This activity was funded by Alnylam Pharmaceuticals. The medical content was developed independently by M3 and Professor Violaine Planté-Bordeneuve.

Highlights from

AAN 2021, EAN 2021, ESC-HF 2021 & PNS 2021

VIRTUAL, APRIL - JULY 2021

Amyloidosis Conference Highlights

Why early intervention matters in cardiac hATTR amyloidosis

Take-home messages
  • CMR imaging-based techniques and novel mapping techniques allow non-invasive myocardial tissue characterisation, which can be used to monitor cardiac amyloid load
  • Therapies such as gene silencers can decrease cardiac amyloid load if started early in the course of disease

Importance of early diagnosis: patient case

Ali Yilmaz, Professor of Cardiovascular Imaging, started his presentation at Heart Failure & World Congress on Acute Heart Failure 2021, by discussing the case of a patient who had a 6-year delay in cardiac amyloidosis diagnosis.


2014

Symptoms: dyspnoea on exertion

Cardiovascular magnetic resonance (CMR) imaging:

  • Concentric left ventricular (LV) hypertrophy
  • Severe aortic stenosis

Contrast imaging:

  • Minor degree of late gadolinium enhancement (LGE), more pronounced in the atrial septal wall

Diagnosis: severe aortic valve stenosis Treatment: aortic valve replacement


2020

Symptoms: still suffering from dyspnoea on exertion

CMR:

  • LV hypertrophy was not decreased

Contrast imaging:

  • Extensive and impressive increase in LGE

Diagnosis: cardiac amyloidosis


2021

The patient died in 2021 from cardiovascular causes

This patient had signs of cardiac amyloidosis in 2014, but a missed diagnosis led to progression of cardiac amyloid load across the next 6 years, and ultimately the patient's death.

Importance of early diagnosis: the ATTR-ACT study

Professor Yilmaz further highlighted the need for early diagnosis with results from the ATTR-ACT study. In this study, patients with hATTR amyloidosis with cardiomyopathy treated with tafamidis (n=264) had better outcomes at 30 months than patients who received placebo (n=177) (survival at 30 months: 70.5% vs 57.1%, p<0.001),1 however, subgroup analysis showed that these benefits were specific to patients with NYHA Class I or II, not patients with Class III. This indicates that treatment with tafamidis is less effective in patients with more advanced stages of cardiomyopathy and therefore early diagnosis and treatment is essential.

Methods of disease assessment

Professor Yilmaz emphasised that it is important to have early and accurate markers of disease severity that allow for:

  • individual staging
  • assessment of individual prognosis
  • assessment of individual therapy response

"We are happy that in the last year a number of non-invasive imaging techniques have been developed." CMR imaging using T1 mapping and extracellular volume (ECV) measurement in the myocardium allow non-invasive assessment of the degree of cardiac amyloid load (with increasing T1 or ECV reflecting an increase in myocardial amyloid load).

Professor Yilmaz recommends that these methods should be used to monitor disease progression in cardiac amyloidosis (as described in a position statement from the German cardiac society):2

  • During specific drug therapy, the use of electrocardiogram, transthoracic echocardiography (including strain measurements) and CMR including LGE and T1 mapping (if available) is recommended every 12 months
  • After remission or in stable condition without therapy, CMR including LGE and T1 mapping is recommended in case of suspected disease progression due to serum biomarkers and/or echocardiographic findings every 12-24 months

Various staging systems have also been proposed to assess the degree of cardiac amyloidosis, but these are yet to be compared or confirmed with non-invasive imaging data.

Gene silencer therapies: the APOLLO study

The APOLLO study was a large global study analysing the efficacy of patisiran in patients with hATTR amyloidosis with polyneuropathy. The study included a large cardiac subpopulation (n=126), analysis of which showed that patisiran treatment decreased the mean frequency of cardiac hospitalisation and all-cause mortality across 18 months versus placebo (exposure-adjusted rates 10.1 vs 18.7 per 100 patient-years).3

Improvement of many cardiac markers were also observed (change from baseline at 18 months):3

  • Geometric mean NT-proBNP: decreased with patisiran by 55% relative to placebo (p=7.7x10-8)
  • LS mean LV wall thickness: -1.0 mm with patisiran versus -0.1 mm with placebo (p=0.017)
  • LS mean global longitudinal strain: 0.08% increase with patisiran versus 1.46% increase with placebo (p=0.015)
  • LS mean cardiac output: -0.18 L/min decrease with patisiran versus -0.56 L/min decrease with placebo (p=0.044)

The proportion of patients with cardiac adverse events (AEs), cardiac serious AEs and cardiac failure AEs were similar between patients in the patisiran and the placebo groups. The most frequently reported AEs in the patisiran group were peripheral oedema (29.7%) and infusion-related reactions (18.9%). Only one patient discontinued patisiran, and this was due to an infusion-related reaction.4

Success of early diagnosis and treatment with gene silencing therapies: patient case

The second patient case presented by Professor Yilmaz showed great contrast to the first and illustrated how a combination of the factors discussed can result in improved patient outcomes.


2018

CMR:

  • LV hypertrophy, particularly pronounced in the anterior portion of the interventricular septum

Contrast imaging:

  • Minor, diffuse patching of LGE - suggestive of early-stage disease

T1 mapping:

  • Native T1 = 1,097 ms

Diagnosis: cardiac amyloidosis Treatment: patisiran followed by inotersen


2020

CMR:

  • LV mass had decreased
  • Decrease in thickness of anterior interventricular septum

Contrast imaging:

  • No LGE

T1 mapping:

  • Native T1 = 948 ms

Early diagnosis of this patient with CMR, contrast imaging and T1 mapping led to appropriate and successful treatment with gene silencers, and a decrease in cardiac amyloid load across 2 years.

LS: least squares; NT-proBNP: N-terminal pro B-type natriuretic peptide; NYHA: New York Heart Association

Based on: Yilmaz A. Time for a change: why early intervention matters. Presented at Heart Failure & World Congress on Acute Heart Failure 2021, 29 June-1 July 2021

  1. Maurer M S, Schwartz J H et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379(11):1007-1016
  2. Yilmaz A, Bauersachs J et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 2021;110(4):479-506
  3. Solomon S D, Adams D et al. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation 2019;139(4):431-443
  4. Adams D, Gonzalez-Duarte A et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21

Top image: Eraxion

Article image: yodiyim

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.

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