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Effect of Levothyroxine on Left Ventricular Ejection Fraction in Patients With Subclinical Hypothyroidism and Acute Myocardial InfarctionA Randomized Clinical Trial

Educational Objective
To learn whether levothyroxine treatment improves left ventricular function in patients with acute myocardial infarction and subclinical hypothyroidism.
1 Credit CME
Key Points

Question  Does levothyroxine treatment improve left ventricular function in patients with subclinical hypothyroidism presenting with acute myocardial infarction?

Findings  In this randomized clinical trial that included 95 participants with subclinical hypothyroidism and acute myocardial infarction, treatment with levothyroxine, compared with placebo, did not significantly improve left ventricular ejection fraction after 52 weeks (mean left ventricular ejection fraction, 53.8% vs 56.1%, respectively).

Meaning  These findings do not support treatment of subclinical hypothyroidism in patients with acute myocardial infarction.

Abstract

Importance  Thyroid hormones play a key role in modulating myocardial contractility. Subclinical hypothyroidism in patients with acute myocardial infarction is associated with poor prognosis.

Objective  To evaluate the effect of levothyroxine treatment on left ventricular function in patients with acute myocardial infarction and subclinical hypothyroidism.

Design, Setting, and Participants  A double-blind, randomized clinical trial conducted in 6 hospitals in the United Kingdom. Patients with acute myocardial infarction including ST-segment elevation and non–ST-segment elevation were recruited between February 2015 and December 2016, with the last participant being followed up in December 2017.

Interventions  Levothyroxine treatment (n = 46) commencing at 25 µg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L or identical placebo (n = 49), both provided in capsule form, once daily for 52 weeks.

Main Outcomes and Measures  The primary outcome measure was left ventricular ejection fraction at 52 weeks, assessed by magnetic resonance imaging, adjusted for age, sex, type of acute myocardial infarction, affected coronary artery territory, and baseline left ventricular ejection fraction. Secondary measures were left ventricular volumes, infarct size (assessed in a subgroup [n = 60]), adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression.

Results  Among the 95 participants randomized, the mean (SD) age was 63.5 (9.5) years, 72 (76.6%) were men, and 65 (69.1%) had ST-segment elevation myocardial infarction. The median serum thyrotropin level was 5.7 mU/L (interquartile range, 4.8-7.3 mU/L) and the mean (SD) free thyroxine level was 1.14 (0.16) ng/dL. The primary outcome measurements at 52 weeks were available in 85 patients (89.5%). The mean left ventricular ejection fraction at baseline and at 52 weeks was 51.3% and 53.8%, respectively, in the levothyroxine group compared with 54.0% and 56.1%, respectively, in the placebo group (adjusted difference in groups, 0.76% [95% CI, −0.93% to 2.46%]; P = .37). None of the 6 secondary outcomes showed a significant difference between the levothyroxine and placebo treatment groups. There were 15 (33.3%) and 18 (36.7%) cardiovascular adverse events in the levothyroxine and placebo groups, respectively.

Conclusions and Relevance  In this preliminary study involving patients with subclinical hypothyroidism and acute myocardial infarction, treatment with levothyroxine, compared with placebo, did not significantly improve left ventricular ejection fraction after 52 weeks. These findings do not support treatment of subclinical hypothyroidism in patients with acute myocardial infarction.

Trial Registration  isrctn.org Identifier: http://www.isrctn.com/ISRCTN52505169

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Article Information

Corresponding Author: Salman Razvi, MD, Translational and Clinical Research Institute, Newcastle University, Gateshead Health NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, United Kingdom (salman.razvi@ncl.ac.uk).

Accepted for Publication: May 15, 2020.

Author Contributions: Dr Razvi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Junejo, Pearce, Zaman, Razvi.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Jabbar, Hollingsworth, Razvi.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Jabbar, Stocken, Razvi.

Obtained funding: Pearce, Razvi.

Administrative, technical, or material support: Ingoe, Junejo, Parikh, Austin, Hollingsworth, Pearce, Greenwood, Zaman.

Supervision: Jabbar, Junejo, Carey, Parikh, Hollingsworth, Stocken, Pearce, Greenwood, Zaman, Razvi.

Conflict of Interest Disclosures: Dr Austin reported receiving personal fees from Abbott Vascular and AstraZeneca and grants from TA Sciences outside the submitted work. Dr Hollingsworth reported receiving a Medical Research Council New Investigator Research Grant (G1100160, 2012-2015) during the conduct of the study. Dr Pearce reported receiving personal fees from Quidel, Sanofi, and Berlin Chemie and nonfinancial support from Apitope BV outside the submitted work. Dr Razvi reported receiving grants from the National Institute for Health Research (NIHR) and nonfinancial support from Amdipharm Pharmaceuticals UK Ltd during the conduct of the study and personal fees from Merck Plc and Abbott Pharmaceuticals Pvt Ltd outside the submitted work. No other disclosures were reported.

Funding/Support: Dr Razvi was funded by an NIHR Career Development Fellowship (CDF-2012-05-231). The research was supported in part by the NIHR infrastructure at the University of Leeds.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. Levothyroxine was provided free of cost by Amdipharm Pharmaceuticals UK Ltd.

Data Sharing Statement: See Supplement 4.

Additional Contributions: Independent trial steering committee: Janis Hickey (chair), Akheel Syed (independent member). Independent data and safety monitoring committee: Colin Dayan (chair), Steff Lewis (statistician), Rajiv Das (magnetic resonance [MR] expert). Tim Hodgson, MClinSci (senior research radiographer), Louise Ward, DCR(R) (radiographer), Dorothy Wallace, MClinSci (radiographer) (Newcastle MR Centre, Newcastle University); Petra Bijsterveld, MA (senior research nurse and MR manager) (University of Leeds); Thomas Chadwick, PhD (clinical trials statistician) (Population Health Sciences Institute, Newcastle University); James Wason, PhD (professor of biostatistics) (Newcastle University); Yan Hunter Blair (Newcastle Pharmacy Production Unit, Newcastle upon Tyne Hospitals); and Ruth Wood (randomization software) and Lee Munro, BSc (trial manager) (Newcastle Clinical Trials Unit, Newcastle University). None of the individuals named above received compensation for their role in the study.

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