Tafamidis reduces mortality, CV hospitalizations in transthyretin amyloid cardiomyopathy
Tafamidis, an oral disease-modifying agent used to delay the loss of peripheral nerve function in transthyretin amyloid polyneuropathy (ATTR-PN), is shown to improve survival and reduce hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the ATTR-ACT trial.
Trial results, reported at the European Society of Cardiology (ESC) Congress 2018, showed that tafamidis, given at a dose of 20 mg or 80 mg once daily, significantly reduced the risk of all-cause mortality and cardiovascular (CV)-related hospitalizations at 30 months compared with placebo (p=0.0006).
Compared with patients randomized to receive placebo (n=177), those receiving tafamidis (n=264) had a 30 percent reduction in the risk of all-cause mortality (29.5 percent vs 42.9 percent; hazard ratio [HR], 0.70; 95 percent confidence interval [CI], 0.51 to 0.96; p=0.0259) and a 32 percent reduction in the risk of CV-related hospitalizations (52.3 percent vs 60.5 percent; HR, 0.68; 95 percent CI, 0.56 to 0.81) at 30 months.
“These benefits of tafamidis were independent of aetiology [ie, pathogenic mutations in TTR (ATTRm) or deposition of wild-type protein (ATTRwt)] or drug dose,” reported principal investigator Professor Claudio Rapezzi of the University of Bologna, Italy. “Tafamidis also reduced declines in 6-minute walking distance and quality of life compared with placebo.”
The non-NSAID benzoxazole derivative, which binds to the thyroxine-binding sites of both variant and wild-type transthyretin, was well tolerated in the trial, with a favourable safety profile compared with placebo.
In the trial, conducted in 48 sites across 13 countries, treatment-related adverse events (TRAEs) associated with tafamidis were generally mild to moderate. Rates of permanent treatment discontinuation due to TRAEs or dose reductions were lower with tafamidis vs placebo. Rates of diarrhoea and urinary tract infections, previously reported in ATTR-PN, were also lower compared with placebo.
“Our findings provide strong evidence that tafamidis is an effective therapy for patients with ATTR-CM, a condition for which treatment options have been limited to supportive care, with a median survival of 2.5–3.6 years after diagnosis if untreated,” he commented.
“ATTR-CM is much more underdiagnosed than rare, and is estimated to occur in 13 percent of hospitalized patients with heart failure [HF] with preserved ejection fraction and 16 percent of patients undergoing transcatheter aortic valve replacement for severe aortic stenosis,” he continued. [Eur Heart J 2015;36:2585-2594; Eur Heart J 2017;38:2879-2887] “With bone scintigraphy having resulted in a paradigm shift in the diagnosis of ATTR-CM, the condition can now be easily diagnosed when suspected.”
In the ATTR-ACT trial, all patients had HF at baseline, with the majority being in New York Heart Association (NYHA) Class II or III. Mean left ventricular ejection fraction was 48.4 percent in the tafamidis group and 48.6 percent in the placebo group. The patients’ median age was 74.5 and 74.1 years, respectively, with more than 75 percent of patients in each group having ATTRwt disease.
“ATTR-ACT is the first large, prospective, blinded study to show improvements in mortality and CV-related hospitalizations in a dedicated HF population with ATTR-CM. The effects on outcomes appeared 12–18 months after initiation of treatment,” noted discussant Dr Jacob George of the Kaplan Medical Center in Rehovot, Isreal.
“However, the mortality benefit of tafamidis appeared to be attenuated in patients with NYHA Class III HF. The outcome of CV hospitalizations also favoured placebo rather than tafamidis,” he continued. “As such, caution should be taken when administering tafamidis to patients with advanced HF.”