Results from small series of selected patients with

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1 Excess Coronary Artery Bypass Graft Mortality Among Women With Hypothyroidism Dlear Zindrou, MD, Kenneth M. Taylor, MD, and Jens Peder Bagger, MD Cardiothoracic Directorate, Hammersmith Hospital, and Faculty of Medicine, Imperial College School of Science, Technology, and Medicine, London, England Background. The impact of thyroid disease on patients undergoing coronary artery bypass grafting has been reported in only small series of selected patients. Methods. We investigated 30-day mortality of patients on thyroxine replacement therapy undergoing isolated coronary artery bypass grafting from 1993 to 2000 and identified variables of importance for outcome. Results. A total of 3,631 patients (606 women) had isolated coronary artery bypass grafting of whom 58 patients (30 women) were treated for hypothyroidism. The mortality rate was higher among women with thyroxine replacement (16.7%, 95% confidence interval [CI] 5.6 to 34.7) than those without thyroxine replacement (5.9%, 95% CI 4.1 to 8.2; p 0.02) and no difference between men with (3.6%, 95% CI 0.1 to 17.8) and without (2.6%, 95% CI 2.0 to 3.2) thyroxine treatment (p 0.8). Intake of diuretics (p < 0.001) was directly associated with mortality whereas intake of aspirin (p 0.01), levothyroxine dose (p 0.03), and serum thyroxine level (p 0.01) were inversely associated with mortality among women on thyroxine replacement. Conclusions. Women on thyroxine replacement therapy undergoing coronary artery bypass grafting had an increased mortality rate. We speculate that insufficient thyroid hormone replacement could partly play a role in this outcome. (Ann Thorac Surg 2002;74:2121 5) 2002 by The Society of Thoracic Surgeons Results from small series of selected patients with thyroid disease undergoing coronary artery bypass grafting (CABG) suggest that mild or moderate hypothyroidism does not negatively affect outcome [1 3]. There are no reports on larger series of nonselected patients with hypothyroidism undergoing CABG. We therefore examined CABG mortality among a consecutive series of patients with hypothyroidism and attempted to identify clinical variables of importance for the outcome of patients on thyroxine replacement therapy. Material and Methods Accepted for publication July 22, Address reprint requests to Dr Bagger, Cardiothoracic Directorate, Hammersmith Hospital, Du Cane Rd, London W12 0NN, England; p.bagger@ic.ac.uk. All patients on thyroxine replacement therapy undergoing isolated CABG between 1 January 1993 and 31 December 2000 at the Hammersmith Hospital were enrolled in this study. The clinical information included age, sex, angina status according to the Canadian Cardiovascular Society classification, diabetes mellitus, history of previous myocardial infarction, heart failure, hypertension, renal function, body mass index, operative priority, poor left ventricular function (ejection fraction 0.35), and number of diseased coronary arteries. We registered the number of years the patients had had thyroid disease, the initial diagnosis, and treatment of the thyroid disease as well as other medical treatment. We furthermore included preoperative serum free thyroxine (normal range 10 to 26 pmol/l) and thyroid-stimulating hormone (normal range 0.3 to 3.8 mu/l) measurements. Operative data included number and types of conduits, bypass time, aortic cross-clamp time, type of myocardial preservation, and surgeon. All data were validated after computer entry by one of the investigators (DZ). The outcome was 30-day mortality rate. Operation Procedure Anesthesia was induced by intravenous barbiturates and opiates (thiopentone and fentanyl) followed by pancuronium and continued with nitrous oxide and intermittent administration of volatile anesthetic agents. Myocardial protection was performed according to the surgeon s preference by cold crystalloid cardioplegia (standard St Thomas solution), cold blood cardioplegia, or intermittent aortic cross-clamp and ventricular fibrillation at a moderate mean core hypothermia of 32.4 C. As a rule aspirin was discontinued 1 week before the operation. Statistical Analysis Comparison of variables was performed using the 2 and Mann-Whitney U tests as appropriate. Binomial exact confidence intervals (CI) for mortality were calculated and Fisher s exact test was used for testing among groups. Univariate logistic regression tests were used for the identification of variables associated with mortality, and statistically significant variables were included in a forward stepwise multiple regression analysis. All analyses were made using the STATA statistics software package (Timberlake Consultants, Kent, UK) on a per by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)

2 2122 ZINDROU ET AL Ann Thorac Surg CORONARY BYPASS GRAFTING AND HYPOTHYROIDISM 2002;74: Table 1. Baseline Characteristics of Patients With Hypothyroidism by Gender Men Women n 28 (48%) n 30 (52%) Men Versus Women p Value Age (years) Redo operation 5 (17.9%) 1 (3.3%) 0.07 Angina pectoris CCS III and IV 14 (50.0%) 19 (63.3%) 0.3 Diabetes mellitus 6 (21.4%) 10 (33.3%) 0.3 History of congestive heart failure 6 (21.4%) 4 (13.3%) 0.5 Hypertension 12 (42.9%) 19 (63.3%) 0.1 Previous myocardial Infarction 14 (50.0%) 13 (43.3%) 0.7 Serum creatinine ( mol/l) Body mass index 30 6 (21.4%) 9 (30.0%) 0.4 Urgent operative priority 1 (3.6%) 1 (3.3%) 0.9 Left ventricular ejection fraction 35% 2 (7.1%) 2 (6.7%) 0.9 Beta blocker 15 (53.6%) 16 (53.3%) 0.9 Diuretics 3 (10.7%) 11 (36.7%) 0.02 Aspirin 23 (82.1%) 26 (86.7%) 0.6 Thyroxine dose ( g) Duration of thyroid disease (years) Thyroid-stimulating hormone (mu/l) (n 45) Serum free thyroxin (pmol/l) (n 45) Number of diseased coronary arteries Number of distal anastomoses Left internal mammary artery graft 26 (92.9%) 29 (96.7%) 0.5 Bypass time (minutes) Cross-clamp time (minutes) Values are mean SD or number (%) of patients. CCS Canadian Cardiovascular Society. sonal computer. A p value less than 0.05 (two-tailed) was considered statistically significant. Results Overall 3,631 patients (606 women) had isolated CABG during the period 1993 to Of these patients 58 (30 women) were treated for hypothyroidism. The prevalence of women on thyroxine replacement therapy (5%) was higher than that among men (0.9%; p ). Clinical Characteristics The study population stratified by sex is shown in Table 1. There were no clinically important differences between men and women with the exception that women were more often on diuretic therapy than men (8 women were taking diuretics owing to hypertension). There was a tendency to more men having redo operations and more women being hypertensive. Women had a higher mean level of free thyroxine than men. Characteristics of female patients stratified by outcome are shown in Table 2. Among nonsurviving women, there was a high prevalence of subjects on diuretics, a tendency to a low prevalence of subjects on aspirin, a tendency to more subjects having a history of heart failure, and a tendency to taking a lower daily dose of levothyroxine as compared with surviving women. Of all 58 patients, 13% of women and 10% of men had an initial diagnosis of hyperthyroidism. Of these hyperthyroid patients 50% of women and 67% of men were treated with radioiodine and the remaining patients of each group with partial thyroidectomy. The patients were on thyroid replacement therapy for an average of more than 10 years. Operation Characteristics There were no significant differences between women and men with respect to the number of distal graft anastomoses and arterial conduits. Neither type of myocardial preservation (p 0.2) nor the surgeon (p 0.7) was related to outcome. Although bypass time and aortic cross-clamp time were shorter in women than in men these variables did not differ between female survivors and nonsurvivors (Tables 1 and 2). Three patients had no arterial conduit owing to poor quality of the internal mammary arteries. Mortality There was a total of 6 deaths among patients on thyroxine replacement therapy. The mortality rate of 16.7% (95% CI 5.6 to 34.7; 5 patients) among women with hypothyroidism was higher than among women without hypothyroidism (5.9%, 95% CI 4.1 to 8.2; p 0.02). There was no mortality difference between men with hypothyroidism (3.6%, 95% CI 0.1 to 17.8) and without hypothyroidism

3 Ann Thorac Surg ZINDROU ET AL 2002;74: CORONARY BYPASS GRAFTING AND HYPOTHYROIDISM 2123 Table 2. Baseline Characteristics of Women With Hypothyroidism by Outcome Survivors Deaths Survivors Versus Deaths n 25 (83%) n 5 (17%) p Value Age (years) Angina pectoris CCS III and IV 16 (64%) 3 (60%) 0.9 Diabetes mellitus 7 (28%) 3 (60%) 0.2 History of congestive heart failure 2 (8.0%) 2 (40%) 0.06 Hypertension 15 (60%) 4 (80%) 0.4 Previous myocardial Infarction 11 (44%) 2 (40%) 0.9 Serum creatinine ( mol/l) Body mass index 30 6 (24%) 3 (60%) 0.1 Urgent operative priority 1 (4.0%) 0 (0.0%) 0.7 Left ventricular ejection fraction 35% 1 (4.0%) 1 (20%) 0.2 Beta blocker 14 (56%) 2 (40%) 0.5 Diuretics 7 (28%) 4 (80%) 0.03 Aspirin 23 (92%) 3 (60%) 0.06 Thyroxine dose ( g) Duration of thyroid disease (years) Serum free thyroxin (pmol/l) (n 24) Thyroid-stimulating hormone (mu/l) (n 24) Number of diseased coronary arteries Number of distal anastomoses Bypass time (minutes) Cross-clamp time (minutes) Values are mean SD or number (%) of patients. No missing variables among deaths. CCS Canadian Cardiovascular Society. (2.6%, 95% CI 2.0 to 3.2; p 0.8). Four of the women on thyroxine replacement therapy died of progressive heart failure and 1 died of ventricular arrhythmias. One male patient with hypothyroidism (and diabetes) died of progressive heart failure. Among all patients with thyroid disease (n 58), the prevalence of diabetes was almost threefold higher among patients who died (67%) than among patients who survived (23%; p 0.02). Treatment with diuretics, the dose of levothyroxine, the level of free thyroxine, and intake of aspirin were independent variables associated with deaths among women on thyroxine replacement therapy (Table 3). Comment Table 3. Variables Associated With 30-Day Mortality in Women With Hypothyroidism (n 30) Covariate n Regression Coefficient p Value 95% Confidence Interval Diuretics Serum free thyroxine Aspirin Levothyroxine dose A 30-day mortality rate of 16.7% after isolated CABG among women on thyroxine replacement therapy exceeds by far the mortality rate expected in the general female population undergoing this operation [4]. However, the mortality rate of men treated for hypothyroidism did not differ from the outcome among men without this disease. Outcome from CABG among patients with thyroid disease has been reported only in small series of selected patients. Myerowitz and colleagues [1] reported no operative mortality in a total of 23 euthyroid and hypothyroid patients undergoing CABG. However, patients with poor left ventricular function were excluded and there was no information on concomitant diseases. Similarly Drucker and Burrow [2] excluded patients requiring emergency surgery and gave no information on coexisting diseases in 20 hypothyroid patients; there were at least 4 women in this study of whom 1 died in the early postoperative phase. Ladenson and colleagues [3] found an operative mortality of 18% in 17 hypothyroid patients (10 women) undergoing isolated CABG (n 11) or combined CABG-valvular surgery or aortic surgery or both. Generally women are thought to have a higher mortality rate after CABG than men [4]. Several reasons have been suggested to explain this difference. Women have been reported to have smaller caliber coronary arteries, which could result in more technical difficulties during the operation; internal mammary arteries have been less frequently used in women; and referral bias may exist, with women being considered for surgery at a later stage of their disease and at an older age [4]. In the present

4 2124 ZINDROU ET AL Ann Thorac Surg CORONARY BYPASS GRAFTING AND HYPOTHYROIDISM 2002;74: population with hypothyroidism, however, coronary artery calibers caused no additional operative problems in women, as women in fact had shorter bypass and aortic cross-clamp times than men despite having almost the same number of distal anastomoses. Furthermore there was no difference with respect to number and type of diseased coronary vessels or to the use of internal mammary artery conduits between men and women, and age did not differ between the sexes. There were more women on diuretics than men but otherwise no obvious clinical differences between the sexes that could explain the excessive mortality among women on thyroxine replacement therapy. There was a 60% occurrence rate of diabetes among female hypothyroid patients who died after CABG. There is no unequivocal explanation for the high mortality rate among women with both endocrine diseases. Thyroid disease can result in increased arterial levels of free fatty acids (FFA), depending on the rate of FFA delivery from adipose tissue, synthesis of FFA in the liver, and the rate of FFA oxidation [5]. Also, augmented lipolytic activity with increased concentration of circulating FFA is the consequence of insulin deficiency/ resistance [6]. Increased FFA levels result in augmented myocardial uptake of FFA [7]. In the myocardium excess fatty acids and their intermediates may increase ischemic damage and oxygen requirements, generate arrhythmias, and diminish glucose utilization during an ischemic event (eg, CABG) [8]. Furthermore, animal experiments have shown that thyroid hormones and insulin interact in the regulation of myocardial isomyosin expression [9]. Our finding of an inverse relationship between death rate and both levothyroxine dose and free thyroxine concentration among women suggests that some of these patients might have been on too low a dose of thyroxine replacement. This is supported by the fact that the patients in a study designed to reduce levothyroxine dose to the lowest dose needed to suppress thyroidstimulating hormone had a 40% higher daily levothyroxine dose than female patients who died in the present study [10]. Furthermore, women who died in the present study were on a 60% lower levothyroxine dose than the acknowledged mean daily replacement dose of 125 g in hypothyroid patients [11]. In this context patients with mild to moderate hypothyroidism have been reported to have decreased fibrinolytic activity and increased number of circulating platelets [12, 13]. That may explain to some extent our finding that intake of aspirin was inversely related to mortality among women with hypothyroid disease. On the other hand, long-term fixed-dose thyrotropin suppression with levothyroxine may be achieved with too high a dose of thyroxine. The resulting increase in cardiac oxygen demands and structural and functional abnormalities of the heart [14] may be considered to represent an increased risk in relation to CABG. Individual levothyroxine dose tailoring (the lowest dose of levothyroxine that results in a predefined low concentration of thyrotropin) has been reported to improve or abolish these cardiac abnormalities [10]. Also, insulin sensitivity of human adipocytes is impaired in both hyperthyroidism and hypothyroidism as compared with euthyroid control subjects [15]. There are several limitations to the present study. The size of our population with thyroid disease comprised less than 2% of the total population and resulted in relatively few deaths after CABG. Because we did not measure thyroid function preoperatively in the whole population (n 3,631) we are likely to have underestimated the true prevalence of hypothyroidism. We furthermore did not measure thyroid function in all hypothyroid patients before the operation. Finally the majority of patients with thyroid disease had a multitude of additional risk factors in relation to CABG. Our population on thyroxine replacement therapy might appear slightly atypical as compared with the general CABG population for several reasons: relatively young age; a low rate of urgent surgery; a low rate of poor left ventricular function; and no left main artery stem disease. None of these limitations can however explain the mortality difference between women and men undergoing CABG. That both the prevalence of thyroid disease and the mortality rate in the present study was about five times higher among women than among men offers to some extent an explanation with respect to the generally perceived mortality difference between the sexes. In conclusion we found an increased CABG mortality rate among women on thyroxine replacement therapy. The fact that the female mortality rate was inversely related to the daily dose of levothyroxine and to thyroxine level suggests that some degree of insufficient thyroid hormone replacement could be related to this outcome. The possible benefits of individual optimization of thyroxine treatment on outcome require further assessment in future prospective studies. References 1. Myerowitz PD, Kamienski RW, Swanson DK, et al. Diagnosis and management of the hypothyroid patient with chest pain. J Thorac Cardiovasc Surg 1983;86: Drucker DJ, Burrow GN. Cardiovascular surgery in the hypothyroid patient. Arch Intern Med 1985;145: Ladenson PW, Levin AA, Didgway EC, Daniels GH. Complications of surgery in hypothyroid patients. Am J Med 1984;77: Edwards FH, Carey JS, Grover FL, Bero JW, Hartz RS. Impact of gender on coronary bypass operative mortality. Ann Thorac Surg 1998;66: Ginsberg HN, Goldberg IJ, Tuck C. Endocrine effects on lipids. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. Philadelphia: Lippincott Williams & Wilkins, 2001: Nesto WR, Zarich S. Acute myocardial infarction in diabetes mellitus. Circulation 1998;97: Bagger JP. Effects of antianginal drugs on myocardial energy metabolism in coronary artery disease. Pharmacol Toxicol 1990;66(Suppl 4): Oliver MF, Opie LH. Effect of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 1994;343: Haddad F, Masatsugu M, Bodell PW, Qin A, McCue SA, Baldwin KM. Role of thyroid hormone and insulin in control of cardiac isomyosin expression. J Mol Cell Cardiol 1997;29:

5 Ann Thorac Surg ZINDROU ET AL 2002;74: CORONARY BYPASS GRAFTING AND HYPOTHYROIDISM Mercuro G, Panzuto MG, Bina A, et al. Cardiac function, physical exercise capacity, and quality of life during longterm thyrotropin-suppressive therapy with levothyroxine: effect of individual dose tailoring. J Clin Endocrinol Metab 2000;85: Wiersinga WM. Hypothyroidism and myxedema coma. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia: WB Saunders, 2001: Chadarevian R, Bruckert E, Leenhardt L, Giral P, Ankri A, Turpin G. Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. J Clin Endocrinol Metab 2001;86: Van Doormaal JJ, van der Meer J, Oosten HR, Halie MR, Doorenbos H. Hypothyroidism leads to more smallsized platelets in circulation. Thromb Haemost 1987;18: Biondi B, Fazio S, Carella C, et al. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993;77: Pedersen O, Richelsen B, Bak J, Arnfred J, Weeke J, Schmitz O. Characterization of the insulin resistance of glucose utilization in adipocytes from patients with hyper- and hypothyroidism. Acta Endocrinol 1988;119: