Dong Wook Shin, MD, DrPH, MBA
A study presented at the 2017 Cancer Survivorship Symposium revealed a long-term cardiovascular risk associated with administration of levothyroxine. The risk of coronary heart disease and ischemic stroke was found to be higher in patients with thyroid cancer who received a thyroidectomy, and levothyroxine dosage appeared to play a major role in that risk.1
This is particularly noteworthy in the current context of recent controversy surrounding the overdiagnosis of thyroid cancer. “In most industrialized countries, the incidence of thyroid cancer has significantly increased in recent decades,” said investigator Dong Wook Shin, MD, DrPH, MBA. “In Korea in particular, we have observed a 10-fold increase in the past decade alone.” This drastic increase in incidence rates has caused concerns regarding overdiagnosis and, consequently, overtreatment. Therefore, according to Shin, assistant professor of the Cancer Survivorship Clinic at Seoul National University Cancer Hospital, Korea, balancing the benefits and harms of thyroid stimulating hormone (TSH) suppression is an important issue.
Until recently, suppression of TSH was routinely prescribed to patients with thyroid cancer to reduce recurrence of their disease after total thyroidectomy, with or without radioactive iodine (RAI) ablation, which often translated into a lifetime treatment.
Hyperthyroidism is a well-known risk factor for atrial fibrillation and ischemic stroke, and has been reported to cause angina or myocardial infarction in patients with underlying coronary heart disease. Therefore, in the study presented by Shin and col- leagues, they assumed that overt or subclinical hyperthyroidism induced by long-term administration of supra-physiologic dos- age of levothyroxine can be associated with an elevated cardiovascular risk.
According to a previous single-center study, 606 patients reported increased long-term cardiovascular mortality in patients with differentiated thyroid cancer, particularly in those patients who had low TSH levels. The study assessed the risk of cardiovascular mortality in patients with differentiated thyroid carcinoma, evaluated all-cause mortality, and explored the relation between TSH level and these outcome parameters. It demonstrated that overall cardiovascular mortality, including deaths from myocardial infarction, stroke, abdominal aortic aneurysm, and pulmonary embolism were composite outcomes.2
Patients with differentiated thyroid cancer had an increased risk of cardiovascular and all-cause mortality, with hazard ratios (HRs) of 3.35 (95% CI, 1.66-6.74) and 4.40 (95% CI, 3.15-6.14), respectively. Within the differentiated thyroid cancer group, TSH level was predictive for cardiovascular mortality; the adjusted HR was 3.08 (95% CI, 1.32-7.21) for each 10-fold decrease in geometric mean TSH level.1However, this study was matched to controls from a separate general population cohort, limiting the comparability of the 2 groups.
The retrospective cohort study led by Shin used claims data from the Korean National Health Insurance database. From this database, Shin and his colleagues selected cases of patients who received thyroidectomy to treat their thyroid cancer from 2003 to 2013. After exclusion criteria, 182,419 patients were selected and matched to noncancer controls by propensity score matching in a 1:1 ratio based on baseline age, sex, residence, insurance premium level, disability, hypertension levels, and diabetes mellitus status.
The study looked for coronary heart disease and incidence of ischemic stroke over a mean follow-up of 4.3 years. Patients were categorized into quartiles based on their dosage of levothyroxine.
The study found that patients with thyroid cancer had an elevated risk for both coronary heart disease (HR, 1.15; 95% CI, 1.19-1.22), and for stroke (HR, 1.15; 95% CI, 1.09-1.22). The risk was particularly marked among those patients who received a total thyroidectomy, and for those who took a higher dosage of levothyroxine.
Patients with thyroid cancer were also more likely to develop atrial brillation when they were administered a high dose of levothyroxine. However, levothyroxine dose does not appear to make a significant difference in the risk of ischemic stroke upon atrial brillation occurrence.
The increased risk in the third and fourth quartile of the study can be explained by hyperthyroidism, which can cause atrial bril- lation, Shin explained. However, it appears that ischemic stroke developed by atrial brillation comprises only a small proportion of ischemic stroke incidence (4.4% in the study). “Other studies suggest systolic hypertension, arterial stiffness, enhanced LDL oxidation, hypercoagulability, and change in heart function can be caused by hyperthyroidism,” Shin said.
Among the patients with thyroid cancer, those who took either a lower or higher dose of levothyroxine showed increased risk for both coronary heart disease and ischemic stroke, suggesting a “J-shaped pattern” in the risk.
In the first quartile of the study, the increased risk may be linked to hypothyroidism, which is also associated with dyslipidemia, LDL oxidation, atherosclerosis, and diastolic hypertension. Notably, the second quartile group of the study showed an even lower risk of developing coronary heart disease or ischemic stroke compared with the noncancer control group. Shin said that this may be due to differences in the patients themselves rather than in the treatment: “Thyroid cancer screening by ultrasonography in Korea is provided at the patient’s own cost. Those who elect to receive private health screening are likely to be more engaged in healthier behavior, vigilant follow-up, and proactive prevention.”
“Our study, to our knowledge, is the rst to directly investigate the relative risk of coronary heart disease and ischemic stroke incidence among thyroid cancer patients. We also found that the post-thyroidectomy levothyroxine dosage, which serves as a proxy marker for level of TSH suppression, is key in such risk,” Shin said.
The study did have some limitations, including the relatively short follow-up period. The investigators used levothyroxine dos- age as a proxy marker for the level of TSH suppression, so they could not make any specific interpretations about optimal TSH targets. They also did not include data on the type of thyroid cancer or stage for the study cohort but, according to Shin, they did not believe this affected their investigation.
“As addressed by recently revised guidelines, the results of our study call for more caution for the type of thyroidectomy chosen and TSH suppression therapy,” Shin concluded.
- Shin DW, Suh B, Yoon JM, et al. Risk of coronary heart disease and ischemic stroke in thyroid cancer patients taking levothyroxine. J Clin Oncol. 2017;35(suppl 5S; abstr 105).
- Klein Hesselink EN, Klein Hesselink MS, de Bock GH, et al. Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: an observational study. J Clin Oncol. 2013;31(32):4046-4053. doi: 10.1200/JCO.2013.49.1043.