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Shah et al. Vessel Plus 2021;5:53 https://dx.doi.org/10.20517/2574-1209.2021.76 Page 7 of 11

80 MG in Comparison to Placebo in Subjects Diagnosed with Transthyretin Cardiomyopathy (ATTR-ACT)
clinical trial compared tafamidis meglumine vs. placebo in patients with either wild-type or hereditary
ATTR cardiomyopathy. A total of 441 patients were randomized in a 2:1:2 fashion to treatment with
tafamidis at 80 mg daily vs. tafamidis at 20 mg daily vs. placebo. 76% of the enrolled patients had wild-type
TTR amyloidosis, and the patients across all study arms were predominantly males. Tafamidis was dosed at
either 80 mg or 20 mg once daily for a total follow-up of 30 months. Outcomes analysis was done using the
Finkelstein-Schoenfeld method, a hierarchical rank-sum analysis. Firstly, tafamidis resulted in an average
decrease in all-cause mortality by 30%, with an average overall mortality of 29.5% vs. 42.9% at 30 months in
the tafamidis vs. placebo. This equated to a 13.4% absolute difference in mortality, and a number of 7.5
patients needed to treat to prevent 1 death after 30 months of treatment. Secondly, the annual
cardiovascular-related hospitalization rate was 0.48 vs. 0.70 in the tafamidis vs. placebo arms, a 32% relative
risk reduction in cardiovascular hospitalizations . Secondary outcomes analyses showed tafamidis resulted
[20]
in improved 6-min walk distance by an average of 75.7 meters, reduction in the decline in KCCQ-OS score
by an average of 13.7 points, a smaller increase in NT-pro-BNP levels by an average of 735 pg/mL at 12
months, and 2181 pg/mL at 30 months, and a smaller decrease in left ventricular stroke volume by an
average of 6.3 mL at 30 months . Kaplan-Meier survival analysis revealed that tafamidis showed mortality
[20]
benefit after an average of 18 months of treatment. Improvements in 6-min walk distance and quality-of-life
metrics like the KCCQ-OS questionnaire were noted in the tafamidis arm at 6 months.

There were no serious adverse effects that were more common in the tafamidis arms than placebo.
Interestingly, the pre-specified subgroup of patients with NYHA functional class III symptoms prior to
enrollment showed an increased rate of cardiovascular-related hospitalizations in the tafamidis vs. control
arm.

Tafamidis meglumine was granted FDA approval for ATTR cardiomyopathy of either wild-type or
hereditary etiology. Tafamidis has rapidly become the most widely-used pharmacotherapy for ATTR
cardiomyopathy; however, associated costs remain a significant barrier to broader access. Dosing initially
was 80 mg daily (4 × 20mg pills) in cardiomyopathy. Tafamidis free acid (Vyndamax®, Pfizer Inc) 61 mg
daily is now available and comes with the advantage of a lower pill burden compared to tafamidis
meglumine .
[21]

Diflunisal
Diflunisal (Dolobid®, Merk & Co) is a decades-old generic nonsteroidal anti-inflammatory molecule, a
salicylic acid derivative, which has more recently been found to be complex with the TTR protein’s two
thyroxine binding sites. The resultant protein complex stabilizes the TTR tetramer form and inhibits protein
misfolding that would otherwise result in degradation and the production of TTR monomers. Initial
research on diflunisal employed the National Institutes of Health mission to repurpose old drugs and
focused on hereditary TTR amyloid polyneuropathy. It was subsequently followed by single-center open-
label and retrospective studies on the use of diflunisal in TTR amyloid cardiomyopathy [22,23] . Approximately
57%-90% of patients managed with diflunisal had ATTRwt cardiomyopathy, 79%-82% had either NYHA
functional Class I or II symptoms, 83%-87% of the patients were of the white race, and 87%-88% were males.
Diflunisal was dosed at 250 mg orally twice daily, and the median duration of therapy ranged from 15-23
months. In Kaplan-Meier analysis, diflunisal was associated with an improvement in the time to death or
heart transplantation, with a median time of 5.4 years compared to 2.2 years for patients with ATTR-CM
not on treatment . This was comparable to outcomes with tafamidis. Based on this limited data, it is
[23]
hypothesized that the survival benefit with diflunisal may be comparable with tafamidis. Diflunisal appears
to be generally well-tolerated, with low rates of thrombocytopenia and renal dysfunction. Gastrointestinal
adverse effects are less common but in the setting of routine concomitant use of histamine blockers or