Adherence to levothyroxine prescription in patients with hypothyroidism

Background : Hypothyroidism occurs in 1-2% of the general population, is associated with significant morbidity and requires continuous treatment with levothyroxine. Aim : To determine the effectiveness, adherence and safety of levothyroxine therapy in patients with hypothyroidism. Material and Methods : The Morisky-Green adherence test was applied, and effectiveness was determined by measuring thyroid-stimulating hormone (TSH) in 330 patients with with hypothyroidism; the mean age was 64+-15 years and 76% was women. Results : Median TSH was 2.09 mIU/L (interquartile range: 1.16-3.61 mIU/L). Two hundred thirty-five (71%) patients had TSH levels in the euthyroid range, 64 (19%) in the hypothyroid range and 31 (9%) in the hyperthyroid range. Complete, moderate and lack of adherence with levothyroxine was reported in 283 (86%), 29 (9%) and 18 (5%) of patients, respectively. The presence of anemia (odds ratio (OR): 0.37, 95% confidence intervals (CI): 0.15-0.98) or the need of doses over 100 µg/day (OR: 0.47, 95%CI: 0.28-0.80) increased the probability of having an abnormal TSH level. Conclusions : In a large proportion of these patients, TSH levels were controlled, and most patients were adherent to levothyroxine therapy. (Rev

T hyroid hormone (levothyroxine) replacement therapy, because of its excellent effectiveness and safety, is indicated as a continuous treatment when a diagnosis of hypothyroidism is confirmed 1 ; levothyroxine is one of the most commonly prescribed drugs in the world and the second most frequently consumed drug in the United States of America 1 . In Colombia, previous prescription studies showed that it is a widely used drug, mainly by women (80% of the population) approximately 60 years of age. It is estimated that the global prevalence of hypothyroidism is 1% to 2% in the general population 1-3 .
In Colombia, hypothyroid patients are managed with a variety of forms of levothyroxine and are periodically monitored to ensure maintenance of TSH levels in the euthyroid range (TSH between 0.4 and 4 mIU/L), with the aim of improving their symptoms and reducing possible complications. However, epidemiological studies have shown that only between 40 and 60% of those affected are within the control range established for their pathology 4,5 .
Given that hypothyroidism is a common disease and its only management consists of thyroid hormone replacement therapy, it is of interest to obtain data on its treatment, generating tools that enable better decisions that benefit the patient and the health system. Therefore, the objective was to determine the effectiveness of, adherence to and safety of levothyroxine therapy in a sample of patients diagnosed with hypothyroidism in the city of Medellín, Colombia, from 2016 to 2017.

Materials and Methods
An observational follow-up study was performed in a cohort of patients diagnosed with hypothyroidism under continuous management with levothyroxine in any of the different presentations, over 18 years of age, of any gender, who were residents in the metropolitan area of the city of Medellín, Colombia, between August 1, 2016, and June 30, 2017, and who were cared for at the IPS Universitaria-Universidad de Antioquia.
A simple random sample of all the patients in treatment at the institution was obtained, with an error of 5%, a confidence level of 95% and an expected control of 50%, which corresponded to 330 subjects. The variables of interest in the clinical histories were obtained. Additionally, information on adherence to the therapy was obtained through a personal interview that was conducted by the attending physician, and TSH samples were obtained by duly qualified laboratory personnel after each of the patients signed an informed consent form.
The following variables were collected and entered into a database: ky-Green test. Patients were classified as highly adherent if all responses were negative, moderately adherent if they had a positive response and non-adherent if they had more than one positive response.
The effectiveness was defined according to the TSH value obtained in the test performed by the authors during the study period. Values between 0.4 and 4 mIU/L were classified as euthyroidism, values less than 0.4 mIU/L were classified as hyperthyroidism, and values greater than 4 mIU/L were classified as hypothyroidism.
This study was endorsed by the Bioethics Committee of the Universidad Tecnológica de Pereira under the category "research with minimal risk". Personal data of the study subjects were not considered, and the ethical principles established by the Declaration of Helsinki were respected.

Data analysis
The data were analyzed with the statistical package SPSS Statistics version 25.0 for Windows (IBM Corp. 2017, Armonk, NY. USA). Frequencies, proportions and measures of central tendency were established (mean, standard deviation, median and interquartile ranges). The c 2 test was used to compare categorical variables. For logistic regression, the dependent variable was the control of hypothyroidism (yes/no) based on the TSH result, and the independent variables were the variables with levels of statistical significance in the bivariate analyses of each group. A value of p < 0.05 indicated statistical significance.

Results
A total of 330 patients with hypothyroidism treated with levothyroxine, with an mean age of 62.9 ± 15.1 years were included; the patients were predominantly female (n = 251; 76.1%). The vast majority of patients were of urban origin (n = 297; 90%). The symptoms reported most frequently were drowsiness and fatigue, and the most common comorbidities present in the research subjects were dyslipidemia and arterial hypertension (table 1).
From the TSH results obtained after standardized measurement, a total of 235 (71.2%) patients had TSH levels that placed them in the euthyroid range, while, 64 (19.4%) were classified as hypothyroid and the remaining 31 (9.4%) were classified as hyperthyroid ( Table 2). The median TSH of all the patients treated with levothyroxine was 2.09 mIU/L, (interquartile range: 1.16 mIU/L -3.61 mIU/L), with a minimum value of 0.01 mIU/L and maximum value of 76.8 mIU/L.
Regarding the assessment of follow-up care in the last year, there were 117 (35.5%) patients who had two follow-up consultations, followed by 111 (33.6%) who visited four times, 50 (15.2%) who had three consultations, 24 (7.3%) who had a single consultation and the remaining 28 (8.4%) who visited at different frequencies throughout the year.
A low frequency of adverse reactions was reported by the patients, with only eight (2.4%) individuals presenting any complaint in this regard. Epigastralgia was the most frequent adverse reaction (three cases, 0.9%), followed by headache (two cases, 0.6%), and the remaining patients experienced heart palpitations, dry mouth and tremor. The Morisky-Green adherence test was given to all patients receiving levothyroxine therapy, and it showed that 85.8% (n = 283) of the patients showed complete adherence to the medication. Among the remaining patients, 29 (8.8%) showed moderate adherence and 18 (5.4%) were classified as non-adherent.
Initially, bivariate analyses were performed to identify possible variables associated with the lack of hypothyroidism control, serving as the dependent variable. The multivariate analysis adjusted by gender and age showed that having a diagnosis of anemia (p = 0.028; OR: 0.3; 95%CI: 0.15-0.98) or needing doses higher than 100 µg/day (p = 0.005; OR: 0.47; 95%CI: 0.28-0.80) significantly increased the probability of having uncontrolled hypothyroidism by 63% and 53%, respectively.

Discussion
We showed the effectiveness of and adherence to thyroid hormone replacement therapy in a Colombian population based on TSH values for each patient, a method that provides a high level of certainty and reliability of the results presented. Additionally, each patient was assessed to determine their comorbidities and adverse reactions to levothyroxine therapy.
The sociodemographic characteristics in this sample of patients from the city of Medellín were as expected based on the epidemiology of hypothyroidism, as well as the management with levothyroxine for patients with this disease 6 . For example, a study conducted in Colombia regarding the use of thyroid hormone around the country found almost the same proportion of females (79.1% vs 76.1% current study) and mean population age (63.2 years vs 62.9 years, respectively) 2 .
Most of the comorbidities of the patients evaluated are related to the cardiovascular system, such as dyslipidemia and arterial hypertension, which treating physicians should be aware of due to the risk generated by these pathologies, as well as the growing evidence that shows hypothyroidism as an additional cardiovascular risk factor 7,8 . Other comorbidities found, such as depression, have also been found more frequently in patients with hypothyroidism, which can provide even more information on the current knowledge of hypothyroidism 9 .
Among the patients with hypothyroidism treated with levothyroxine in this sample, a high proportion had TSH values within the recommended range of control, and both the median and interquartile ranges remained within the levels that have been established to ensure adequate management of the pathology 4 . In addition, these values were higher than those reported by Somwaru   A high adherence to therapy was found in the majority of patients, which is an important outcome because chronic pathologies, such as hypertension, diabetes mellitus and hypothyroidism, are generally associated with poor daily medication compliance. This result highlights the requirements of a good level of commitment and knowledge of the disease, as well as the need for hormone replacement with levothyroxine, to achieve adequate symptom control, which is in accordance with reports from countries such as Spain and India, which also have adherence rates close to 90% 13,14 .
It is also clear the importance of the physician-patient relationship and the education that the physician can provide together with the health team in order to improve adherence to therapies for chronic pathologies and guarantee better health outcomes. The physician-patient relationship may be influenced by the doctor's interest in the consultation, in part by the doctor's satisfaction with his or her job and workplace, as well as by the patient's compliance with follow-up. It is necessary to have a better understanding of the reasons why in some diseases there may be a better doctor-patient relationship and why this leads to better adherence 15 .
This study shows some limitations of an observational study, namely, the identification of patients from a single city in the country, treatment provided by the same health service provider, and reliance on a single variable (TSH) to define the control status of each case. However, some strengths are present, such as the sample size, the standardized and uniform technique of measuring TSH levels in all subjects, and the measurement of adherence by a trained physician.

Conclusions
With the results obtained, it can be concluded that a high proportion of the hypothyroidism patient sample have TSH levels in the euthyroid range and are most often adherent to levothyroxine therapy; in addition, few adverse reactions occurred. These data generate confidence in the quality of care and the medicines they are receiving. This study provides information on the adherence to and effectiveness of hypothyroidism therapy and is one of the few studies in the literature that has addressed this issue, particularly in a middle-income country such as Colombia.