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Tafamidis improves outcome in transthyretin amyloid cardiomyopathy

ESC Congress News 2018 - Munich, Germany

In a Hot Line presentation yesterday, Professor Claudio Rapezzi (University of Bologna, Bologna, Italy) reported exciting data from the phase III ATTR-ACT trial in 441 patients with transthyretin amyloid cardiomyopathy (ATTR-CM), demonstrating that tafamidis, a selective transthyretin stabiliser, is able to improve survival and quality of life in this patient population.(1)

Myocardial Disease
Cardiovascular Pharmacotherapy

rappezi-esc-congress-news-2018.jpgProf. Rapezzi notes that, “ATTR-CM can be inherited as an autosomal dominant trait caused by mutation in the TTR gene (ATTRm), or by deposition of wild-type transthyretin protein (ATTRwt), previously called senile systemic amyloidosis. Awareness of the disease among cardiologists is low, and ATTR-CM is therefore underdiagnosed.” Although prevalence is uncertain, studies using a non-biopsy approach to diagnosis (total body scintigraphy with bone tracers)(2) demonstrate a prevalence of at least 13% in hospitalised heart failure patients with preserved ejection fraction,(3) 16% in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis(4) and 5% in patients with presumed hypertrophic cardiomyopathy.(5) According to Prof. Rapezzi, “Treatments have been limited to supportive care, with no guideline-based recommended treatment, and the median survival of untreated patients is only around 3.5 years after diagnosis.(6,7)”

Current treatment options for ATTR-CM are extremely limited; none are able to prolong survival or improve quality of life.

Tafamidis, a novel non-NSAID benzoxazole derivative, binds to the transthyretin thyroxine binding sites with high affinity and selectivity inhibits dissociation of tetramers into monomers, the rate-limiting step in the formation of TTR amyloid. “Although tafamidis was the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in transthyretin amyloid polyneuropathy,” explains Prof. Rapezzi, “its role in ATTR-CM has not yet been explored in any randomised clinical trial and ATTR-CM remains a treatment orphan disease.”

The ATTR-ACT trial investigated the efficacy and safety of tafamidis (80 mg or 20 mg once daily for 30 months; n=264) vs placebo (n=177) in patients with hereditary and wild-type ATTR-CM who had a typical echocardiogram, transthyretin amyloid in any biopsy tissue, a plasma NT-proBNP ≥600 pg/mL and a 6-minute walk test of >100 m. The primary efficacy endpoint was a hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalisations. Secondary endpoints included change from baseline to month 30 in the 6-minute walk test and the Kansas City Cardiomyopathy Questionnaire overall score.

“Tafamidis is the first treatment demonstrated to improve survival and quality of life in patients with ATTR-CM.”

rappezi-3-esc-congress-news-2018.jpg“Compared with placebo, tafamidis demonstrated a significant reduction in all-cause mortality (29.5% vs 42.9%; hazard ratio [HR] 0.70; 95% confidence intervals [CI] 0.51–0.96; p=0.0259) and cardiovascular-related hospitalisations (0.48 vs 0.70; relative risk reduction 0.68; 95% CI 0.56–0.81; p<0.0001), as well as an improvement in quality of life,” says Prof. Rapezzi. “Tafamidis also significantly reduced the decline in 6-minute walk test distance compared with placebo and had a good safety profile. The extent of the tafamidis benefit was independent of aetiology (wild-type vs hereditary) and drug dose (80 vs 20 mg),” he continues. Patients in New York Heart Association Class III experienced a higher hospitalisation rate despite therapy. “This observation,” says Prof. Rapezzi, “together with the fact that the mortality benefit was seen after 18 months of treatment, highlights the importance of treating patients as soon as possible!”

Prof. Rapezzi stresses, “It is important to note that the overall benefit observed with tafamidis was not only statistically, but also clinically, meaningful. This treatment could make a real difference to the lives of individuals diagnosed with hereditary or wild-type ATTR-CM.”

1. Maurer MS, et al. N Engl J Med 2018;August 27:doi:10.1056/NEJMoa1805689.
2. Castano A, et al. JAMA Cardiol 2016;1:880–889.
3. Gonzalez-Lopez E, et al. Eur Heart J 2015;36:2585–2594.
4. Castano A, et al. Eur Heart J 2017;38:2879–2887.
5. Damy T, et al. Eur Heart J 2016;37:1826–1834.
6. Grogan M, et al. J Am Coll Cardiol 2016;68:1014–1020.
7. Gillmore JD, et al. Eur Heart J 2018;39:2799–2806.


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Notes to editor

About the European Society of Cardiology

The European Society of Cardiology brings together healthcare professionals from more than 150 countries, working to advance cardiovascular medicine and help people lead longer, healthier lives.

About ESC Congress 2018

ESC Congress is the world’s largest and most influential cardiovascular event contributing to global awareness of the latest clinical trials and breakthrough discoveries. ESC Congress 2018 takes place 25 to 29 August at the Messe München in Munich, Germany. Explore the scientific programme