https://orcid.org/0000-0002-3686-8624
Abstract
Objective
Hormone replacement therapy with levothyroxine is considered the treatment of choice for hypothyroidism; however, non-adherence is a major contributor to poor treatment outcomes. This study aimed to evaluate levels of drug adherence (DA) to levothyroxine therapy among Omani adults with hypothyroidism and to explore related sociodemographic and clinical factors.
Methods
A national, multi-center, cross-sectional survey was carried out from August to December 2021 at 18 primary healthcare centers across all governorates of Oman. A total of 415 Omani adults were recruited. Data were collected using a pre-tested, Arabic-language questionnaire completed by trained researchers during face-to-face interviews with the participants. Level of DA was determined using the 8-item Morisky Medication Adherence Scale (MMAS-8).
Results
A total of 400 Omani adults participated in the study (response rate: 96.4%). The mean age was 41.9 ± 12.4 years old (range: 18–78 years) and 90.3% were female. According to their MMAS-8 scores, 157 (39.2%), 139 (34.8%), and 104 (26.0%) participants demonstrated low, medium, and high DA, respectively. No significant correlations were observed between level of DA and any sociodemographic or clinical characteristics, including age, gender, education, duration of treatment, and family history of thyroid disease (p > 0.050).
Conclusions
Only a quarter of Omani patients with hypothyroidism reported high levels of adherence to levothyroxine treatment, likely as a result of lack of awareness of the disease and the importance of maintaining an euthyroid state. Further studies using more objective measures of DA are recommended to determine correlates of non-compliance to levothyroxine therapy among Omani patients.
Introduction
Hypothyroidism is a chronic condition in which there is a failure of the thyroid gland to produce sufficient amounts of thyroid hormone to meet the metabolic demands of the bodyCitation1. It is one of the most common endocrine disorders seen worldwide, with a prevalence ranging from 3.05% in Europe to 4.6% and 9.5% in the USA and 11% in IndiaCitation2–5. Nevertheless, while the treatment of hypothyroidism is relatively simple—with affected patients being prescribed levothyroxine, a manufactured form of the thyroid hormone thyroxine—medication non-adherence is a major cause of treatment failure as well as unnecessary healthcare costsCitation6–8.
Medication adherence (or compliance) is defined by the World Health Organization as “the degree to which the person’s behavior corresponds with the agreed recommendations from a healthcare provider” with respect to timing, dosage, and the frequency of medication-taking during the prescribed length of timeCitation9–10. There are five interactive dimensions of non-adherence: (1) healthcare system/team factors, such as access to care and the degree of stress associated with healthcare visits; (2) patient-related factors, especially psychological factors; (3) therapy-related factors, including any unpleasant side-effects of taking the medication; (4) condition-related factors, such as duration of therapy; and (5) socioeconomic factors, including unstable living conditions, lack of family or social support, medication cost, and health insuranceCitation11.
Non-adherence to medication in patients with chronic illnesses has long been recognized as a public health problem; it is estimated that approximately only 50% of patients with long-term drug regimens follow treatment recommendationsCitation12. With regards to hypothyroidism, little information is available regarding adherence to treatment, with the estimated rate of non-adherence ranging from 22% to 82%Citation13. In the USA, a study showed that 68.4% of patients with hypothyroidism achieved high medication adherence rates of 80% or greater in the first year of treatmentCitation12. On the other hand, a study from Lebanon revealed that only 14.5% of the participants showed high adherence, 30.6% medium adherence, and 54.9% low adherenceCitation14. Another study from a tertiary care hospital in South India showed overall medication adherence rates of 34.6% and 40.4%, based on the 8-item Morisky Medication Adherence Scale (MMAS-8) and Belief about Medicines Questionnaire, respectivelyCitation15.
Non-adherence to levothyroxine treatment can be improved by identifying causative factors, potentially improving overall health system processes and patient satisfactionCitation16–17. Existing data regarding patient compliance with hypothyroidism treatment in Oman are scarce. As such, the primary objective of this study was to determine the prevalence of and explore factors affecting adherence to levothyroxine therapy among Omani adults with hypothyroidism.
Methods
Study design
A national, multi-center, cross-sectional study was carried out from August to December 2021 at 18 primary healthcare centers across Oman. As the number of health centers varies between each of the 11 governorates of Oman depending on the population and number of wilayats (counties) in each region, four health centers were randomly selected from each of the highly populated governorates and one health center from the less populated governorates.
Inclusion and exclusion criteria
The target population included adult patients (≥18 years) of both genders who attended the selected health center during the study period with confirmed diagnoses of hypothyroidism (based on biochemical criteria of thyroid function) and who had been receiving oral levothyroxine therapy for at least 6 months. In Oman, the only available type of levothyroxine medication is the oral tablet and the other format are not used. Patients with congenital abnormalities, thyroid cancers, pregnant women, those on lithium or steroid medications, were excluded from the study as they usually follow-up within secondary and tertiary healthcare settings, rather than exclusively in primary care. In addition, patients with subclinical hypothyroidism, mental illness or dementia, non-Arabic or English speakers, and those with no time to participate in the survey were also excluded.
Sample size
The necessary sample size for the study for the 18 health centers was found to be 400 based on an anticipated drug adherence (DA) prevalence rate of 50%, with a 5% margin of error, 5% alpha error, and at a 95% confidence level. An online sample size tool was used for the calculation (Raosoft Inc., Seattle, Washington). Utilizing a systematic random sampling strategy in which every fifth patient was selected, a total of 415 participants were recruited. According, to the Ministry of Health Annual Health of 2018, the total population of Oman was 2,579,236Citation18. The target population for each Governorate was calculated based on their proportional population size relative to the total population.
Data collection
A pre-tested and well-structured Arabic-language questionnaire was used for the purposes of data collection. The questionnaire was completed during face-to-face interviews conducted by trained researchers and took approximately 10 min. The questionnaire was divided into three main parts. Part one covered the participants’ sociodemographic characteristics, including their age, gender, level of education and degree, marital status, employment status, total monthly income, financial status, smoking status, alcohol consumption, and frequency of physical activity. The second part assessed detailed medical information regarding their hypothyroidism diagnosis and its causes, the presence of comorbidities, and treatment type, duration, dosage, and frequency. In addition, the participants were asked if they had received counseling regarding the disease and its treatment from their physicians and pharmacists.
The final section of the questionnaire consisted of the MMAS-8, a pretested, structured, self-reported tool that assesses level of adherence to prescribed medications and related behaviors. First administered to patients with hypertension, the MMAS-8 has a reliability score of 0.83 and sensitivity of 93% and has been validated in various different DA settings, including for thyroid replacement therapyCitation19–22. Arabic translation and linguistic validation for MMAS-8 were done and provided by the original author. Besides, the Arabic version of the MMAS-8 scale has been widely used and validated in numerous studies involving Arab population for several disease groups across various countries, including Palestine, Egypt, and Saudi ArabiaCitation23–27. The findings from these studies can be applied to many counties including Oman. A recent study conducted in Libya using the Arabic version of the scale demonstrated satisfactory internal consistency (α = 0.70) and moderate split-half reliability (r = 0.65)Citation28.
Seven of the eight items are yes/no questions designed to evaluate specific medication-taking behaviors, such as forgetfulness, feeling hassled about adhering to the treatment plan, or discontinuing the regimen because the medication makes the patient feel worse, with one point being given to each response of “yes”. The remaining item, which assesses the frequency with which the patient has difficulty remembering to take all of their medication, is scored on a 5-point Likert scale from 0 (never/rarely) to 4 (all the time). Total MMAS-8 scores range from 0 to 8, with level of DA categorized into low (scores of <6), medium (scores of 6–7), and high (scores of 8) adherenceCitation19.
Statistical analysis
The data analysis was carried out using the Statistical Package for the Social Sciences (SPSS), version 23 (IBM Corp., Armonk, New York). Descriptive statistics were used to describe the characteristics of the sample. For categorical variables, frequencies and percentages were reported, whereas means and standard deviations were used to present continuous variables. Pearson’s Chi-squared (χ2) test or Fisher’s exact test (for low cell frequencies) was used to test significance as appropriate, with a p value of ≤0.05 considered statistically significant.
Ethics
Ethical approval for this study was obtained from the Research & Ethics Committee of the Directorate General of Planning & Studies, Ministry of Health, Oman (#MOH/CSR/21/24497) and the Medical Research & Ethics Committee of the College of Medicine & Health Sciences, Sultan Qaboos University, Oman (#SQU-EC/335/2021). All participants were briefed regarding the objectives of the study and were informed that their participation was voluntary in nature and that they had the right to withdraw at any time. Written informed consent was received from all of the subjects prior to their participation in the study. The participants’ anonymity and confidentiality were ensured at all times, with each individual assigned a unique identification number for the purposes of data analysis.
Results
A total of 400 Omani adults responded to the survey and were included in the final analysis (response rate: 96.4%). The mean age was 41.9 ± 12.4 years old (range: 18–78 years). Overall, 361 participants (90.3%) were female and 39 (9.8%) were male. A total of 325 participants (81.3%) were married, 47 (11.8%) were single, 19 (4.8%) were widowed, and nine (2.3%) were divorced. Two-thirds of the cohort (n = 278; 69.5%) were unemployed. One third (n = 147; 36.8%) had a secondary school education, while 111 (27.8%) held an undergraduate degree, 75 (18.8%) had a primary education, 62 (15.5%) were illiterate, and only five (1.3%) held a postgraduate degree (). Only 12 participants (3.0%) held healthcare-related degrees.
Table 1. Sociodemographic characteristics of patients with hypothyroidism in Oman (N = 400).
One-third of the respondents (n = 159; 39.8%) had a total monthly income of 501–1,000 Omani rials (equivalent to approximately $1,300–2,600 USD) and another third (n = 157; 39.3%) had an income of ≤500 Omani rials (equivalent to approximately ≤$1,300 USD). Most participants (n = 337; 84.3%) reported that income did not affect their regular follow-up. Regarding region of residence, most of the participants (n = 84; 21.0%) were from Muscat, followed by North Batinah (n = 78; 19.5%), and Ad Dakhiliyah (n = 53; 13.3%), with the remaining participants from other governorates (). Almost one-third of the cohort (n = 136; 34.0%) reported that they exercised regularly. Few of the participants (n = 4; 1.0%) were current smokers and none reported consuming alcohol.
Around one-third of the participants (n = 145; 36.3%) had chronic illnesses. Most of the participants (n = 264; 66.0%) did not know their specific type of hypothyroidism and the majority (n = 327; 81.8%) did not know the cause of their condition. More than half of the participants (n = 232; 58.0%) had been taking oral levothyroxine for <5 years while the remainder (n = 168; 42.0%) had been on the medication for >5 years. More than half (n = 238; 59.5%) reported receiving information about the disease from their doctors and 272 (68.0%) had received instructions regarding the treatment. In addition, 299 (74.8%) had received instructions about the treatment from pharmacists. A total of 193 participants (48.3%) had a family history of thyroid disease.
Based on their MMAS-8 scores, a total of 157 (39.2%), 139 (34.8%), and 104 (26.0%) of the participants demonstrated low, medium, and high adherence to oral levothyroxine treatment, respectively. The mean MMAS-8 score was 5.97 ± 1.91. There was no significant correlation between level of adherence to oral levothyroxine treatment and any of the participants’ sociodemographic or clinical characteristics ( and ).
Table 2. Relationship between level of adherence to levothyroxine treatment and sociodemographic characteristics among patients with hypothyroidism in Oman (N = 400).
Table 3. Relationship between level of adherence to levothyroxine treatment and disease-related clinical characteristics among patients with hypothyroidism in Oman (N = 400).
Discussion
Based on the findings of the current study, only a quarter (26.0%) of Omani adults with hypothyroidism reported high adherence to levothyroxine treatment, with the remainder demonstrating low (39.2%) to medium (34.8%) adherence. A cross-sectional study of 337 Lebanese patients buying levothyroxine from community pharmacies reported similar low-to-medium rates of adherenceCitation14. In comparison, other studies conducted in non-Middle-Eastern countries have shown better adherence rates. For example, an observational cross-sectional study among 320 adult patients with hypothyroidism in northeastern Italy indicated high, medium, and low DA rates of 87%, 10.9%, and 1.9%, respectivelyCitation29. Another study of 289 adults attending an outpatient thyroid clinic in Karachi, Pakistan, reported high, medium, and low DA rates of 32%, 40%, and 27%, respectivelyCitation30.
In the present study, DA was not found to be significantly correlated with any sociodemographic or disease-related characteristics. In contrast, Kumar et al. reported that levothyroxine adherence was linked with gender among Pakistani patients, with significantly higher rates of DA observed among men compared to women (p = 0.0002)Citation30. Although research shows that women appear to be less compliant than men when it comes to taking medications in general, it is important to note that there are many variables which may influence this relationship, including gender disparities in drug utilization, prescription, and monitoringCitation31–32. In contrast, El Helou et al. did not find gender to be related to DA among Lebanese patients (p = 0.187)Citation14. Higher mean DA scores were observed among retired patients compared to unemployed or employed patients (p = 0.008) as well as among patients with no comorbidities (p = 0.002). Moreover, the researchers found a significant, inverse correlation between mean DA scores and age, with increasing age associated with decreasing adherence (p = 0.004)Citation14.
Patients with higher monthly incomes generally demonstrate better DA; this is to be expected, as such patients are more likely to be able to afford to pay for medicationsCitation30–31. This factor was not found to be significant in the current study; however, given that the healthcare system in Oman is subsidized by the government, it is logical that medication affordability would not play a significant role in patient adherence in this specific populationCitation30. Nevertheless, other healthcare system-related factors have been noted to affect DA, including regular follow-up (p < 0.001), sufficient information about the condition (p < 0.001), and regular thyroid function testing (p < 0.001)Citation14,Citation30. Furthermore, Kumar et al. reported other significant factors, including side-effects of the medication, needing assistance to take the medication, and a family history of thyroid diseaseCitation30.
The low rate of compliance with medication among Omani patients with hypothyroidism can be attributed to several factors, including a fundamental lack of knowledge regarding the disease and its causes and complications. This was apparent as the majority of participants in the present study were not aware of either their specific type of hypothyroidism or its cause, despite claiming to have received adequate information concerning the disease from their treating physicians. This discrepancy in findings could be due to the length of the questionnaire itself, or the possibility that the participants had difficulty in understanding certain questions. Adherence rates to self-administered drug therapies among patients with chronic diseases can be improved by enhancing health literacy, including the implementation of patient-level educational interventions involving the provision of sufficient information regarding the nature of the disease and its causes and treatmentCitation33.
Moreover, choice of levothyroxine formulation has been shown to have an effect on medication-taking behaviorsCitation7,Citation29. In particular, Cappelli et al. found that patients taking oral levothyroxine tablets were significantly more likely to forget to take their medication, feel hassled about sticking to the treatment plan, and have difficulty remembering to take their medication compared to those receiving treatment in liquid form (p < 0.001), although there was no correlation with overall level of DACitation29. In addition, the researchers proposed that the timing of medication administration could have an impact on adherence and preference of drug formulation, as several patients reported that taking the liquid medication at breakfast was more convenient. With regards to levothyroxine, choice of drug formulation is linked to the timing of administration, as oral tablets must be taken 30–60 min before eating whereas liquid formulations can be taken while eating. Guglielmi et al. similarly observed that patients who took liquid formulations of levothyroxine at breakfast time reported a significant improvement in quality of life (p < 0.01), a finding which the researchers attributed to the fact that the patients found it easier to remain compliant to treatmentCitation34.
Duration of treatment has also been found to impact adherence to levothyroxine therapy, although the nature of this relationship appears to be conflictingCitation7,Citation30. According to a retrospective analysis of insurance claims data in the USA, the overall rate of DA fell by 11.6% between 6 and 12 months of drug administrationCitation7. In contrast, Kumar et al. found that DA was higher among patients who had been taking levothyroxine for >5 years compared to those who had been taking the drug for 1–5 years (p < 0.001)Citation30. Although no significant relationship was noted between DA and treatment duration in the current study, this may be because more than half of the patients had been diagnosed less than 5 years previously. It is possible that DA might increase with treatment duration due to a better understanding of the disease, thereby enhancing patient compliance and minimizing the risk of complications. Unfortunately, because the nature of the disease is chronic, levothyroxine treatment must be taken consistently in order to maintain a lifelong euthyroid stateCitation16,Citation35. It is therefore paramount that hypothyroid patients are made aware of the importance of remaining compliant with treatment throughout their lifetime.
Various strategies could be implemented in order to improve rates of DA in Oman. These may include encouraging physicians and pharmacists to become more involved in patient educational initiatives, promoting self-monitoring or self-management interventions, or prescribing less complex dosing regimens as well as more preferable pharmaceutical formulations, such as liquid solutionsCitation33,Citation35. A review of the literature confirmed that the bioequivalence of levothyroxine is maintained regardless of choice of formulation; as such, it may be beneficial for healthcare practitioners to suggest that patients with a history of non-compliance to oral levothyroxine tablets switch to soft-gel capsules or liquid solutionsCitation35.
In addition, there is a need for further research to determine psychosocial and cultural factors affecting non-adherence to medication in Oman, such as fear of judgment or social discrimination. It is possible that Omani patients may associate medicine-taking behaviors with negative emotions such as frustration or embarrassment, or may perceive the act of taking medicines as a burden or reminder of their illnessCitation36. In some cases, non-compliance with treatment recommendations may indicate a fundamental lack of trust in the prescriber or healthcare system at largeCitation37. Overall, there is a need for additional studies to determine factors which affect intention and motivation to adhere to treatment recommendations among Omani patients, as well as factors underpinning the prioritization of medicine-taking behaviorsCitation38. Besides, few studies have focused on the costs of hypothyroidism in general, and little research is available on the burden of non-adherence to treatment. A recent study showed that hypothyroidism is associated with significant direct and indirect economic burden in the United StatesCitation39. However, there are no similar studies from Oman or even from the region related to this issue.
Strengths and limitations
To the best of the authors’ knowledge, this study is the first to report the prevalence of medication compliance among patients with hypothyroidism in Oman. As a national, multi-center, cross-sectional survey, the findings of this study represent the entire country and provide a foundation from which to gain a more concrete picture of the situation across the country. Moreover, the choice of face-to-face interviews as the primary method of data collection may have facilitated the establishment of a stronger rapport with the respondents, ultimately leading to the absence of any missing data. However, an important limitation is that the level of medication adherence was based on self-reported measures and not confirmed by more objective methods, such as by measuring the number of empty pill leaflets or using drug cards. Self-reported data is often subject to biases such as response and recall biases that can lead to an under- or overestimation of findingsCitation40. Nonetheless, level of DA in this study was based on a well-known, internationally validated scaleCitation19–22. Finally, the results from this study describe only associations between variables; as such, no causal inferences can be drawn from any of the analyses described herein.
Conclusion
Hypothyroidism is a chronic medical illness which necessitates strict compliance to treatment in order to ensure disease control. Nevertheless, as with other chronic illnesses, patients with hypothyroidism often have difficulty remaining compliant to treatment. Based on these findings, patients with hypothyroidism in Oman showed low-to-moderate adherence to levothyroxine treatment. Although no associations were found between DA level and the patients’ sociodemographic and disease characteristics, the present study highlights the need for further measures to improve medication adherence among Omani patients, for instance patient education and regular follow-up. Improving medication compliance demands a multi-faceted approach with robust efforts from both health practitioners and patients.
Transparency
Author contributions
R.K, R.R, and S.J conceived the presented research idea and went through literature review. R.R, and S.J under the supervision of M.K and R.K. designed the research methodology and the questionnaire format. R.R, and S.J were involved in the data collection and date entry. R.R, S.J, M.K and R.K analyzed and interpreted the results. R.R and S.J were a major contributor in writing the manuscript in consultation with R.K. and M.K. R.K was the research supervisor who guided R.R and S.J throughout the project. All authors read and approved the final manuscript.
Ethics statement
The study received ethical approval from the Research and Ethics Committee of the Directorate General of Planning and Studies, Ministry of Health, Oman (#MOH/CSR/21/24497). and the Medical Research & Ethics Committee of the College of Medicine & Health Sciences, Sultan Qaboos University, Oman (#SQU-EC/335/2021). Informed consent was obtained from all participants prior to their inclusion in the study.
Acknowledgements
Authors would like to thank the patients for their participation in this study as well as the staff of the local health centers for their cooperation with this project. Special thanks to are also extended to Dr Shadha Al Ghusaini, Dr Tamadher Yahya and Dr Amani Al Mughaizawi for their continuous support. We would like to express gratitude to Donald E. Morisky and his group. The MMAS-8 Scale, content, name, and trademarks are protected by US copyright and trademark laws. Permission for use of the scale and its coding is required. A license agreement is available from MMAR, LLC., Donald E. Morisky, ScD, ScM, MSPH, 14725 NE 20th St Bellevue, WA 98007, USA
Declaration of funding
This project was funded by an internal grant from the College of Medicine and Health Sciences of Sultan Qaboos University, Muscat, Oman [grant #RF/MED/FAMCO/20/03]. This study was not part of a student thesis."
Declaration of financial/other relationships
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Data availability statement
The datasets used and/or analyzed during this study are available from the corresponding author upon reasonable request.
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