Tafamidis for Transthyretin Amyloid Cardiomyopathy: The Solution or Just the Beginning of the End?

Rodney H. Falk

Disclosures

Eur Heart J. 2019;40(12):1009-1012. 

In This Article

Abstract and Introduction

Introduction

Transthyretin (TTR) cardiomyopathy is caused by the deposition of amyloid derived from the breakdown products of either mutant TTR (ATTRm) or wild-type TTR (ATTRw). Tafamidis is a stabilizer of TTR, specifically designed to decrease or prevent amyloidogenesis.[1] The recently-published ATTR-ACT trial was an international multicentre blinded trial of 441 patients with transthyretin (TTR) cardiomyopathy, caused either by ATTRw (76.1%) or ATTRm (23.9%).[2] Patient received either placebo, tafamidis 80 mg, or tafamidis 20 mg daily in a 2:2:1 randomization. The lower dose of tafamidis was chosen because it had been studied in familial amyloid polyneuropathy and had been shown to slow progression of early disease.[3] An 80 mg tafamidis dose was included because, in vitro, it causes more stabilization of TTR than 20 mg.[4,5] In addition, tafamidis is approved for use in early-stage familial amyloid polyneuropathy patients in many non-North American countries, and experience has shown that more advanced disease responds poorly,[6] suggesting that 20 mg could be a suboptimal dose.

The ATTR-ACT trial showed striking results; over a 30-month period all-cause. mortality was reduced from 42.9% to 29.5% and cardiovascular-related hospitalizations fell from 0.70 annually to 0.48, a relative risk reduction of 0.68. Although the trial was designed with a combined hierarchical endpoint of death and decrease in cardiovascular-related hospitalizations,[7] both mortality and morbidity endpoints individually achieved statistical significance. This is a remarkable result in such a small heart failure trial, as most patients with ATTR cardiomyopathy have extensive myocardial infiltration by the time congestive heart failure occurs, with the extracellular volume of the left ventricle averaging 60%.[8] One might conclude that ATTR cardiomyopathy is now a disease with an effective treatment for all sufferers, but a careful analysis of the results suggests that such a conclusion is premature.

As always in clinical trials, examination of the ATTR-ACT results leads to more questions. Some of these remain unanswerable, and others merely unanswered for the moment but potentially answerable with additional analyses. Two results of the trial are particularly worth addressing. The first revolves around the relative efficacy of the two tafamidis doses. The primary analysis showed a benefit of tafamidis over placebo but, despite initial concerns that 20 mg daily may be an inadequate dose, both this and 80 mg dose appeared to be equally effective. This is intriguing, as the onset of heart failure in amyloid cardiomyopathy rarely occurs before the heart is extensively infiltrated, and one might expect that patients with transthyretin cardiomyopathy might have a poor response to 20 mg tafamidis, similar to more advanced TTR amyloid neuropathy patients.

Given the similarity of response in the 20 mg and 80 mg groups, it would seem that the lower dose of tafamidis achieves sufficient stabilization in the majority of patients to demonstrate a positive response. Assuming this to be the mechanism, we are left with two additional questions: might there still be a subgroup of patients in whom suboptimal stabilization of TTR by tafamidis leads to progression and death, and, among those with a high level of TTR stabilization who died, what can the deaths of patients who received tafamidis teach us about the natural history of the disease? The former question is likely to be answered by analysis of TTR stabilization in the study patients,[4] with a comparison of outcomes based on degree of stabilization, and the latter is addressed below.

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