Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
ELECTRONIC SUBMISSION FOR CONSIDERATION IN THE UNIVERSITY OF TORONTO MEDICAL JOURNAL TITLE: Assessment and Treatment of Thyroid Function in Heart Failure Clinics - Incidence of Abnormal Thyroid Function and Impact on Heart Failure Decompensation. AUTHOR NAMES: Daniel M Shafran* BSc (Hon) 1 Debra L Isaac MD FRCPC 1,2 AUTHOR AFFILIATIONS: 1 Faculty of Medicine, University of Calgary |1403 29th Street NW Calgary, AB 2 Director, Cardiac Transplant, Foothills Medical Center; Clinical Professor, Faculty of Medicine, University of Calgary |1403 29th Street NW Calgary, AB … CORRESPONDING AUTHOR EMAIL ADDRESS: [email protected] ABSTRACT BACKGROUND Abnormal thyroid function (TF) is associated with cardiac dysfunction and may result in decompensation in patients with pre-existing heart failure (HF). International HF guidelines recommend routine assessment and treatment of TF. It is unclear to what extent TF is monitored in Canadian clinics, what the incidence of abnormal TF is in HF patients, and how UTMJ ORIGINAL RESEARCH SUBMISSION Page 1 of 19 DM Shafran TF abnormalities impact outcomes. METHODS Retrospective review was performed for all patients managed at 3 hospital-based HF clinics in Calgary from November 2010 to January 2011. RESULTS Charts of 773 patients were reviewed. Of these, 719 (93.0%) patients had some documentation of TFTs; 592 (76.6%) had TFTs in the previous 12 months, and 54 (7.0%) had no record of TFTs. 21.3% (165) of patients had documented abnormal TF. Of 658 patients with normal TFTs (treated or not), 30.2% (199) decompensated compared with 41.0% (25) with abnormal TFTs (P=0.1109). Decompensation rates in patients with normal TFTs versus patients whose TFTs were abnormal or never measured were 30.2% (199) and 47.8% (55) respectively (P=0.0003). CONCLUSIONS TF abnormalities are common in Calgary HF Clinic patients. The rate of HF decompensation is significantly lower in patients with normal TFTs than in those with unmeasured or abnormal TFTs. Further investigation is required to further evaluate the role of assessment and treatment of TF in reducing HF decompensation. KEYWORDS: thyroid, heart failure, decompensation, cardiac function MANUSCRIPT TEXT BACKGROUND Heart failure (HF) is a common problem that affects as many as 2% of the population in the western world, and carries an incidence of 5-10 people per 1000 each year.1 Recently, the prevalence of HF was shown to be 0.7% in persons aged 45 to 54 years and 8.4% in patients aged 75 and older.2 HF currently affects approximately 400,000 Canadians; with an aging population and improved survival from acute coronary syndromes, both the incidence and prevalence of HF is expected to rise, with some estimates suggesting it will nearly double by the UTMJ ORIGINAL RESEARCH SUBMISSION Page 2 of 19 DM Shafran year 2030.3 Additionally, HF imparts a significant economic burden upon the healthcare system. In British Columbia alone, the cost of managing HF exceeds 90 million dollars annually. 3 Much of this cost is due to hospitalizations. In Canada in 2005/06, there were 54,333 hospitalizations due to HF.4 As 23.6% of patients who survive primary admission are readmitted within one year,5 many of these hospitalizations were readmissions. Multidisciplinary cardiac function clinics are dedicated to improving outcomes in patients with HF via the use of recent therapies and practice guidelines, patient education, and careful follow-up. A key element of these clinics is prevention and early intervention of potential precipitants of decompensation. Incidents of decompensation of HF can be reduced not only through the proper utilization of evidence-based therapies, but also through early follow-up after discharge.6 However, despite these therapies and interventions, acute decompensation can occur for many reasons. Among these are potentially correctable precipitants, including the presence of thyroid dysfunction. The thyroid gland’s influence on the cardiovascular system is well documented. 7 By influencing heart rate, contractility, and systemic vascular resistance (SVR), the thyroid has a profound effect on the heart. Consequently, both hyper- and hypothyroidism may adversely impact the course of HF. Adding to the potential magnitude of the impact of thyroid dysfunction on HF is the influence of subclinical hyper- and hypothyroidism. In these conditions, patients are generally asymptomatic and have normal levels of T3 and T4 despite abnormally decreased or increased levels of TSH, respectively. These subclinical conditions have significant effects: subclinical hyperthyroidism is associated with an increased resting heart rate, atrial arrhythmias, and increased left ventricular UTMJ ORIGINAL RESEARCH SUBMISSION Page 3 of 19 DM Shafran mass.13 Subclinical hypothyroidism (scHypo) has been shown to exert all the same effects of overt hypothyroidism on the cardiovascular system, albeit to a lesser degree; the reason for this is still unknown.14 Screening for and treatment of thyroid disease may reduce hospital admissions and episodes of acute decompensation in patients with HF. Indeed, a prospective study recently showed increased hospitalizations and poorer prognosis in HF patients who developed scHypo. 15 Additionally, one recent observational study showed hyperthyroidism is present in nearly 10% of patients presenting with new-onset atrial fibrillation to the emergency department.16 This presents another avenue through which the diagnosis and treatment of thyroid disease may reduce the burden on the healthcare system. Furthermore, it has been shown that even a mildly altered thyroid status is associated with increased mortality in cardiac patients. 17 Due to the profound effects the thyroid exerts on the heart, The Canadian Cardiovascular Society, Heart Failure Society of America, and the European Society of Cardiology have all included in their guidelines the recommendation to assess thyroid function in HF patients. 18,19,20 In a recent trial, however, only 36% of HF patients had thyroid function tests (TFTs) performed while awaiting implantation of a left ventricular assist device (LVAD).21 Furthermore, only 40% of HF patients in an American HF clinic had TFTs appropriately assessed, defined as TFT measurements every 6 months for patients receiving amiodarone, and every 12 months for patients not receiving amiodarone.22 We aimed to determine to what extent TFTs are monitored in Canadian multidisciplinary cardiac function clinics, the incidence of abnormal thyroid function in HF patients, and how thyroid function abnormalities impact outcomes. UTMJ ORIGINAL RESEARCH SUBMISSION Page 4 of 19 DM Shafran METHODS A retrospective chart review of all patients enlisted at the cardiac function clinics at three sites in Calgary was performed. All data was collected between November 16, 2010 and January 28, 2011. It was recorded whether TFTs were performed within the previous 12 months, earlier than 12 months prior, or if there was an absence of any record of TFTs. For those patients with a record of TFTs, his/her most recent TFTs were recorded. One of five diagnoses was assigned: euthyroid, hypothyroid, hyperthyroid, subclinical hypothyroid, or subclinical hyperthyroid. A euthyroid designation was assigned to patients in whom TSH was within the normal range. Distinguishing between subclinical or overt hypo- or hyperthyroidism proved more difficult, as T3/T4 was rarely measured. In these cases, a designation of a subclinical diagnosis was given to patients with abnormal TSH values and no reported history or symptoms of overt thyroid disease. In patients with a history of atrial arrhythmia, a diagnosis of overt or subclinical thyroid dysfunction was dependent on whether the treating clinician felt the arrhythmia was secondary to thyroid dysfunction (in which case it would be overt) or due to another cause (subclinical). Whether or not patients were receiving treatment for thyroid disease was noted. Patients receiving thyroid-altering medication despite no record of TFTs were considered to have thyroid dysfunction, with the presumption that either TFTs were performed prior to the creation of Alberta’s online lab result database, in a province outside of Alberta, or a clinical diagnosis was the impetus for initiating therapy. Additionally, the occurrence of any episodes of acute decompensation in the past 12 months, as defined by non-scheduled hospitalization for a cardiac-related cause, emergency department visit for a cardiac-related cause, intravenous diuretics during a clinic appointment, or a doubling of the dose of oral diuretics were documented. Any history of amiodarone use was recorded. UTMJ ORIGINAL RESEARCH SUBMISSION Page 5 of 19 DM Shafran All data was input into spreadsheet software for analysis. Simple counts and division determined the number and proportion of patients belonging to different categories by diagnosis, time of most recent TFT, amiodarone use, etc. Data was stratified by clinic site. Patients with thyroid dysfunction were defined as adequately controlled if they were on thyroid medication and their latest TFTs were within normal range; inadequately controlled patients were on thyroid medication and had TFTs outside of normal limits. Fisher’s exact test was used to determine significance between rates of binary outcomes. RESULTS The study included 773 HF patients from three cardiac function clinics. 719 (93.0%) patients had previous records of TFTs. 592 (76.6%) patients had TFTs performed in the previous 12 months. 127 (16.4%) had their most recent TFTs performed greater than 12 months prior (Figure 1). There was, however, variability in the frequency of TFT testing between sites. At Hospital A, TFT testing in the previous 12 months had occurred in only 69.4% (347 of 500) of patients; Hospital B tested TFTs in 84.4% (130 of 154) of patients, while Hospital C tested 96.6% (115 of 119) of patients’ TFTs over the same time period. Accordingly, the proportion of patients tested for thyroid dysfunction greater than 12 months earlier ranged from a high of 22.2% (111) at Hospital A to a low of 1.7% (2) at Hospital C (Figure 2). Of the 719 patients with recorded TFTs, 165 (22.9%) had thyroid dysfunction. 7 (4.2%) had hyperthyroidism, 111 (67.3%) had hypothyroidism, 6 (3.6%) were subclinically hyperthyroid, and 41 (24.8%) were subclinically hypothyroid (Figure 3). UTMJ ORIGINAL RESEARCH SUBMISSION Page 6 of 19 DM Shafran Among the 165 patients with thyroid dysfunction, adequate control was achieved in 104 (63.0%). 31 (18.8%) were receiving thyroid-altering medication yet were inadequately controlled, and 30 (18.2%) were not receiving any treatment for their thyroid disease. 8 (4.8%) patients were receiving thyroid medication despite no record of TFTs. Approximately one-third (254, or 32.9%) of all patients suffered an acute episode of decompensation (hospital admission or ED visit for a cardiac-related reason, intravenous diuretics or doubling of regular diuretic dose) in the preceding 12 months. Of those patients, 211 (83.1%) had TFTs performed in the previous year, 13 (5.1%) had their most recent TFTs performed greater than 12 months earlier, and 30 (11.8%) patients had no history of TFTs. As in the frequency of TFT testing, there was also variability amongst sites in terms of episodes of decompensation. Hospital A saw a significantly lower proportion (29.0%) of patients decompensate in the previous year than Hospital C (42.9%) (P<0.005). 608 (78.7%) of all patients did not have any evidence of thyroid disease. Of these, 192 (31.6%) decompensated in the past 12 months, whereas in patients with thyroid disease (regardless of presence or adequacy of treatment), 62 (37.6%) decompensated over the same period of time. This difference was not statistically significant (P=0.1611). In those whose thyroid disease was adequately controlled, 37 (35.6%) decompensated. In those whose thyroid disease was inadequately controlled 11 (35.5%) decompensated. Altogether, 48 (35.6%) patients receiving treatment for thyroid disease – whether they were adequately controlled or not – decompensated. Of those receiving no treatment for their thyroid UTMJ ORIGINAL RESEARCH SUBMISSION Page 7 of 19 DM Shafran disease, 14 (46.7%) decompensated in the previous 12 months. However, the difference between number of episodes of acute decompensation between patients receiving and not receiving treatment was not determined statistically significant (P=0.2993) by Fisher’s exact test. The proportion of patients who suffered an episode of acute decompensation with normal TFTs, either naturally or with treatment, versus patients whose TFTs were abnormal were 199 (30.2%) and 25 (41.0%) respectively (P=0.1109). Almost 1 in 5 patients (141, 18.2%) had a history of use of amiodarone, with 118 (15.3%) currently taking it., 3 patients (2.1%) who had never taken amiodarone had no record of a thyroid workup. However, 13 patients (11.0%) currently taking amiodarone had not had TFTs measured in the previous year. 122 (86.5%) patients with a history of use of amiodarone had TFTs performed in the previous 12 months while 470 (74.4%) patients with no history of amiodarone had their TFTs measured in the past year, significantly less than in those with a history of amiodarone use (P<0.005). Among patients with a history of amiodarone use, 42.6% (60 of 141) had thyroid dysfunction, which was significantly more than the 16.6% (105 of 632) of patients who had never used the drug (P<0.0001). DISCUSSION Dedicated cardiac function clinics measured TFTs in 93.0% of all patients, a much higher rate than the 36% reported in patients awaiting LVAD implantation 21 and 40% in an American heart failure clinic.22 However, only 76.6% of patients had thyroid workups performed in the previous year, and at one site, that number dipped as low as 69.4%. What is promising, however, is that real improvement in the frequency of TFT testing is possible, as one site tested 96.6% of their UTMJ ORIGINAL RESEARCH SUBMISSION Page 8 of 19 DM Shafran patients in the previous 12 months. It is therefore not unreasonable to suggest that annual TFT testing in HF patients could approach 100%, especially in patients followed by dedicated cardiac function clinics. Contrary to what we expected, the clinic with the best record of TFT testing (96.6% in the previous year) suffered from the highest proportion of patients experiencing episodes of acute decompensation (42.9%). The clinic with the worst record of TFT testing (69.4% in the previous year) had a decompensation rate of 32.9%. Clearly, there exist a multitude of reasons why a HF patient may decompensate, though the significant difference in rate of decompensation between the two sites is cause for concern. Since all sites achieved the same levels of adequate control of thyroid dysfunction, the answer likely lies somewhere beyond the thyroid’s influence. Part of this result may be artifact, in that patients with increased surveillance allowed for more frequent diuretic adjustment or hospitalizations. Further investigation into the cause of these decompensations is certainly warranted. The overall results from thyroid treatment are more encouraging. 46.7% of patients receiving no treatment for thyroid disease decompensated, compared to 35.6% of patients receiving thyroid treatment. While the finding that the reduction of episodes of decompensation with treatment is not statistically significant, it is a trend that warrants further investigation and a larger sample size to better assess its validity. Interestingly, there was negligible difference in the rate of decompensation in patients whose thyroid disease was adequately (35.6%) or inadequately (35.5%) controlled. This may indicate that even partial correction of thyroid dysfunction imparts some benefit, and is consistent with others’ findings that decreases in thyroid hormone are proportional to severity of heart disease.23 UTMJ ORIGINAL RESEARCH SUBMISSION Page 9 of 19 DM Shafran A third (32.9%) of all patients suffered an episode of acute decompensation in the preceding 12 months. The rate of decompensation was higher in patients with thyroid disease (37.6%) than in euthyroid patients (31.6%), though this difference was not statistically significant. However, patients with normal TFTs - either naturally or after treatment - decompensated at a significantly lower rate than patients with abnormal or unmeasured TFTs (30.2% vs. 47.8%, P=0.0003). This discrepancy cannot be attributed strictly to thyroid dysfunction - unmeasured TFTs may be due to patients who routinely miss appointments or are noncompliant with their medication, physicians who are unaware of or choose not to follow guidelines, or other factors. This result emphasizes the importance of ensuring that adequate testing and appropriate treatment for thyroid dysfunction and other comorbidities is properly performed. 92.1% of all thyroid disease in the study was either overt or subclinical hypothyroidism. This finding seems to indicate that both overt and subclinical hypothyroidism are much more common conditions in heart failure patients than is hyperthyroidism. This may be due to the fact that a lack of T3 and T4 has more immediate effects on cardiac function, such as increasing afterload and diastolic pressure, and decreasing cardiac output by up to 50%. 7 Conversely, effects of hyperthyroidism, such as ventricular hypertrophy, require an extended course of excess thyroid hormone in order to manifest themselves.7 In light of evidence that increased levels of TSH are associated with more hospital admissions in patients with HF,15 these findings further stress the importance of regular performance of TFTs in HF patients, and illustrate the prevalence of hypothyroidism in this population. In addition, the prevalence of hypothyroidism in these patients is cause for one to at least consider the utility of making thyroid replacement therapy more widespread in HF patients. Trials to this effect are already underway. 24 UTMJ ORIGINAL RESEARCH SUBMISSION Page 10 of 19 DM Shafran The prevalence of thyroid disease in this patient population was notably higher than estimates for the general population. While one study on the prevalence of thyroid disease found 11.7% of people in the general public to have thyroid dysfunction 25, 22.9% of HF patients in this study are either currently receiving treatment for pre-existing thyroid disease or had an abnormal result on their most recent TFT. This finding is likely due to two main factors: first, the age of HF patients is generally much higher than that of the general population, and the prevalence of thyroid disease increases with age.25 The lack of demographic data collected here is a significant limitation of this study. Second, the common use of amiodarone in these patients is also likely to have contributed to the high rate of thyroid dysfunction. 18.2% of patients had a history of use of amiodarone, and 15.3% of patients were currently taking the drug. Amiodarone is known to cause thyroid dysfunction, thought to be the result of the effect of its iodine-containing moiety. 26 Accordingly, 42.6% of patients with a history of use of amiodarone had thyroid dysfunction, compared to only 16.6% of patients who had never used the drug. It is therefore important that thyroid-safe alternatives to amiodarone be developed, especially for use in patients with HF. In the meantime, patients with a history of amiodarone administration were monitored more carefully for thyroid dysfunction than amiodarone-naïve patients: 86.5% of patients with a history of amiodarone use had their TFTs measured in the past year compared to 74.4% of patients with no amiodarone history. In conclusion, dedicated cardiac function clinics performed TFTs in approximately three-quarters of patients in the past year, well outperforming the rate of HF patients at other centers. However, there was significant variability between sites, and it is not an unreasonable goal for cardiac function clinics to measure annual TFTs in every patient. Subclinical and overt hypothyroidism was profoundly more prevalent than either form of hyperthyroidism, and thyroid UTMJ ORIGINAL RESEARCH SUBMISSION Page 11 of 19 DM Shafran dysfunction of all types was twice as prevalent in HF patients as in the general population. Further investigation with larger sample sizes is necessary to show whether the trends observed here are significant: the first suggesting that patients with thyroid disease decompensated more often than euthyroid patients, and the second suggesting that patients with adequately or inadequately controlled thyroid disease decompensated less often than those without treatment. However, these trends, in addition to the prevalence of hypothyroidism in HF patients, lend further credence to the possibility that thyroid hormone supplementation may be beneficial in HF patients. Further investigation is required to determine whether the burden of HF patients on the healthcare system can be diminished via increased thyroid function testing and treatment. ACKNOWLEDGMENTS CONFLICTS OF INTEREST The authors have no conflicts of interest to declare. SUPPORTING INFORMATION REFERENCES 1. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart (British Cardiac Society). 2007;93(9):1137-46. 2. Redfield MM, Jacobsen SJ, Burnett JC, et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA : the Journal of the American Medical Association. 2003;289(2):194-202. UTMJ ORIGINAL RESEARCH SUBMISSION Page 12 of 19 DM Shafran 3. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):e21-181. 4. Public Health Agency of Canada. Tracking Heart Disease and Stroke in Canada. 2009. 5. Lee DS, Johansen H, Gong Y, et al. Regional outcomes of heart failure in Canada. The Canadian Journal of Cardiology. 2004;20(6):599-607. 6. Krumholz HM, Chen YT, Wang Y, et al. Predictors of readmission among elderly survivors of admission with heart failure. American Heart Journal. 2000;139(1 Pt 1):72-7. 7. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007;116(15):1725-35. 8. Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T 3 in euthyroid humans. Journal of Clinical Investigation. 2005;115(9):2524–2533. 9. Forfar JC, Muir AL, Sawers SA, Toft AD. Abnormal left ventricular function in hyperthyroidism: evidence for possible reversible cardiomyopathy. N Engl J Med 1982;307:1165-70. 10. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501-509. UTMJ ORIGINAL RESEARCH SUBMISSION Page 13 of 19 DM Shafran 11. Mintz G, Pizzarello R, Klein I. Enhanced left ventricular diastolic function in hyperthyroidism: noninvasive assessment and response to treatment. J Clin Endocrinol Metab 1991;73:146-50. 12. Danzi S, Klein I. Thyroid hormone and the cardiovascular system. Minerva Endocrinologica. 2004;29:139–150. 13. Schneck, JB, Rizvi AA, Lin T. Severe primary hypothyroidism manifesting with torsades de pointes. Am J Med Sci 2006; 331(3):154-156. 14. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29:76–131. 15. Silva-Tinoco R, Castillo-Martinez L, Orea-Tejeda A, Orozco-Gutierrez JJ, Vazquez-Diaz O, Montano-Hernandez P, Flores-Rebollar A, Reza- Albarran A. Developing thyroid disorders is associated with poor prognosis factors in patient with stable chronic heart failure. Int J Cardiol. 2009. 16. Buccelletti F, Carroccia A, Marsiliani D, Gilardi E, Silveri NG, Franceschi F. Utility of routine thyroid-stimulating hormone determination in new-onset atrial fibrillation in the ED. Am J Emerg Med. 2010 17. Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, L’Abbate A, Pingitore A. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007;167:1526–1532. UTMJ ORIGINAL RESEARCH SUBMISSION Page 14 of 19 DM Shafran 18. JMO Arnold, P Liu, C Demers, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management. Can J Cardiol 2006;22(1):23-45. 19. Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, et al. Executive Summary: HFSA 2010 Comprehensive Heart Failure Practice Guideline. Journal of Cardiac Failure. 2010 Jun ;16(6):475-539 20. Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2008;29: 2388–2442. 21. Uriel N, Pak SW, Colombo P, Song R, Mancini D, Naka Y, Jorde UP. Thyroid deficiency is common in advanced heart failure and associated with increased operative mortality after assist device implantation. J of Heart and Lung Transplantation 2010; 29: S25. 22. Middleton SC, Spencer AP. Assessment of hypothyroidism in patients with chronic heart failure. Pharmacotherapy 2004;24(3):358-361. 23 Schmidt-Ott UM, Ascheim DD. Thyroid hormone and heart failure. Curr Heart Fail Rep. 2006;3:114–119. 24. Gerdes A, Iervasi G. Thyroid replacement therapy and heart failure. Circulation. 2010;122:385-93. UTMJ ORIGINAL RESEARCH SUBMISSION Page 15 of 19 DM Shafran 25. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–530. 26. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med. 2005;118(7):706. FIGURES AND FIGURE CAPTIONS UTMJ ORIGINAL RESEARCH SUBMISSION Page 16 of 19 DM Shafran Figure 1: Frequency of timing of most recent assessment of TFTs of 773 HF patients followed by three cardiac function clinics (A, B, and C). UTMJ ORIGINAL RESEARCH SUBMISSION Page 17 of 19 DM Shafran Figure 2: Percentage of timing of TFTs of 773 patients performed at three cardiac function clinics. UTMJ ORIGINAL RESEARCH SUBMISSION Page 18 of 19 DM Shafran Figure 3: Frequency of various thyroid dysfunction diagnoses amongst HF patients with thyroid dysfunction. UTMJ ORIGINAL RESEARCH SUBMISSION Page 19 of 19