Keywords
antithyroid drugs - drug-induced agranulocytosis - carbimazole - hyperthyroidism - thyrotoxicosis
Introduction
Nearly 1% of the adult population develop hyperthyroidism and are commonly treated with antithyroid drugs (ATDs). Methimazole or its carbethoxy derivative, carbimazole, is most frequently prescribed in nonpregnant populations and propylthiouracil (PTU) in pregnant women.[1]
[2] The most serious side effect of ATDs is agranulocytosis, which can be treated by early management if the patient has been given the necessary education to promptly self-diagnose the initial presenting symptoms.[3] Agranulocytosis has a reported frequency of up to 0.18% annually as per the literature in the west and usually manifests as a high-grade fever or sore throat.[4]
[5] There have been 19 confirmed fatalities secondary to ATD-induced agranulocytosis in the United Kingdom alone.[6] Thus, great emphasis has been placed on educating patients about the early recognition of this side effect and instructing them to stop ATD therapy and seek urgent medical attention and a blood test if they develop these symptoms.[6] Studies investigating patients' knowledge of agranulocytosis are scarce, and a 2014 United Kingdom study suggested that nearly 60% of patients taking ATDs were unaware of the common symptoms of agranulocytosis.[7] A recent study by Beshyah et al revealed suboptimal awareness about ATD-induced agranulocytosis among patients receiving ATD in the UAE and only three-quarters of the physicians prescribing ATD admitted providing routine verbal education to their patients with no standardized patient information leaflet.[8] To the best of our knowledge, there have been no educational interventional studies in the UAE on improving the awareness of agranulocytosis in patients with hyperthyroidism taking ATDs (carbimazole and PTU).
Thus, the objective of our study was to assess the knowledge of patients at the Division of Endocrinology, Department of Internal Medicine, Tawam Hospital, a tertiary care hospital in Al Ain, UAE, who were diagnosed with hyperthyroidism and taking carbimazole or PTU regarding their awareness of the symptoms of agranulocytosis and understanding of what steps to take if such symptoms developed. We also aimed to briefly estimate the magnitude of this issue by retrospectively analyzing electronic patient medical records to determine the frequency of hyperthyroidism and ATD use in our hospital and to identify any inpatient admissions due to confirmed agranulocytosis secondary to ATDs.
Patients and Methods
Our primary study was a questionnaire-based, prospective study on adult patients (aged ≥18 years) with confirmed hyperthyroidism who were taking ATDs. All patients attended the Tawam Hospital endocrine clinic between January 2023 and March 2024 and were asked to complete a paper-based survey through direct interviewing by a medical professional. Informed consent was obtained from each patient.
The standard questionnaire was based on previously published work[7] and was designed to assess patients' knowledge about agranulocytosis symptoms and the immediate steps required upon symptom observation ([Table 1]). It included specific questions focusing on key information about two important aspects: (1) the patient's understanding of the symptoms of agranulocytosis and (2) the patient's response if they observe any symptoms of agranulocytosis and what steps they need to follow. The patients were then given an information leaflet on carbimazole-induced agranulocytosis (English and Arabic version; [Fig. 1]) and received face-to-face or telephonic education. They completed a follow-up questionnaire 3 to 6 months later to assess information retention and improvements in their awareness of agranulocytosis.
Table 1
Patient responses to the questionnaire regarding the awareness of ATD side effects, before and after patient education (N = 68)
|
Questions
|
Initial visit patient survey
|
Post-education patient survey
|
p-value
|
|
Responses
|
n (%)
|
Responses
|
n (%)
|
|
1
|
Did you receive any information on the side effects of antithyroid drugs from your healthcare professional when the medication was started?
|
Yes
|
41 (60.3)
|
Yes
|
67 (98.5)
|
< 0.00001
|
|
2
|
Are you aware of the common symptoms of agranulocytosis (severe reduction in your white cells responsible for maintaining immunity), such as fever and sore throat?
|
Yes
|
41 (60.3)
|
Yes
|
67 (98.5)
|
< 0.00001
|
|
3
|
How confident are you about the knowledge of the side effects of antithyroid drugs?
|
Confident/very confident
|
34 (50)
|
Confident/very confident
|
68 (100)
|
< 0.00001
|
|
4
|
How would you rate the quality of information about the side effects of antithyroid drugs received so far?
|
Good/excellent
|
33 (48.5)
|
Good/excellent
|
63 (92.6)
|
< 0.00001
|
|
5
|
What do you feel about the amount of information received about the side effects of antithyroid drugs?
|
About right/too much
|
41 (60.3)
|
About right/too much
|
67 (98.5)
|
< 0.00001
|
|
6
|
Imagine that you get a sore throat while on the antithyroid medication. What would you do next?
|
See the GP and stop taking the tablets
|
16 (23.5)
|
See the GP and stop taking the tablets
|
67 (98.5)
|
< 0.00001
|
|
7
|
Suppose that on the following day, your sore throat is worse and you are still taking the antithyroid medication. What action would you take?
|
Seek immediate medical advice
|
64 (94.1)
|
Seek immediate medical advice
|
67 (98.5)
|
0.17
|
|
8
|
If you could not get immediate medical advice and you were still on antithyroid medication, would you stop now?
|
Yes
|
35 (51.5)
|
Yes
|
65 (95.6)
|
< 0.00001
|
Abbreviation: GP, general practitioner/doctor.
Fig. 1 Patient information leaflet about symptoms of carbimazole-/propylthiouracil-related agranulocytosis and the advice on the next steps in case of developing these symptoms.
The main purpose of the questionnaire was to assess the patient's existing knowledge and attitude toward understanding carbimazole-/PTU-related agranulocytosis. It was also used to collect demographic data and information on their hyperthyroidism condition and the duration of treatment. We calculated the sample size as 43 patients, based on the regional population and an estimated frequency of hyperthyroidism with a margin of error of 3% and a 95% confidence interval, and aimed to include at least 50 patients. We assessed changes in patients' knowledge before and after education using a simple 2 × 2 chi-square test. A p-value of less than 0.05 was considered statistically significant.
Our secondary study was a retrospective analysis of electronic patient medical records with the aim of estimating the number of previous episodes of serious ATD-related agranulocytosis requiring admission to our hospital. We used the International Classification of Diseases, 10th Revision,[9] code E05 (hyperthyroidism) to identify patients taking either carbimazole or PTU from December 2012 to December 2022, from which we extracted all records of inpatient admission with a discharge diagnosis of D70 (agranulocytosis), especially D70.2 (other drug-induced agranulocytosis). All patient data were handled according to the applicable regulations to maintain data protection and confidentiality. No identifiable patient information was used other than the medical record/serial number.
Results
We enrolled 71 patients in our study. However, three patients were excluded due to incomplete data collection, and the final cohort comprised 68 patients who completed the initial and follow-up surveys. The mean age was 43.7 years (standard deviation [SD] ± 17.1), and there were 48 (70.6%) females and 58 (85.3%) Emiratis. Sixty-four patients (94.1%) had hyperthyroidism due to Graves' disease, and the remaining four (5.9%) had toxic multinodular goiter. All the patients were taking carbimazole, with a current mean dose, calculated over the last 8 weeks, of 8.1 mg (SD ± 7.4 mg) and a maximum dose received since ATD initiation of 26.3 mg (SD ± 12.0 mg). None of the patients were taking PTU. [Table 2] presents the demographics and clinical data of the study cohort.
Table 2
Demographics and clinical data of patients participating in the questionnaire regarding awareness of ATD side effects (N = 68)
|
Characteristics
|
Responses
|
n (%)/mean ± SD
|
|
1
|
Age
|
In years
|
43.7 ± 17.1
|
|
2
|
Sex
|
Female
|
48 (70.6)
|
|
3
|
Nationality
|
Emirati
Egyptian
Filipino
Other
|
58 (85.3)
2 (2.9)
2 (2.9)
6 (8.8)
|
|
4
|
Diagnosis
|
Graves' disease
Toxic multinodular goiter
|
64 (94.1)
4 (5.9)
|
|
5
|
Antithyroid treatment duration
|
In months
|
44.1 ± 33.2
|
|
6
|
Medication dosage and current therapy (mean dose calculated over a period of 8 wk)
|
Carbimazole (mg)
|
8.1 ± 7.4
|
|
7
|
Medication dosage maximum since antithyroid therapy initiation
|
Carbimazole (mg)
|
26.3 ± 12.0
|
|
8
|
Previous follow-ups
|
Number of previous endocrine clinic visits
|
11.7 ± 9.1
|
Abbreviation: ATD, antithyroid drug; SD, standard deviation.
Regarding specific questions, when asked, “Did you receive any information on the side effects of ATDs from your healthcare professional when the medication was started?” 41 (60.3%) participants responded that they received adequate information. However, after providing patient education and an information leaflet on carbimazole-induced agranulocytosis, this self-reported awareness improved to 67 (98.5%) at the 3- to 6-month follow-up. When initially asked, “Are you aware of the common symptoms of agranulocytosis (severe reduction in your white cells responsible for maintaining immunity), such as fever and sore throat?” 41 (60.3%) patients answered “yes,” and this awareness improved to 67 (98.5%) at the follow-up after 3 to 6 months.
Similarly, patients' self-reported confidence in identifying ATD side effects improved from 50% (34/68) to 100% (68/68) on follow-up after receiving education. To assess the patient's knowledge regarding the correct steps in case of agranulocytosis symptom development, they were asked, “Imagine that you get a sore throat while on the antithyroid medication. What would you do next?” Only 16 patients (23.5%) chose the correct option in the initial survey. However, this improved to 65 patients (95.6%) in the follow-up survey. We observed significant changes/improvements in patient knowledge before and after education for all questions/domains (p < 0.00001) except for the question, “Suppose that on the following day, your sore throat is worse and you are still taking the antithyroid medication. What action would you take?” Most patients (64, 94.1%) answered this correctly in the initial survey, stating that they would seek immediate medical advice, and although this improved to 67 (98.5%) after education, the difference was not statistically significant (p = 0.17). [Table 1] presents the differences in responses between the two surveys.
To assess the prevalence of ATD-induced agranulocytosis requiring hospital admission, we performed a retrospective chart review of all patients on carbimazole from December 2012 to December 2022. There were 2,460 patients taking carbimazole during this period (average: 246 patients/y). Of them, nine were admitted with severe carbimazole-induced agranulocytosis during the 10-year study period (average: 0.9 cases/y; [Table 3]). Because carbimazole was the only ATD used by the patients in our primary study, we excluded all patients taking PTU from this retrospective analysis. The estimated annual frequency of severe agranulocytosis requiring inpatient treatment in patients taking carbimazole was 0.37%, providing a rough estimate of severe carbimazole-induced agranulocytosis, although many patients with agranulocytosis might not have required hospital admission and might have been missed by this assessment method. None of the nine patients with severe agranulocytosis died, and all except one (11.1%) developed it within 3 months of carbimazole therapy initiation.
Table 3
Clinical data of patients on carbimazole admitted to Tawam Hospital with severe agranulocytosis in the past 10 years (n = 9)
|
No.
|
Characteristics
|
n (%)/mean ± SD
|
|
1
|
Age (y)
|
51.9 ± 16.9
|
|
2
|
Gender
|
Females: 6 (66.7)
|
|
3
|
Nationality
|
Emirati: 2 (22.2)
Others: 7 (77.8)
|
|
4
|
Thyroid-related diagnosis
|
Graves' disease: 8 (88.9)
Toxic nodule: 1 (11.1)
|
|
5
|
Duration of prior antithyroid drugs (d)
|
42.6 ± 40.3
|
|
6
|
Current carbimazole dose (mg)
|
18.9 ± 11.4
|
|
7
|
Length of inpatient stay (days)
|
2.8 ± 3.3
|
|
8
|
Awareness of agranulocytosis risk as documented in medical records
|
4 (44.4)
|
Abbreviation: SD, standard deviation.
Discussion
Patients who develop ATD-induced agranulocytosis typically present with fever (93.8%) and sore throat (68.7%), with the presence of either of these symptoms in 100% of cases.[6]
[7] Similar survey of western countries reported that patients lacked knowledge about the side effects of ATDs, particularly their association with agranulocytosis, and most participants were unfamiliar with the typical symptoms of agranulocytosis.[7]
[10] Furthermore, nearly one-fifth stated that they had not received specific information from health care professionals regarding at least one of these topics,[7]
[10] and detailed interviews revealed that nearly half of the patients on ATD therapy had experienced symptoms of agranulocytosis at some point, among whom only half underwent the necessary blood test. Agranulocytosis (neutropenia) is a life-threatening condition. Patients at risk of chemotherapy-induced neutropenic sepsis usually have a well-defined pathway.[11] In contrast, ATD-induced agranulocytosis does not receive the same recognition or understanding among patients or professionals. In the initial survey in our study, when asked the all-important question regarding stopping ATD upon developing the classic symptoms of agranulocytosis if they were unable to get immediate medical advice, 33 (48.5%) of patients chose to continue ATD therapy. This reluctance to discontinue ATDs in the presence of deteriorating symptoms is alarming. A similar survey done in the UAE showed inconsistent knowledge, attitude, and practice among both physicians and patients around ATD-induced agranulocytosis and the need for more structured and standardized education from advocacy groups.[8] Our study demonstrated that the provision of written information (patient information leaflets) and patient education by health care professionals significantly improved patient awareness of ATD-induced agranulocytosis (p < 0.00001). Our findings are similar to those of other studies conducted in Western countries.[10] Previous studies have reported that the highest risk of agranulocytosis usually occurred in the first 3 months after ATD initiation.[12]
[13] Thus, it is crucial to remind newly diagnosed patients of this fact and provide them with written and verbal education during the early phase of treatment. Our 10-year retrospective medical record analysis of ATD-induced agranulocytosis requiring hospital admission estimated the annual frequency of severe agranulocytosis as 0.37%, which is similar to the low frequency reported in a previous study.[5]
This study has several limitations, including its small sample size, potential reliability and recollection bias issues associated with patient surveys, and bias in the patient selection methods due to its nonrandomized design. It also did not include the details around patients' level of education, which may have affected the survey results. Furthermore, the frequency of severe agranulocytosis requiring hospital admission determined in this study was assessed using only a retrospective electronic chart analysis and may not be representative of the true prevalence or incidence of this condition, potentially missing cases of agranulocytosis that were treated elsewhere or not sufficiently severe for hospital admission.
Conclusion
Carbimazole-induced agranulocytosis occurs infrequently in patients with hyperthyroidism. Thus, it is important to provide these patients with structured education and information leaflets on this side effect. We demonstrated that information leaflets and education on carbimazole-induced agranulocytosis information leaflets and patient education can improve awareness of symptom identification and steps required in cases of suspected agranulocytosis. Thus, uniform, high-quality patient information (verbal/written) about ATD-induced agranulocytosis should be provided to patients so that they can take timely and appropriate action. The patient information card (English/Arabic) developed for our study is in use at the local hospital, but it is important to implement this patient education and dispense this information card in all pharmacies in the UAE when ATDs are dispensed.
