Veterans on thyroid hormone therapy: off-range TSH linked to higher cardiovascular death risk

A retrospective cohort study of 705,307 adults who received thyroid hormone treatment in the US Veterans Health Administration found a higher risk of cardiovascular death when blood tests showed too much or too little thyroid hormone. The results were published in JAMA Network Open. The data cover January 1, 2004, to December 31, 2017, with a median follow-up of 4 years (IQR, 2–9 years) jamanetwork.comJAMA Network Openjamanetwork.comOpen source ↗.

Of the patients, 625,444 (88.7%) were men, and the median age was 67 years. Overall, 75,963 patients (10.8%) died of cardiovascular causes, including myocardial infarction, heart failure or stroke. Mortality and cause of death were taken from the National Death Index.

Design and thresholds

Two cohorts were analyzed: 701,929 adults with at least two thyrotropin (TSH) measurements after treatment start, and 373,981 patients with at least two free thyroxine (FT4) measurements. Euthyroidism was defined as TSH 0.5–5.5 mIU/L and FT4 0.7–1.9 ng/dL. Exogenous hyperthyroidism meant TSH below 0.5 mIU/L or FT4 above 1.9 ng/dL. Exogenous hypothyroidism meant TSH above 5.5 mIU/L or FT4 below 0.7 ng/dL.

Hormone levels were entered as time-varying covariates in Cox proportional hazards models, so a patient's status could change during follow-up. The models were adjusted for age, sex and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia jamanetwork.comJAMA Network Openjamanetwork.comOpen source ↗.

Hazard ratios

Compared with euthyroidism, exogenous hyperthyroidism was associated with higher cardiovascular mortality: the adjusted hazard ratio (AHR) was 1.39 (95% CI, 1.32–1.47) at TSH below 0.1 mIU/L and 1.29 (95% CI, 1.20–1.40) at FT4 above 1.9 ng/dL. For exogenous hypothyroidism, the AHR was 2.67 (95% CI, 2.55–2.80) at TSH above 20 mIU/L and 1.56 (95% CI, 1.50–1.63) at FT4 below 0.7 ng/dL.

The authors conclude that the findings emphasize the importance of maintaining euthyroidism in patients receiving thyroid hormone treatment.

The design has limits. Most participants were men, so the results may apply differently to younger adults and to less represented groups. Medical records cannot always show why levels were out of range or whether another illness influenced both test results and the risk of death. The study also could not show how much the risk would change after a dose adjustment.