascular mortality.Increased risk of arrhytmiaSIR: 2.71 (1.63-4.24)

All cause mortalityCardiovascular events compared with data on age-specific mortality and morbidity

3888 hyperthyroid patients

Population based cohort –study


Flynn et al2006

UK



titel30 16-12-2007

1. Increased all-cause mortality in treated hyperthyroid patients. RR 1.12 (CI 1.03-1.20) only in patients older 60 years., in patients with nodular thyroid disease but not in patients with Graves’disease

2. Increased CV mortality (RR1.19 (CI 1.07-1.32) cerebrovascular disease mortality (RR 1.40)

3. Decreased all-cause mortality with development of hypothyroidism that was treated

( RR 0.52)

1. Causes of death compared to controls

2. Mortality of patients with Graves’ disease compared to multinodulargoiter

2793 individuals with overt hyperthyroidism, treated with radioiodine compared to 2793 reference subjects

Prospective Case control study


Mesto et al 2007

Finland



titel31 16-12-2007

Overt hyperthyroidism Conclusions

Hyperthyroidism increases CV morbidity ( AF, Le VH) and mortality

In those who have been treated for hyperthyroidism the increasedrisk of arrhythmia persists with increased CV mortality (cerebrovascular and cardiovascular disease) in some (Franklyn, Metso) but not all studies (Flynn ).

The increased mortality is probably explained by hyperthyroidismResults based on 4 different populations (USA, Sweden, Finland, UK)

Most patients with increased CV risks had multinodular goiter and were treated with higher doses of radioiodine

Levothyroxine - treated hypothyroidism after radioiodine seems to protect against excess mortality (Franklyn, Metso)

titel32 16-12-2007

A 67 year old woman presents with palpitations and is found to be in atrial fibrillation at a rate of 120 beats per minute. The only other finding on physical examinationis a goiter, which is known to be long-standing. Echocardiography shows neither valvular disease nor left ventricular systolic dysfunction. The serum TSH is less than 0.05 mU/l, and the serum fT3 and FT4 concentrations are in the normal range. Should the thyroid dysfunction be treated?

“clinical vignette”

titel33 16-12-2007

SUBCLINICAL HYPERTHYROIDISM

Definition:TSH below normal range usually suppressed ,normal fT4 fT3

Etiology:Exogenous subclinical hyperthyroidismAsssociated with LT4 therapyEndogenous subclinical hyperthyroidismGraves’ diseaseMultinodular goitreAutonomously functioning noduleActivating mutations of TSH R Bieberman et al. 2001Transient:Thyroiditis de Quervain, silent, postpartumDrug induced amiodarone, interferon

dd low TSHNon thyroidal illness , dopamine , corticosteroids

titel34 16-12-2007

SUBCLINICAL HYPERTHYROIDISM

PrevalenceVaries according to iodine intake, age and functional sensitivity of TSH assay

Parle et al. 1991 6%Sawin et a. 1994 1.8Hollowel et al 2002 0.7%after exclusion of patients with thyroid disease

Approximately 25% of patients on LT4 have low TSH

PROGRESSION TO OVERT HYPERTHYROIDISMWiersinga et al.1995 5% per yearSanrock et al.1993 4% per yearSawin et al. 1991 3 % over 4 years

with autonomously functioning nodules

Persons with low but detectable TSH may recover spontaneously

titel35 16-12-2007

Serum thyrotropin measurement in the communityMeyerovitch et al Arch Intern Med, 2007

422242 patients included

No history or treatment for thyoid disorders

95 % normal TSH( 0.35-5.5 mU/l), 1.2% decreased TSH (< 0.35 mU/l), 3 % were elevated (< 5.5-10 mU/L), 0.7 % were highly elevated (< 10 mu/l)

After 5 years of follow-up in the group with suppressed TSH 51.2% became normal

titel36 16-12-2007Copyright restrictions may apply.Meyerovitch, J. et al. Arch Intern Med 2007;167:1533-1538.

Distribution of second thyrotropin (TSH) results compared with the category of the first TSH measurement in patients with no medical treatment between measurements

titel37 16-12-2007

SUBCLINICAL HYPERTHYROIDISMAND CARDIOVASCULAR MORBIDITY AND MORTALITY

Rationale for therapy?

titel38 16-12-2007

Subclinical Hyperthyroidism and hypertension Walsh et al, Clin Endocrinol, 2006

Cross-sectional study of 2033 participants in the Busselton Thyroid Study with no history of thyroid disease

SBP, DBP and prevalence of hypertension

The prevalence of hypertension was higher in a group of subjects with subclinical hyperthyroidism ( n= 35) than in euthyroid patients OR 2.8 ( CI 1.3-6.0)

titel39 16-12-2007

CV Morbidity: Left ventricular hypertrophy in subclinical hyperthyroidism ?

Biondi et al MGullu et al Mercuro et al Cardiac mass increase- posterior wall thickening- interventricular wall thickening- left ventricular mass increased- decreased isovolumetric relaxation time- decreased exercise capacity

Dorr et al. Cross-sectional population based study, 2005Doppler echocardiography : no increased incidence in LVMI (left

ventricular mass index)

Iqbal et al., Cross-sectional population based study,2007Transthoracal echography : No change in LVMI Changes in myocardial velocities measured by PTWD pulsed waved

tissue doppler (= diastolic dysfunction)

titel40 16-12-2007

AF and subclinical hyperthyroidism

Tenerz et al, J Int Med, 1990

Prevalence AF: 8/40 patients

follow-up 2 years: + 3 patients

= 11/40 = 28 % subclinical hyperthyroidism

10 % euthyroid patients

titel41 16-12-2007

Sawin et al, N Engl J Med, 1994

2007 individuals of the Framingham Cohort

≥ 60 years, no AF at the start of the study

61 persons : TSH ≤ 0.1 mU/L

187 persons : TSH 0.1 – 0.4 mU/L

1576 persons: TSH 0.4 – 5 mU/L

183 persons: TSH ≥ 5 mU/L

titel42 16-12-2007

TSH < 0.1 mU/L 21 % 3 RR

TSH 0.1 – 0.4 mU/L 18 % 1.8

normal TSH 8 %

Sawin et al, N Engl J Med, 1994

titel43 16-12-2007

Auer et al, Lancet, 2002

23 638 patients613 subclinical hyperthyroidism (TSH < 0.4 mU/L)

AF

513 with normal TSH: 2.3 % RR78 with TSH ≤ 0.4: 12.7 % 5.2 (2.1 – 8.7)

After correction for age, other risk factors(hypertension, LVH, cardiomyopathy)

3No follow-up of cardiovascular morbidity, mortality

titel44 16-12-2007

Gammage et al, Arch Intern Med 2007

5860 subjects 65 years and olderMain outcome measures: thyroid function ( fT4 and TSH) and the presence of AF on resting ECG126 (2.2%) had subclinical hyperthyroidismIncreased prevalence of AF in patients with subclinical hyperthyroidism, compared to euthyroid individuals ( 9.5 % vs 4.7%) OR 2.27 Logistic regression showed fT4 concentration to be independently associated with risk of AF (even in euthyroid patients with normal TSH)

titel45 16-12-2007

Mortality: Parle et al, Lancet, 2001

1191 persons ≥ 60 years, without T4 treatment, noantithyroid drugsserum TSH measured“baseline” , follow-up: 10 years

Standardized mortality ratio (SMR)

2.1 (1 – 4.5) after 2 years

2.2 (1.2 – 4) after 3 years

1.9 4 years

2 5 years

↑ mortality= ↑ mortality of cardiac and cerebrovascularevents

titel46 16-12-2007

SUBCLINICAL HYPERTHYROID.

EXCESS VASCULAR MORTALITYCommunity basedcohort study :1160 patients aged 60 years or over not receiving T4 therapy or antithyroidmedications withsubclinicalhyperthyroidismfollowed over 10 yearsParle et al. 2000

An estimate of relative and absolute excess mortality from all causes based on data searches and time-to-event meta-analysis of cohort studies

Seven cohorts = 290 patients with subclinical hyperthyroidism

All Cause mortality and subclinical hyperthyroidism

Pooled HR 1.72 ( 1.35-2.19)

Absolute excess mortality calculated for US women and menCalculated with pooled HR and standard life table methods applied to a US reference population

titel54 16-12-2007

Subclinical hyperthyroidism and CV system

Subclinical hyperthyroidism increases CV morbidity(AF ) and overall mortality

All cause mortality was increased two –fold The absolute excess mortality largely depends on age of diagnosis.

In contrast to all cause mortality ,mortality of coronary artery disease was not increased .

No placebo controlled studies on mortality after the treatment of subclinical hyperthyroidism.

titel55 16-12-2007

The patient of the “vignette”

Surks et al., JAMA, 2004

titel56 16-12-2007

Hypothyroidism and the CV system

Subclinical hypothyroidism and the CV system

Effects of treatment of hypothyroidism on CV system

titel57 16-12-2007

Hypothyroidism and the CV system

Sir Dr William Smith Greenfield 1878

“ There was edema of the skin - much serous effusion

in the pericardium…the heart was large…the arteries

were everywhere thickened , the larger one

atheromatous ”

titel58 16-12-2007

Clinical Hypothyroidism

BradycardiaMild hypertensionNarrowed pulse pressureDecreased cardiac contractilityAccelerated atherosclerosisCoronary atherosclerosisProlongation of the QT interval with ventricular irritability (rarely torsade de pointes)

titel59 16-12-2007

A 69-year old woman is found to have a serum TSH of 7.9 mU/l on routine screening. Her only symptomsare mild fatigue, which has been present for more than 10 years , and difficulty losing weight. The results of the physical examination are normal, exceptfor a small, firm thyroid with a slightly irregularsurface. The serum cholesterol level is 220 mg/ dl, the LDL-C is 140 mg/dl, and a test for antibodiesagainst thyroperoxydase is positive. Should treatment with thyroxine be initiated?

“clinical vignette”

titel60 16-12-2007

Age-specific Distribution of Serum TSH and Thyroid antibodies in the United States Population ; Implications of subclinical hypothyroidism J CEM , 2007 Surks MI, Hollowell JG

“TSH distribution progressively shifts toward higher concentrations with age. The prevalence of subclinical hypothyroidism may be significantly overestimated unless an age-specific range for TSH is employed”

titel61 16-12-2007

Hypothyroidism (clinical and subclinical) and CV morbidity and mortality

Experimental data suggest that hypothyroidism may prolong life span in different animal models (reduced metabolic rate)

Overt hypothyroidism is associated with major CV risk factors such as hypertension, dyslipidemia, systemic inflammation, and insulin resistance.

Similar effects on cardiometabolic risk factors have been reported for subclinical hypothyroidism

titel62 16-12-2007

Lipids

Cross sectional data: conflicting results : total cholesterol values in patients with subclinical hypothyroidism are similar to those of normal subjects

Colorado survey: statistically higher total and LDL cholesterol in subjects withMild thyroid failure vs. Euthyroid subjects ( TC 224 mg/dl, vs.216mg/dl)

Dia JCEM Mc Dermott fig3

Canaris et al., 2000

titel63 16-12-2007

Hak et al., Ann Intern Med, 2000

Association of aorta atherosclerosis and myocardial infarction is strongerin subclinical hypothyroidism and associated thyroid autoimmunity

titel64 16-12-2007Hak at al. 2000

titel65 16-12-2007

Subclinical hypothyroidism and the risk of coronary heart disease : A meta-analysis Rodondi et al, AJM, 2006

Systematic review of all available data till April 2005

titel66 16-12-2007

Subclinical hypothyroidism and the risk of coronary heart disease : A meta-analysis Rodondi et al, AJM, 2006

Review indicates that subclinical hypothyroidism is

associated with an increased risk of CHD (summary

OR for coronary artery disease: 1.81 (1.38-2.39)

Did not include the Gussekloo paper and three newly

published articles ( Walsch, Rodondi, Cappola)

titel67 16-12-2007

Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all cause mortality Singh et al In J Cardiol, 2007

Prevalence at baseline

titel68 16-12-2007


Risk of developing CHD

titel69 16-12-2007


All cause mortality

titel70 16-12-2007

The relation of thyroid dysfunction with all-cause and circulatory mortalityVolzke et al, J Clin Endocrinol Metab, 2007

Pooling of studies revealed a NS HR for circulatory disease HR 1.21 ( 0,86- 1.69)Pooling of studies revealed a S HR for all-cause mortality HR 1.25 ( 1.03- 1.53)

An estimate of relative and absolute excess mortality from all causes based on data searches and time-to-event meta-analysis of cohort studies

Seven cohorts = 1580 patients with subclinical hypothyroidism

All Cause mortality and subclinical hypothyroidism

HR 1.03 (CI 0.78-1.35)In cohorts from the communityHR 1.76 ( CI 1.36- 2.30)In cohorts with comorbidities

titel75 16-12-2007

Discrepancies among meta-analyses

All analyses quoted heterogeneity

Different end point analysed ( CV mortality or all cause mortality)

Data analysis of different publications may give some clues (severity of subclinical dysfunction, age of the population, comorbidity…) to the detrimental effects of subclinical hypothyroidism

titel76 16-12-2007

The Fremantle Diabetes studyAustraliaChubb et al,clin Endocrinol 2006

Subclinical hypothyroidism and mortality in women with type 2 diabetes

Mild thyroid dysfunction in cardiac patientsItalyIervasi et Arch Intern Med 2007

Subclinical hypothyroidism and mortality in patients with heart disease

Interaction of subclinical hypothyroidism with other CV risk factors on CV related- and total mortality

titel77 16-12-2007

Gussekloo et al, JAMA, 2004

Prospective follow-up of 85 years old in Leiden

599 participants

Aims: to determine the impact of subclinical thyroid dysfunction

on performance and survival in old age

Prevalence of subclinical hypothyroidism: 12 %

After 4 years of follow-up:

Lower cardiovascular mortality + morbidity

subclinical hyperthyroidism: ↑ CV mortality

titel78 16-12-2007

Gussekloo et al., JAMA, 2004

Fig 2 cumulative mortality of participants

titel79 16-12-2007

Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease Walsh et al, Arch Intern Med, 2005

2108 subjects measurement of TSH and fT4

Cross sectional analysis of coronary artery disease

Longitudinal follow-up of cardiovascular mortality and

coronary artery events after a mean follow-up of 20

years

119 subjects with subclinical hypothyroidism

Mean age 51,3 years

titel80 16-12-2007

Prevalence Odds Ratios for Coronary Heart Disease in the Cross-sectional Analysis of All Subjects*

Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease , according to category of TSH elevationWalsh et al, Arch Intern Med, 2005 Cross-sectional data

titel81 16-12-2007

Hazard Ratios for Coronary Heart Disease Events (Fatal and Nonfatal) in the Longitudinal Analysis of Subjects Free of Coronary Heart Disease at Baseline*

Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease ,according to category of TSH elevationWalsh et al, Arch Intern Med, 2005

titel82 16-12-2007

Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease Walsh et al, Arch Intern Med, 2005Conclusions

At entry the prevalence of CHD was significantly increased after adjustment for age and sex in severe subclinical hypothyroidism ( TSH > 10 mU/l), but not in patients with mild to moderate hypothyroidism ( TSH 4.1- 10 mU/l)During the 20 years of follow-up ; the incidence of CHD disease was significantly increased in patients with severe SH ,whereas the increase was of borderline significance in the group with mild SHNo increased incidence of mortality from CVD in patients with SH of any degree

titel83 16-12-2007

Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events and deathRodondi et al , Arch. Intern Med, 2005

2730 men and women aged 70 to 79 years of age

4 years of follow-up

End-points: congestive heart failure, coronary artery

disease, stroke, peripheral arterial disease

Cardio-vascular-related and total mortality

titel84 16-12-2007

Cumulative congestive heart failure (CHF) events in older subjects according to thyrotropin (TSH) levels

titel85 16-12-2007

Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events and death, according to category of TSH elevation Rodondi et al , Arch. Intern Med, 2005

Subclinical Hypothyroidism and the Risk of Cardiovascular-Related and Total Mortality NS

titel86 16-12-2007

Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events and deathConclusions Rodondi et al , Arch. Intern Med, 2005

At entry, no association existed between SH and the prevalence of CVD including congestive heart failure (CHF)

The incidence of CHF during the 4 year follow-up period was significantly increased in patients with moderate (TSH: 7-9.9 ) and severe SH (TSH > 10 mU/L), but not in patients with mild SH (TSH ,4.5-6.9 mU/L)

No association with increased death from CVD or the risk of incident CHD

titel87 16-12-2007

Interventional studies and effects on atherosclerosis

Angiographic studyPerk et al. Can J Card 1997greater progression of coronary atherosclerosis in subclinical hypothyroidism compared to patients withnormal TSH

One underpowered study did not show an increase in cardiovascular morbidity and mortality in patients treatedwith T4 (only 29 patients , follow-up :12 years)Peterson et al.,Arch Intern Med , 1990

No placebo controlled trial available

titel88 16-12-2007

SUBCLINICAL HYPOTHYROIDISMConclusions

Taken together the studies suggest that the incidence of cardiovascular disorders may be increased in subclinical hypothyroidism, particularly those with a TSH > 10 mU/L

The data support the idea that patients under 80 yearswith TSH > 10 mU/ L may benefit from treatment, but this remains to be proved in prospective randomized trials

The studies also suggest that subjects with mild SH ( TSH < 10mU/L) and patients older than 80 years show no increased CVD risk and that treatment would probably not be beneficial in the prevention of CVD

titel89 16-12-2007

Mortality and vascular outcomes in patients treated for thyroid dysfunctionFlynn et al., JCEM, 2006

15889 patients treated for hypothyroidism between 1993 and 2001. Incident cases : 7904 patients

Primary outcome :All cause mortality (SMR)Circulatory mortality and cancer mortality (SMR)

Secondary end points:Serious vascular events , circulatory disease and cerebrovascular disease ( SIR= standardized incidence ratio )

titel90 16-12-2007

Mortality and vascular outcomes in patients treated for thyroid dysfunctionFlynn et al., JCEM, 2006

Prevalence of treated hypothyroidism: 3.4%8.4 % of these patients had diabetes ( three times increased risk)Over 8 years mortality : SMR 1.03 (CI 0.99-1.07) : ns excess of 73 deaths, but there was an increase in cardiovascular disease mortality : 1.11( CI 1.00-1.23)Over 8 years serious vascular events :SIR 1.10 (CI 1.06-1.15 ): s. excess of 181 cases, adjusted for age, sex and diabetesOver 8 years there was an increased morbidity related to ischemic heart disease, dysrhythmias and cerebrovascular disease

titel91 16-12-2007

Mortality and vascular outcomes in patients treated for thyroid dysfunction . ConclusionsFlynn et al., JCEM, 2006

Despite treatment for primary hypothyroidism with T4 patients are at increased risk of morbidity associated with vascular disease.

This risk is ongoing beyond the initial years of treatment

Biological explanations:Primary hypothyroidism was diagnosed late.Treatment with T4 may not fully reverse the atherosclerosis process

Treatment with T4 was not optimal ( normal TSH)

titel92 16-12-2007

Mortality and vascular outcomes in patients treated for thyroid dysfunction

Shortcomings of the studyFlynn et al., JCEM, 2006

Reliance on SMR record-linkage (general practitioners)No adjustments for concurrent medications , ie statins

Unadjusted confounders ie smoking

titel93 16-12-2007

Subclinical hypothyroidism :To treat?

High risk of progression to clinical hypothyroidism

Data on cardiovascular morbidity and mortality are controversial

dyslipidemia, endothelial dysfunction, hypercoagulation,

↓ fibrinolysis = substrates for ↑ cardiovascular mortality

No placebo-controlled studies on hard clinical endpoints (CV mortality en morbidity)

Only placebo controlled studies on surrogate endpoints:cholesterol- endothelial function- carotis intima media thickness

( Razvi et al, J CEM, 2007)

titel94 16-12-2007

The patient of the “vignette”

Surks et al., JAMA, 2004

Sufficient

Sufficient

Sufficient :Razvi et al, 2007

Subclinical thyroid dysfunction and the heartDifficult exercise

cardiovascular complications of thyroid dysfunction · cardiovascular complications of thyroid...

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