Key Information
Background
Amyloidosis is a heterogeneous group of disorders caused by the extracellular deposition of insoluble misfolded proteins, leading to end-organ damage. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a subtype in which a protein known as transthyretin accumulates within the heart tissue, progressively resulting in restrictive cardiomyopathy and heart failure. Due to the progressive nature of ATTR-CM, clinical management requires efficacious regimens to manage the debilitating condition and Tafamidis shows promising results in this regard.
Main body
ATTR-CM poses a significant challenge due to its nature and limited therapeutic options. Tafamidis is a novel therapy designed to stabilize the transthyretin tetramers, inhibiting the formation of amyloid fibrils. It has emerged as a promising treatment and the only FDA-approved drug for ATTR-CM. Tafamidis' role in slowing disease progression and improving outcomes in patients with ATTR-CM has been demonstrated in the major randomized control trial ATTR-ACT with promising open-label extension studies, some still ongoing. Additionally, real-world evidence supports its use in clinical practice, showing its role in reducing morbidity and mortality associated with this condition. Clinical evidence shows its efficacy in improving symptoms and cardiac function in patients. Case studies also reveal significant benefits to patients like reducing myocardial damage, reversal of atrial fibrillation, and resolution of heart failure symptoms. Real-world outcomes and clinical trials show a consistent reduction in amyloid deposition, cardiovascular-related hospitalizations, and all-cause mortality with Tafamidis therapy.
Conclusion
Tafamidis is an essential component of the treatment of ATTR-CM and this narrative review synthesizes the current evidence regarding safety, efficacy, and utilization in real practice. While it shows promising effects, its effectiveness may also vary and high cost precludes real-world large-scale studies. Overall, Tafamidis emerges as a valuable therapeutic option for managing ATTR-CM.
Background
ATTR-CM is a type of systemic amyloidosis characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils in the myocardium. TTR, also known as pre-albumin, is a 127 amino acid, 55 kDa protein produced primarily in the liver and is a transporter of thyroxine (T4) and the retinol-binding protein-retinol (Vitamin A) complex [1external link, opens in a new tab]. In the autosomal dominant hereditary or variant ATTR subtype (ATTRv), the incorporation of pathogenic variant subunits into TTR heterotetramers leads to TTR tetramer destabilization, whereas in the wild-type ATTR subtype (ATTRwt) dissociation, misfolding, and aggregation of tetramer are caused by age and not a mutation. This latter type was previously called senile systemic amyloidosis [1external link, opens in a new tab, 2external link, opens in a new tab].
There are more than 120 pathogenic mutations in TTR resulting in variable phenotypic presentations [3external link, opens in a new tab], but the most common mutation (Val122Ile) occurs in approximately 3.4% of the African American population and exclusively has cardiac involvement [4external link, opens in a new tab]. The ATTR-ACT trial demonstrated a high prevalence of these three TTR mutations: Val122Ile, Thr60Ala, and Ile68Leu [5external link, opens in a new tab].
The accumulation of TTR amyloid fibrils in the cardiac muscle results in ventricular wall thickening and reduced elasticity. This manifests as a diastolic dysfunction and progresses into restrictive cardiomyopathy [5external link, opens in a new tab]. Infiltration of the conduction system can lead to conduction disease and atrial arrhythmias. On histopathology, these deposits appear with a green birefringence when viewed under cross-polarized light after staining with Congo red [6external link, opens in a new tab].
ATTR-CM is an under-identified etiology of heart failure. While echocardiography and cardiac magnetic resonance are commonly used diagnostic modalities, emerging data highlights the potential of Technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99m Tc-DPD) scintigraphy [3external link, opens in a new tab, 7external link, opens in a new tab, 8external link, opens in a new tab]. This non-biopsy method is both sensitive and specific and can detect subclinical amyloid deposition before the onset of heart failure symptoms, an increase in left ventricular mass, or a rise in cardiac biomarkers [9external link, opens in a new tab]. Up to 15% of older adults with heart failure may have unrecognized ATTRwt as suggested by recent studies [3external link, opens in a new tab]. Early diagnosis is an important determinant of ATTR-CM prognosis, with genetic counseling and familial screening in cases of ATTRv [10external link, opens in a new tab, 11external link, opens in a new tab].
Early diagnosis and treatment of ATTR-CM results in improved outcomes. Tafamidis is the only FDA-approved therapy for the treatment of ATTR-CM. A study evaluating the efficacy of Tafamidis in subjects with familial amyloid polyneuropathy showed the potential of Tafamidis to decrease neurological progression but did not lead to a statistically significant result and hence was not approved by the FDA [12external link, opens in a new tab].
Tafamidis, a non-NSAID benzoxazole derivative, is a monovalent TTR kinetic stabilizer that inhibits the crucial rate-limiting step of TTR amyloidogenesis via selective binding with negative cooperativity (KdS ~ 2 nM and ~ 200 nM) to one of two normally vacant thyroxine-binding sites of the native tetramer. Single-site binding corresponds with complete stabilization [13external link, opens in a new tab] of the weaker dimer–dimer interface against dissociation under both denaturing and physiological conditions [14external link, opens in a new tab].
The rate-limiting step involves the dissociation of the native TTR tetramer into monomers. Monomers lose their original form in a process known as misfolding. They cluster to form oligomers which aggregate to form insoluble amyloid fibrils. Tafamidis acts on the crucial rate-limiting step by inhibiting dissociation, hence stabilizing the tetramer and reducing the availability of amyloid fibrils.
Tafamidis resulted in reduced cardiovascular-related events and all-cause mortality in the ATTR-ACT trial [15external link, opens in a new tab, 16external link, opens in a new tab]. Tafamidis improved the survivability of patients with NYHA Classes I–III, but the most effect was seen in patients with Classes I and II. While there were reduced cardiovascular-related hospitalizations in NYHA I and II, there was a paradoxical increase in those who had NYHA III symptoms [16external link, opens in a new tab]. The increased rate of hospitalization in this subgroup is likely due to the increased survival in this subgroup of patients with advanced severity of disease [17external link, opens in a new tab]. However, further analysis up to 58 months of follow-up revealed statistically divergent curves of survival benefit in the NYHA Class III subset that had little benefit in the original trial [18external link, opens in a new tab].
Methodology
A literature search was conducted to identify relevant studies and publications on Tafamidis' efficacy in managing ATTR-CM. Table Table1.1external link, opens in a new tab. Databases such as PubMed, MEDLINE, EMBASE, and Cochrane Library were searched. The search strategy included keywords such as "Tafamidis," "transthyretin cardiac amyloidosis," "cardiac disease," "Tafamidis efficacy," "clinical trials," "cardiac disease treatment," and related terms. Inclusion criteria include studies reporting on the use of Tafamidis in managing ATTR-CM, including clinical trials and observational studies. Non-English language studies were excluded. No time limit was placed on the search. Two reviewers conducted the selection process independently, with disagreements resolved through discussion or consultation with a third reviewer. A qualitative narrative analysis approach was employed to explore and synthesize the narrative elements present in the selected studies. This involved identifying common themes and patterns.