From Pages to Practice

By Angela Chen, MBBS, MPH

Published September 12, 2018


After 6 months of travel, I was back at the tertiary hospital mothership as an internal medicine resident. Cardiology was the usual blur of beepers, codes, ECGs, and chest pain reviews. I met Dee (not her real name) during this time. She was a 65-year-old cardiac-amyloid patient on palliative care. This was her fifth admission in 3 months for heart failure exacerbation. Previously, Dee had been a bubbly middle-school teacher who made glass jewelry and enjoyed South Australia’s Fleurieu coastline; now she was dying from amyloid cardiomyopathy. During the previous 6 months, she had been living with New York Heart Association (NYHA) Class IV heart failure symptoms. She was chronically breathless and bedbound. This admission would be Dee’s last. A code was called for hypotension and reduced oxygen saturation. Dee held her husband’s hand and said, “enough.” The medical emergency team arrived, but the final plan simply read “comfort measures only.”

Transthyretin amyloid cardiomyopathy is a life-threatening disease caused by the accumulation of amyloid fibrils (composed of misfolded transthyretin protein) in the myocardium. Patients can also develop arrhythmias if the fibrils accumulate in the conduction system of the heart. Treatment is limited to supportive care, and median survival ranges between 2.5 and 3.6 years after diagnosis, depending on the disease subtype.

Transthyretin is a protein synthesized by the liver that transports thyroxine and vitamin A complex. Amyloid fibrils are produced when the large transthyretin protein dissociates into intermediaries. Tafamidis is a novel medication that binds to the thyroxine-binding sites on transthyretin, preventing dissociation and amyloid fibril production.

In this week’s issue of NEJM (and published online first on August 27th), researchers examined the efficacy and safety of tafamidis in patients with transthyretin amyloid cardiomyopathy. In the multicenter, placebo-controlled, double-blind, phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), 441 adults (age, <90 years) with biopsy-proven amyloid deposits and clinical, biochemical, or echocardiographic evidence of cardiac failure were randomized in a 2:1:2 ratio to receive tafamidis (80 mg or 20 mg) or placebo daily for 30 months. The primary outcome was all-cause mortality, followed by frequency of cardiovascular-related hospitalizations, in a pooled analysis of 264 tafamidis (80 mg or 20 mg) recipients and 177 placebo recipients.

Tafamidis was superior to placebo in the combined analysis of mortality and frequency of cardiovascular-related hospitalizations (win ratio, 1.7; 95% CI, 1.26–2.29; P< 0.001), and in separate analysis of each component (hazard ratio for all-cause mortality, 0.70; 95% CI, 0.51–0.96 and relative risk reduction for cardiovascular-related hospitalizations, 0.68; 95% CI, 0.56–0.81). These improvements were observed in all prespecified subgroups except for patients with NYHA Class III heart failure (i.e., patients with the most severe disease) at enrollment. In this group, tafamidis was associated with an increased frequency of cardiac-related hospitalizations. Otherwise, the safety profiles of tafamidis and placebo were similar, and no meaningful differences in safety profiles were observed between the 80-mg and 20-mg doses of tafamidis.

The authors concluded that in patients with transthyretin amyloid cardiomyopathy, tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations as compared with placebo. However, patients with more severe disease (NYHA Class III heart failure symptoms) did not benefit from the drug. Nonetheless, tafamidis represents an intervention for a serious lethal disease for which no effective regimen currently exists. Perhaps in the future, the availability of tafamidis or other similar treatments at the time of diagnosis will help improve the prognosis in patients like Dee.

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Angela is a 2018-2019 NEJM editorial fellow. She is an endocrine fellow who trained at Flinders Medical Centre and the Royal Adelaide Hospital. Angela recieved her medical degree from the University of Adelaide, and masters of public health from the University of Sydney. Her clinical and research interests are in the areas of glucocorticoid and cardiovascular endocrinology and diabetes medicine.