New Treatment Reduces Adverse Effects of Cardiomyopathy by One-Third

Researchers say tafamidis may also slow cognitive functional decline; findings were lauded by an independent expert who called cardiovascular benefits ''substantial."

With Mathew Maurer, MD, and Ayan Patel, MD

Of late, there has been a growing call for endocrinologists to incorporate the risk of heart failure into the management plan of patients with type 2 diabetes,1 a similar consideration has arisen regarding amyloid cardiomyopathy.2

ATTR-CM, or transthyretin-related amyloid cardiomyopathy, is a rare, progressive, and underdiagnosed condition that has been linked to progressive heart failure (HF).2,3 To date, treatment has been limited to supportive care, as there have been no professional or clinical guidelines to inform management of this disorder.

However, findings from a phase 3 randomized control trial support the use of tafamidis to improve outcomes in patients diagnosed with transthyretin amyloid cardiomyopathy.

Type 2 diabetes raises the risk of heart failure, necessitating care of cardiomyopathy.

Results Confirm Efficacy of the ATTR-CM Trial

Tafamidis (Vyndaqel, Pfizer) dramatically reduced mortality by 30% and cardiovascular (heart failure) hospitalizations by 32% in an international, multicenter, placebo-controlled clinical trial following patients who were diagnosed with transthyretin amyloid cardiomyopathy,according to researchers from Columbia University Medical Center.

The results of the ATTR-ACT trial were presented in a session on late-breaking data at the European Society of Cardiology Congress in Munich, Germany, and were simultaneously published online in the New England Journal of Medicine.4

Beyond a reduction in cardiovascular events, other beneficial outcomes were found, lead author Mathew S. Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at the Columbia University Medical Center and the College of Physicians and Surgeons in New York City, told EndocrineWeb. "The drug improved or slowed down the functional decline in these patients, a common occurrence in the those diagnosed with cardiovascular disease. In effect, there was a 13% absolute difference in mortality.”4

One concrete measure we identified during the study was an improvement in the six-minute hall walk,4 Dr. Maurer said. “When both groups were compared, those receiving the active drug were able to walk 73 meters farther than the group who received placebo.”

Gaining a Deeper Understanding of Transthyretin Amyloid Cardiomyopathy

The median survival for untreated patients with cardiomyopathy is about 2.5 years after diagnosis of the mutation type, ATTRm, and 3.6 years for the wild-type, ATTRwt, linked with aging.4

"The prevalence of the condition is not well known," Dr. Maurer said. "This is inherited in an autosomal dominant fashion. If both parents had it, the patient would have a 50-50 chance." While it is considered a rare disease, Dr. Maurer said, "most of us [specialists in the field] believe it may not turn out to be so rare."

The disease is caused by the destabilization of a transport protein called transthyretin, composed of four identical subunits. Transthyretin is primarily synthesized in the liver; it transports thyroxine and retinol-binding protein-retinol (vitamin A) complex. When the structure of the subunits dissociates, it results in misfolded proteins that aggrege into amyloid fibrils and deposit mainly in the heart.

The drug, tafamidis, acts as a stabilizer of the transthyretin, Dr. Maurer said. "It's an oral drug that fits between the 'leaves' of the protein and prevents them from falling apart. It works by slowing down the progression of the disease by inhibiting the [destabilization] of the protein.''

Delving into the Study Protocol for Treatment of Cardiomyopathy

Some 441 patients with transthyretin amyloid cardiomyopathy were recruits to this international, multicenter, placebo-controlled, double-blind study.4 The investigators enrolled patients from 48 sites in 13 countries.

One group (n=264) receiving the drug took 80 mg, the other 20 mg; 177 received the placebo. The mean age was 74.5 years in the treated groups and 74.1 years old in the placebo group. About one-quarter of the patients overall had the mutation form of cardiomyopathy while 75% were diagnosed as having the wild-type.4

Tafamidis was linked with lower all-cause mortality than placebo (29.5% versus 42.9%; hazard ratio, 0.70; 95% CI , 0.51 to 0.96). Outcomes in the treatment group also were lower for the rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year, 95% CI, 0.56 to 0.81.)4

Participants who were taking the drug demonstrated a slower rate of falling off in distance for the 6-minute walk test (P < 0.001) and a lower rate of decline in KCCQ-OS score (P < 0.001).4

The sample size of more than 400 was estimated to give the study power to at least 90% to detect a 30% mortality decline, a reduction in cardiovascular-related hospitalizations from 2.5 to 1.5 over the 30-month follow-up period, or both.4 Patients were screened from December 2013 through August 2015 to achieve full enrollment.

Screening For and Treating Patients with Cardiomyopathy

The study results are extremely favorable, and offer ''an important step forward in the treatment of these patients," said Ayan Patel, MD, professor of medicine at Tufts University School of Medicine, who reviewed the findings for EndocrineWeb and was not involved in the study.

"It points to the need for diagnosing patients with cardiomyopathy,'' since the results offer an effective treatment, he said. Dr. Patel, too, suspects the condition has been under-diagnosed, meaning there are more patients who would benefit from treatment but first need to be identified.

Nuclear imaging tests are an effective means of detecting the uptake of transthyretin, he told EndocrineWeb, and it has become more commonly utilized. "There is an increasing recognition of the need to diagnosing these patients early," he said. With an effective drug treatment, that interest can be expected to grow.

Dr. Patel suggested that practitioners should have an index of suspicion about the disease. "That is going to be based on, for example, a patient who has heart failure, especially if they have a preserved ejection fraction and evidence on imaging of increased wall thickness."

A history of carpal tunnel syndrome should also raise suspicion, he said, as deposition of amyloid is likely to be related to both conditions.

Practitioners ''should think about this diagnosis in their differential," Dr. Maurer agreed, pointing out that patients are usually older, over age 60, with typical symptoms of heart failure.

Tafamidis was given an orphan drug designation for ATTR-ACT in both the European Union and the United States in 2012 and in Japan in 2018. The Food and Drug Administration (FDA) put tafamidis on fast track status in 2017 and granted it a breakthrough therapy designation in 2018.5,6

The experts could not predict when FDA approval might be granted to market tafamidis for treatment of cardiomyopathy in the US but they were optimistic that once the trial data was reviewed, the process would be expedited given the clinical benefit to a growing number of patients.

Dr. Maurer was co-principal investigator of the steering committee for the study, funded by Pfizer. Dr. Patel had no financial conflicts with regard to discussing this study.

Continue Reading:
Diabetes and Heart Failure: What Endocrinologists Need To Know
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