Tafamidis found to increase survival over liver transplant in hATTR
But therapy candidate linked to poorer heart, nerve outcomes in study
Adults with hereditary transthyretin amyloidosis (hATTR), a group of disorders that includes familial amyloid polyneuropathy (FAP), lived longer after treatment with tafamidis versus undergoing a liver transplant, a study reported.
However, patients treated with tafamidis experienced a faster decline in neurological and heart-related outcomes than did those who underwent the kidney transplant.
The higher mortality among transplant recipients likely was due to early complications — namely rejection and/or infection — arising from the procedure, the researchers suggested. In contrast, better long-term nerve and heart outcomes in those with a new liver may have resulted from the restoration of functional TTR protein.
“Patients treated with tafamidis would present a better survival but also a faster deterioration of their cardiac and neurological statuses as compared with [liver transpant patients],” the team wrote.
The study, “Comparison between tafamidis and liver transplantation as first-line therapy for hereditary transthyretin amyloidosis,” was published in the Journal of Protein Folding Disorders.
Comparing outcomes of liver transplant versus tafamidis use
FAP is a form of hATTR, a group of inherited conditions characterized by the misfolding of the TTR protein. That triggers the formation of aggregates or clumps, called amyloid fibrils, that build up to harmful levels in different body tissues.
In FAP, amyloid fibrils tend to accumulate in peripheral nerves — those outside the brain and spinal cord — leading to nerve damage, or polyneuropathy. Other tissues also may be affected, including the heart, kidneys, and eyes.
Because TTR is produced in the liver, a liver transplant was the first treatment that was found to improve the course of neuropathy and survival. Since then, other therapies have been developed to suppress TTR production or stabilize the protein to prevent misfolding.
One such TTR stabilizer is tafamidis (sold under the brand name Vyndaqel and Vyndamax), an oral therapy approved in Europe for FAP and in the U.S. for a form of amyloidosis that affects the heart.
According to the researchers — a team from across France — no study has directly compared the outcomes of a liver transplant versus tafamidis in hATTR patients.
Here, the team examined the medical files of 345 adults with hATTR and selected 72 pairs — 144 patients in total — who either underwent a liver transplant or were treated with tafamidis as a first-line therapy. These patients were matched across several demographic and clinical characteristics.
Among them, 69% had heart involvement, and 38% had a polyneuropathy disability (PND) score greater than one, a stage marked by sensory disturbances in the lower extremities that don’t compromise a person’s ability to walk.
During a median follow-up of almost six years, 38 patients (26%) died: 32 (44%) were from the liver transplant group and six (8%) from the tafamidis group. The relative mortality risk was 65% lower in patients treated with tafamidis compared with those who underwent a liver transplant.
“Better survival observed in the tafamidis group was due to an excess mortality that arose likely from the complications classically reported early after surgery in [liver transplant],” the team wrote. These included graft complications and infections, they noted.
Conversely, the poorer neurological outcome, defined by a worsening PND score, was reached in 19 (26%) transplant patients and 45 (63%) tafamidis-treated patients. In contrast to mortality, those treated with tafamidis had a sevenfold higher risk of worsening polyneuropathy than transplant patients.
A cardiac outcome, which combined heart failure, hospitalization for a cardiovascular event, or death due to a cardiovascular event, was attained in 42 individuals (29%). Among them, 20 (28%) received a liver transplant, and 22 (31%) were treated with tafamidis. Likewise, those treated with tafamidis had a threefold higher risk of heart worsening than transplant patients.
Researchers argued that a higher efficacy of liver transplant over tafamidis may be explained by the full restoration of functional TTR protein production.
Tafamidis better for males, patients with heart problems
In a subgroup analysis, tafamidis outperformed liver transplant for males, those with a late disease onset (beyond age 50), and those with a low PND score. It also worked better for individuals with cardiac dysautonomia, or heart problems caused by impairments in the autonomic nervous system, which controls non-conscious body functions. Survival was not better in any of the subgroups with a liver transplant as compared with tafamidis.
By comparison, liver transplant outperformed tafamidis regarding the neurological endpoint across all subgroups, except for patients harboring TTR gene mutations other than V30M, the most common FAP-causing genetic defect.
In this [matched] comparison … first-line therapy with tafamidis would be associated with a better overall survival but with a poorer stabilization of cardiac and neurological statuses.
A liver transplant was significantly better than tafamidis for females, those with early disease onset (under age 50), patients with thin walls separating the two lower heart chambers, and those without cardiac dysautonomia. No subgroup had a better cardiac outcome with tafamidis.
Prediction analysis showed thinning of the heart chamber walls was associated with worse survival and poorer neurological and cardiac outcomes, regardless of therapy.
For patients treated with tafamidis, low levels of hemoglobin — the protein that carries oxygen in red blood cells — at treatment start were associated with poor survival and cardiac outcome. Older age at surgery was linked to worse survival and poorer neurological and cardiac outcomes among transplant patients.
During follow-up, second-line therapies for tafamidis-treated patients included Onpattro (patisiran) in 21 cases, a liver transplant in 16, Tegsedi (inotersen) in four, and revusiran in one case. For transplant patients, second-line therapies included tafamidis in 11 cases and Onpattro in three cases.
“In this [matched] comparison between tafamidis with [liver transplant] in patients with [hATTR], first-line therapy with tafamidis would be associated with a better overall survival but with a poorer stabilization of cardiac and neurological statuses,” the researchers wrote. “Close multidisciplinary monitoring of patients carrying [hATTR] and treated with disease-modifying therapies including tafamidis is mandatory to adapt therapy.”
“This hypothesis-generating analysis pleads for future studies that will assess the comparative efficacy of the anti-amyloid therapies,” they concluded.
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