Early treatment of ATTR-CM with tafamidis increases survival

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and life-threatening rare disease caused by unstable transthyretin proteins that misfold and aggregate into insoluble amyloid fibrils that deposit in the heart and other organs of the body. Tafamidis, a transthyretin stabilizer, is the first disease-modifying therapy approved for ATTR-CM. Clinical Assistant Professor Khoo Chun Yuan, Consultant Cardiologist at the National Heart Centre Singapore, discusses the importance of early diagnosis and treatment of ATTR-CM patients.

ATTR-CM: A fatal disease that is underdiagnosed
ATTR-CM is a fatal disease caused by the extracellular deposition of insoluble transthyretin (TTR) amyloid fibrils in the heart. [Nat Rev Cardiol 2010;7:398-408]. ATTR-CM may be hereditary (ATTRv) or acquired as a consequence of an age-related degenerative process (wild-type; ATTRwt). The median survival from diagnosis of patients with untreated ATTR-CM is approximately 2.5 years and 3.6 years for patients with ATTRv and ATTRwt, respectively. [Circ Heart Fail 2022;15:e008193]

Awareness of ATTR-CM remains low and misdiagnosis or delayed diagnosis is relatively common. [ESC Heart Fail 2021;8:2647-2659] Traditionally, ATTR-CM is diagnosed through endomyocardial biopsy. Biopsy specimens are collected from multiple sites and tested for amyloid deposits by Congo red staining, and precursor proteins are definitively identified with mass spectrometry or immunohistochemistry. [J Am Coll Cardiol 2019;73:2872-2891] Nowadays, with advances in technology, a definitive diagnosis of ATTR-CM can be achieved noninvasively for most patients through a combination of bone scintigraphy and testing for light-chain amyloidosis (Figure 1). [Eur Heart J 2021;42:3599-3726]

“Often, patients have multisystemic involvement, requiring an index of suspicion in identification and multidisciplinary approach,” said Khoo.

Treatment options for ATTR-CM
The management of ATTR-CM patients includes a comprehensive approach to administer supportive care, as well as amyloid-specific therapy. Supportive care involves treating cardiac complications that may occur as a result of amyloid infiltration, such as heart failure (HF) symptoms and arrhythmias.

Supportive care
“HF may result due to restrictive cardiomyopathy,” explained Khoo. “Most of the HF medications, including ACE inhibitors, angiotensin-receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), or beta-blockers, have not demonstrated the same benefits in ATTR-CM. Patients may also tend to develop hypotension with these medications. Loop diuretics and mineralocorticoid antagonists (MRAs) are usually given to treat fluid overload.”

In patients with ATTR-CM and atrial fibrillation, anticoagulation and consideration of rate/rhythm control is indicated, she added. “However, the usual rate control agents (beta-blockers, digoxin, calcium channel blockers) may not be well tolerated. There is a concern about digoxin and calcium channel blockers binding to amyloid fibrils and increasing risks of toxicity, hence these agents are generally avoided. Beta-blockers can cause hypotension in some patients. Amiodarone is an option in patients who cannot tolerate beta-blockers,” said Khoo.

Amyloid-specific treatment
“Disease-modifying amyloid therapies can be broadly divided into TTR silencers, TTR stabilizers, and TTR disruptors. The efficacy of TTR silencers has mainly been shown in ATTR-polyneuropathy (ATTR-PN) patients, and they are therefore used for ATTR-PN. Clinical trials are still ongoing to determine the efficacy of TTR silencers in ATTR-CM patients,” Khoo shared.

Tafamidis, a TTR stabilizer, is currently the only proven disease-modifying therapy to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) and ATTR-ACT Long-term extension (LTE) studies, tafamidis reduced mortality and cardiovascular-related hospitalizations in ATTR-CM patients compared with placebo. [Circ Heart Fail 2022;15:e008193]

Tafamidis has received Class I recommendations in both the 2021 ESC Heart Failure Guidelines and the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure for the treatment of ATTR-CM patients. It has also received Health Science Authority (HSA) approval for treatment of ATTR-CM in Singapore, added Khoo.

“Diflunisal, another TTR stabilizer, has reported efficacy from small studies, but there are no randomized trials to support its use in ATTR-CM treatment,” she pointed out.

TTR disruptors work to degrade and clear amyloid fibril deposits. Doxycycline and green tea extract have only been tested in small studies with limited evidence of efficacy in amyloidosis. Several investigational agents are undergoing clinical trials. [Ann Pharmacother 2021;55:1502-1514]

Importance of early treatment
“As ATTR-CM is a progressively debilitating disease, there is benefit in early diagnosis and treatment. Transthyretin stabilizers and silencers reduce, but cannot reverse, the deposition of amyloid fibrils. Patients at a more advanced stage of the disease have generally been excluded from studies involving amyloid disease-modifying treatment. Furthermore, patients at an earlier stage of the disease have been shown to yield greater benefit from treatment,” said Khoo.

A recently published analysis of the ATTR-ACT LTE trials showed a clinically significant 41-percent reduction in the risk of all-cause mortality among patients treated with continuous tafamidis, compared with patients who first received a placebo in the ATTR-ACT before transitioning to tafamidis in the long-term extension study. Patients in the continuous tafamidis arm had a median survival of 67.0 months (95 percent confidence interval [CI], 47.0–N/E), compared with only 35.8 months (95 percent CI, 29.7-41.1) in patients in the placebo-to-tafamidis arm (Figure 2). [Circ Heart Fail 2022;15:e008193]

Overall, the preliminary 5-year survival rate was 53.2 percent in the continuous tafamidis group and 32.4 percent in the placebo-to-tafamidis group. Mortality reductions were generally consistent across the subgroups. The preliminary 5-year survival rate in patients with ATTRwt was 57.8 percent with continuous tafamidis treatment and 36.3 percent in the placebo-to-tafamidis group, while in patients with ATTRv, the figures were 39.1 percent for continuous tafamidis and 20.9 percent for placebo to tafamidis (Table 1). [Circ Heart Fail 2022;15:e008193]

Take home messages
“Early treatment initiation is important in making a difference to patient’s disease trajectory,” emphasized Khoo, who also advocates adopting a holistic treatment approach. “As this is a chronic progressive disease which may involve multiple family members (in the case of ATTRv-CM), social support and screening for depression are also of utmost importance.”