Long-Term Outcome in Patients With Heart Failure Treated With Levothyroxine

An Observational Nationwide Cohort Study

Mette Nygaard Einfeldt; Anne-Marie Schjerning Olsen; Søren Lund Kristensen; Usman Khalid; Jens Faber; Christian Torp-Pedersen; Gunnar H Gislason; Christian Selmer


J Clin Endocrinol Metab. 2019;104(5):1725-1734. 

In This Article

Abstract and Introduction


Context: Hypothyroidism has detrimental effects on the cardiovascular system, but controversy remains concerning the benefits of levothyroxine (L-T4) substitution in patients with heart failure (HF).

Objective: Examining the effects of L-T4 in patients with HF.

Design: Retrospective cohort study.

Setting and Participants: All Danish citizens aged ≥18 years diagnosed with HF between 1997 and 2012. L-T4 treatment was identified from nationwide registers. Incidence rate ratios (IRRs) were calculated with Poisson regression models.

Main Outcome Measures: All-cause mortality, myocardial infarction (MI), cardiovascular death, and major adverse cardiovascular events (MACEs).

Results: A total of 224,670 patients were diagnosed with HF [mean age 70.7 (SD ± 14.7) years, 53% male]. Of these, 6560 patients were treated with L-T4 at baseline, and 9007 patients initiated L-T4 during follow-up. A total of 209,103 patients did not receive L-T4. During a median follow-up of 4.8 years [interquartile range (IQR) 9.2] 147,253 patients died. Increased risk of all-cause mortality (IRR 1.25; 95% CI, 1.21 to 1.29; IRR 1.13; 95% CI, 1.10 to 1.16), cardiovascular death (IRR 1.23; 95% CI, 1.18 to 1.27; IRR 1.11; 95% CI, 1.08 to 1.15), and MACE (IRR 1.26; 95% CI, 1.22 to 1.31; IRR 1.05; 95% CI, 1.02 to 1.09) was observed for treatment ongoing at baseline and initiated during follow-up, respectively. Increased risk of MI (IRR 1.32; 95% CI, 1.23 to 1.41) was observed for ongoing treatment, and reduced risk (IRR 0.87; 95% CI, 0.81 to 0.93) was observed for incident treatment.

Conclusion: Ongoing and incident L-T4 treatment in patients with HF was associated with an increased risk of all-cause mortality, cardiovascular death, and MACE. Increased risk of MI was observed for ongoing treatment, and reduced risk was observed for incident treatment.


Heart failure (HF) is among the most common hospital discharge diagnoses of patients aged ≥65 years. With a mortality rate of ~60% within 5 years of diagnosis[1–3] it is a major public health problem with an estimated annual cost of $39 billion in the United States alone.[4] Hypothyroidism is the most common thyroid dysfunction, with almost 5% of the European and US population being treated with levothyroxine (LT4) substitution.[5,6] Patients with HF often have a condition known as low T3 syndrome, that is, low serum levels of T3, which means that less of the active hormone is available to the heart by transport from the blood plasma.[7] Also, inside the cardiomyocytes, less T3 seems available because of lower activity of the D2 deiodinase, causing less T3 to be produced from T4, but probably also because of increased D3 deiodinase activity causing inactivation of T3. The consequences of this syndrome are not well understood, and it has been suggested that it might slow the metabolism of the failing heart, which could be of potential benefit, but a harmful effect cannot be ruled out.[7,8] Several studies have indicated cardiovascular benefit of T4 substitution treatment with L-T4, including a decrease in total plasma cholesterol in patients with hypercholesterolemia[9,10] and reversal of some of the cardiovascular manifestations of hypothyroidism,[11] and even an improvement in left ventricular function has been suggested in patients treated with L-T4.[12,13]

During treatment of hypothyroidism with L-T4, the common pattern found in serum is a high T4/T3 ratio, with low L-T3 levels in blood. This pattern could further exacerbate the T3-deficient state in a patient with chronic HF by limiting the source of external T3 available to the cardiomyocytes, potentially worsening the prognosis in L-T4–treated patients with HF.[14]

However, L-T4 substitution treatment in patients with HF has not been adequately studied, and controversy has developed, with data limited to only a few studies.[15–17] This study was conducted to examine the relationship between L-T4 treatment and all-cause mortality, cardiovascular death, major adverse cardiovascular events (MACEs), and myocardial infarction (MI) in patients with HF.