Research reveals that treatment of heart attack patients for a common condition, underactive thyroid, with levothyroxine does not improve heart muscle function, so is unlikely to be of benefit.
The results of a double-blind randomised clinical trial which was carried out in six UK hospitals and led by experts at Newcastle University, UK are published today in JAMA.
Mild or subclinical hypothyroidism is a condition in which the body doesn’t produce enough thyroid hormones and is very common affecting approximately 10% of the adult population.
Management of the condition is currently haphazard due to the lack of high quality evidence either for or against treatment.
Some clinicians may treat whereas others may not – and this is particularly the case in high risk conditions such as heart attacks.
Observational studies have previously suggested that patients with cardiac problems, including heart attacks, and subclinical hypothyroidism are at higher risk of death.
This clinical trial demonstrates that treatment with levothyroxine does not improve cardiac function in patients who have had a heart attack and therefore is unlikely to be beneficial.
Dr. Salman Razvi, Senior Lecturer and Consultant Endocrinologist, Newcastle University and the Queen Elizabeth Hospital in Gateshead, explains: “The results of this trial will help clinicians reconsider offering treatment with levothyroxine to tens of thousands of patients with subclinical hypothyroidism worldwide.
The results of this trial demonstrate that there are no significant improvements for patients with heart attacks who are given levothyroxine.
“On this basis, screening for and subsequent treatment of subclinical hypothyroidism in patients who have had a heart attack to preserve or improve heart function is not justified.”
The clinical trial
In the trial, 95 patients were recruited with 46 receiving levothyroxine and 49 a placebo. After 12 months, heart function improved in both groups—but there was no greater improvement in those receiving levothyroxine.
Limitations of the trial include the low dose offered initially which may have reduced the therapeutic effect and there may be a more significant improvement in patients were patients to start treatment sooner (average 17 days after heart attack).
In addition, 4 in 10 patients with subclinical hypothyroidism on the initial blood test had normalised their levels when rechecked a few days later.
The team will now be making this research available as part of the evidence to change existing guidelines.
Dr. Razvi adds: “To any patient who has had a heart attack and has been diagnosed with subclinical hypothyroidism, I would advise that they consult their GP on whether levothyroxine is likely to be of benefit.
The results of our trial suggest that all such patients should have their thyroid function rechecked after a few weeks. Treatment with levothyroxine should not be started routinely in such patients. Furthermore, international guidelines should be amended to reflect this finding.”
Hypothyroidism is a commonly encountered clinical condition that affects between 4-10% of the population . Overt hypothyroidism is diagnosed when low levels of the thyroid hormones result in elevated levels of thyroid-stimulating hormone (TSH) above 4.0 mU/L whereas, subclinical hypothyroidism is diagnosed when TSH levels are elevated above the upper limit of the assay reference range with normal thyroid hormone levels.
Thyroid hormones play a paramount role in the normal function of the heart and vascular physiology. Thus, hypothyroidism produces significant cardiovascular effects.
Hypothyroidism is known to affect cardiac contractility, which is often diastolic in nature and can lead to decreased cardiac output. Similarly, increased systemic vascular resistance, decreased arterial compliance, and atherosclerosis are common pathophysiological changes that occur in hypothyroidism [3,4].
Although thyroid hormone deficiency, either clinical or subclinical, is an established risk factor for cardiovascular disease, it is unusual to find three-vessel coronary artery disease in a middle-aged woman in our setup who had an insignificant family history and no long-standing coronary artery disease risk factors.
On review of the literature, a case to similar ours was reported from Japan, where a 38-year-old woman with hypothyroidism presented with unstable angina and subsequently underwent CABG . Another case was reported from China, where a patient with hypothyroidism, type 2 diabetes mellitus, and hypertension underwent CABG .
Similar cases have been reported from Asia, involving men and women both [7,8]. Many studies conducted across the globe revealed a significant association between subclinical hypothyroidism and subsequent development of ischemic heart disease (IHD) [9-11].
A 2017 meta-analysis of 55 cohort studies concluded that hypothyroidism is associated with higher risks of IHD, cardiac mortality, and all-cause mortality when compared with euthyroidism in the general public or in patients with preexisting cardiac disease.
It also noted that subclinical hypothyroidism with elevated TSH levels is associated with an increased risk of IHD events, especially in those with values greater than 10 mIU/L, similar to our case .
The findings of these studies show that even subclinical hypothyroidism is a risk factor for coronary artery disease, not alone overt hypothyroidism. In contrast, the European Prospective Investigation into Cancer and Nutrition (EPIC)‐Norfolk study did not show any increased risk of coronary artery disease .
Moreover, thyroxine replacement therapy is considered as the mainstay treatment for overt hypothyroidism. The use of thyroid replacement therapy can accelerate the development of ischemic heart disease or aggravate the progression of an already existing cardiac disease.
This could be due to increased cardiac contractility and improved metabolism, which eventually leads to oxygen supply-demand mismatch resulting in myocardial ischemia and possibly myocardial infarction. One such case was reported in Japan, where the administration of levothyroxine aggravated the patient’s clinical condition .
Similarly, Flynn et al. reported a population-based study of patients with elevated TSH levels (defined as greater than 4 mIU/L) and treated with levothyroxine presented with greater risk for cardiovascular events .
In another study, no evidence was found to suggest clinically meaningful differences in the pattern of long term health outcomes including all-cause mortality, heart failure, IHD, stroke/transient ischemic attack, and atrial fibrillation in patients on thyroid replacement therapy when TSH concentrations were within normal limits and thus, further emphasizing the need of randomized controlled trials of levothyroxine treatment examining vascular and cardiovascular outcomes .
Hence, it is crucial to conduct large scale studies aimed at investigating possible risk factors including thyroid replacement therapy that lead to the development of coronary artery disease in patients with subclinical or overt hypothyroidism, especially in our locality where there is a scarcity of data available on this subject.
Thyroid hormones play an important role in regulating the heart and vascular physiology. Hypothyroidism, either overt or subclinical, is associated with significant cardiovascular effects. Three vessel disease is a relatively uncommon cardiovascular manifestation of hypothyroidism as most patients present with diastolic dysfunction.
Thyroid replacement therapy can accelerate the development of cardiovascular disease or aggravate the underlying heart conditions according to some reports. Therefore, more studies should be conducted to investigate and evaluate the risk factors in hypothyroid patients that can lead to the development of coronary artery disease.
2. 2013 ETA guideline: management of subclinical hypothyroidism. Pearce SHS, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, Wemeau JL. Eur Thyroid J. 2013;2:215–218. [PMC free article] [PubMed] [Google Scholar]
5. Myxedema coma and cardiac ischemia in relation to thyroid hormone replacement therapy in a 38-year-old Japanese woman. Taguchi T, Iwasaki Y, Asaba K, Takao T, Hashimoto K. Clin Ther. 2007;29:2710–2714. [PubMed] [Google Scholar]
6. Coronary artery bypass grafting in a patient with history of esophagectomy, hypothyroidism, hypertension and type 2 diabetes mellitus: a case report. Zhang YY, YE JC, Lei WE, Zhang SJ. Chin Med J (Engl) 2012;125:2062–2064. [PubMed] [Google Scholar]
7. Off-pump coronary artery bypass grafting for unstable angina pectoris combined with hypothyroidism and chronic renal failure; report of a case. Hirano Y, Matsumoto Y, Endoh M, Kasashima F, Abe Y, Sasaki H. https://europepmc.org/abstract/med/12174627. Kyobu Geka. 2002;55:799–802. [PubMed] [Google Scholar]
8. A case report on successful coronary artery bypass grafting (CABG) for angina pectoris combined with hypothyroidism (Article in Japanese) Furukawa K, Ooteki H, Doi K, Shiraishi R. https://europepmc.org/abstract/med/9095585. Kyobu Geka. 1997;50:275–278. [PubMed] [Google Scholar]
9. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. Tseng FY, Lin WY, Lin CC, Lee LT, Li TC, Sung PK, Huang KC. J Am Coll Cardiol. 2012;60:730–737. [PubMed] [Google Scholar]
10. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. Imaizumi M, Akahoshi M, Ichimaru S, et al. J Clin Endocrinol Metab. 2004;89:3365–3370. [PubMed] [Google Scholar]
11. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. Razvi S, Weaver JU, Vanderpump MP, Pearce SH. J Clin Endocrinol Metab. 2010;95:1734–1740. [PubMed] [Google Scholar]
12. What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants. [Oct;2019 ];Ning Y, Cheng YJ, Liu LJ, et al. BMC Med. 2017 15:21. [PMC free article] [PubMed] [Google Scholar]
13. Initial thyroid status and cardiovascular risk factors: the EPIC‐norfolk prospective population study. Boekholdt SM, Titan SM, Wiersinga WM, et al. Clin Endocrinol (Oxf) 2010;72:404–410. [PubMed] [Google Scholar]
14. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. J Clin Endocrinol Metab. 2010;95:186–193. [PubMed] [Google Scholar]
15. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. [Oct;2019 ];Thayakaran R, Adderley NJ, Sainsbury C, et al. BMJ. 2019 366:0. [PMC free article] [PubMed] [Google Scholar]
More information: Effect of Levothyroxine on Left Ventricular Ejection Fraction in patients with subclinical hypothyroidism and Acute myocardial infarction, JAMA (2020). DOI: 10.1001/jama.2020.9389