Management of ATTR-CM with tafamidis: Challenges and opportunities

The advent of tafamidis ushers in a promising new era in the treatment and management of transthyretin amyloid cardiomyopathy (ATTR-CM), with longer-term clinical data attesting to its efficacy and safety. Despite this, ATTR-CM remains an easily overlooked and potentially fatal cause of heart failure. Furthermore, its elusive diagnosis often results in late or misdiagnosis. Clinical Assistant Professor Tang Hak Chiaw, Senior Consultant with the Department of Cardiology at the National Heart Centre Singapore, speaks on the challenges and opportunities on the diagnosis and management of ATTR-CM patients while sharing his experience of using tafamidis.

Introduction
ATTR-CM is a progressive, potentially fatal, and infiltrative cardiomyopathy caused by extracellular deposition of insoluble transthyretin (TTR) amyloid fibrils in the myocardium. [ESC Heart Fail 2019;6:1128-1139] Symptoms include dyspnoea, fatigue, orthostatic hypotension, and syncope, while infiltration of the conduction system may result in bundle-branch block, sinoatrial disease, and atrial fibrillation. [N Engl J Med 2018;379:1007-1016]

The epidemiology of ATTR-CM has yet to be elucidated. “We do not have local prevalence data on ATTR-CM,” said Tang. “The prevalence of TTR amyloid in heart failure with preserved ejection fraction (HFpEF) depends on the diagnostic modalities, age, and sex of population studied.”

“In one 2015 study on patients (≥60 years old) hospitalised for HFpEF, the prevalence of ATTR-CM was determined to be 13 percent using nuclear scintigraphy,” said Tang. [Eur Heart J 2015;36:2585-2594] Such findings suggest that the prevalence of ATTR-CM may be substantially higher than traditionally believed and is mainly perceived as rare because it is under-recognized and underdiagnosed.

Challenges in screening and diagnosis
“Screening and diagnosis of ATTR-CM is challenging on a few fronts,” explained Tang. “Firstly, there is a low general awareness of ATTR-CM. Most clinicians perceive ATTR-CM as a rare disease and do not usually consider this condition as a differential diagnosis when treating patients with heart failure.

Secondly, misdiagnosis due to phenotypically similar conditions is common. ATTR-CM patients are usually elderly with multiple comorbidities. The signs and symptoms of TTR amyloid are more likely to be attributed to these comorbidities, such as hypertension, diabetes, or coronary artery disease. 

Thirdly, it was not long ago that the diagnosis of ATTR-CM still required endomyocardial biopsy, which is invasive and carries a definite risk. Currently, nuclear scintigraphy can be used to make the diagnosis in a large majority of ATTR-CM patients, but this service is still not widely available, especially in this part of the world. Lastly, until recently, there was a lack of availability of disease-modifying treatments, which rendered accurate diagnosis less relevant,” elaborated Tang.

Opportunities for early diagnosis and management
ATTR-CM is gaining recognition and interest owing to several main areas of development: studies that indicate the condition may be underdiagnosed in a significant proportion of patients with heart failure; nuclear imaging techniques, which allow early and accurate noninvasive diagnosis; and the emergence of therapies approved for the treatment of ATTR-CM. [Circulation 2020;142:e7-e22]

Tafamidis, the first disease-modifying therapy for ATTR-CM, has been approved by the Health Sciences Authority in Singapore since February 2020.

Tafamidis in ATTR-CM: Longer-term follow-up data confirm efficacy and safety with higher dose
In the original ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy) study, both doses of tafamidis meglumine (80 and 20 mg) effectively reduced all-cause mortality and the frequency of CV-related hospitalizations in patients with ATTR-CM compared with placebo. [N Engl J Med 2018;379:1007-1016] The study was not powered to assess the relative efficacy of each tafamidis dose, and both doses appeared to have comparable efficacy (Figure 1a).

However, when ATTR-ACT was combined with the long-term extension data (median follow-up of 51 months), there was a significant survival benefit with tafamidis meglumine 80 mg, with a 30-percent relative reduction in the risk of death compared with tafamidis 20 mg (p=0.0374). These data were further supported by analyses that accounted for the baseline imbalance in age, NT-proBNP, and 6MWT, which are prognostic factors for survival in patients with ATTR-CM or HF. Adjustments by these covariates also showed a significant difference between the doses (Figure 1b). [Eur J Heart Fail 2021;23: 277-285]

NT-proBNP levels, which are significantly associated with increased mortality in ATTR-CM, were reduced in almost half (45.5 percent) of patients on tafamidis meglumine 80 mg compared with one-quarter (23.3 percent) of those on 20 mg. [Eur J Heart Fail 2021;23:277-285]

Importantly, safety in the ATTR-ACT combined with LTE was similar to the ATTR-ACT study alone, and the incidence of adverse events in both tafamidis meglumine doses was comparable to placebo. [Eur J Heart Fail 2021;23:277-285]

Clinical experience with tafamidis in ATTR-CM 
“The preparation that is approved and available in Singapore is tafamidis free acid 61 mg (Vyndamax^TM), which is bioequivalent to tafamidis meglumine 80 mg,” said Tang. Vyndamax offers patients more convenience as it comes in a single capsule, compared with four capsules of tafamidis meglumine 20 mg. 

The introduction of tafamidis has transformed the management of ATTR-CM. “For the first time, clinicians can actually tell an ATTR-CM  patient that there is a specific agent that can make him or her feel better and live longer. This is definitely a great advancement, compared with the generally grim outlook in the past when the disease was previously diagnosed,” said Tang, who has several patients, with age ranging from 50 to over 80 years old, currently on Vyndamax. 

“My follow-up of patients with this medication is understandably short as it was only introduced in Singapore last year. My patients generally have stabilisation of heart failure symptoms and improvement in biomarkers like NT-proBNP. Apart from one patient who experienced giddiness that required dose reduction, the medication is well-tolerated,” shared Tang.