Fast Five Quiz: Treatment of Hereditary (Familial) Amyloid Transthyretin-Related (hATTR) Amyloidosis

Jefferson R. Roberts, MD; Victoria M.F. Mank, MD

Disclosures

May 24, 2021

TTR tetramer stabilizers, associated with improved survival in transthyretin cardiac amyloidosis (TTR-CA), stabilize the native TTR tetramer structure, preventing amyloid fibril formation and leading to a reversal of peripheral neurologic impairment by acting as the dimer-dimer interface.

Diuretic agents must be used with caution in the setting of amyloidosis. The restrictive effect of the disease causes poor ventricular compliance and low end-diastolic volumes. Patients with hATTR amyloidosis often require a higher filling pressure to distend the stiffened heart, and because diuretic therapy reduces preload, stroke volume and systolic blood pressure may decline even further. In addition, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) are poorly tolerated in cardiac amyloidosis and should be avoided in amyloidosis.

Individuals with hATTR amyloidosis should avoid using local heating appliances, such as hot water bottles; patients with hATTR amyloidosis have decreased perception of temperature and pain, placing them at higher risk for burn injuries.

Certain calcium channel blockers should be avoided in patients with hATTR amyloidosis due to accumulation within the amyloid deposits, increasing the risk for cardiac complications.

Several therapies for hATTR amyloidosis have recently been approved. These include:

  • Inotersen (Tegsedi), an antisense oligonucleotide that inhibits the hepatic production of TTR. It is used to treat adults with stage 1 and 2 peripheral nerve disease (polyneuropathy), as well as polyneuropathy caused by hATTR amyloidosis in adult patients.

  • Patisiran (Onpattro), an RNA interference therapeutic infusion for the treatment of polyneuropathy caused by hATTR amyloidosis in adult patients.

  • Tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel) are oral transthyretin stabilizers used in the treatment of the heart disease (cardiomyopathy) caused by transthyretin-mediated amyloidosis (ATTR-CM) in adult patients.

Additional therapies under investigation include:

  • Diflunisal (Dolobid), a nonsteroidal anti-inflammatory drug that is approved for the treatment of arthritis. A phase 1 study showed that at a dosage of 250 mg twice daily, diflunisal successfully complexes to the thyroxine binding site and kinetically stabilizes circulating TTR tetramers, inhibiting release of the TTR monomer required for amyloidogenesis. In a randomized, placebo-controlled study of 130 patients with transthyretin-related familial amyloid polyneuropathy (TTR-FAP), the use of diflunisal reduced the rate of progression in neurologic impairment and preserved quality of life compared with placebo over 2 years.

  • Tolcapone (Tasmar), a dopamine promoter with an orphan drug designation for the treatment of ATTR that occupies the T4-binding sites located at the TTR dimer-dimer interface and prevents amyloidogenesis by stabilizing the tetramer. An added benefit is that it also inhibits TTR cytotoxicity.

Learn more about hATTR amyloidosis treatment options.

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