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Levothyroxine therapy in HF may increase risk for death
Among patients with heart failure, levothyroxine therapy may increase risk for all-cause death, major adverse cardiovascular events and CV death, independent of whether the patient is treated before or after the heart failure diagnosis, according to an analysis of Danish registry data.
Heart failure patients often develop low levels of triiodothyronine, leading to a potential intramyocardial state of hypothyroidism due to the down-regulation of T3 genes that reduce intracellular metabolism in the cardiomyocytes, Mette Nygaard Einfeldt, MD, head of the department of endocrinology at Hvidovre Hospital, Denmark, and colleagues wrote in the study background, adding that substitution with levothyroxine may further lower levels of T3 due to impaired conversion of thyroxine into T3.
“Our study showed an association between levothyroxine substitution treatment in patients with heart failure and an increased risk for all-cause mortality, cardiovascular death and major adverse cardiac events,” Einfeldt told Endocrine Today. “As our study was purely observational, we were unable to make any conclusions regarding an underlying causality.”
In a registry-based, historical cohort study, Einfeldt and colleagues analyzed data from 224,670 patients with a first-time diagnosis of heart failure between 1997 and 2012 (mean age, 71 years; 53% men), including 6,560 patients treated with levothyroxine therapy at baseline and 9,007 patients who initiated levothyroxine therapy during follow-up. Researchers identified comorbidities, including ischemic heart disease, atrial fibrillation, diabetes and previous stroke, via the Danish National Patient Register. For patients prescribed levothyroxine therapy, researchers estimated daily dose by comparing cumulated dosage and the elapsed time between seven successive prescriptions for levothyroxine. Primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (fatal and nonfatal), CV death and major adverse CV events. Incidence rates were calculated as the number of events per 1,000 person-years, stratified by levothyroxine treatment status and average daily dosage. Researchers estimated incidence rate ratios (IRRs) with time-dependent Poisson regression models.
The researchers found that patients treated with levothyroxine therapy at baseline and during follow-up were more likely to be women vs. the overall study population (79% at baseline; 68% during follow-up; 47% overall).
During a median follow-up time of 4.8 years, 147,253 (66%) patients died, whereas 35,725 experienced an MI and 122,881 experienced a major adverse cardiac event.
In assessing all-cause mortality, researchers found that treatment with levothyroxine at baseline was associated with a 25% increased risk for death (95% CI, 1.21-1.29), whereas initiating levothyroxine during follow-up was associated with a 13% increased risk for death (95% CI, 1.1-1.16), according to adjusted IRRs. Risk was markedly higher for younger patients, according to researchers: Adjusted IRR for patients younger than 65 years showed treatment with levothyroxine at baseline was associated with a 58% increased risk for death (95% CI, 1.41-1.78).
Additionally, adjusted IRRs showed that baseline levothyroxine therapy use was associated with a 23% increased risk for CV death (95% CI, 1.18-1.27), according to researchers. Initiation of the therapy during follow-up was associated with an 11% increased risk for CV death (95% CI, 1.08-1.15), with risk again rising substantially for patients younger than 65 years. Risk for major adverse CV events rose by 26% (95% CI, 1.22-1.31) and 5% (95% CI, 1.02-1.09), respectively, for patients who initiated levothyroxine at baseline or during follow-up, again with increased risk observed for younger patients. The association between levothyroxine therapy and MI was dependent on whether treatment was ongoing at the time of HF diagnosis or initiated later.
Sensitivity analyses adjusting for ischemic heart disease or use of loop diuretics at baseline did not change the findings, according to researchers.
“Since the underlying cause of the observed association is unknown, we would advise clinicians to carefully consider treatment with levothyroxine in patients with heart failure,” Einfeldt said. “If treatment with levothyroxine is decided, it should be initiated at lower dosages with slow up-titration.”
Einfeldt said a randomized controlled trial is warranted to evaluate the prognostic impact of thyroid dysfunction and thyroid hormone substitution in patients with heart failure. – by Regina Schaffer
For more information:
Mette Nygaard Einfeldt, MD, can be reached at Hvidovre Hospital, Department of Endocrinology, Kettegård Alle 30, 2650 Hvidovre, Denmark; email: mette@einfeldt.net.
Disclosures: The authors report no relevant financial disclosures.