Efficacy Of Methimazole Versus Radioiodine in Patients With Hyperthyroidism: A Meta-analysis Of Randomized Controlled Trials

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Abdelsattar, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3542960/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The efficacy of methimazole compared to radioactive iodine (RAI) therapy for hyperthyroidism remains uncertain. Here, we conducted a meta-analysis to compare methimazole to RAI in the treatment of hyperthyroid patients. Methods: We conducted a meta-analysis including English-randomized clinical trials (RCTs) published before March 5, 2023, to address this issue. The primary outcome was euthyroidism rate, while secondary outcomes included hypothyroidism, relapse, persistent hyperthyroidism, and cure rate. Review Manager software was used for analysis. Results: Six studies were included including 761 patients. The methimazole group had non-significantly higher rates of euthyroidism (RR = 2.09, 95% CI [0.90, 4.87], P = 0.09). The RAI group significantly increased the rates of hypothyroidism (RR = 0.06, 95% CI [0.03, 0.15], P < 0.00001). There were no significant differences in relapse, persistent hyperthyroidism, or cure rates between the two treatments (RR = 1.34, 95% CI [0.31, 5.86], P = 0.70), (RR = 0.4, 95% CI [0.07, 2.13], P = 0.28), and (RR = 0.84, 95% CI [0.58, 1.20], P = 0.34), respectively. Conclusion: Methimazole was not inferior to RAI in curing hyperthyroid patients, with comparable relapse rates. Methimazole is an effective alternative to ablative therapies like RAI with a lower risk of hypothyroidism. Health sciences/Endocrinology Health sciences/Endocrinology/Endocrine system and metabolic diseases Health sciences/Endocrinology/Endocrine system and metabolic diseases/Thyroid diseases Methimazole radioactive iodine relapse hyperthyroidism Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Hyperthyroidism is the overproduction of thyroid hormones caused by excessive thyroid gland activity. It is defined by low serum thyroid stimulating hormone (TSH) and high serum levels of thyroid hormones: thyroxine (T4) and triiodothyronine (T3), or subclinical, as defined by low serum TSH but normal serum T4 and T3 concentrations [ 1 ]. Hyperthyroidism commonly manifests as Graves' disease or a toxic multinodular goiter (TMNG). While Graves' disease is characterized by diffuse enlargement of the gland as a result of autoantibodies that interact with TSH receptors, TMNG is a non-autoimmune heterogeneous thyroid enlargement with autonomously hyperfunctioning thyroid nodules [ 1 , 2 ]. Hyperthyroidism has been linked to an increase in morbidity and mortality, primarily from cardiovascular causes such as atrial fibrillation, coronary heart disease, heart failure, pulmonary hypertension, and stroke, as well as osteoporosis, cancer, and lung diseases [ 1 , 3 , 4 ]. There are several treatment options available, including antithyroid drugs (ATDs), radioiodine therapy, and surgery. Surgery is considered for large nodules, nodules that are resistant to other treatments, or coexisting thyroid cancer [ 5 ]. Radioiodine therapy (RAI) is preferred by physicians in some centers, such as the USA, as the treatment of choice, which may be attributed to its simplicity, effectiveness, low cost, and being a definitive approach for the high recurrence rates associated with ATDs [ 2 , 6 ]. However, RAI is associated with radiation exposure, hypothyroidism, and worsening of Graves' ophthalmopathy [ 1 ]. Furthermore, compliance with lifelong, regular levothyroxine replacement may be challenging. Levothyroxine replacement was also linked to abnormal TSH levels, causing subclinical hypo- or hyperthyroidism, which can lead to coronary heart disease or atrial fibrillation [ 7 , 8 ]. The three cornerstones of antithyroid drug therapy are methimazole (MMI), carbimazole, and propylthiouracil. These medications prevent the thyroid gland from producing thyroid hormones. MMI is the active metabolite of carbimazole after its decarboxylation in the liver. MMI has a longer half-life and fewer side effects compared to propylthiouracil. The American Thyroid Association recommends that MMI be used in almost every patient who opts for ATD therapy [ 2 ]. ATDs are the basis of treatment in several centers, such as Europe, Latin America, and Japan, and their use is increasing in the USA [ 2 , 6 ]. This could be due to ATDs' ability to induce remission rather than hypothyroidism and lifelong treatment associated with RAI and surgery. ATDs, on the other hand, are associated with major adverse events and hyperthyroidism relapse, which are common with high doses and short-term treatment [ 9 – 11 ]. A meta-analysis showed that long-term antithyroid drug treatment was associated with fewer complications and higher remission rates than short-term treatment [ 9 ]. Therefore, long-term antithyroid drugs may be a viable alternative to RAI therapy. Multiple clinical trials compared methimazole (MMI) to RAI therapy and found it to be superior or non-inferior, while others concluded that MMI is ineffective [ 12 – 20 ]. Therefore, we conducted this first meta-analysis to compare the efficacy of methimazole to RAI in hyperthyroid patients. Methods This meta-analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 21 ]. Literature Search Strategy We used the terms "methimazole", "Carbimazole", "antithyroid", "radioactive iodine", "hyperthyroidism", "toxic multinodular", and "graves" in searching PubMed, Scopus, Cochrane Library, and Web of Science in all fields from inception till March 5, 2023. Supplementary file 1 shows the full search strategy for each database. No search filters were used, and the references of the eligible papers were also searched for any other relevant studies. Study selection and eligibility criteria Two independent authors manually screened the retrieved records in two steps: title and abstract screening, followed by full-text screening. For any discrepancies, a third author was consulted. We chose prospective randomized controlled trials (RCTs) comparing methimazole versus radioiodine therapy for patients with hyperthyroidism that were reported in full articles. Non-randomized clinical trials, observational studies, conference abstracts, and studies reported in languages other than English were not considered. Data extraction The lead author created Excel spreadsheets that included baseline data, study characteristics, and outcomes of interest. Two authors independently extracted study characteristics such as study ID, details of treatment regimens, sample size, study design, follow-up duration, and inclusion criteria; baseline data such as age, gender, and gland weight; and outcomes of interest such as euthyroidism, hypothyroidism, relapse rate, rate of persistent hyperthyroidism, and cure rate which included both patients who achieved euthyroidism and hypothyroidism statuses. A third senior author settled any disagreements. Any incomplete or incompatible data were handled using the Cochrane Handbook's recommended methods [ 22 ]. Risk of bias assessment The second version of the Cochrane Risk of Bias tool [ 23 ] was used to assess the quality of the included studies in the following domains: A) bias arising from the randomization process, B) bias resulting from deviations from intended interventions, C) bias resulting from missing outcome data, D) bias in outcome measurement, and E) bias in the selection of the reported results. The domains were classified as low, moderate, or high risk. Two authors conducted the evaluation independently, with discussions with a third author in the event of disagreements. Statistical analysis We used Review Manager (RevMan) version 5.4 in our analysis. A P-value of less than 0.05 was used to define significant results. We used the pooled RR and 95% confidence interval (CI) for dichotomous variables. Because the studies' study designs and treatment effect measures were similar, we initially used the fixed effect model assuming that the studies were homogeneous. The Mantel-Haenszel equation was used to pool heterogeneous data in the random-effects meta-analysis model. We looked at the forest plots visually to assess statistical heterogeneity. We calculated its magnitude using Chi-Square tests as well. When the chi-square P-value was less than 0.05, significant heterogeneity was found. We could not assess the risk of publication bias using Egger's funnel-plot-based methods because our analysis included fewer than ten studies [ 24 ]. Results Literature search results: We searched several databases, including PubMed, Web of Science, Cochrane Library, and Scopus, which resulted in 5606 studies. After removing 2553 duplicates and screening the titles and abstracts, 2991 articles were excluded for not meeting our inclusion criteria, leaving 62 full-text articles for eligibility evaluation. Ultimately, five RCTs were included in the meta-analysis [ 12 – 15 , 17 , 19 ]. (Fig. 1 ). Summary of the included studies: The meta-analysis included a total of 761 patients, with 370 patients receiving methimazole and 391 patients receiving radioactive iodine [ 12 – 15 , 17 , 19 ]. The age range of the patients was between 36 to 70 years. The study involved six trials, four of which were conducted in Iran [ 12 – 15 ], one in Sweden [ 19 ], and one in China [ 17 ]. Table 1 provides a comprehensive summary of the trials included in the analysis. Additionally, Table 2 presents the baseline characteristics of the patients. Table 2 Baseline characteristics of enrolled patients in each included study. Study Name Groups Number of patients Age mean ± SD Males Gland weight mean ± SD Free T3 mean ± SD Free T4 mean ± SD TSH mean ± SD Torring et al. 1996 Methimazole 71 38.2 ± 9.52 12 NR NR 57.85 ± 21.12 NR Radioactive iodine 41 ± 545 5 NR NR 55 ± 19 NR Azizi et al. 2005 Methimazole 31 47 ± 5 6 36 ± 7 11.5 ± 1.3 45.1 ± 0.87 0.012 ± 0.001 Radioactive iodine 51 ± 648 10 35 ± 8 10.4 ± 1 3.12 ± 0.96 0.014 ± 0.001 Chen et al. 2009 Methimazole 177 36.8 ± 13.6 59 57.13 ± 3.2 26.6 ± 15.3 3.04 ± 18.8 0.7 ± 0.7 Radioactive iodine 209 ± 13.736.9 63 60.53 ± 4.6 25.1 ± 14.3 45.4 ± 18.4 0.92 ± 0.99 Azizi et al. 2021 Methimazole 35 ± 3.969.6 9 49 ± 7 NR 17.2 ± 1.9 0.04 ± 0.03 Radioactive iodine 36 ± 4.169.7 10 48 ± 8 NR 17.7 ± 1.6 0.04 ± 0.03 Azizi et al. 2022 Methimazole 53 ± 649.5 10 48 ± 7 NR 27.3 ± 5 0.085 ± 0.018 Radioactive iodine 54 ± 5.750 10 50 ± 6 NR 28.2 ± 3.6 0.083 ± 0.17 Table 2 Baseline characteristics of enrolled patients in each included study. SD = Standard deviation, TSH = thyroid stimualating hormone. Study ID Study design, country, and timing Criteria Sample size Treatment regimen Methimazole duration of therapy (months) Add-on therapy Reason of hyperthyroidism Torring et al. 1996 RCT, Sweden, between November 1983 and June 1990 Patients with hyperthyroidism caused by Graves’ disease and without a history of previous thyroid disease. Total = 112 Methimazole = 71 RAI = 41 Methimazole Dose = 21.6g RAI Dose = single oral activity of iodine-131 18 months Propylthiouracil Propranol Graves’ disease Azizi et al. 2005 RCT, Iran, between March 1989 and June 2002 Patients older than 40 years of age, diagnosed with hyperthyroidism due to diffuse toxic goiter. Total = 82 Methimazole = 31 RAI = 51 Methimazole Dose = 0.9g + maintenance dose (2.5–10mg daily) RAI Dose = single dose of 131I about 236.43 ± 117.66 MBq Two months then a maintenance dose NR diffuse toxic goiter Chen et al. 2009 RCT,China, between January 1998 and August 1999 Newly diagnosed hyperthyroidism; no previous thyroid treatment; thyroid function serum tests; 24-h uptake of 131I > 40% Total = 386 Methimazole = 177 RAI = 209 Methimazole Dose = 1.35g RAI Dose = single dose of 131I about 236.43 ± 117.66 MBq 18 months NR Graves’ disease Azizi et al. 2021 RCT, Iran, between September 2006 and February 2017 Untreated patients with subclinical hyperthyroidism, aged ≥ 65 years Total = 71 Methimazole = 35 RAI = 36 Methimazole Dose = 18g RAI Dose = N/A 60 months NR Toxic multinodular goiter diffuse or multinodular goiter Azizi et al. 2022 RCT, Iran, April 2005 Untreated patients with Toxic multinodular goiter, aged ≤ 60 years Total = 106 Methimazole = 52 RAI = 54 Methimazole Dose = 40.32 ± 14.4g and dropped to 17.28 ± 5.6g by the end of 12 years RAI Dose = single dose 16.7 ± 2.7 mCi 144 months NR Toxic multinodular goiter Quality assessment: The included trials were assessed for bias risk using the ROB 2 tool, which classified them according to the low to high-risk level. The summary of the bias risk is shown in (Figs. 2 and 3 ) The overall risk of bias for most of the studies was determined to be high, with the exception of Azizi et al. 2021 [ 13 ], which was found to have some concerns. Randomization process bias: most studies were considered to have a low risk of bias. However, Azizi et al. 2005 [ 12 ] and Chen et al. 2009 [ 17 ] were judged to have a high risk of bias due to inadequate randomization procedures. Intended interventions bias: two studies were judged to have a low risk of bias. However, Torring et al. 1996 [ 19 ], Azizi et al. 2005 [ 12 ] and Azizi et al.2019 [ 15 ] were judged to have a high risk of bias due to the statistical analysis performed to calculate the impact of assignments being an as-treated analysis, and the loss during follow-up exceeding 5% of the study population. Missing outcome data bias: most studies were considered to have a low risk of bias. However, Azizi et al. 2005 [ 12 ] considered a high risk of bias due to a high rate of missing outcome data and the lack of mention of reasons for exclusion in the intervention group. Measurement outcome bias: despite using appropriate outcome measurement methods, the outcome assessors knew about the intervention received by study participants; however, the outcome was not influenced by this knowledge, so we judged all studies to have a low risk of bias. Selection of the reported result bias: all studies were considered to have some concerns due to the lack of protocol registration. Efficacy outcomes: Euthyroid Our analysis of Euthyroid included five studies [ 12 – 14 , 17 , 19 ] with a total of 361 patients in the methimazole arm and 378 patients in the RAI arm, which revealed no significant risk reduction between methimazole and RAI (RR = 2.09 (95% CI [0.90, 4.87], P = 0.09). High heterogeneity was observed (P < 0.00001, I 2 = 96%), which could not be resolved. (Fig. 4 ). Hypothyroidism Our analysis of Hypothyroidism included five studies [ 12 – 14 , 17 , 19 ] with 361 patients in the methimazole arm and 378 patients in the RAI arm, which revealed a significant increase in hypothyroidism favoring RAI (RR = 0.09 (95% CI [0.02, 0.36], P = 0.0008). High heterogeneity was observed (P = 0.0002, I 2 = 82%) which was solved by excluding Chen et al. 2009 [ 17 ] (P = 0.37, I 2 = 4%) and the results remained significant and favored the RAI (RR = 0.06 (95% CI [0.03, 0.15], P < 0.00001) (Fig. 5 ). Persistent hyperthyroidism Our analysis of persistent hyperthyroidism included four studies [ 12 , 14 , 17 , 19 ] with 325 patients in the methimazole arm and 343 patients in the RAI arm, which revealed no significant difference between them (RR = 1.15 (95% CI [0.10, 12.92], P = 0.91). High heterogeneity was observed (P < 0.0001, I 2 = 87%), which was solved by excluding Chen et al. 2009 [ 17 ] (P = 0.21, I 2 = 36%) and the results remained non-significant (RR = 0.4 (95% CI [0.07, 2.13], P = 0.28) (Fig. 6 ). Relapse Our analysis of relapse included three studies [ 15 , 17 , 19 ] with 289 patients in the methimazole arm and 302 patients in the RAI arm, which revealed no significant difference between them (RR = 1.34 (95% CI [0.31, 5.86], P = 0.70). High heterogeneity was observed (P < 0.0001, I 2 = 90%) which could not be solved (Fig. 7 ). Cure rate Our analysis of the Cure rate included five studies [ 12 , 13 , 15 , 17 , 19 ] with 362 patients in the methimazole arm and 378 patients in the RAI arm, which revealed no significant difference between both groups (RR = 0.84 (95% CI [0.58, 1.20], P = 0.34). High heterogeneity was observed (P < 0.00001, I 2 = 98%), which could not be resolved. (Fig. 8 ). Discussion There is no consensus over which of the two treatments is superior. This meta-analysis is the first to compare the efficacy and safety of methimazole (MMI) therapy versus radioactive iodine (RAI) therapy in hyperthyroid patients. We looked at the effect of methimazole and RAI on the occurrence of euthyroidism and hypothyroidism, as well as the relapse rate, the rate of persistent hyperthyroidism, and the cure rate. Our meta-analysis found that methimazole achieved a higher rate of euthyroidism than RAI; however, the results did not reach statistical significance. The goal of hyperthyroidism treatment is to return patients to euthyroid status. Current literature suggests that euthyroidism is more prevalent with ATDs. A retrospective analysis found that 90% of patients remained euthyroid through 80 months of follow-up [ 25 ], whereas a substantial number of patients receiving thyroid replacement therapy in the Colorado and retrospective studies were not euthyroid [ 8 , 26 , 27 ]. Long-term MMI was found to attain a significantly higher prevalence of euthyroidism than RAI in a previous observational study [ 28 ]. However, ATDs failure has been linked to goiter size in the presenting patients [ 29 ]. A larger goiter was associated with a longer time to reach euthyroidism [ 30 ]. All of the RCTs included in our analysis significantly favored methimazole over RAI in achieving euthyroidism, except for the Chen et al. 2009 [ 17 ] study, which had patients with larger goiters at baseline. Therefore, predictive factors at the baseline may favor one therapy over the other. The meta-analysis found that RAI treatment significantly increased the incidence of hypothyroidism compared to MMI, and the finding was consistent across all included studies. Over the course of 20 years, a large retrospective study of patients with hyperthyroidism treated with RAI found that the prevalence of hypothyroidism increased with the follow-up duration, reaching 28% after five years and 60% at the end [ 31 ]. Villagelin et al. [ 28 ] found in their retrospective analysis that the RAI arm had a significantly higher percentage of hypothyroidism than long-term MMI at 12, 24, 36, 48, and 60 months of follow-up and ophthalmopathy worsening was significantly more prevalent in the RAI group. The high correlation between hypothyroidism and RAI could be attributed to variation in replacement therapy absorption or the lack of variation in endogenous thyroid hormone production. Hypothyroidism is considered a risk factor for developing or worsening RAI-related ophthalmopathy [ 32 ]. This issue may be resolved if post-radioiodine hypothyroidism is prevented early [ 33 ]. MMI, on the other hand, had a significantly lower incidence of hypothyroidism, which may make the development and worsening of ophthalmopathy less frequent. The cure rate was not significantly different between the two groups. The two treatments, however, treated hyperthyroidism patients differently. The cure for hyperthyroidism is to become euthyroid or hypothyroid. MMI causes euthyroidism, whereas RAI frequently causes hypothyroidism. The main disadvantage of antithyroid drug treatment for hyperthyroidism is hyperthyroidism relapse, which occurs in 20 to 70% of cases when therapy is discontinued [ 2 ]. A network meta-analysis suggested significantly higher relapse rates with ATDs when compared to RAI and thyroidectomy [ 34 ]. However, it is not necessary to discontinue antithyroid therapy, and methimazole can be used indefinitely. In our study, MMI and RAI relapse rates were found to be comparable. Chen et al. 2009 [ 17 ] and Torring et al. 1996 [ 19 ] found that the MMI group had a higher relapse rate than the RAI group after administering MMI to patients for 18 months before discontinuing it. Azizi et al. 2019 [ 15 ] noticed that the MMI group had a significantly lower relapse rate than the RAI group; however, methimazole was administered for the entire 96-month follow-up period. This is in line with a recent prospective randomized trial’s findings, which showed that patients who continued taking MMI experienced significantly lower rates of relapse than those who stopped the medication [ 35 ]. Moreover, side effects were very rare in patients who received long-term methimazole [ 9 , 15 , 28 ]. Furthermore, over a 10-year period, long-term methimazole was significantly less expensive than RAI [ 12 ]. Long-term methimazole can be a viable, safe, and less expensive alternative therapy to RAI. MMI and RAI both had comparable persistent hyperthyroidism. Chen et al. 2009 [ 17 ] found that MMI had a significantly higher incidence of persistent hyperthyroidism than RAI; however, this may be attributed to the patients’ goiter size at baseline [ 2 , 36 ]. Our study has several limitations. First, we found significant heterogeneity in all of our outcomes, which could not be resolved in three of them. Second, the therapy duration and dose regimen of methimazole in the included studies varied, which may have introduced heterogeneity into our results. Third, due to the small number of trials that assessed our outcomes, we were unable to perform subgroup analysis and thus could not determine the efficacy of different methimazole doses and therapy durations, as well as the efficacy of MMI on the various causes of hyperthyroidism. Fourth, due to limited data, we were unable to assess the efficacy of methimazole in patients with various risk factors that influence the likelihood of response, such as age, smoking status, and thyroid gland weight. Conclusion Methimazole and radioactive iodine therapy both demonstrated comparable cure rates. Although methimazole was less effective than RAI in achieving hypothyroidism, it was more effective in achieving euthyroidism, which may have the advantage of having a lower rate of development and progression of hypothyroidism-induced ophthalmopathy. Long-term methimazole treatment is safe, inexpensive, and may be associated with a lower relapse rate; however, more studies are needed to confirm that. Future studies should focus, as well, on the efficacy of methimazole in patients with a variety of risk factors that influence the likelihood of response. Abbreviations ATDs Antithyroid drugs CI Confidence interval MMI Methimazole PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses RAI Radioiodine therapy RCTs Randomized controlled trials ROB Risk of bias RR Risk ratio TMNG Toxic multinodular goiter TSH Thyroid-stimulating hormone Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials All data analyzed during this study are included in this published article or listed in the references. Competing interests The authors declare that they have no competing interests. Funding None Authors' contributions M.A. led the team and was responsible for developing the search strategy, conducting full text screening, and collecting data. he also resolved any conflicts that arose during the screening and quality evaluation phases and prepared the tables. 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Additional Declarations No competing interests reported. Supplementary Files supplementaryfile11.docx Supplementary file 1: Full search strategy for each database. A table shows the search strategy used in each of the database. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3542960","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":245161508,"identity":"7141f693-ab87-421c-91ee-4c17858471a8","order_by":0,"name":"Mohamed Abd-ElGawad","email":"","orcid":"","institution":"Fayoum University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Abd-ElGawad","suffix":""},{"id":245161509,"identity":"dc7090eb-ff27-42c9-8238-c4e01d9c59df","order_by":1,"name":"Mahmoud Shaban Abdelgalil","email":"data:image/png;base64,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","orcid":"","institution":"Ain Shams University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mahmoud","middleName":"Shaban","lastName":"Abdelgalil","suffix":""},{"id":245161510,"identity":"1bb99992-b824-4bae-81f8-57f54170f0d4","order_by":2,"name":"Nada K. Abdelsattar","email":"","orcid":"","institution":"Fayoum University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nada","middleName":"K.","lastName":"Abdelsattar","suffix":""},{"id":245161511,"identity":"1e661d41-8da2-4e7c-be49-8d00b85f2429","order_by":3,"name":"Hazem Mohamed Salamah","email":"","orcid":"","institution":"Zagazig University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hazem","middleName":"Mohamed","lastName":"Salamah","suffix":""},{"id":245161512,"identity":"007d9cc8-3c38-4eb2-aa8c-55f1f76d1cf9","order_by":4,"name":"Mohamed Abdelmonem Kamel","email":"","orcid":"","institution":"Fayoum University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"Abdelmonem","lastName":"Kamel","suffix":""}],"badges":[],"createdAt":"2023-11-02 10:14:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3542960/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3542960/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":46029682,"identity":"ef48378b-3031-4669-a94a-6c2b4224901d","added_by":"auto","created_at":"2023-11-07 17:50:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70501,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram shows the detailed process of the search strategy and study selection.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/fb0a96035ebd2a0dcf4c4a43.png"},{"id":46030617,"identity":"9a959d9d-8e6e-42dc-b39c-d00eab8af921","added_by":"auto","created_at":"2023-11-07 17:58:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14171,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of assessment of the risk of bias.\u003c/p\u003e","description":"","filename":"Figure2Riskofbiassummary.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/8d622cddc1c285c636e8a771.png"},{"id":46029687,"identity":"d652ef84-cac6-4b11-811d-348dae47c945","added_by":"auto","created_at":"2023-11-07 17:50:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":35067,"visible":true,"origin":"","legend":"\u003cp\u003eDetailed risk of bias\u003c/p\u003e","description":"","filename":"Figure3Detailedriskofbias.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/361a0e96f077c6c12aa64de0.png"},{"id":46029681,"identity":"79a40215-94a1-4716-86a4-6df4aa11ff4d","added_by":"auto","created_at":"2023-11-07 17:50:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":9870,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot shows the risk ratio of euthyroidism.\u003c/p\u003e","description":"","filename":"Figure4Euthyroidoutcome.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/d1ff0153ef2b2d4ffe3d598c.png"},{"id":46029684,"identity":"03ac6a28-9d18-4ba5-8cc2-32a20f356ce3","added_by":"auto","created_at":"2023-11-07 17:50:45","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":35389,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot shows the risk ratio of hypothyroidism; A) results before solving heterogeneity and B) results after solving the heterogeneity.\u003c/p\u003e","description":"","filename":"Figure5Hypothyroidismoutcome.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/f46b485b07e07332979a6863.png"},{"id":46029685,"identity":"22385e2b-e734-4f47-828c-9507dc89011b","added_by":"auto","created_at":"2023-11-07 17:50:45","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":30877,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot shows the risk ratio of persistent hyperthyroidism; A) results before solving heterogeneity and B) results after solving the heterogeneity.\u003c/p\u003e","description":"","filename":"Figure6Persistenthyperthyroidism.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/dfa8753b084b493bedb787dc.png"},{"id":46029689,"identity":"3cac7582-3713-4f7a-89d1-1031e3ebea00","added_by":"auto","created_at":"2023-11-07 17:50:45","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":9016,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot shows the risk ratio of relapse rate.\u003c/p\u003e","description":"","filename":"Figure7Relapse.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/413ec1b0d81ac511f2a7b680.png"},{"id":46029688,"identity":"9fbaa873-c6f2-412f-be5c-22fe4ae83d4f","added_by":"auto","created_at":"2023-11-07 17:50:45","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":9821,"visible":true,"origin":"","legend":"\u003cp\u003eA forest plot shows the risk ratio of cure rate.\u003c/p\u003e","description":"","filename":"Figure8Curerate.png","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/48f490e993e5e3ee3ec9cdc4.png"},{"id":48518847,"identity":"09cb724f-e6d0-4da8-b27c-da4c8eb8e221","added_by":"auto","created_at":"2023-12-20 08:29:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":674614,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/63d636d8-8c5c-4360-9a7c-0c393ad278d1.pdf"},{"id":46030618,"identity":"024e6727-820c-41de-a528-aff5acd5f8b0","added_by":"auto","created_at":"2023-11-07 17:58:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17145,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary file 1:\u003c/strong\u003e Full search strategy for each database. A table shows the search strategy used in each of the database.\u003c/p\u003e","description":"","filename":"supplementaryfile11.docx","url":"https://assets-eu.researchsquare.com/files/rs-3542960/v1/e8b6b58e5e7f01ff243368b2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy Of Methimazole Versus Radioiodine in Patients With Hyperthyroidism: A Meta-analysis Of Randomized Controlled Trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHyperthyroidism is the overproduction of thyroid hormones caused by excessive thyroid gland activity. It is defined by low serum thyroid stimulating hormone (TSH) and high serum levels of thyroid hormones: thyroxine (T4) and triiodothyronine (T3), or subclinical, as defined by low serum TSH but normal serum T4 and T3 concentrations [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hyperthyroidism commonly manifests as Graves' disease or a toxic multinodular goiter (TMNG). While Graves' disease is characterized by diffuse enlargement of the gland as a result of autoantibodies that interact with TSH receptors, TMNG is a non-autoimmune heterogeneous thyroid enlargement with autonomously hyperfunctioning thyroid nodules [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHyperthyroidism has been linked to an increase in morbidity and mortality, primarily from cardiovascular causes such as atrial fibrillation, coronary heart disease, heart failure, pulmonary hypertension, and stroke, as well as osteoporosis, cancer, and lung diseases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There are several treatment options available, including antithyroid drugs (ATDs), radioiodine therapy, and surgery. Surgery is considered for large nodules, nodules that are resistant to other treatments, or coexisting thyroid cancer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRadioiodine therapy (RAI) is preferred by physicians in some centers, such as the USA, as the treatment of choice, which may be attributed to its simplicity, effectiveness, low cost, and being a definitive approach for the high recurrence rates associated with ATDs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, RAI is associated with radiation exposure, hypothyroidism, and worsening of Graves' ophthalmopathy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Furthermore, compliance with lifelong, regular levothyroxine replacement may be challenging. Levothyroxine replacement was also linked to abnormal TSH levels, causing subclinical hypo- or hyperthyroidism, which can lead to coronary heart disease or atrial fibrillation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe three cornerstones of antithyroid drug therapy are methimazole (MMI), carbimazole, and propylthiouracil. These medications prevent the thyroid gland from producing thyroid hormones. MMI is the active metabolite of carbimazole after its decarboxylation in the liver. MMI has a longer half-life and fewer side effects compared to propylthiouracil. The American Thyroid Association recommends that MMI be used in almost every patient who opts for ATD therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eATDs are the basis of treatment in several centers, such as Europe, Latin America, and Japan, and their use is increasing in the USA [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This could be due to ATDs' ability to induce remission rather than hypothyroidism and lifelong treatment associated with RAI and surgery. ATDs, on the other hand, are associated with major adverse events and hyperthyroidism relapse, which are common with high doses and short-term treatment [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A meta-analysis showed that long-term antithyroid drug treatment was associated with fewer complications and higher remission rates than short-term treatment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, long-term antithyroid drugs may be a viable alternative to RAI therapy.\u003c/p\u003e \u003cp\u003eMultiple clinical trials compared methimazole (MMI) to RAI therapy and found it to be superior or non-inferior, while others concluded that MMI is ineffective [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Therefore, we conducted this first meta-analysis to compare the efficacy of methimazole to RAI in hyperthyroid patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis meta-analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eLiterature Search Strategy\u003c/h2\u003e \u003cp\u003eWe used the terms \"methimazole\", \"Carbimazole\", \"antithyroid\", \"radioactive iodine\", \"hyperthyroidism\", \"toxic multinodular\", and \"graves\" in searching PubMed, Scopus, Cochrane Library, and Web of Science in all fields from inception till March 5, 2023. \u003cb\u003eSupplementary file 1\u003c/b\u003e shows the full search strategy for each database. No search filters were used, and the references of the eligible papers were also searched for any other relevant studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and eligibility criteria\u003c/h2\u003e \u003cp\u003eTwo independent authors manually screened the retrieved records in two steps: title and abstract screening, followed by full-text screening. For any discrepancies, a third author was consulted. We chose prospective randomized controlled trials (RCTs) comparing methimazole versus radioiodine therapy for patients with hyperthyroidism that were reported in full articles. Non-randomized clinical trials, observational studies, conference abstracts, and studies reported in languages other than English were not considered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData extraction\u003c/h2\u003e \u003cp\u003eThe lead author created Excel spreadsheets that included baseline data, study characteristics, and outcomes of interest. Two authors independently extracted study characteristics such as study ID, details of treatment regimens, sample size, study design, follow-up duration, and inclusion criteria; baseline data such as age, gender, and gland weight; and outcomes of interest such as euthyroidism, hypothyroidism, relapse rate, rate of persistent hyperthyroidism, and cure rate which included both patients who achieved euthyroidism and hypothyroidism statuses. A third senior author settled any disagreements. Any incomplete or incompatible data were handled using the Cochrane Handbook's recommended methods [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias assessment\u003c/h2\u003e \u003cp\u003eThe second version of the Cochrane Risk of Bias tool [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] was used to assess the quality of the included studies in the following domains: A) bias arising from the randomization process, B) bias resulting from deviations from intended interventions, C) bias resulting from missing outcome data, D) bias in outcome measurement, and E) bias in the selection of the reported results. The domains were classified as low, moderate, or high risk. Two authors conducted the evaluation independently, with discussions with a third author in the event of disagreements.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003e We used Review Manager (RevMan) version 5.4 in our analysis. A P-value of less than 0.05 was used to define significant results. We used the pooled RR and 95% confidence interval (CI) for dichotomous variables. Because the studies' study designs and treatment effect measures were similar, we initially used the fixed effect model assuming that the studies were homogeneous. The Mantel-Haenszel equation was used to pool heterogeneous data in the random-effects meta-analysis model. We looked at the forest plots visually to assess statistical heterogeneity. We calculated its magnitude using Chi-Square tests as well. When the chi-square P-value was less than 0.05, significant heterogeneity was found.\u003c/p\u003e \u003cp\u003eWe could not assess the risk of publication bias using Egger's funnel-plot-based methods because our analysis included fewer than ten studies [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eLiterature search results:\u003c/h2\u003e \u003cp\u003eWe searched several databases, including PubMed, Web of Science, Cochrane Library, and Scopus, which resulted in 5606 studies. After removing 2553 duplicates and screening the titles and abstracts, 2991 articles were excluded for not meeting our inclusion criteria, leaving 62 full-text articles for eligibility evaluation. Ultimately, five RCTs were included in the meta-analysis [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSummary of the included studies:\u003c/h2\u003e \u003cp\u003eThe meta-analysis included a total of 761 patients, with 370 patients receiving methimazole and 391 patients receiving radioactive iodine [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The age range of the patients was between 36 to 70 years. The study involved six trials, four of which were conducted in Iran [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], one in Sweden [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], and one in China [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e provides a comprehensive summary of the trials included in the analysis. Additionally, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the baseline characteristics of the patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of enrolled patients in each included study.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy Name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMales\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGland weight\u003c/p\u003e \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFree T3\u003c/p\u003e \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFree T4\u003c/p\u003e \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTSH\u003c/p\u003e \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTorring et al. 1996\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethimazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e57.85\u0026thinsp;\u0026plusmn;\u0026thinsp;21.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRadioactive iodine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026plusmn;\u0026thinsp;545\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e55\u0026thinsp;\u0026plusmn;\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAzizi et al. 2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethimazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e47\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e45.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.012\u0026thinsp;\u0026plusmn;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRadioactive iodine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026plusmn;\u0026thinsp;648\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.014\u0026thinsp;\u0026plusmn;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eChen et al. 2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethimazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e36.8\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57.13\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.04\u0026thinsp;\u0026plusmn;\u0026thinsp;18.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRadioactive iodine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026plusmn;\u0026thinsp;13.736.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60.53\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e45.4\u0026thinsp;\u0026plusmn;\u0026thinsp;18.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAzizi et al. 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethimazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026plusmn;\u0026thinsp;3.969.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRadioactive iodine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026plusmn;\u0026thinsp;4.169.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAzizi et al. 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMethimazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026plusmn;\u0026thinsp;649.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e27.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.085\u0026thinsp;\u0026plusmn;\u0026thinsp;0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRadioactive iodine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026plusmn;\u0026thinsp;5.750\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e28.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.083\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of enrolled patients in each included study. SD\u0026thinsp;=\u0026thinsp;Standard deviation, TSH\u0026thinsp;=\u0026thinsp;thyroid stimualating hormone.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy ID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design, country, and timing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCriteria\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTreatment regimen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMethimazole duration of therapy (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAdd-on therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eReason of hyperthyroidism\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTorring et al. 1996\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT, Sweden, between November 1983 and June 1990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with hyperthyroidism caused by Graves\u0026rsquo; disease and without a history of previous thyroid disease.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u0026thinsp;=\u0026thinsp;112\u003c/p\u003e \u003cp\u003eMethimazole\u0026thinsp;=\u0026thinsp;71\u003c/p\u003e \u003cp\u003eRAI\u0026thinsp;=\u0026thinsp;41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethimazole Dose\u0026thinsp;=\u0026thinsp;21.6g\u003c/p\u003e \u003cp\u003eRAI Dose\u0026thinsp;=\u0026thinsp;single oral activity of iodine-131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePropylthiouracil Propranol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGraves\u0026rsquo; disease\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzizi et al. 2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT, Iran, between March 1989 and June 2002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients older than 40 years of age, diagnosed with hyperthyroidism due to diffuse toxic goiter.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u0026thinsp;=\u0026thinsp;82\u003c/p\u003e \u003cp\u003eMethimazole\u0026thinsp;=\u0026thinsp;31\u003c/p\u003e \u003cp\u003eRAI\u0026thinsp;=\u0026thinsp;51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethimazole Dose\u0026thinsp;=\u0026thinsp;0.9g\u0026thinsp;+\u0026thinsp;maintenance dose (2.5\u0026ndash;10mg daily)\u003c/p\u003e \u003cp\u003eRAI Dose\u0026thinsp;=\u0026thinsp;single dose of 131I about 236.43\u0026thinsp;\u0026plusmn;\u0026thinsp;117.66 MBq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTwo months then a maintenance dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ediffuse toxic goiter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChen et al. 2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT,China, between January 1998 and August 1999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNewly diagnosed hyperthyroidism; no previous thyroid treatment; thyroid function serum tests; 24-h uptake of 131I\u0026thinsp;\u0026gt;\u0026thinsp;40%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u0026thinsp;=\u0026thinsp;386\u003c/p\u003e \u003cp\u003eMethimazole\u0026thinsp;=\u0026thinsp;177\u003c/p\u003e \u003cp\u003eRAI\u0026thinsp;=\u0026thinsp;209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethimazole Dose\u0026thinsp;=\u0026thinsp;1.35g\u003c/p\u003e \u003cp\u003eRAI Dose\u0026thinsp;=\u0026thinsp;single dose of 131I about 236.43\u0026thinsp;\u0026plusmn;\u0026thinsp;117.66 MBq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGraves\u0026rsquo; disease\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzizi et al. 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT, Iran, between September 2006 and February 2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUntreated patients with subclinical hyperthyroidism, aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u0026thinsp;=\u0026thinsp;71\u003c/p\u003e \u003cp\u003eMethimazole\u0026thinsp;=\u0026thinsp;35\u003c/p\u003e \u003cp\u003eRAI\u0026thinsp;=\u0026thinsp;36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethimazole Dose\u0026thinsp;=\u0026thinsp;18g\u003c/p\u003e \u003cp\u003eRAI Dose\u0026thinsp;=\u0026thinsp;N/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eToxic multinodular goiter\u003c/p\u003e \u003cp\u003ediffuse or multinodular goiter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzizi et al. 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT, Iran, April 2005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUntreated patients with Toxic multinodular goiter, aged\u0026thinsp;\u0026le;\u0026thinsp;60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u0026thinsp;=\u0026thinsp;106\u003c/p\u003e \u003cp\u003eMethimazole\u0026thinsp;=\u0026thinsp;52\u003c/p\u003e \u003cp\u003eRAI\u0026thinsp;=\u0026thinsp;54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethimazole Dose\u0026thinsp;=\u0026thinsp;40.32\u0026thinsp;\u0026plusmn;\u0026thinsp;14.4g and dropped to 17.28\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6g by the end of 12 years\u003c/p\u003e \u003cp\u003eRAI Dose\u0026thinsp;=\u0026thinsp;single dose 16.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 mCi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e144 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eToxic multinodular goiter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment:\u003c/h2\u003e \u003cp\u003eThe included trials were assessed for bias risk using the ROB 2 tool, which classified them according to the low to high-risk level. The summary of the bias risk is shown in (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) The overall risk of bias for most of the studies was determined to be high, with the exception of Azizi et al. 2021 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], which was found to have some concerns.\u003c/p\u003e \u003cp\u003eRandomization process bias: most studies were considered to have a low risk of bias. However, Azizi et al. 2005 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and Chen et al. 2009 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] were judged to have a high risk of bias due to inadequate randomization procedures.\u003c/p\u003e \u003cp\u003eIntended interventions bias: two studies were judged to have a low risk of bias. However, Torring et al. 1996 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], Azizi et al. 2005 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and Azizi et al.2019 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] were judged to have a high risk of bias due to the statistical analysis performed to calculate the impact of assignments being an as-treated analysis, and the loss during follow-up exceeding 5% of the study population.\u003c/p\u003e \u003cp\u003eMissing outcome data bias: most studies were considered to have a low risk of bias. However, Azizi et al. 2005 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] considered a high risk of bias due to a high rate of missing outcome data and the lack of mention of reasons for exclusion in the intervention group.\u003c/p\u003e \u003cp\u003eMeasurement outcome bias: despite using appropriate outcome measurement methods, the outcome assessors knew about the intervention received by study participants; however, the outcome was not influenced by this knowledge, so we judged all studies to have a low risk of bias.\u003c/p\u003e \u003cp\u003eSelection of the reported result bias: all studies were considered to have some concerns due to the lack of protocol registration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy outcomes:\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003eEuthyroid\u003c/h2\u003e \u003cp\u003eOur analysis of Euthyroid included five studies [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] with a total of 361 patients in the methimazole arm and 378 patients in the RAI arm, which revealed no significant risk reduction between methimazole and RAI (RR\u0026thinsp;=\u0026thinsp;2.09 (95% CI [0.90, 4.87], P\u0026thinsp;=\u0026thinsp;0.09). High heterogeneity was observed (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;96%), which could not be resolved. (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eHypothyroidism\u003c/h2\u003e \u003cp\u003eOur analysis of Hypothyroidism included five studies [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] with 361 patients in the methimazole arm and 378 patients in the RAI arm, which revealed a significant increase in hypothyroidism favoring RAI (RR\u0026thinsp;=\u0026thinsp;0.09 (95% CI [0.02, 0.36], P\u0026thinsp;=\u0026thinsp;0.0008). High heterogeneity was observed (P\u0026thinsp;=\u0026thinsp;0.0002, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;82%) which was solved by excluding Chen et al. 2009 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] (P\u0026thinsp;=\u0026thinsp;0.37, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;4%) and the results remained significant and favored the RAI (RR\u0026thinsp;=\u0026thinsp;0.06 (95% CI [0.03, 0.15], P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePersistent hyperthyroidism\u003c/h2\u003e \u003cp\u003eOur analysis of persistent hyperthyroidism included four studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] with 325 patients in the methimazole arm and 343 patients in the RAI arm, which revealed no significant difference between them (RR\u0026thinsp;=\u0026thinsp;1.15 (95% CI [0.10, 12.92], P\u0026thinsp;=\u0026thinsp;0.91). High heterogeneity was observed (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;87%), which was solved by excluding Chen et al. 2009 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] (P\u0026thinsp;=\u0026thinsp;0.21, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;36%) and the results remained non-significant (RR\u0026thinsp;=\u0026thinsp;0.4 (95% CI [0.07, 2.13], P\u0026thinsp;=\u0026thinsp;0.28) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRelapse\u003c/h2\u003e \u003cp\u003eOur analysis of relapse included three studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] with 289 patients in the methimazole arm and 302 patients in the RAI arm, which revealed no significant difference between them (RR\u0026thinsp;=\u0026thinsp;1.34 (95% CI [0.31, 5.86], P\u0026thinsp;=\u0026thinsp;0.70). High heterogeneity was observed (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;90%) which could not be solved (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCure rate\u003c/h2\u003e \u003cp\u003eOur analysis of the Cure rate included five studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] with 362 patients in the methimazole arm and 378 patients in the RAI arm, which revealed no significant difference between both groups (RR\u0026thinsp;=\u0026thinsp;0.84 (95% CI [0.58, 1.20], P\u0026thinsp;=\u0026thinsp;0.34). High heterogeneity was observed (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;98%), which could not be resolved. (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere is no consensus over which of the two treatments is superior. This meta-analysis is the first to compare the efficacy and safety of methimazole (MMI) therapy versus radioactive iodine (RAI) therapy in hyperthyroid patients. We looked at the effect of methimazole and RAI on the occurrence of euthyroidism and hypothyroidism, as well as the relapse rate, the rate of persistent hyperthyroidism, and the cure rate.\u003c/p\u003e \u003cp\u003eOur meta-analysis found that methimazole achieved a higher rate of euthyroidism than RAI; however, the results did not reach statistical significance. The goal of hyperthyroidism treatment is to return patients to euthyroid status. Current literature suggests that euthyroidism is more prevalent with ATDs. A retrospective analysis found that 90% of patients remained euthyroid through 80 months of follow-up [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], whereas a substantial number of patients receiving thyroid replacement therapy in the Colorado and retrospective studies were not euthyroid [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Long-term MMI was found to attain a significantly higher prevalence of euthyroidism than RAI in a previous observational study [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, ATDs failure has been linked to goiter size in the presenting patients [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. A larger goiter was associated with a longer time to reach euthyroidism [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. All of the RCTs included in our analysis significantly favored methimazole over RAI in achieving euthyroidism, except for the Chen et al. 2009 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] study, which had patients with larger goiters at baseline. Therefore, predictive factors at the baseline may favor one therapy over the other.\u003c/p\u003e \u003cp\u003eThe meta-analysis found that RAI treatment significantly increased the incidence of hypothyroidism compared to MMI, and the finding was consistent across all included studies. Over the course of 20 years, a large retrospective study of patients with hyperthyroidism treated with RAI found that the prevalence of hypothyroidism increased with the follow-up duration, reaching 28% after five years and 60% at the end [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Villagelin et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] found in their retrospective analysis that the RAI arm had a significantly higher percentage of hypothyroidism than long-term MMI at 12, 24, 36, 48, and 60 months of follow-up and ophthalmopathy worsening was significantly more prevalent in the RAI group. The high correlation between hypothyroidism and RAI could be attributed to variation in replacement therapy absorption or the lack of variation in endogenous thyroid hormone production. Hypothyroidism is considered a risk factor for developing or worsening RAI-related ophthalmopathy [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This issue may be resolved if post-radioiodine hypothyroidism is prevented early [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. MMI, on the other hand, had a significantly lower incidence of hypothyroidism, which may make the development and worsening of ophthalmopathy less frequent.\u003c/p\u003e \u003cp\u003eThe cure rate was not significantly different between the two groups. The two treatments, however, treated hyperthyroidism patients differently. The cure for hyperthyroidism is to become euthyroid or hypothyroid. MMI causes euthyroidism, whereas RAI frequently causes hypothyroidism.\u003c/p\u003e \u003cp\u003eThe main disadvantage of antithyroid drug treatment for hyperthyroidism is hyperthyroidism relapse, which occurs in 20 to 70% of cases when therapy is discontinued [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A network meta-analysis suggested significantly higher relapse rates with ATDs when compared to RAI and thyroidectomy [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, it is not necessary to discontinue antithyroid therapy, and methimazole can be used indefinitely. In our study, MMI and RAI relapse rates were found to be comparable. Chen et al. 2009 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and Torring et al. 1996 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] found that the MMI group had a higher relapse rate than the RAI group after administering MMI to patients for 18 months before discontinuing it. Azizi et al. 2019 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] noticed that the MMI group had a significantly lower relapse rate than the RAI group; however, methimazole was administered for the entire 96-month follow-up period. This is in line with a recent prospective randomized trial\u0026rsquo;s findings, which showed that patients who continued taking MMI experienced significantly lower rates of relapse than those who stopped the medication [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Moreover, side effects were very rare in patients who received long-term methimazole [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Furthermore, over a 10-year period, long-term methimazole was significantly less expensive than RAI [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Long-term methimazole can be a viable, safe, and less expensive alternative therapy to RAI.\u003c/p\u003e \u003cp\u003eMMI and RAI both had comparable persistent hyperthyroidism. Chen et al. 2009 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] found that MMI had a significantly higher incidence of persistent hyperthyroidism than RAI; however, this may be attributed to the patients\u0026rsquo; goiter size at baseline [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, we found significant heterogeneity in all of our outcomes, which could not be resolved in three of them. Second, the therapy duration and dose regimen of methimazole in the included studies varied, which may have introduced heterogeneity into our results. Third, due to the small number of trials that assessed our outcomes, we were unable to perform subgroup analysis and thus could not determine the efficacy of different methimazole doses and therapy durations, as well as the efficacy of MMI on the various causes of hyperthyroidism. Fourth, due to limited data, we were unable to assess the efficacy of methimazole in patients with various risk factors that influence the likelihood of response, such as age, smoking status, and thyroid gland weight.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMethimazole and radioactive iodine therapy both demonstrated comparable cure rates. Although methimazole was less effective than RAI in achieving hypothyroidism, it was more effective in achieving euthyroidism, which may have the advantage of having a lower rate of development and progression of hypothyroidism-induced ophthalmopathy. Long-term methimazole treatment is safe, inexpensive, and may be associated with a lower relapse rate; however, more studies are needed to confirm that. Future studies should focus, as well, on the efficacy of methimazole in patients with a variety of risk factors that influence the likelihood of response.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eATDs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntithyroid drugs\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eMMI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMethimazole\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePRISMA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRAI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadioiodine therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRCTs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRandomized controlled trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eROB\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk of bias\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRisk ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTMNG\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eToxic multinodular goiter\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTSH\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThyroid-stimulating hormone\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data analyzed during this study are included in this published article or listed in the references.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003eAuthors' contributions\u003c/p\u003e\n\u003cp\u003eM.A. led the team and was responsible for developing the search strategy, conducting full text screening, and collecting data. he also resolved any conflicts that arose during the screening and quality evaluation phases and prepared the tables. M.S.A. contributed to the quality assessment, conducted the meta-analysis, and wrote the results section. N.K.A. participated in the full-text screening, quality assessment, and data extraction. H.M.S. authored the introduction, methods, and discussion sections, and edited the manuscript. M.A.K. supervised all the authors throughout the process and conducted peer-review. The final manuscript was reviewed and approved by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDe Leo S, Lee SY, Braverman LE. Hyperthyroidism. 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Outcome of radioiodine-131 therapy in hyperfunctioning thyroid nodules: a 20 years\u0026rsquo; retrospective study. Clinical Endocrinology. 2005;62:331\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKung AW, Yau CC, Cheng A. The incidence of ophthalmopathy after radioiodine therapy for Graves\u0026rsquo; disease: prognostic factors and the role of methimazole. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 1994;79:542\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J. A Prospective Study of the Effects of Radioiodine Therapy for Hyperthyroidism in Patients with Minimally Active Graves\u0026rsquo; Ophthalmopathy. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2005;90:5321\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSundaresh V, Brito JP, Wang Z, Prokop LJ, Stan MN, Murad MH, et al. Comparative Effectiveness of Therapies for Graves\u0026rsquo; Hyperthyroidism: A Systematic Review and Network Meta-Analysis. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2013;98:3671\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLertwattanarak R, Kunavisarut T, Sriussadaporn S. Benefits of Long-Term Continuation of Low-Dose Methimazole Therapy in the Prevention of Recurrent Hyperthyroidism in Graves\u0026rsquo; Hyperthyroid Patients: A Randomized Prospective Controlled Study. International Journal of Endocrinology. 2022;2022:1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNedrebo B, Holm P, Uhlving S, Sorheim J, Skeie S, Eide G, et al. Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves\u0026rsquo; disease. European Journal of Endocrinology. 2002;:583\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Methimazole, radioactive iodine, relapse, hyperthyroidism","lastPublishedDoi":"10.21203/rs.3.rs-3542960/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3542960/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe efficacy of methimazole compared to radioactive iodine (RAI) therapy for hyperthyroidism remains uncertain. Here, we conducted a meta-analysis to compare methimazole to RAI in the treatment of hyperthyroid patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe conducted a meta-analysis including English-randomized clinical trials (RCTs) published before March 5, 2023, to address this issue. The primary outcome was euthyroidism rate, while secondary outcomes included hypothyroidism, relapse, persistent hyperthyroidism, and cure rate. Review Manager software was used for analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eSix studies were included including 761 patients. The methimazole group had non-significantly higher rates of euthyroidism (RR = 2.09, 95% CI [0.90, 4.87], P = 0.09). The RAI group significantly increased the rates of hypothyroidism (RR = 0.06, 95% CI [0.03, 0.15], P \u0026lt; 0.00001). There were no significant differences in relapse, persistent hyperthyroidism, or cure rates between the two treatments (RR = 1.34, 95% CI [0.31, 5.86], P = 0.70), (RR = 0.4, 95% CI [0.07, 2.13], P = 0.28), and (RR = 0.84, 95% CI [0.58, 1.20], P = 0.34), respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eMethimazole was not inferior to RAI in curing hyperthyroid patients, with comparable relapse rates. Methimazole is an effective alternative to ablative therapies like RAI with a lower risk of hypothyroidism.\u003c/p\u003e","manuscriptTitle":"Efficacy Of Methimazole Versus Radioiodine in Patients With Hyperthyroidism: A Meta-analysis Of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-07 17:50:40","doi":"10.21203/rs.3.rs-3542960/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0cb47376-8b98-4087-9f9c-e8afea8f9db9","owner":[],"postedDate":"November 7th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":25883665,"name":"Health sciences/Endocrinology"},{"id":25883666,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases"},{"id":25883667,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Thyroid diseases"}],"tags":[],"updatedAt":"2023-12-20T08:29:16+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-07 17:50:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3542960","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3542960","identity":"rs-3542960","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}