Risk of Incident Circulatory Disease in Patients Treated for Differentiated Thyroid Carcinoma With No History of Cardiovascular Disease

Konstantinos A. Toulis; David Viola; George Gkoutos; Deepiksana Keerthy; Kristien Boelaert; Krishnarajah Nirantharakumar

Disclosures

Clin Endocrinol. 2019;91(2):323-330. 

In This Article

Abstract and Introduction

Abstract

Context: The incidence of differentiated thyroid cancer (DTC) is increasing, yet the prognosis is favourable and long-term survival is expected. Exogenous TSH suppression has been used for many years to prevent DTC recurrence and may be associated with increased risks of circulatory diseases.

Design: Risks of circulatory disease in patients treated for DTC were compared to randomly matched patients without DTC (controls) up to a 1:5 ratio using age, sex, body mass index (BMI) and smoking as the matching parameters in a population-based, open cohort study using The Health Improvement Network.

Patients: A total of 3009 patients treated for DTC with no pre-existing cardiovascular disease were identified and matched to 11 303 controls, followed up to median of 5 years.

Results: A total of 1259 incident circulatory events were recorded during the observation period. No difference in the risk of ischaemic heart disease (IHD) (adjusted hazards ratio [aHR]: 1.04, 95% CI: 0.80-1.36) or heart failure (HF) (aHR: 1.27, 95% CI: 0.89-1.81) was detected. The risk of atrial fibrillation (AF) and stroke was significantly higher in patients with DTC (aHR: 1.71, 95% CI: 1.36-2.15 and aHR: 1.34, 95% CI: 1.05-1.72, respectively). In a sensitivity analysis limited to newly diagnosed patients with DTC, only the risk of AF was consistently elevated (aHR: 1.86, 95% CI: 1.33-2.60).

Conclusions: The increased risk of AF in patients who have undergone treatment for DTC but without pre-existing CVD may warrant periodic screening for this arrhythmia. Whereas no evidence of increased risk of IHD or HF was observed, the increased risk of stroke/TIA warrants further investigation.

Introduction

The lifetime risk of developing thyroid cancer is approximately 1 in 180 for women and 1 in 480 for men in the UK,[1,2] where approximately 3300 new cases are recorded every year and incidence rates have increased by 149% from the 1970s.[1] The observed increases are largely attributable to the increased detection of papillary thyroid carcinomas,[3] which, together with follicular carcinomas, constitute differentiated thyroid cancer (DTC), the most common form (90%) of the disease. In general, the prognosis of DTC is favourable, and this is reflected in the disease-specific mortality rates, which have decreased by 46% since the early 1970s.[4] Therefore, long-term survival is expected in patients diagnosed and treated for differentiated thyroid cancer.[5]

Whilst the role of thyroid-stimulating hormone (TSH) in thyroid tumorigenesis is still under investigation,[6,7] it is well established that the proliferation of DTC cells remains responsive to TSH stimulation.[8] Hence, medium- to long-term TSH suppression is recommended for high- and intermediate-risk thyroid cancer patients,[9] whereas maintaining TSH levels at the lower end of the reference range is encouraged for the low-risk patients.[9,10]

Importantly, there is mounting evidence that exogenous subclinical thyrotoxicosis as a result of TSH suppression therapy may be detrimental with regard to long-term cardiovascular health by impairing cardiac contractility and arterial elasticity,[11–13] exacerbating angina and inducing atrial fibrillation (AF) in high-risk patients.[14] Moreover, in preparation of adjuvant thyroid ablation therapy, when indicated, patients with DTC may also undergo a transient hypothyroid phase, in settings where recombinant human TSH is not used. During this phase, a decrease in cardiac output and cardiac contractility as well as an increase in peripheral vascular resistance may be expected.

The aforementioned mechanism via which detrimental cardiovascular impact may be observed in patients with DTC was not demonstrated in a study involving 366 patients with thyroid cancer.[15] In contrast, a more recent observational study reported a three-fold increased risk of cardiovascular mortality in 414 patients with DTC compared to matched controls and suggested that this increase was associated with lower serum TSH concentrations.[16] Differences in baseline cardiovascular risk and in sample constitution (the positive study included a diverse range of thyroid cancers,[16] whereas the negative one included only advanced tumours[15]) may account, at least partly, for the notable discrepancies in their estimates.[16]

Considering the increasing incidence of thyroid cancer, the favourable long-term prognosis (which necessitates a holistic management of risk factors associated with mortality other than just disease-specific risks), the potential cardiovascular impact of exogenous thyrotoxicosis and the conflicting nature of the reports, we designed and performed a study to clarify the circulatory risk in patients treated for DTC. Specifically, we explored whether DTC patients with no history of circulatory disease differed in the incidence of new-onset CVD events compared to matched controls.

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