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Recent data shed light on link between subclinical thyroid disease and cardiac events

Issue: September 2012

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The association between subclinical thyroid disease and CV events has been previously established in the literature. However, several recent studies have again brought attention to the link between subclinical thyroid disease and CV events, as well as the controversy over diagnostic testing and potential treatments.

Cardiology Today interviewed leading experts in the fields of cardiology and endocrinology about the clinical implications and future research initiatives surrounding this observation.

“Subclinical or mild hypothyroidism affects roughly 5% to 10% of the general population and tends to be more prevalent in women and as one gets older. It has been controversial for a few decades whether this needs treatment, and frequently it is not treated by a number of people, as the evidence for any benefits is not available,” Salman Razvi, MD, FRCP, of Gateshead Health National Health Service Foundation Trust and Newcastle University in the United Kingdom, said in an interview. Razvi was the lead author on a study, published in Archives of Internal Medicine in May that found that treatment of subclinical hypothyroidism with levothyroxine was associated with fewer ischemic heart disease events in younger individuals.

 

Salman Razvi, MD, FRCP, and colleagues published a paper this year on the treatment of subclinical hypothyroidism that has encouraged debate among endocrinologists and cardiologists alike. 

Photo by: Mr. Gary Turner; reprinted with permission

The population prevalence of subclinical hyperthyroidism, however, is dependent on age, sex and iodine intake, and rates have been shown to vary among clinical studies, according to a seminal paper by David S. Cooper, MD, of the division of endocrinology and metabolism and professor of medicine at The Johns Hopkins University School of Medicine, and Bernadette Bondi, MD, of the department of clinical and molecular endocrinology and oncology at the University of Naples Federico II in Naples, Italy.

“For most patients who have more mildly low or high serum [thyroid-stimulating hormone] concentrations in between the extremes (ie, 0.1-0.5 mU/L and 5-10 mU/L, respectively), no firm recommendations can be made, and the decision to treat or not to treat a patient will be based on various clinical factors,” Cooper and Biondi wrote.

Thyroid dysfunction, CVD link

Data from a prospective cohort study published by Collet et al in the Archives of Internal Medicine in May demonstrated that the association between the risk for CHD, incident AF and mortality with subclinical hyperthyroidism is especially evident when thyrotropin levels are lower than 0.10 mIU/L.

The study of 52,674 patients (median age, 59 years; 58.5% women) selected from 10 cohorts was conducted by Tinh-Hai Collet, MD, of the department of ambulatory care and community medicine at the University of Lausanne in Switzerland, and colleagues. Median follow-up was about 9 years.

Of those patients, 50,486 were euthyroid and 2,188 (4.2%) had endogenous subclinical hyperthyroidism.

CHD events were analyzed in 22,437 patients from six cohorts (3.2% with subclinical hyperthyroidism) and incident AF was analyzed in 8,711 patients from five cohorts (9.3% with subclinical hyperthyroidism). The researchers reported that 8,527 patients died during follow-up, including 1,896 patients who died of CHD.

Age and sex-adjusted analyses revealed that subclinical hyperthyroidism was related to increased total mortality (95% CI, 1.06-1.46); CHD mortality (95% CI, 1.02-1.62); CHD events (95% CI, 0.99-1.46); and AF (95% CI, 1.16-2.43).

In a separate study presented at the Joint 15th International Congress of Endocrinology and 14th European Congress of Endocrinology meeting in Florence, Italy, in May, Christian Selmer, MD, research fellow at Gentofte University Hospital in Copenhagen, Denmark, and colleagues reported a physiological relationship between all levels of thyroid dysfunction and risk for AF. This was substantiated with a higher risk in patients with overactive thyroid glands, even when the condition was very mild or at the high end of “normal,” and a lower risk in patients with underactive thyroid glands.

Selmer’s team used nationwide registries to identify individual-level linkage among 525,100 patients (mean age, 51.7 years; 39.5% men) who consulted their general practitioner from 2000 to 2009. Of these, 504,113 (96%) patients were euthyroid; 1,474 (0.3%) had clinical hypothyroidism; 10,679 (2%) had subclinical hypothyroidism; 3,421 (0.7%) had clinical hyperthyroidism; and 5,414 (1%) had subclinical hyperthyroidism.

The study concluded that patients with thyroid-stimulating hormone (TSH) levels of 0.1 mU/L and between 0.1 mU/L and 0.2 mU/L had an 80% and 50% greater risk for AF, respectively. Patients who exhibited a higher range of normal TSH levels of 0.2 mU/L to 0.4 mU/L had a 30% increased risk.

The researchers found clinical and subclinical hypothyroidism related to a lower risk for AF, whereas subclinical hyperthyroidism and “high-normal” thyroid function levels displayed a significant risk factor for AF.

Another study led by Fen-Yu Tseng, MD, PhD, of the department of internal medicine at National Taiwan University College of Medicine in Taipei, Taiwan, evaluated the relationship between subclinical hypothyroidism and all-cause and CVD mortality.

The researchers used a baseline cohort of 115,746 patients in Taiwan aged at least 20 years who had no history of thyroid disease.

“Our data revealed that subclinical hypothyroidism was associated with increased risk for all-cause and CVD mortality, especially in older subjects,” Tseng and colleagues wrote.

During the 10-year follow-up period, there were 3,669 deaths (680 due to CVD), according to the study. Additional data confirmed that compared with patients with euthyroidism, after adjustments, the RR for all-cause mortality was 1.3 (95% CI, 1.02-1.66) and the RR for CVD mortality was 1.68 (95% CI, 1.02- 2.76).

“We have found that old age and female sex increase the prevalence of subclinical hypothyroidism. Patients with subclinical hypothyroidism had higher BMIs and increased frequency of hyperlipidemia, diabetes and hypertension compared with euthyroid subjects. Furthermore, subclinical hypothyroidism is independently associated with an increased risk for all-cause and CVD mortality after adjusting for the aforementioned confounders,” the researchers concluded.

The results were published in the Journal of the American College of Cardiology in June.

The role of levothyroxine

Some data now suggest that levothyroxine could be the solution to treating patients with subclinical thyroid disease. Retrospective information gathered by researchers in the United Kingdom provides a glimpse into what may be the next treatment option for these patients.

In the absence of any randomized control trial data suggesting or showing any benefit of treating subclinical thyroid disease with levothyroxine, Razvi said he and colleagues thought it would be best to tackle the issue from a “real-life” approach.

To do so, the researchers obtained data on 3,093 patients aged 40 to 70 years and 1,642 patients aged older than 70 years using the United Kingdom General Practitioner Research Database, a large primary care database of more than 10 million patients. Patient data were recorded in 2001 and outcomes were examined until March 2009. All patients had new subclinical hypothyroidism (serum thyrotropin levels of 5.01-10 mIU/L).

Separate analyses were performed for both younger and older patients. HRs for fatal and nonfatal events were calculated following adjustments for conventional ischemic heart disease risk factors, baseline serum thyrotropin levels and initiation of levothyroxine treatment as a time-dependent covariate.

Levothyroxine was used to treat 52.8% of younger patients and 49.9% of older patients during a median follow-up period of 7.6 years.

“My hypothesis, even before I did the analysis, was that, based on previous meta-analyses, age may be a significant factor that affects [CVD] and this condition. Therefore, we analyzed these two groups separately,” Razvi said in an interview.

Sixty-eight incident ischemic heart disease events occurred among 1,634 younger patients treated with levothyroxine vs. 97 events in 1,459 untreated patients (HR=0.61; 95% CI, 0.39-0.95). In older patients, however, 104 events occurred among 819 treated patients vs. 88 events in 823 untreated patients (HR=0.99; 95% CI, 0.59-1.33).

“At baseline, there wasn’t any difference between who was treated vs. who wasn’t, with reference to the other CV risk factors,” Razvi said. “But when we looked for a number of surrogate risk markers, things like contact with a health professional and number of different CV medications, they were similar in both groups.”

 

Richard Stein

Richard Stein, MD, spokesman for the American Heart Association and professor of medicine and director of the urban community cardiology program at New York University School of Medicine, said this is one of the more interesting papers he has seen this year.

“It’s an impressive-looking trend in a relatively small number of cardiac patients, but a large group of patients in a study, and it raises an interesting question: Should we treat people with [subclinical hypothyroidism] to reduce their risk for a cardiac event?”

Clinical implications of treatment

Although it is a topic of debate among endocrinologists and cardiologists alike, Stein said the study by Razvi and colleagues does not form the basis for changing treatment of subclinical thyroid disease.

“In real life, patients who are treated for this condition seem to do well, and it is entirely safe to be treating. But, it’s probably only worthwhile in the younger age groups, and it may not have an impact in older individuals,” Razvi said.

However, due to the retrospective nature of the study, Razvi said it is slightly more difficult to conclude that it could be translated into clinical practice.

Peter A. Singer, MD, professor of clinical medicine and chief of the clinical endocrinology department at Keck School of Medicine at the University of Southern California, said doctors should rely on clinical judgment, as well as these findings.

“There are certainly no contraindications to treating, and people treat all the time; but I don’t think this single article alone is enough to say you should go ahead and treat, but it is one new piece of the puzzle,” Singer said.

According to Kenneth D. Burman, MD, researcher for the endocrine section of Washington Hospital Center and professor in the department of medicine at Georgetown University, Washington, D.C., further long-term, prospective studies are needed to determine the relationship between subclinical hypothyroidism, hyperthyroidism (both treated and untreated) and CV events.

“At present, levothyroxine therapy should be used mainly with consideration of thyroid function tests, TSH and the clinical context. I would tend to agree with the guidelines that suggest levothyroxine treatment should be considered in patients with TSH values above the upper normal range and less than 10 mU/L, and should be administered to patients with TSH values greater than 10 mU/L,” Burman said.

 

David S. Cooper

The plan for treating subclinical hypothyroidism (serum TSH concentrations 5-9 mU/L) was published in Cooper and Biondi’s paper. In the paper, they wrote that subclinical hypothyroidism may be associated with greater CV risk in young and middle-aged patients compared with those aged older than 65 years, and that levothyroxine may be justified as a form of treatment.

“If levothyroxine replacement has a beneficial effect, treatment should be continued and serum TSH concentrations should be assessed every 6 to 12 months to ensure that they remain within the normal range. Patients can progress to overt hypothyroidism; therefore, increases in levothyroxine might be needed during follow-up,” they wrote.

However, in the absence of any “clear-cut benefits,” Cooper and Biondi wrote that levothyroxine therapy should be stopped and serum TSH concentrations should be screened at annual visits. Additionally, the researchers wrote that the treatment of subclinical hypothyroidism is not recommended in elderly patients (aged older than 75 years) due to a lack of quality of life and symptomatic evidence.

Age-associated TSH levels

Anne R. Cappola, MD, ScM, associate professor of medicine at Penn Medicine and physician at Perelman Center for Advanced Medicine in Philadelphia, said older patients may not benefit from this treatment because of an “age-associated shift in the distribution of TSH levels toward higher levels with increasing age.”

 

Anne R. Cappola

Studies of older patients suggest no increase in CV risk from leaving those with mild elevations untreated, she said.

“Not surprisingly, the older population (>70 years) had twice as many nonfatal and fatal CV events as the younger population (40 to 70 years). In younger patients, the absolute difference in incidence of these events was 2.2% over a 7.6-year period. This is less of an effect on CV risk than statins, but still noteworthy,” Cappola said of the study by Razvi and colleagues.

“One of the reasons that treating an older person with [subclinical hypothyroidism] might not help is because there is nothing wrong with them in the first place,” Cooper said. “The high TSH that you’re diagnosing as being [subclinical hypothyroidism] is just the normal aging process and just the normal level of TSH elevating, and is not necessarily indicative of an underlying thyroid problem.”

Cooper said the Razvi et al study adds some evidence to the idea that even if patients feel healthy, treating them is reasonable and might even benefit them in terms of CV outcomes.

Future directions

“It is probably time we did a proper randomized controlled trial of the right patient age group (younger individuals) to look at CVD and outcomes,” Razvi said, adding that the problem has mainly been funding such a trial, with little to no commercial interest in levothyroxine. However, such a trial is about to develop in Europe, he said.

Currently, Nicolas Rodondi, MD, MAS, of the department of general internal medicine, Inselspital University of Bern in Switzerland, is collaborating with University of Glasgow (linking with Greater Glasgow Health Board) in Scotland; Leiden University Medical Centre in the Netherlands; University College Cork in Ireland; and thyroid experts from the University of California for the Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial (TRUST).

According to the TRUST website, the objective is to determine whether there are benefits and/or drawbacks to administering levothyroxine to older patients with subclinical hypothyroidism.

During a 5-year period, the TRUST researchers plan to follow 3,000 patients aged older than 65 years to understand how to treat subclinical hypothyroidism. Half of the patients will be treated with levothyroxine, and the other half will be given placebo. Both of the groups will be monitored and evaluated on their response to the treatments. The European Union is funding the research. – by Samantha Costa