Cardiovascular complications of thyroid dysfunction

Transcription

1 Cardiovascular complications of thyroid dysfunction Brigitte Velkeniers Department of Internal Medicine-Endocrinology UZ-Brussel Free University of Brussels (VUB)

2 2 titel Klein I, Circulation, 2007

3 Direct effects of T 3 on the heart 3 titel

4 Klein N Engl J Med titel

5 T 3 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) 5 titel

6 Klein, N Engl J Med, titel

7 Effects of treatment of hyperthyroidism on cardiovascular morbidity and mortality Subclinical thyroid dysfunction and the cardiovascular system 7 titel

8 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?) 8 titel

9 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 thyroid gland 9 titel

10 Cardiac symptoms in hyperthyroid patients chronotropic alterations: sinus tachycardia atrial fibrillation shortened PR intervals inotropic alterations: increased CI increased stroke volume decreased ejection period diastolic relaxation shortened 10 titel

11 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 11 titel

12 Cellular mechanisms of AF and hyperthyroidism Genomic and non genomic actions on atrial ion channels Enlargement of atrium as a result of the expanded blood volume High 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, titel

13 Prevalence of AF % 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 Force N Engl J Med, Page RL titel

14 Is the frequency of stroke and systemic embolism increased in thyrotoxic AF? Very controversial Thrombo-embolic risk in thyrotoxic AF increases with age men o associated cardiomyopathy (ischemic or valvular disease,congestive heart failure) Danish National Registry No controlled studies have evaluated the impact of anticoagulation on morbidity and mortality 14 titel

15 Only one study included treated patients with hyperthyroidism AFASAK study Peterson, lancet 1989 Thromboembolic events : 16 in warfarin arm (5%) 12 in aspirin arm (4%) 13 in placebo group ( 4%) Insufficient to draw conclusions 15 titel

16 Antithrombotic therapy should be chosen based on associated risks and the risk of bleeding, as stated by international guidelines 16 titel

17 Objectives of treatment Rhythm control (β-blockade) treatment of hyperthyroidism (anti-thyroid drugs, I 131 ) 17 titel

18 Timing of spontaneous restoration to sinus rhythm after attainment of euthyroidism Shimizu et al, Thyroid, titel

19 Proportion of patients remaining in sinus rythm with time after cardioversion Shimizu et al, Thyroid, titel

20 Hyperthyroid-tachycardiomyopathy Rate related left ventricular dysfunction and heart failure Pre cardioversion Post cardioversion With the courtesy of Prof Guy Van Camp 20 titel

21 Hyperthyroidism and left ventricular hypertrophy and mortality Left VH = risk factor for: ischemic heart disease CVA heart failure ventricular arrhytmia sudden death 21 titel

22 1.5% 13.3% 0.5% Dorr et al., JCEM, 2005 Association of hyperthyroidism and Left Ventricular Hypertrophy Cross sectional survey in West-Pomerania, Germany 1510 participants 22 titel

23 Dorr et al., JCEM, 2005 Association of hyperthyroidism and Left Ventricular Hypertrophy OR and 95% CI Cross sectional survey in West-Pomerania, Germany 1510 participants 23 titel

24 Follow-up after treatment of hyperthyroidism: morbidity en mortality 24 titel

25 Main studies on cardiovascular mortality in treated overt hyperthyroidism Study Design Subjects Main measures Main outcome Goldman et al 1988 USA Retrospective cohort-study Part of the Cooperative Thyrotoxicosis Therapy follow up Study 17.2 years follow-up 1763 hyperthyroid subjects, treated with radioactive iodine Mortality data and causes of death compared with data on agespecific mortality Increase in all cause mortality (SMR, 1.3; 95% CI, ), risk of fatal events due to circulatory system disease (SMR, 1.4; 95% CI, ) 25 titel

26 Main studies on cardiovascular mortality in treated overt hyperthyroidism Study Design Subjects Main measures Main outcome Hall et al 1993 Sweden Case-control study; 15-year follow-up hyperthyroid patients after radioiodine treatment Causes of death matched with a cause of death register (matched) Increased risk of death from cardiovascular disease (SMR 1.65; 95% CI, ) Nyirenda et al 2005 Scotland Retrospective (medical records), casecontrol study; 20-year followup 2230 patients with toxic multinodular goiter or Graves disease Number of hospitalizations for cardio or cerebrovascular disease or death compared to matched control patients Increased risks of cardiovascular diseases in toxic goiter (RR, 1.50; 95% CI, ) and Graves disease (1.42; 95% CI, ) despite restoration of euthyroidism 26 titel

27 Main studies on cardiovascular mortality in treated overt hyperthyroidism Study Design Subjects Main measures Main outcome Franklyn et al 1998 UK Retrospective Populationbased cohortstudy At least 7 years and some patients 40 years person years of followup 7209 hyperthyroid subjects, treated with radioactive iodine Mortality data and causes of death compared with data on sex and agespecific mortality Increase in all cause mortality (SMR, 1.1; 95% CI, ), risk of fatal events due to cardiovascular disease (SMR, 1.2; 95% CI, ), and cerebrovascular disease (SMR, 1.4; 95% CI, ) Mean follow-up 14.6 years 27 titel

28 Main studies on cardiovascular mortality in treated overt hyperthyroidism Study Design Subjects Main measures Main outcome Franklyn et al 2005 UK Populationbased survey UK Mean followup 6 years 2668 individuals with overt hyperthyroidism, aged 40 years or older, treated with radioiodine 1. Causes of death compared with age- and periodspecific mortality 2. Influence of T4 therapy and subclinical thyroid dysfunction on mortality 1. Increased all-cause (SMR, 1.14; 95 % CI, ) and cardiovascular mortality (SMR 1.19; 95% DI ) in hyperthyroid patients. 2. Decreased all-cause, mortality (HR, 0.65; 95% CI ) and circulatory mortality (HR, 0.65; 95% CI, ) during T4 therapy of post radioiodine hypothyroidism compared to periods without T4 substitution. 28 titel

29 Main studies on cardiovascular mortality in treated overt hyperthyroidism Study Design Subjects Main measures Main outcome Flynn et al 2006 UK Population based cohort study Mean follow-up 5 years 3888 hyperthyroid patients All cause mortality Cardiovascular events compared with data on agespecific mortality and morbidity No increase in all-cause mortality or cardiovascular mortality. Increased risk of arrhytmia SIR: 2.71 ( ) 29 titel

30 Main studies on cardiovascular mortality in treated overt hyperthyroidism Study Design Subjects Main measures Main outcome Mesto et al 2007 Finland Prospective Case control study Mean follow-up 9 years 2793 individuals with overt hyperthyroidism, treated with radioiodine compared to 2793 reference subjects 1. Causes of death compared to controls 2. Mortality of patients with Graves disease compared to multinodular goiter 1. Increased all-cause mortality in treated hyperthyroid patients. RR 1.12 (CI ) 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 ) cerebrovascular disease mortality (RR 1.40) 3. Decreased all-cause mortality with development of hypothyroidism that was treated ( RR 0.52) 30 titel

31 Overt hyperthyroidism Conclusions Hyperthyroidism increases CV morbidity ( AF, Le VH) and mortality In those who have been treated for hyperthyroidism the increased risk 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 hyperthyroidism Results 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) 31 titel

32 clinical vignette 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 examination is 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? 32 titel

33 SUBCLINICAL HYPERTHYROIDISM Definition: TSH below normal range usually suppressed,normal ft4 ft3 Etiology: Exogenous subclinical hyperthyroidism Asssociated with LT4 therapy Endogenous subclinical hyperthyroidism Graves disease Multinodular goitre Autonomously functioning nodule Activating mutations of TSH R Bieberman et al Transient: Thyroiditis de Quervain, silent, postpartum Drug induced amiodarone, interferon dd low TSH Non thyroidal illness, dopamine, corticosteroids 33 titel

34 SUBCLINICAL HYPERTHYROIDISM Prevalence Varies according to iodine intake, age and functional sensitivity of TSH assay Parle et al % Sawin et a Hollowel et al % after exclusion of patients with thyroid disease Approximately 25% of patients on LT4 have low TSH PROGRESSION TO OVERT HYPERTHYROIDISM Wiersinga et al % per year Sanrock et al % per year Sawin et al % over 4 years with autonomously functioning nodules Persons with low but detectable TSH may recover spontaneously 34 titel

35 Serum thyrotropin measurement in the community Meyerovitch et al Arch Intern Med, patients included No history or treatment for thyoid disorders 95 % normal TSH( mu/l), 1.2% decreased TSH (< 0.35 mu/l), 3 % were elevated (< 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 35 titel

36 Distribution of second thyrotropin (TSH) results compared with the category of the first TSH measurement in patients with no medical treatment between measurements 36 Copyright restrictions titel may apply. Meyerovitch, J. et al. Arch Intern Med 2007;167:

37 SUBCLINICAL HYPERTHYROIDISM AND CARDIOVASCULAR MORBIDITY AND MORTALITY Rationale for therapy? 37 titel

38 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 ) 38 titel

39 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, 2005 Doppler echocardiography : no increased incidence in LVMI (left ventricular mass index) Iqbal et al., Cross-sectional population based study,2007 Transthoracal echography : No change in LVMI Changes in myocardial velocities measured by PTWD pulsed waved tissue doppler (= diastolic dysfunction) 39 titel

40 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 40 titel

41 Sawin et al, N Engl J Med, 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 mu/l 1576 persons: TSH mu/l 183 persons: TSH 5 mu/l 41 titel

42 TSH < 0.1 mu/l 21 % 3 RR TSH mu/l 18 % 1.8 normal TSH 8 % Sawin et al, N Engl J Med, titel

43 Auer et al, Lancet, patients 613 subclinical hyperthyroidism (TSH < 0.4 mu/l) AF 513 with normal TSH: 2.3 % RR 78 with TSH 0.4: 12.7 % 5.2 ( ) After correction for age, other risk factors (hypertension, LVH, cardiomyopathy) 3 No follow-up of cardiovascular morbidity, mortality 43 titel

44 Gammage et al, Arch Intern Med subjects 65 years and older Main outcome measures: thyroid function ( ft4 and TSH) and the presence of AF on resting ECG 126 (2.2%) had subclinical hyperthyroidism Increased 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) 44 titel

45 Mortality: Parle et al, Lancet, persons 60 years, without T 4 treatment, no antithyroid drugs serum 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 years 2 5 years mortality= mortality of cardiac and cerebrovascular events 45 titel

46 SUBCLINICAL HYPERTHYROID. EXCESS VASCULAR MORTALITY Community based cohort study :1160 patients aged 60 years or over not receiving T4 therapy or antithyroid medications with subclinical hyperthyroidism followed over 10 years Parle et al titel

47 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

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49 290

50 All Cause mortality and subclinical hyperthyroidism Pooled HR 1.72 ( )

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

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54 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. 54 titel

55 The patient of the vignette Surks et al., JAMA, titel

56 Hypothyroidism and the CV system Subclinical hypothyroidism and the CV system Effects of treatment of hypothyroidism on CV system 56 titel

57 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 57 titel

58 Clinical Hypothyroidism Bradycardia Mild hypertension Narrowed pulse pressure Decreased cardiac contractility Accelerated atherosclerosis Coronary atherosclerosis Prolongation of the QT interval with ventricular irritability (rarely torsade de pointes) 58 titel

59 clinical vignette A 69-year old woman is found to have a serum TSH of 7.9 mu/l on routine screening. Her only symptoms are mild fatigue, which has been present for more than 10 years, and difficulty losing weight. The results of the physical examination are normal, except for a small, firm thyroid with a slightly irregular surface. The serum cholesterol level is 220 mg/ dl, the LDL-C is 140 mg/dl, and a test for antibodies against thyroperoxydase is positive. Should treatment with thyroxine be initiated? 59 titel

60 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 agespecific range for TSH is employed 60 titel

61 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 61 titel

62 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 with Mild thyroid failure vs. Euthyroid subjects ( TC 224 mg/dl, vs.216mg/dl) Dia JCEM Mc Dermott fig3 Canaris et al., titel

63 Association of aorta atherosclerosis and myocardial infarction is stronger in subclinical hypothyroidism and associated thyroid autoimmunity Hak et al., Ann Intern Med, titel

64 64 titel Hak at al. 2000

65 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 titel

66 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 ( ) Did not include the Gussekloo paper and three newly published articles ( Walsch, Rodondi, Cappola) 66 titel

67 Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all cause mortality Singh et al In J Cardiol, 2007 Prevalence at baseline 67 titel

68 Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all cause mortality Singh et al In J Cardiol, 2007 Risk of developing CHD 68 titel

69 Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all cause mortality Singh et al In J Cardiol, 2007 All cause mortality 69 titel

70 The relation of thyroid dysfunction with all-cause and circulatory mortality Volzke et al, J Clin Endocrinol Metab, 2007 Pooling of studies revealed a NS HR for circulatory disease HR 1.21 ( 0, ) Pooling of studies revealed a S HR for all-cause mortality HR 1.25 ( ) 70 titel

71 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

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73 1580

74 All Cause mortality and subclinical hypothyroidism HR 1.03 (CI ) In cohorts from the community HR 1.76 ( CI ) In cohorts with comorbidities

75 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 75 titel

76 Interaction of subclinical hypothyroidism with other CV risk factors on CV related- and total mortality The Fremantle Diabetes study Australia Chubb et al,clin Endocrinol 2006 Mild thyroid dysfunction in cardiac patients Italy Iervasi et Arch Intern Med 2007 Subclinical hypothyroidism and mortality in women with type 2 diabetes Subclinical hypothyroidism and mortality in patients with heart disease 76 titel

77 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 77 titel

78 Fig 2 cumulative mortality of participants Gussekloo et al., JAMA, titel

79 Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease Walsh et al, Arch Intern Med, 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 79 titel

80 Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease, according to category of TSH elevation Walsh et al, Arch Intern Med, 2005 Cross-sectional data Prevalence Odds Ratios for Coronary Heart Disease in the Crosssectional Analysis of All Subjects* 80 titel

81 Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease, according to category of TSH elevation Walsh et al, Arch Intern Med, 2005 Hazard Ratios for Coronary Heart Disease Events (Fatal and Nonfatal) in the Longitudinal Analysis of Subjects Free of Coronary Heart Disease at Baseline* 81 titel

82 Subclinical Thyroid dysfunction as a risk factor for cardiovascular disease Walsh et al, Arch Intern Med, 2005 Conclusions 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 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 SH No increased incidence of mortality from CVD in patients with SH of any degree 82 titel

83 Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events and death Rodondi et al, Arch. Intern Med, 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 83 titel

84 Cumulative congestive heart failure (CHF) events in older subjects according to thyrotropin (TSH) levels 84 titel

85 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 85 titel

86 Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events and death Conclusions 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: ) and severe SH (TSH > 10 mu/l), but not in patients with mild SH (TSH, mu/l) No association with increased death from CVD or the risk of incident CHD 86 titel

87 Interventional studies and effects on atherosclerosis Angiographic study Perk et al. Can J Card 1997 greater progression of coronary atherosclerosis in subclinical hypothyroidism compared to patients with normal TSH One underpowered study did not show an increase in cardiovascular morbidity and mortality in patients treated with T4 (only 29 patients, follow-up :12 years) Peterson et al.,arch Intern Med, 1990 No placebo controlled trial available 87 titel

88 SUBCLINICAL HYPOTHYROIDISM Conclusions 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 years with 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 88 titel

89 Mortality and vascular outcomes in patients treated for thyroid dysfunction Flynn et al., JCEM, patients treated for hypothyroidism between 1993 and 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 ) 89 titel

90 Mortality and vascular outcomes in patients treated for thyroid dysfunction Flynn 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 ) : ns excess of 73 deaths, but there was an increase in cardiovascular disease mortality : 1.11( CI ) Over 8 years serious vascular events :SIR 1.10 (CI ): s. excess of 181 cases, adjusted for age, sex and diabetes Over 8 years there was an increased morbidity related to ischemic heart disease, dysrhythmias and cerebrovascular disease 90 titel

91 Mortality and vascular outcomes in patients treated for thyroid dysfunction. Conclusions Flynn 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) 91 titel

92 Mortality and vascular outcomes in patients treated for thyroid dysfunction Shortcomings of the study Flynn et al., JCEM, 2006 Reliance on SMR record-linkage (general practitioners) No adjustments for concurrent medications, ie statins Unadjusted confounders ie smoking 92 titel

93 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) 93 titel

94 The patient of the vignette Sufficient Sufficient Surks et al., JAMA, 2004 Sufficient :Razvi et al, titel

95 Subclinical thyroid dysfunction and the heart Difficult exercise