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


Clin Endocrinol. 2019;91(2):323-330. 

In This Article


In this population-based, cohort study involving 14 312 participants (3009 patients treated for DTC and without pre-existing cardiovascular disease, matched to 11 303 controls), we show a significant, consistent increase in the risk of incident atrial fibrillation in patients treated for DTC compared to matched individuals. Similarly, the risk of stroke/TIA was found to be elevated in patients treated for DTC, although this finding was not evident in the sensitivity analyses. Conversely, a diagnosis of DTC was not associated with excess risk of ischaemic heart disease or heart failure in the affected individuals compared to that of the general population over the course of the ensuing years. To our knowledge, this population-based longitudinal open cohort study is one of the largest studies to examine the association between DTC and circulatory disease, analysing over 3000 patients with DTC against 11 303 controls matched on age, BMI, sex and smoking status.

The finding that the diagnosis of DTC was consistently associated with a 1.7- to 1.9-fold increase in risk of atrial fibrillation in multiple adjusted analyses, as well as the persistent hazard risk even when only incident patients with DTC were considered, may reflect a consistent, true effect at the population level. Our finding is in line with previous reports on 518[26] and 756 patients[27] with DTC indicating that the risk of AF is elevated in those patients. Potential mechanisms underlying this observed association may include the positive chronotropic and dromotropic effect induced by TSH suppression therapy. Impaired ventricular relaxation, elevation of left atrial pressure, ischaemia resulting from increased resting heart rate and re-entry have all been postulated as mechanisms leading to AF in the setting of overt and subclinical thyrotoxicosis.[28]

Whether this holds true in the setting of TSH suppression therapy as a part of DTC management is still unclear, specifically in view of studies which do not confirm a link between the aggressiveness of TSH suppression and AF.[26] Of note, the present study involved individuals with no record of circulatory disease at baseline. Hence, it is plausible that the incidence of atrial fibrillation may be even higher in patients with DTC and pre-existing cardiovascular disease. Notwithstanding the latter, and in light of the findings of our study, a high clinical suspicion for AF-related signs and symptoms as well as periodical screening for AF may be advisable in the management of patients with DTC, even in the absence of a history of CVD. Finally, this consistent increased susceptibility to AF observed in patients with DTC may constitute an additional point to be taken into account when assessing the risk/benefit of TSH suppression therapy in low-risk patients with DTC and more specifically, a further argument in favour of active avoidance of overtreatment with levothyroxine. The latter might also be applicable to intermediate and high-risk patients, in whom moderate TSH suppression was found to be associated with a better outcome, whereas more aggressive TSH suppressive treatment may not be necessary even in patients diagnosed with metastatic disease.[29]

Considering that AF increases risk of cardiac thrombus formation and that AF was found to be increased in patients with DTC, it is plausible to anticipate a parallel increase in the risk of stroke/TIA. In fact, a significant increase in the risk of stroke/TIA was found in patients with DTC, although the magnitude of effect was modest (effect size = 1.34, lower 95% = 1.05, close to neutrality) and does warrant caution in interpretation. Importantly, this finding should be regarded as inconclusive, since it was not confirmed in the sensitivity analysis limiting to incident cases of DTC. Mirroring the latter, a recent meta-analysis suggested that the risk of stroke was not higher in patients with subclinical thyroid disorders.[30] In all, although data regarding the risk of stroke/TIA in patients treated for DTC are inconclusive, optimal management of AF would be recommended to reduce any potential risk of stroke and even aggressive stroke preventive measures might be considered on a case-by-case basis.

Reassuringly, we found no evidence that the risks of ischaemic heart disease and heart failure are elevated in patients with DTC. These findings are consistent with the absence of a direct pathophysiologic link between DTC and ischaemic heart disease (other than the cardiac effects of exogenous subclinical thyrotoxicosis). It is also consistent with a study reporting a neutral effect of DTC on cardiovascular mortality[15] and a recent study reporting comparable long-term cardiovascular outcomes between euthyroid and hyperthyroid patients.[31] On the other hand, our findings may be seen as complementary to those of a recent elegant study reporting several baseline factors associated with increased CVD risk among thyroid cancer survivors.[32] Unfortunately, direct comparison of the reported CVD outcomes in this study is not feasible, because of the differences in study design, handling of the baseline CVD disease, definition of CVD outcomes and the primary research hypothesis. Finally, our results may be regarded as conflicting with a well-designed, observational study reporting a three times greater cardiovascular mortality in patients with DTC compared to controls.[16] However, several key methodological differences may provide a context for interpretation. First, primary outcomes are essentially different (cardiovascular mortality as opposed to cardiovascular events in the present study), and thus, any direct comparison is not straightforward. Secondly, differences in the constitution of the control group (controls with renal disease and proteinuria were excluded, whereas included in our study), the matching procedure (smoking and BMI were included as matching variables in our study) and pre-existing cardiovascular disease (10 patients had previously documented circulatory disease in the latter, whereas CVD was an exclusion criterion in our study) may all be relevant. Moreover, since their primary outcome was rare, their analysis was based on a limited number of CVD deaths in patients with DTC (only 22 were recorded), rendering it prone to type I error. However, it should be noted that the results may be complementary. Considering that a significantly higher all-cause mortality rate was noted in our study and that it was not feasible to readily establish the cause of death within the present study design, it is plausible that an element of increased CVD mortality contributed to the observed increased mortality. This hypothesis requires further evaluation.

The above findings were based on an analysis of a large DTC cohort with the highest number of CVD outcomes reported in the literature to date, constructed using appropriate matching procedures. On the other hand, the extent and aggressiveness of TSH suppression therapy were not captured in the present study design and this is acknowledged as a limitation of the study to be taken into consideration when interpreting its findings. A large proportion of TSH measurements were conducted in a tertiary (hospital) setting, and therefore, not available for analysis. The previous audits evaluating the management of DTC in the primary care reported that the degree of TSH suppression should be expected to be in line with British guidelines[10] with reasonable accordance between specialist and nonspecialist care.[33,34] Whilst current guidelines do not recommend long-term TSH suppression in low-risk patients with DTC,[9,10] previous guidelines have advocated medium to long-term TSH suppression in most patients.[35] Therefore, a proportion of patients may have been subjected to TSH overtreatment by current standards. Moreover, the disease stage was not captured due to the nature of data set (primary care database). Yet, there is no evidence to suggest that either cumulative radioiodine doses or external beam radiotherapy is related to circulatory events,[16] although cumulative radioiodine dose might be related to the AF risk.[26] Finally, a subset of the study control population was under treatment with levothyroxine (hypothyroidism was not an exclusion criterion) and a proportion of them, especially those who were overtreated at any point of time, should be assumed to be a similar risk of developing AF as the exposed counterparts. This residual confounding, however, is expected to dilute the magnitude of the observed effect.[36]

In conclusion, our findings suggest that the risk of AF is consistently higher in patients treated for DTC, even in the absence of pre-existing cardiovascular disease. Whilst it is still inconclusive whether the risk of stroke or TIA is elevated and until further research becomes available, early diagnosis and optimal management of AF in the setting of thyroid cancer should be implemented. Reassuringly, no significant difference in the risk of incident ischaemic heart disease or heart failure was found in patients treated for DTC and no pre-existing cardiovascular disease.