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March 18, 2021
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Transthyretin cardiac amyloidosis: A guide on tafamidis use, navigating medication access

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Amyloidosis is a disease in which specific precursor proteins misfold into beta-pleated sheets. Misfolded proteins adhere to form oligomers resulting in insoluble amyloid fibrils that deposit into tissue.

Lucianne West
Kaitlin Siela

Fibril deposition in the myocardial tissue, also known as cardiac amyloidosis (CA), causes thickening of both ventricles, as well as interatrial septal thickening, which may lead to diastolic dysfunction. Other complications of CA include atrial fibrillation, heart block, valvular regurgitation and pericardial effusions.

The two main types of amyloid that may result in CA include immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). ATTR is then further divided into wild-type variant (ATTRwt) and hereditary or mutant variant (ATTRm). AL-CA is more aggressive than ATTR-CA, and current treatment includes chemotherapy. Treatment for ATTR-CA includes therapy for the complications of the disease, as well as three main classes of medications that work at different targets on the amyloid fibril production pathway, including TTR silencers, fibril disruptors and TTR stabilizers. Until recently, there were no therapies for ATTR-CA shown to reduce morbidity and mortality in this patient population.

Presentation, treatment for ATTR-CA

ATTR-CA often presents with signs and symptoms of acute HF or arrhythmias. In these patients, neurohormonal antagonists typically used in HF are often poorly tolerated. This is due to the amyloid patients’ inability to enhance stroke volume in response to vasodilation. Additionally, digoxin use is typically avoided due to the potential of digoxin toxicity as a result of digoxin binding to amyloid fibrils, even when normal circulating levels appear therapeutic. The mainstay of treatment for patients with ATTR-CA with subsequent HF includes fluid management with diuretics and sodium restrictions. Close monitoring is required, as a delicate balance is necessary to ensure adequate diuresis without excessive reduction of filling pressures. In select patients, heart transplantation is also a consideration.

Various pharmacologic treatment options are available that target different phases of the ATTR disease process. TTR silencers block TTR synthesis at the translational level in hepatocytes. The overall reduction in plasma TTR leads to a decrease in amyloid deposition into the myocardium. Two medications that work in this pathway include patisiran (Onpattro, Alnylam) and inotersen (Tegsedi, Akcea).

Patisiran, a small interfering RNA (siRNA), binds and degrades TTR mRNA, inhibiting TTR synthesis. The APOLLO trial published in 2018 studied IV patisiran in patients with hereditary transthyretin amyloidosis with polyneuropathy. The study showed a statistical improvement in neuropathy impairment scores compared with placebo. Although this study was not specifically in the ATTR-CA population, a subgroup analysis showed that in the cardiac subpopulation, patisiran also conferred a significant change in N-terminal pro-B-type natriuretic peptide from baseline to 18 months in favor of patisiran, and was associated with better cardiac structure and function compared with placebo.

The NEURO-TTR trial, also published in 2018, evaluated subcutaneous inotersen in patients with ATTRm with polyneuropathy in the presence or absence of cardiomyopathy. Unlike patisiran, inotersen showed no significant difference in echocardiographic variables in patients with cardiac involvement. However, a small prospective study evaluating the effect of inotersen on structural and functional cardiac parameters showed stabilization of disease progression. Trials to assess both agents specifically in the CA patient population are ongoing. In the meantime, these agents may be a promising option for patients with polyneuropathy and cardiac involvement.

Another class of medications used for ATTR include fibril disruptors. These medications act by targeting the mature amyloid fibrils. Doxycycline in combination with tauroursodeoxycholic acid, green tea extract and turmeric all have limited data supporting their use for this indication and are not recommended after the emergence of FDA-approved therapies.

Transthyretin stabilizers have quickly become the most utilized class of medications for ATTR-CA. The transthyretin tetramer has two thyroxine binding sites, which are the target of both diflunisal and tafamidis (Vyndamax and Vyndaqel, FoldRx/Pfizer). Diflunisal has shown promising results for hereditary amyloid polyneuropathy and can be used off-label for ATTR-CA due to limited data. However, close monitoring is warranted given nonsteroidal anti-inflammatory drug properties, and should be avoided in patients with severe thrombocytopenia and renal dysfunction (estimated glomerular filtration rate [eGFR] < 40 mL/min/1.73 m2).

In contrast, tafamidis is the only pharmacologic agent shown to reduce morbidity and mortality in patients with ATTR-CA. The ATTR-ACT trial published in The New England Journal of Medicine by Mathew S. Maurer, MD, medical director of The HCM Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, and colleagues in 2018 was a large breakthrough in ATTR-CA management. This landmark trial randomly assigned 441 patients with ATTR-CA in a 2:1:2 ratio to 80 mg tafamidis, 20 mg tafamidis or placebo for 30 months. The primary analysis, which hierarchically assessed all-cause mortality followed by frequency of CV-related hospitalizations, favored the pooled tafamidis group (all-cause mortality: 29.5% vs. 42.9%; HR = 0.7, 95% CI, 0.51-0.96; CV-related hospitalizations: 0.48 per year vs. 0.7 per year, RR = 0.68; 95% CI, 0.56-0.81). There was no significant difference in rates of adverse events between the treatment and placebo groups. Of note, there was no significant difference in outcomes for the prespecified subgroup analyses, including tafamidis dose.

Practical considerations for use of tafamidis

The ATTR-ACT trial led to FDA approval of tafamidis for treatment of ATTRwt and ATTRm CA in adults to reduce CV mortality and CV-related hospitalization. With growing use, various barriers and questions from health care providers have arisen. There are currently two different formulations of tafamidis available: Vyndaqel and Vyndamax. Tafamidis (Vyndaqel) 80 mg daily and tafamidis meglumine (Vyndamax) 61 mg daily have been compared in pharmacokinetic studies and shown to have no clinically significant difference. To achieve the 80 mg dose of tafamidis, patients must take four 20 mg capsules daily. It is likely the manufacturer of these agents will phase out one of the formulations — likely tafamidis given high pill burden — but a plan for removal of one of the agents from the market has not yet been defined.

Other considerations when initiating tafamidis include whether or not combination therapy should be utilized and at what point in disease progression tafamidis should be prescribed. In the ATTR-ACT trial, patients were excluded if they were receiving concurrent treatment with NSAIDs, tauroursodeoxycholate and doxycycline. Additionally, given there are limited to no data supporting the use of TTR fibril disruptors in improving outcomes for patients with CA, treatment with these agents should be avoided. For patients without neuropathy, TTR silencers should not be recommended for treatment until results of ongoing trials are published. For patients with advanced disease, there may be minimal benefit of initiating disease-modifying agents, specifically tafamidis. Although this is not a contraindication as defined by the manufacturer, the American Heart Association Scientific Statement on Cardiac Amyloidosis recommends against the use of TTR stabilizers in patients with NYHA class IV symptoms, those who are minimally ambulatory (walk < 100 m on a 6-minute walk test), and those with advanced renal dysfunction (eGFR < 25), as these patients were ineligible for inclusion in the ATTR-ACT trial. Additionally, the benefit to starting or resuming tafamidis after heart transplantation is unclear, as patients who had undergone transplant were excluded in the ATTR-ACT trial.

The primary barrier to patient access to tafamidis and tafamidis meglumine is cost. The average wholesale price of tafamidis and tafamidis meglumine is $750 per 61 mg capsule and $187.50 per 20 mg capsule ($750 per 80 mg dose), respectively. Although patient assistance and financial resources are available (Table), the process for patients to obtain specialty medications is often cumbersome, involving prior authorizations, multiple parties with different motivations, and inefficient communication. As described in a paper published in Circulation in August, a shared, standardized and transparent process for coverage decisions is needed to improve patient access to medications. Although there are limited safety concerns with use of tafamidis, overall potential benefit, complexity of medication regimens and access to therapy should be considered, and shared decision-making between the patient and provider is critical.