Early diagnosis and treatment of transthyretin amyloid cardiomyopathy significantly improves outcomes
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a significantly underdiagnosed, life-threatening disease caused by the deposition of transthyretin amyloid fibrils in the heart. Dr Soon Chao Yang, Interventional Cardiologist at The Heart Doctors Clinic in Mount Alvernia Hospital, Singapore, reviews the data on early treatment of ATTR-CM, and shares his clinical experience with tafamidis.
The hidden burden of ATTR-CM
Once thought to be a rare disease, ATTR-CM is gaining recognition through enhanced clinical awareness, improved noninvasive diagnostic imaging techniques, and the emergence of effective management strategies. Accumulation of wild-type transthyretin-derived amyloid in the heart is a common finding in very elderly patients, and often, an unrecognized cause of diastolic heart failure in the elderly. [Circ J 2019;84:15-17]
If left untreated, patients often progress to end-stage heart failure with a poor prognosis. Early diagnosis and treatment are crucial for a better prognosis before prolonged amyloid deposition, which eventually leads to symptomatic organ dysfunction. [Orphanet J Rare Dis 2022;17:262]
Just correctly diagnosing ATTR-CM can have a big impact. According to a Spanish economic analysis study, correct diagnosis of ATTR-CM compared with nondiagnosis of the disease reduces mortality and cardiovascular (CV) hospitalizations, and leads to savings for the national health system. [Expert Rev Pharmacoecon Outcomes Res 2021;21:1127-1133]
Tafamidis: A game-changer for ATTR-CM
Tafamidis, a selective transthyretin stabilizer, is a game-changer in the treatment of ATTR-CM. It binds to the transthyretin tetramer and inhibits its dissociation into monomers, thereby inhibiting the amyloidogenic process that leads to ATTR-CM. [N Engl J Med 2018;379:1007-1016] Tafamidis is the only disease-modifying medication for ATTR-CM that showed a reduction in all-cause mortality and improvement in CV outcomes. [Ann Pharmacother 2020;54:470-477]
The US Food and Drug Administration approved tafamidis for the treatment of ATTR-CM in 2019. Tafamidis has since gained approval in over 55 countries including Japan (Mar 2019), Singapore (Feb 2020), and Australia (Sep 2020).
“Prior to the approval of tafamidis, patients diagnosed with ATTR-CM had limited therapeutic options, if any,” said Soon. Previously, symptomatic management for ATTR-CM was the only option, and the treatment of the underlying disease was limited to liver or heart transplantation. [Ann Pharmacother 2020;54:470-477]
“Previously, applying for tafamidis use on a named-patient basis was a tedious process that required multiple levels of red tape, and involved tremendous costs. The approval of tafamidis by the Singapore Health Sciences Authority opened a whole new dimension and was good news for ATTR-CM patients,” said Soon.
Early treatment with tafamidis improves long-term survival
The largest trial of tafamidis (ATTR-ACT or Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) – a double-blind, placebo-controlled, phase III study – randomly assigned 441 patients with ATTR-CM to receive tafamidis or a placebo. [N Engl J Med 2018;379:1007-1016] “Based on the results of the ATTR-ACT study, treatment with tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations,” said Soon. “In addition, tafamidis reduced the decline in functional capacity and quality of life compared with placebo in patients with ATTR-CM.”
Recent analyses of the ATTR-ACT and ATTR-ACT long-term extension (LTE) trials demonstrated the benefits of starting tafamidis treatment early. Patients who received tafamidis in the ATTR-ACT trial and continued with tafamidis in the LTE study had a clinically significant reduction of 41 percent in the risk of all-cause mortality, compared with those who had initially received placebo (Table 1). [Circ Heart Fail 2022;15:e008193]
Real-world data and clinical experience sharing
A recent article reported the early experience of tafamidis treatment in 38 Japanese patients with wild-type transthyretin cardiac amyloidosis. Out of 82 patients with ATTR-CM (mean age 81.7 years), tafamidis was initiated in 38 patients. The common reasons cited for nonadministration were advanced heart failure and patients’ frailty. [Circ J 2022;86:1121-1128] “Tafamidis is suitable for patients with ATTR amyloid cardiomyopathy diagnosed either through genetic testing, cardiac biopsies, or 99mTc-PYP imaging,” commented Soon. “However, in clinical practice, the decision to start tafamidis often involves consideration of various factors such as the patient’s age, disease severity or progression, patient willingness, patient’s frailty, and comorbidities,” he added.
In patients receiving tafamidis, the drug was found to be well-tolerated and the status of disease severity was maintained in the short term. There was no discontinuation of tafamidis due to adverse events. The rate of CV-related hospitalizations per year was 0.19, the 1-year survival rate was 92 percent; whereas in the ATTR-ACT trial cohort, the figures were 0.55 and 89 percent, respectively. In patients who continued tafamidis for 12–18 months, there was no significant deterioration from baseline in high-sensitivity cardiac troponin T level, plasma B-type natriuretic peptide level, left ventricular ejection fraction, interventricular septum wall thickness, or value of left ventricular longitudinal strain. [Circ J 2022;86:1121-1128]
“I have two patients taking tafamidis for ATTR-CM. Both were diagnosed in their 60s, and demonstrated evidence of significant heart failure symptoms, with breathlessness, limited eﬀ ort tolerance, and neuropathy. Since they started on tafamidis, their conditions have stabilized thus far. They have been on tafamidis for less than 6 months and adherence is not an issue. While the long-term outcome remains to be seen, in the short term, both patients subjectively feel better and tafamidis appears to be well tolerated without much-reported side effects,” said Soon, sharing his experience with tafamidis.
“ATTR-CM is a debilitating illness that impacts patients’ lives tremendously. Amyloidosis also has a poor prognosis, with median survival ranging from 2.5 years after a diagnosis of hereditary TTR to 3.5 years after a diagnosis of wild-type TTR. Although TTR amyloidosis frequently causes multisystem involvement, mortality in most cases is related to cardiac involvement,” said Soon.
In patients with cardiac amyloidosis, treatment with tafamidis resulted in a 13.4 percent absolute reduction in overall mortality and a 22 percent absolute reduction in yearly CV hospitalization at 30 months compared to placebo. Tafamidis use was also associated with improvements in heart-failure-related quality of life and functional status. [N Engl J Med 2018;379:1007-1016]
Therefore, tafamidis should be commenced as soon as the diagnosis of ATTR-CM is made, for the best outcome of the patient,“ advised Soon.