and Impact on Heart Failure Decompensation
Daniel M. Shafran, BSc (Hon), Faculty of Medicine, University of Calgary, Alberta Debra L. Isaac, MD, FRCPC, Faculty of Medicine, University of Calgary, Alberta
Director, Cardiac Transplant, Foothills Medical Center; Clinical Professor, Faculty of Medicine, University of Calgary, Alberta
Background
H
eart failure (HF) is a common problem that affects as many as 2% of the population in the western world, and it 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 pa- tients 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 year 2030.3 Addition- ally, 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 hospitalization. According to the 2005/06 surveillance data from the Public Health Agency of Canada there were 54,333 hospitalizations due to HF.4 Many of these hospitalizations were likely readmissions, as 23.6% of patients who survive primary admission for heart failure are readmit- ted with the same diagnosis within one year.5Multidisciplinary cardiac function clinics are dedicated to improving outcomes in patients with HF via the use of the latest evidence-based practice guidelines, patient education, and careful follow-up. Two key goals of these clinics are the 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 dis- charge.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 sys- tem is well documented. By influencing heart rate, contractil- ity, 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.7
Adding to the potential impact of thyroid dysfunction on HF is the influence of subclinical hyper- and hypothyroid- ism. In these conditions, patients are generally asymptomatic and have normal levels of T3 and T4 despite abnormally de- creased or increased levels of TSH. These subclinical condi- tions have significant effects: subclinical hyperthyroidism is associated with an increased resting heart rate, atrial arrhyth-
Corresponding Author: Daniel M Shafran, BSc (Hon) University of Calgary 1403 29th Street NW Calgary, Alberta
Email: [email protected]
Abstract
Abnormal thyroid function (TF) is associated with cardiac dysfunction and may result in decompensa- tion in patients with pre-existing heart failure (HF). International HF guidelines recommend routine as- sessment 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 TF abnormalities impact outcomes.
METHODS: Retrospective review was performed for all patients managed at 3 hospital-based HF clin- ics in Calgary from November 2010 to January 2011. RESULTS: Charts of 773 patients were reviewed. Of these, 719 (93.0%) patients had some documenta- tion of Thyroid Function Tests (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) decom- pensated compared to 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 de- compensation 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 treat- ment of TF in reducing HF decompensation.
mias, and increased left ventricular mass.13 Subclinical hypo- thyroidism (scHypo) has been shown to exert all the same effects of overt hypothyroidism on the cardiovascular system, albeit to a lesser degree. The mechanism in which subclinical thyroid disease, which consists of normal levels of the active hormones T3 and T4, exerts an impact on cardiac function 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 pa- tients who developed scHypo.15 Additionally, another recent observational study showed hyperthyroidism is present in nearly 10% of patients presenting with new-onset atrial fibril- lation 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.18-20 In a recent trial, however, only 36% of HF patients had thyroid function tests (TFTs) performed while awaiting implantation of a left ven- tricular assist device (LVAD).21 Furthermore, only 40% of HF patients in an American HF clinic had TFTs appropriately as- sessed. Appropriate assessment was defined as TFT measure- ments every 6 months for patients receiving amiodarone, and every 12 months for patients not receiving amiodarone.22 In this study, 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 out- comes.
Methods
A retrospective chart review of all patients enlisted at the cardiac function clinics at three sites in Calgary was per- formed. 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 desig- nation 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 subclini- cal 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 second-
ary 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. Pa- tients receiving thyroid-altering medication – despite no re- cord of TFTs – were considered to have thyroid dysfunction, with the presumption that TFTs were (a) performed prior to the creation of Alberta’s online lab result database in 2005, (b) in a province outside of Alberta, or (c) a clinical diag- nosis was the impetus for initiating therapy. Results of TFTs performed in Alberta after 2005, even if performed outside of cardiac function clinics, were available on Alberta’s on- line database. 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, intra- venous diuretics during a clinic appointment, or a doubling of the dose of oral diuretics – were documented. Any history of amiodarone use was recorded.
All data was input into Apple’s Numbers spreadsheet soft- ware for analysis. Simple counts and division determined the number and proportion of patients belonging to different categories by diagnosis, time of most recent TFT, amioda- rone 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).
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)
Research
Assessment and Treatment of Thyroid Function in Heart Failure Clinics – Incidence of Abnormal Thyroid Function and Impact on Heart Failure Decompensation
There was, however, variability in the frequency of TFT testing between sites. At Hospital A, TFT testing in the previ- ous 12 months had occurred in only 69.4% (347 of 500) of patients; Hospital B tested TFTs in 84.4% (130 of 154) of pa- tients, 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).
Figure 2. Percentage of timing of TFTs of 773 patients performed at three cardiac function clinics
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 hy- perthyroid, and 41 (24.8%) were subclinically hypothyroid (Figure 3).
Among the 165 patients with thyroid dysfunction, ad- equate control was achieved in 104 (63.0%). 31 patients (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 ad- mission or ED visit for a cardiac-related reason, intravenous diuretics or doubling of regular diuretic dose) in the preced- ing 12 months. Of those patients, 211 patients (83.1%) had
TFTs performed in the previous year, 13 patients (5.1%) had their most recent TFTs performed greater than 12 months earlier, and 30 (11.8%) patients had no history of TFTs.
Figure 3. Frequency of various thyroid dysfunction diagnoses amongst HF patients with thyroid dysfunction
As with the frequency of TFT testing, there was also vari- ability between 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%) patients did not have any evidence of thyroid disease, of which 192 (31.6%) decompensated in the past 12 months. In patients with thyroid disease, regardless of pres- ence or adequacy of treatment, 62 (37.6%) decompensated over the same period of time. This difference was not statisti- cally significant (P=0.1611) (Table 1).
Table 1. Number and Proportion of Patients Suffering Heart Failure Decom- pensation with Normal and Abnormal Thyroid Function and TFTs
Patient Group (Total N = 773)
Total No. No. (%) of Patients Suffering Decompensation
Total Decompensations
Normal Thyroid Function
Thyroid Dysfunction
Normal TFTs
Abnormal TFTs
In those whose thyroid disease was adequately controlled, 37 (35.6%) decompensated. In those whose thyroid disease was inadequately controlled, 11 (35.5%) decompensated. Al- together, 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 disease, 14 (46.7%) decompensated in the previous 12 months (Table 2). However, the difference between num-
ber of episodes of acute decompensation between patients receiving and not receiving treatment was not statistically significant (P=0.2993). The proportion of patients who suf- fered 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).
Table 2. Proportion Suffering Heart Failure Decompensation in Patients with Heart Failure and Differing Levels of Control of Thyroid Dysfunction
Patient Group No. (%) of Patients
5IZSPJE%ZTGVODUJPO / No. of Patients Decompensation
Treated 135 (81.8)
Adequate Control
Inadequate Control 31 (18.8) 11 (35.5) No Treatment
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 tak- ing amiodarone had not had TFTs measured in the previous year. 122 (86.5%) patients with a history of use of amioda- rone 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) (Table 3).
Table 3. Proportion of Patients with Thyroid Dysfunction With and Without a History of Amiodarone Use
Patient Group No. (%) of Patients
with Thyroid Dysfunction )JTUPSZPG"NJPEBSPOF /
/P)JTUPSZPG"NJPEBSPOF /
Discussion
Dedicated cardiac function clinics measured TFTs in 93.0% of all patients, a much higher rate than the 36% re- ported in patients awaiting LVAD implantation21 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 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 epi-
sodes 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 exists a multi- tude of reasons why a HF patient may decompensate, though the significant difference in rate of decompensation between the two sites raises the concern that the quality of care be- tween sites may have been variable. Since all sites achieved the same levels of adequate control of thyroid dysfunction, the answer likely lies somewhere beyond the thyroid’s influence. Physicians at different sites may have managed patients differ- ently, some with more success than others. Additionally, 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 warranted.
The overall results from thyroid treatment are more en- couraging. 46.7% of patients receiving no treatment for thyroid disease decompensated, compared to 35.6% of pa- tients 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 valid- ity. Interestingly, there was negligible difference in the rate of decompensation in patients whose thyroid disease was ad- equately (35.6%) or inadequately (35.5%) controlled. This may indicate that even partial correction of thyroid dysfunc- tion imparts some benefit, and is consistent with others’ find- ings that further decreases in thyroid hormone in already- hypothyroid patients are proportional to severity of heart disease.23
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 dif- ference was not statistically significant. However, patients with normal TFTs - either naturally or after treatment - decompen- sated at a significantly lower rate than patients with abnormal or unmeasured TFTs (30.2% vs. 47.8%, P=0.0003). This dis- crepancy 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 guide- lines, 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, as is the case in the general population.27 This may be due to the fact that a lack of T3 and T4 has more immediate effects on cardiac function, such as increasing both afterload and diastolic pressure and decreasing cardiac output by up to 50%.7 Conversely, many sequelae of hyper- thyroidism, such as ventricular hypertrophy, require the ef- fects of chronic exposure to high levels of thyroid hormone in order to manifest. For instance, hyperthyroid-induced
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Assessment and Treatment of Thyroid Function in Heart Failure Clinics – Incidence of Abnormal Thyroid Function and Impact on Heart Failure Decompensation
ventricular hypertrophy is primarily the result of increased hemodynamic load. Therefore, hypertrophy would develop over a similar course of time as in a euthyroid, hypertensive patient.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 preva- lence 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 replace- ment therapy more widespread in HF patients. Trials to this effect are already underway.24
A complicating factor in determining the proper frequen- cy and timing of TFTs is the discrepancy between the recom- mendations of the Canadian Cardiovascular Society (CCS), the European Society of Cardiology (ESC), and the Heart Failure Society of America (HFSA). The CCS suggests thyroid testing be included as part of the “initial investigation” of a new diagnosis of heart failure;18 the ESC recommends that thyroid abnormalities be “identified and corrected,” but pro- vide no timeline for this;20 and the HFSA suggests TFTs be done “routinely,” but also fail to provide any specifics regard- ing timing of this testing.19 Certainly, this variability does not lend itself to stringent investigation and follow-up of heart failure patients with possible or proven thyroid dysfunction. As more research into the impact of thyroid disease on car- diac function becomes available, these guidelines must be re- assessed and specific recommendations about the timing of performing TFTs should be made.
The prevalence of thyroid disease in this patient popula- tion was notably higher than estimates for the general popu- lation. 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