ATTR-ACT: Tafamidis Reduces Mortality in Amyloid Cardiomyopathy

Susan Jeffrey

August 27, 2018

MUNICH — Treatment with tafamidis (Vyndaqel, Pfizer) was associated with a reduction in all-cause mortality, as well as cardiovascular hospitalizations, and functional decline vs placebo in a new trial in patients with transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy is a rare disease caused by deposition of amyloid fibrils in the myocardium. It is more common in older men and has a very poor prognosis.

"This is a terrible disease," principal investigator Professor Claudio Rapezzi, MD, University of Bologna, Italy, said at a press conference here. "The mean duration of survival is no more than 2.5 years from the time of diagnosis."

Tafamidis is still investigational but has orphan drug designation from the European Medicines Agency (EMA) and fast track designation from the US Food and Drug Administration (FDA). If approved, it would be the first such treatment for transthyretin amyloid cardiomyopathy.

Rapezzi said that in fact, this condition "is less rare than underdiagnosed," and "it can be easily diagnosed when suspected, so the first point is fostering the suspicion," he said.

"The second point is that tafamidis is effective and safe and offers hope for patients whose life expectancy and quality of life are extremely limited," Rapezzi said. Early diagnosis and early treatment at the beginning of the natural course of disease can be expected now to provide the best results, he added.

Findings of the Efficacy and Safety of Tafamidis in Transthyretin Amyloid Cardiomyopathy (ATTR-ACT) were presented here at the European Society of Cardiology (ESC) Congress 2018, to coincide with their publication online in the New England Journal of Medicine.  

Amyloid Fibrils                                     

Deposition of amyloid fibrils in transthyretin amyloid cardiomyopathy occurs when wild-type or variant transthyretin becomes unstable and misfolds, the authors write.  

"Misfolded monomers or oligomers of transthyretin are deposited in the myocardium, leading to cardiomyopathy and symptoms of heart failure, including dyspnea, fatigue, orthostatic hypotension, and syncope," they note. "Infiltration of the conduction system can lead to bundle-branch block, atrioventricular block, sinoatrial disease, and atrial fibrillation."

A late-onset disease, it occurs predominantly in men age 60 years or older, Rapezzi said. It can be inherited as an autosomal dominant trait caused by pathogenic mutations in the transthyretin gene, TTR, or it can result from deposition of wild-type transthyretin protein, previously called senile systemic amyloidosis, they note.

Treatments have been limited to supportive care, with no guideline-recommended treatment, the authors write.

Tafamidis acts by stabilizing transthyretin, preventing misfolding and the formation of amyloid. It is already approved in the European Union to slow neurologic progression in transthyretin familial amyloid polyneuropathy, in which amyloid is deposited in the nerves after transthyretin misfolding.  It is approved for adult patients with early-stage symptomatic polyneuropathy to delay peripheral nerve impairment.

Since its EU approval in 2011, tafamidis has been approved in Japan, Mexico, Israel, and South Korea.

ATTR-ACT was a multicenter, international, double-blind, placebo-controlled, phase 3 trial. A total of 441 patients were randomly assigned in a 2:1:2 ratio to receiving 80 mg or 20 mg of tafamidis or placebo for 30 months. 

The study included patients with the hereditary form of the disease and with the wild-type form. Patients were stratified by "taking into account the two different etiologies, the two different dosages, and the spectrum of severity of this disease," Rapezzi said.

The primary endpoint was the hierarchical assessment of all-cause mortality, followed by frequency of cardiovascular-related hospitalizations using the Finkelstein–Schoenfeld method. Comparisons were based on pooled tafamidis treatment groups vs placebo, except for specific dose comparisons, the authors note.

Key secondary endpoints were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS), in which higher scores indicate better health status.

"In the primary analysis that hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalization, according to analyses performed with the Finkelstein–Schoenfeld method, treatment with tafamidis was superior to placebo over 30 months (P < .001)," the authors write.

All-cause mortality was reduced by 30% and rates of cardiovascular-related hospitalizations were reduced by 32%, "so impressive results," Rapezzi said.

Benefit was independent of the etiology, hereditary or wild type, and of the dose, he added. 

Table. ATTR-ACT: All-Cause Mortality and Cardiovascular Hospitalization by Treatment

Endpoint Tafamidis Placebo Hazard Ratio (95% Confidence Interval)
All-cause mortality, n (%) 78/264 (29.5) 76/177 (42.9) 0.70 (0.51 - 0.96)
Cardiovascular hospitalization (number per year) 0.48 0.70 0.68 (0.56 - 0.81)


Event curves diverged only after 12 to 18 months, he noted, "so a period of time is necessary to observe the advantage, the benefit," he said.

At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P < .001) and a lower rate of decline in KCCQ-OS score (P < .001).

No safety signals were observed in the trial, he said. The incidence and types of adverse events were similar between the groups, and no difference was seen between doses.

Events were generally mild to moderate in severity, and permanent discontinuation of tafamidis or placebo as a result of adverse events was less common in the tafamidis groups than with placebo.

"Both diarrhea and urinary tract infections, adverse events previously reported in patients with familial amyloid polyneuropathy, were less common in patients who received tafamidis than in those who received placebo," the authors note.

Robust Efficacy

In an accompanying editorial, C. Cristina Quarta, MD, University College London, and Scott D. Solomon, MD, Brigham and Women's Hospital, Boston, Massachusetts, are positive about the results.

"Given the dearth of acceptable treatments for this disorder, these robust efficacy results, combined with a benign safety profile, suggest an important role for tafamidis in the treatment of transthyretin amyloid cardiomyopathy," they write.

They discuss some other therapies  being investigated to treat cardiomyopathy but also neuropathy caused by transthyretin amyloidosis.

"The small interfering RNA therapeutic patisiran and the antisense oligonucleotide inotersen, which interfere with transthyretin production, reduced the progression of neuropathy among patients with stage 1 ATTRm–related disease," they note.  

Earlier this month, the FDA approved patisiran (Onpattro, Alnylam Pharmaceuticals Inc) for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults.

In June, the EMA's Committee for Medicinal Products for Human Use adopted a positive opinion, recommending market authorization for inotersen (Tegsedi, IONIS USA) for the treatment of stage 1 or stage 2 polyneuropathy, also in adults with hATTR.

The NEURO-TTR trial of inotersen and the APOLLO trial of patisiran were recently published online July 5 in the New England Journal of Medicine.

"Further study is needed to determine whether there are important therapeutic differences between transthyretin stabilization and transthyretin knockdown; differences in the outcomes observed among the few trials reported thus far may reflect differences in patient populations, study design, length of followup, or outcomes rather than therapeutic differences," Quarta and Solomon conclude.

"Meanwhile, the results of ATTR-ACT offer hope for patients with this devastating disease and suggest new ways forward in testing therapies for rare diseases," they write.

Sea-Change in Cardiology

Commenting on the findings for | Medscape Cardiology, Richard Becker, MD, University of Cincinnati, Ohio, a spokesperson for the American Heart Association said the trial itself was "highly laudable, highly anticipated."

"There was some experience with the study drug in patients that have amyloid peripheral neuropathy, so there was some precedent, but this was the first time that the medication was used in individuals with cardiac amyloid specifically," Becker said. "The results showed that there was a reduction in the likelihood of heart failure and mortality, so that is really a sea-change in the field of cardiology."

The advent of broader use of cardiac MRI and clear criteria for the diagnosis of amyloid heart disease has perhaps increased awareness of this condition and with that, the number of patients receiving a diagnosis, he added.

"The challenge has always been, and the textbooks have always said, that amyloid heart disease is not treatable, that none of our evidence-based therapies will change outcomes," Becker said. "Now the possibility of having a treatment is what the excitement — and appropriately so — is all about."

ATTR-ACT was funded by Pfizer. Rapezzi reports he has received research grants, speaker fees, and board participation honoraria from Pfizer. Quarta has no disclosures. Solomon reports receiving a grant and personal fees from Alnylam and grants to his institution from Ionis and Eidos. Becker has no relevant disclosures.

European Society of Cardiology (ESC) Congress 2018: Hotline Session 3: #3235. Presented August 27, 2018.

N Engl J Med. Published online August 27, 2018. Full text, Editorial

For more from | Medscape Cardiology, follow us on Twitter and Facebook


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.