Hyperthyroidism is prevalent in 0.2–1.3% of the population in iodine-replete areas, with Graves’ disease accounting for more than 80% of cases (1, 2). Patients with hyperthyroidism, especially those with uncontrolled or prolonged hyperthyroidism, are at an increased risk of cardiovascular morbidity and mortality (3–5). Three treatment modalities exist for Graves’ disease: anti-thyroid drug (ATD) therapy, radioactive iodine ablation (RIA), and thyroidectomy. Current guidelines do not prioritize any one treatment method among these three options as a first-line therapy as all methods have unique advantages and disadvantages (6–8). Nevertheless, ATD is currently used as an initial therapy for Graves’ disease in North America, Europe, and Asia (9–11).

A major drawback of ATD is the low rate of remission (12). With the recommended 12–18 month course of ATD therapy, a remission rate of approximately 30%–40% can be achieved (13). This is problematic considering the importance of prompt resolution of hyperthyroidism to reduce cardiovascular morbidity and mortality in these patients (5). It is recommended that patients with persistently high thyrotropin receptor antibody (TRAb) levels at 12–18 months can continue ATD treatment for an additional 12–18 months or opt for definitive therapy, e.g. RIA or thyroidectomy. However, treatment guidelines do not indicate a clear designation for the subsequent second-line therapy in this situation (6, 7). Previous studies have reported favorable outcomes of long-term (>24 months) treatment with ATDs with low rates of drug-related adverse events in patients with persistent or relapsed hyperthyroidism following a conventional course of ATD treatment (12, 14–17). However, the major outcome variable for measuring the efficacy of long-term ATD therapy in these studies was mostly the remission rate of hyperthyroidism, and the efficacy was not compared with other treatment modalities such as RIA or thyroidectomy. Given the increased risk of cardiovascular events in patients with hyperthyroidism and the improvement in survival associated with effective control of hyperthyroidism, it would be valuable to assess the risk of cardiovascular events in patients with long-standing hyperthyroidism according to different treatment methods following a conventional ATD course. To the best of our knowledge, no previous studies have assessed the direct impact of the type of second-line therapy on cardiovascular risk in the clinical setting of long-standing hyperthyroid patients. Thus, this study aimed to compare the risk of HF, the leading cause of cardiovascular mortality in hyperthyroidism (18–20), in patients who continued ATD after conventional duration of ATD therapy versus those who underwent subsequent RIA.

This study evaluated the risk of HF in patients with long-standing Graves’ disease according to secondary treatment modality following an initial 24-month course of ATD therapy. Compared to their age-and sex-matched controls, patients with long-standing Graves’ disease had a 28%–49% increased risk of HF after adjusting for various confounding factors. Notably, however, patients who achieved remission from hyperthyroidism following RIA within 1 year were not at increased risk for HF, while those who did not achieve remission had a 2.54-fold increased risk. Furthermore, in patients who received ATDs continuously after 24 months of the initial ATD course, the longer ATDs were used, the higher was the risk of HF. Our results show that in patients with long-standing Graves’ disease, early and definitive treatment with RIA should be considered to reduce the risk of HF.

Hyperthyroidism is associated with an increased risk of cardiovascular morbidity and mortality (3). Whether this risk is affected by different therapies for hyperthyroidism has not been fully elucidated. A previous study by Boelaert et al. compared the all-cause mortality rate between ATD therapy and RIA in patients with hyperthyroidism and observed a survival benefit with post-RIA hypothyroidism relative to ATD therapy or RIA not resulting in hypothyroidism (24). However, this study did not specifically investigate cardiovascular risks, and the number of cases was underpowered to show survival gain in the Graves’ disease subset. Ryödi et al. examined the risk of cardiovascular diseases (CVDs) in patients treated with RIA compared to those who underwent thyroidectomy and showed a higher CVD risk in the former but did not include patients treated with ATDs (25). A recent large-scale study (n = 4,189) of patients with Graves’ disease compared the overall survival and occurrence of major adverse cardiovascular events (MACEs) 1 year after diagnosis of Graves’ disease in patients treated with ATDs versus RIA (5). In reference to the control group, the risks of all-cause mortality and MACEs were highest in patients with unresolved hyperthyroidism after RIA by 1 year, followed by patients treated with ATDs. In patients with resolved hyperthyroidism after RIA within 1 year, the survival risk was not elevated, and the risk for MACEs was the lowest. Our study is distinguishable from previous studies in that we assessed the risk of HF according to second-line treatment modality. We selected a unique cohort of patients already treated with first-line ATDs for 24 months, which may represent the real-world clinical practice in which ATD therapy is used as the primary mode of treatment by 54%–97% of clinicians worldwide (8, 10). Our results showed that the risk of HF can be ameliorated by RIA when remission is achieved in patients with chronic hyperthyroidism and that the risk of HF is increased in those requiring a long duration of ATD treatment.

Current guidelines recommend 12–18 months of ATD therapy if used as primary treatment for hyperthyroidism, but there is no general agreement as to which treatment is best for chronic hyperthyroidism after this period (6–8). A recent prospective, randomized trial showed that long-term methimazole for 60–120 months lowered the relapse rate 3-fold at 48 months compared to conventional 18–24 month courses of treatment in patients with Graves’ disease (23). A multicenter cohort study of 908 patients with Graves’ disease in Korea also reported that longer use of ATDs was associated with a lower relapse rate (p = 0.003). The authors of both studies suggest that long-term (>24 months) ATD therapy is safe and effective in terms of reducing relapse rates. However, as hyperthyroidism is closely associated with cardiovascular events, achieving remission should not be the sole factor when considering treatment modalities. Clinicians must also consider increased risk of cardiovascular events when determining optimal second-line therapies for patients with long-standing hyperthyroidism. Our study focused on this point and observed significant differences in the risk of HF according to treatment method.

Notably, the risk of HF increased as ATDs were used for a longer duration in patients in the ATD group ( Figure 3 ). As thyroid function test (TFT) data were not available in our dataset, we could not accurately assess whether biochemical remission was achieved in these patients. However, because ATDs were withdrawn at a certain time point and no further RIA was performed, we can assume that remission was likely to be achieved. If this is the case, using ATDs longer than 24 months can increase the remission rate as reported (12, 14–17, 23) but may not be beneficial to control HF events. In the aforementioned study comparing all-cause mortality in patients treated with ATD and RIA, patients with persistently low thyroid stimulating hormone levels after 1 year of treatment had a 55% increased risk for death, regardless of treatment method (5). This highlights the importance of rapid and effective control of hyperthyroidism to improve survival. In this respect, priority should be given to early resolution of hyperthyroidism in patients already treated with ATDs for the upper limit duration of conventional therapy, as in our study. Further studies with a comprehensive investigation of the remission rate and risk of cardiovascular events with long-term ATD treatment in a single cohort may assist in determining the optimal time to step forward to definitive treatment.

This study had several limitations. First, data on TFT and TRAb were unavailable; thus, our study lacks information on the severity of hyperthyroidism at diagnosis, whether RIA was administered because of heavily uncontrolled hyperthyroidism, and whether biochemical remission was achieved after the treatment. Second, the diagnosis was based on ICD-10 codes, and accurate information about the etiology of hyperthyroidism in these patients is limited. However, Graves’ disease accounts for 82.7% of hyperthyroidism cases in Korea and toxic adenomas for less than 1% (8). Patients who used ATDs for more than 24 months with a diagnosis of hyperthyroidism in Korea would be expected to have Graves’ disease. Third, due to the retrospective design, we could not eliminate the possible bias from clinician preference and patient compliance to ATDs. Fourth, we did not include patients who underwent thyroidectomy for the treatment of hyperthyroidism, due to very small number of these patients. Lastly, we did not evaluate the risk of other CVDs. Growing evidence supports that hyperthyroidism accelerates atherosclerosis (26) and thus increases the risk of MI and stroke (5, 27–29), albeit controversial (18, 30, 31). Further studies evaluating the risk of MI or stroke may provide additional valuable information. Despite these limitations, strengths of this study are the large sample size and a unique cohort of patients with long-standing Graves’ disease. To the best of our knowledge, this is the first study to evaluate the risk of HF according to second-line therapies.

In conclusion, in patients with long-standing hyperthyroidism who underwent a conventional ATD course, the risk of HF differed according to the secondary treatment modality. Risk of HF was lowest in patients with controlled hyperthyroidism after RIA, increased as ATD was required for a prolonged duration, and was highest in patients with uncontrolled hyperthyroidism after RIA. In addition to the goal of achieving remission, is it important to consider the risk of comorbidities when determining the best therapies for long-standing hyperthyroid patients is necessary.

The data analyzed in this study is subject to the following licenses/restrictions: containing information could compromise the privacy of research participants. Requests to access these datasets should be directed to HY, deisy21@naver.com.

The studies involving human participants were reviewed and approved by Institutional Review Board of Korea University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conceptualization: ES and HY. Data curation: ES, MP, JK, ER, SB, and HY. Formal Analysis: ES, MK, and SP. Investigation: ES, MP, JK, ER, JY, NamK, HY, JS, SK, NanK, SB, and HY. Methodology: ES, MK, SP, and HY. Project administration: HY. Resources: ES, MP, JK, ER, JY, NamK, KC, JS, SK, NanK, SB, and HY. Supervision: HY. Visualization: ES, MK, and SP. Writing – original draft: ES and HY. Writing – review & editing: ES, MP, JK, ER, JY, NamK, JS, SK, NanK, KC, SB, and HY. All authors contributed to the article and approved the submitted version.

This work was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Education of Korea (2021R1A2C2008792).

Authors MK and SP were employed by company Hanmi Pharm. Co., Ltd.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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