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3. Treatment of CA: Focus on Transthyretin CA

A comprehensive CCS/Canadian Heart Failure Society (CHFS) joint position statement on the evaluation and management of CA is forthcoming and will include GRADE standard recommendations on the diagnostic workup and therapeutic approaches for management of this disease. For the purposes of this update, practical tips are provided in the context of recent clinical trial evidence for the management of a subtype of amyloidosis known as ATTR. Amyloidosis is a group of heterogeneous disorders in which a specific precursor protein pathologically misfolds, aggregates, and forms amyloid fibrils that deposit extracellularly within various organs including the heart, resulting in organ failure.[16] CA is a form of infiltrative cardiomyopathy that develops when amyloid deposits infiltrate myocardial tissue. This infiltrative process results in progressive ventricular stiffness, wall thickening, and diastolic filling abnormalities, which typically manifest as HFpEF and restrictive physiology.[17] When the disease is severe and advanced, systolic dysfunction might also be seen.[18] The most common subtypes of CA are ATTR and the immunoglobulin light chain amyloidosis (known as AL amyloidosis). ATTR is further categorized into a hereditary form, due to one of numerous disease-causing genetic mutations and the “wild type” ATTR, in which a mutation is not present.[19],[20] Rarely, other types of amyloid proteins can affect the heart, including amyloid A, apolipoprotein A1, heavy chain, and atrial natriuretic peptide. Because recent clinical trial evidence applies only to the pharmacologic treatment of ATTR-CA, it is of the utmost importance to accurately identify the amyloid subtype to initiate specific treatment and avoid inappropriate application of therapy.[21]

Recognizing the possibility of CA

It must be emphasized that the clinical phenotypes of all forms of CA are similar, which makes distinction between subtypes difficult using clinical assessment alone. When CA is suspected, AL amyloidosis should be ruled out using serum free light chains (kappa and lambda), and serum and urine protein electrophoresis with immunofixation. The presence of light chains alone is not specific for AL-CA because > 20% of patients with ATTR have an unrelated monoclonal gammopathy of unknown significance.[22] In this scenario, tissue biopsy (bone marrow or endomyo-cardial) with immunohistochemistry or mass spectrometry is necessary to determine the subtype of CA. Further, when AL amyloidosis has been ruled out, technetium-labelled scintigraphy such as pyrophosphate scan can be used to help confirm a diagnosis of ATTR-CA.[23][25] This imaging modality is > 99% sensitive and 86% specific for ATTR CA, with false positive tests occurring almost exclusively in the setting of AL-CA. In one study, the presence of a positive scan in the absence of a monoclonal gammopathy had 100% specificity and positive predictive value for ATTR-CA.[26]

Practical Tip

In the setting of undifferentiated CA, the presence of light chains does not confirm the diagnosis of AL-CA because monoclonal gammopathy of unknown significance and ATTR-CA can coexist. In such settings, tissue biopsy is frequently necessary to exclude AL-CA.

Technetium-labelled scintigraphy should be performed, where available, to diagnose ATTR-CA when plasma cell dyscrasias have been ruled out. Until recently, treatment of ATTR-CA was mostly supportive in nature with a median survival of 3.5 years[27] after diagnosis. Different therapeutic modalities have been investigated in recent years using transthyretin stabilizers (eg, diflunisal and tafamidis), suppressors of ATTR synthesis (gene silencers), and amyloid fibrils degraders (doxycycline with tauroursodeoxycholic acid or ursodeoxycholic acid and epigallocatechin 3-gallate found in green tea extracts).[28][33] Historically,[31] most studies that have investigated these drugs have been small and observational in nature and used surrogate end points. The recently published Transthyretin Amyloidosis Cardiomyopathy Trial (ATTR-ACT) randomized 441 patients with wild type or mutant (hereditary) ATTR-CA to either tafamidis, a transthyretin tetramer stabilizer, or placebo, and were followed for 30 months.[34] At the end of the study, patients who received tafamidis had significantly lower all-cause mortality (HR, 0.70; 95% CI, 0.51-0.96) and reduced cardiovascular hospitalizations (HR, 0.68; 95% CI, 0.56 to 0.81). Tafamidis also significantly reduced the rate of decline in functional capacity and quality of life (P < 0.001 for both outcomes).[34] As of the time of writing, tafamidis is not approved by Health Canada for the treatment of ATTR-CA (it was recently approved by the US Food and Drug Administration). However, it is the first agent that has been shown in a prospective study to alter patient outcomes by improving survival and reducing cardiovascular hospitalizations. The CCS/CHFS joint position statement will address formal recommendations on the use of tafamidis and other therapeutic options for ATTR-CA on the basis of the totality of published evidence. Pending the availability of ATTR-CA-specific treatments in Canada, and the forthcoming comprehensive amyloid recommendations, it is reasonable to consider the following practical tips.

Patient selection for tafamidis should reflect the inclusion criteria for the major randomized controlled clinical trial that showed clinical benefits of tafamidis over placebo with respect to mortality and cardiovascular hospitalization, including established ATTR-CA and objective evidence of HF (with elevated natriuretic peptides where available).

Patients with New York Heart Association (NYHA) class IV symptoms or severe functional disability, measured using a 6-minute walk test < 100 m, were excluded from ATTR-ACT and should not routinely be considered for treatment with tafamidis.

Subgroup analysis from the ATTR-ACT trial suggested that the reduction in cardiovascular hospitalizations seen with tafamidis might be limited to patients with less severe symptoms (NYHA class I or II).

Because of the complexity in diagnosing CA and the potential for offering advanced or experimental treatment options, consideration should be given to referring patients with CA to experienced centres.

Other agents are currently under investigation, which might modify current treatment recommendations.


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