Transthyretin-stabilizer reduces mortality and hospitalization in patients with transthyretin-related cardiomyopathy

ESC 2018 - Munich

News - Aug. 27, 2018

ATTR-ACT: Transthyretin Amyloid Cardiomyopathy Tafamidis Study

Presented at the ESC congress 2018 by: Claudio Rapezzi (Bologna, Italy)

Introduction and methods

Transthyretin-related cardiomyopathy (ATTR-CM) is an underdiagnosed, life-threatening disease, characterized by intramyocardial accumulation of amyloid fibrils, resulting in restrictive cardiomyopathy and progressive heart failure (HF). ATTR-CM is caused by pathogenic mutations in the transthyretin gene (TTR), which is the hereditary form, or by deposition of wild-type TTR, the acquired form. No guideline-base recommended treatment exists, and treatment is limited to supportive care. Median survival of untreated patients is about 3.5 years after diagnosis. The oral drug tafamidis stabilizes TTR and inhibits or slows down the formation of amyloid fibrils. However, the effect of tafamidis in ATTR-CM patients remains unknown.

The Transthyretin Amyloid Cardiomyopathy Tafamidis (ATTR-ACT) study investigated the efficacy, safety and tolerability of tafamidis meglumine in patients with ATTR-CM and HF. ATTR-ACT included 441 patients (aged 18-90 years) with hereditary or wild-type ATTR-CM and HF who were randomized 2:1:2 to treatment with tafamidis 80 mg once-daily (QD), tafamidis 20 mg QD or placebo for 30 months.

The primary endpoint was the composite of all-cause mortality and the frequency of cardiovascular(CV)-related hospitalizations from baseline to 30 months. Secondary endpoint consisted of exercise tolerance (a change in 6-minute walk test) and quality of life (KCCQ-0S score).

Main results

  • All-cause mortality and CV-related hospitalizations were significantly reduced after treatment with tafamidis, compared to placebo (29.5% vs 42.9%, HR: 0.70, 95%CI: 0.51-0.96, p=0.0259 and 0.48 per year vs. 0.70, RR: 0.68, 95%CI:0.56-0.81, p<0.0001). The curves diverged after about 12-18 months.
  • Quality of life (KCCQ-OS score) was improved, compared to placebo (P<0.0001). Tafamidis demonstrated a reduction of the decline in exercise tolerance (6MWT distance) seen in the placebo group (P<0.0001 for both).
  • There were no significant safety concerns.
  • The benefits of tafamidis were independent of etiology (wild-type vs. hereditary) and drug dose (20 vs. 80 mg).


The ATTR-ACT randomized trial demonstrated that tafamidis is safe and well-tolerated, and it not only reduces all-cause mortality and CV-related hospitalizations, but also reduces the decline of functional capacity and quality of life in patients with ATTR-CM. The separation of the curves suggests that some time is needed to observe an advantage, hinting at that something needs to happen in the myocardium to sort an effect.

An important message is that ATTR-CM is more underdiagnosed than rare. When a suspicion arises, it can easily be diagnosed with bone scintigraphy. In this fatal, progressive condition, early diagnosis and treatment are essential, as maximal benefits are observed at an earlier, and more reversible stage of disease.


During the press conference the question was raised when ATTR-CM should be suspected and whether it would be beneficial to screen for it in younger, asymptomatic patients. Rapezzi answered this question by explaining that ATTR-CM patients show symmetric hypertrophic hearts, with normal ventricles and both end-systolic volume and ejection fraction within normal range. The clue is, however, not in the preservation of ejection fraction, but in the normal ventricles. Wild-type ATTR-CM mainly affects the hearts of patients 60 years of age or older. ATTR-CM caused by a mutation in the ATTR gene is phenotypically more heterogenous with varying degrees of cardiac and neurologic involvement. Hereditary ATTR-CM manifests itself at a younger age. While the baseline profiles of patients with the hereditary form and wildtype form differ, the efficacy and safety profile were exactly the same, said dr. Rapezzi.

Our reporting is based on the information provided at the ESC congress

This article was simultaneously published in NEJM

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