Diflunisal for ATTR Cardiac Amyloidosis

Abstract

Transthyretin (TTR) cardiac amyloidosis is an important, often under-recognized and potentially modifiable cause of heart failure with a preserved ejection fraction. The only proven treatment is liver or combined heart/liver transplantation, which, although effective, is not suitable for the vast majority of older adults with this condition. Diflunisal, a nonsteroidal anti-inflammatory drug, can stabilize the TTR tetramer in vitro and may prevent misfolding monomers and dimers from forming amyloid deposits in the heart. It is one of two small molecules assessed in animal safety studies and human clinical trials of TTR polyneuropathy. The authors conducted a single-arm, open-label investigation with a mean follow-up of 0.9±0.3 years to determine the safety and efficacy of diflunisal administration in a cohort of 13 patients with confirmed wild-type or mutant TTR cardiac amyloidosis. Diflunisal was well tolerated from a hematologic standpoint, although a 6% decline in estimated glomerular filtration rate was noted. Therapy was discontinued in one patient who rapidly developed volume overload. There was no significant mean change in cardiac structure (left ventricular mass: −53 g/m2 change, P=.36), function (ejection fraction: −2% change, P=.61), or biomarkers (Troponin I: +0.03 ng/mL, P=.08; BNP: +93 pg/mL change, P=.52) during the course of therapy. These data suggest that at low dosages and with careful monitoring, diflunisal can be safely administered to compensated patients with cardiac TTR amyloidosis. Further study in a randomized placebo-controlled trial is warranted.

Serial scanning with technetium pyrophosphate (99mTc-PYP) in advanced ATTR cardiac amyloidosis

“…Elaboration of these dynamic processes with reliable noninvasive cardiac imaging techniques will be relevant, not just for tracking disease progression over time, but also for monitoring response to treatments in individual patients as amyloid therapies emerge from clinical trials. 11–17 …”

Transthyretin Cardiac Amyloidosis in Older Americans

“…Diflunisal, FDA-approved as a non-steroidal anti-inflammatory drug, slowed neuropathy progression and improved quality of life in patients with FAP over 2 years but has risks of gastrointestinal bleeding, kidney injury, and heart failure exacerbation [47, 48] with conflicting studies regarding tolerance. [49, 50] Tafamidis is a TTR stabilizer that has no non-steroidal properties. In a phase 2 trial of subjects with senile cardiac amyloidosis, tafamidis effectively achieved and maintained TTR stabilization and was well tolerated.…”

Recent Advances in the Diagnosis and Management of Cardiac Amyloidosis

“…Recently, RNAi with siRNA has been investigated to silence the translation of TTR mRNA in hepatocytes. Preliminary results have demonstrated significant reduction in the circulating levels of TTR, with two compounds undergoing active clinical testing [93]. This may obviate the need for liver transplantation.…”