Disease progression in cardiac transthyretin amyloidosis is indicated by serial calculation of National Amyloidosis Centre transthyretin amyloidosis stage

Abstract

Aims
Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course.

Methods and results
We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P < 0.001; Stage III vs. II, HRs 1.64–2.25; P < 0.001–0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow‐up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58–3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86–4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I‐hATTR‐CM than in wtATTR‐CM (43% vs. 27% at 12 months of follow‐up; P = 0.003).

Conclusions
National Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR‐CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow‐up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I‐hATTR‐CM than in wtATTR‐CM.

Full text

Disease progression in cardiac transthyretin
amyloidosis is indicated by serial calculation of
National Amyloidosis Centre transthyretin amyloidosis
stage
Steven Law
1
, Aviva Petrie
2
, Liza Chacko
1
, Oliver C. Cohen
1
, Sriram Ravichandran
1
, Janet A. Gilbertson
1
,
Dorota Rowczenio
1
, Ashutosh Wechalekar
1
, Ana Martinez‐Naharro
1
, Helen J. Lachmann
1
, Carol J. Whelan
1
,
David F. Hutt
1
, Philip N. Hawkins
1
, Marianna Fontana
1†
and Julian D. Gillmore
1
*
†
1
National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, UK;
2
Eastman Dental Institute,
University College London, London, UK
Abstract
Aims Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at di-
agnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine
how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course.
Methods and results We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hered-
itary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC.
Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark
Kaplan–Meier survival analyses were performed at diagnosis (n=945) and at 6±1(n=432), 12 ±3(n=562), and 24 ±3
(n=316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were per-
formed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mor-
tality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67;P<0.001;
Stage III vs. II, HRs 1.64–2.25;P<0.001–0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44%of
evaluable patients at 6,12, and 24 months of follow‐up respectively, was highly predictive of ongoing mortality at each time
point (HRs 2.58–3.22;P<0.001) and in each genotypic subgroup (HRs 1.86–4.38;P<0.05). Increase in NAC ATTR stage
occurred earlier in V122I‐hATTR‐CM than in wtATTR‐CM (43% vs. 27%at12 months of follow‐up; P=0.003).
Conclusions National Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in
ATTR‐CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout
follow‐up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I‐hATTR‐CM than in wtATTR‐CM.
Keywords Amyloidosis; Amyloid; Transthyretin; TTR; Staging; Cardiomyopathy
Received:
18
June
2020
; Revised:
20
July
2020
; Accepted:
13
August
2020
*Correspondence to: Professor Julian D. Gillmore, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College
London, London, UK. Tel: +
44
(
0
)
20 74332816
; Fax: +
44
(
0
)
20 74332844
. Email: j.gillmore@ucl.ac.uk
†Marianna Fontana and Julian D. Gillmore are joint last authors of this work.
Introduction
Cardiac transthyretin amyloidosis (ATTR‐CM) may be acquired
(wtATTR‐CM) or hereditary (hATTR‐CM). The commonest
hATTR‐CM is that associated with the V122I (p.V142I) TTR var-
iant (V122I‐hATTR‐CM), carried by 3.9% of individuals of
African descent.
1
The prevalence of ATTR‐CM is not known,
but high‐grade cardiac uptake on
99m
technetium‐labelled
3,3‐diphosphono‐1,2‐propanodicarboxylic acid scintigraphy
was reported in 3.9% of men over 75 years of age in a recent
Spanish study.
2
Advances in imaging techniques
3–5
and devel-
opment of validated non‐biopsy diagnostic criteria for ATTR‐
ORIGINAL RESEARCH ARTICLE
©2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any me-
dium, provided the original work is properly cited and is not used for commercial purposes.
ESC HEART FAILURE
ESC Heart Failure 2020;7:3942–3949
Published online 13 September 2020 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12989

CM
6,7
have led to an exponential rise in diagnoses of ATTR‐CM
throughout the world.
8
Without treatment, the natural history of ATTR‐CM is one
of inexorable progression and death within 3–10 years of
diagnosis.
8
Diagnostic delay is common, and patients may
be diagnosed at any time during the disease course.
8,9
Recent
therapeutic advances, including the TTR stabilizer, tafamidis,
and ‘gene‐silencing’therapies, inotersen
10
and patisiran,
11
show promise in transthyretin amyloidosis (ATTR), although
tafamidis is the only such therapy to have specifically been
shown to alter the natural history of ATTR‐CM.
12
However,
a number of Phase 3clinical trials of these or even newer
agents for ATTR‐CM are planned or already in progress.
At the time of diagnosis, prognosis of patients with
ATTR‐CM can be estimated by stratifying them into one of
the three National Amyloidosis Centre (NAC) ATTR stages, ac-
cording to the N‐terminal pro‐B‐type natriuretic peptide (NT‐
proBNP) concentration and Modification of Diet in Renal Dis-
ease estimated glomerular filtration rate (eGFR).
13,14
Median
survival in Stage I, II, and III ATTR‐CM is approximately 6,4,
and 2years, respectively.
13
However, serial calculation of
NAC ATTR stage in order to determine whether patients prog-
ress through the NAC stages during their disease course and
if so whether an increase in NAC ATTR stage is of prognostic
relevance has not previously been undertaken.
We sought to determine the ability of NAC ATTR stage to
predict survival at different times during the disease course
in ATTR‐CM rather than simply at the time of diagnosis and
to determine the prognostic relevance of an increase from
NAC ATTR Stage I to a higher NAC ATTR stage throughout pa-
tient follow‐up.
Methods
Patients
Patients with symptomatic wtATTR‐CM or V122I‐hATTR‐CM,
diagnosed between August 2001 and February 2019 on the
basis of validated criteria,
6,15
who underwent routine clinical
follow‐up at NAC, were included in this retrospective study.
Patients with other amyloidogenic TTR mutations were ex-
cluded because of their typical ‘mixed’phenotype including
amyloid neuropathy. Censor date was 18 October 2019; how-
ever, patients receiving any form of disease‐modifying ther-
apy were censored at the time of initiation of such
treatment in order to exclude the potential influence on sur-
vival of therapeutic intervention; this included diflunisal,
tafamadis, patisiran, inotersen, and enrolment into interven-
tional clinical trials. Symptomatic heart failure management
was according to local protocols.
Nine hundred and forty‐five patients were analysed at di-
agnosis: 432 at 6±1months from diagnosis, 562 at
12 ±3months from diagnosis, and 316 at 24 ±3months from
diagnosis. The differences in numbers of evaluable patients at
each time point were due to a combination of the following:
appointments occurring outside the specified time windows,
patient death, and insufficient follow‐up time before the cen-
sor date. A study consort diagram is shown in Figure
1
.
All patients were managed in accordance with the Declara-
tion of Helsinki and provided informed consent for anony-
mous publication of their data. The study received
institutional review board approval by the Royal Free Hospital
Ethics Committee.
Disease staging
Patients were categorized as NAC ATTR Stage I, defined as
NT‐proBNP ≤3000 ng/L and eGFR ≥45 mL/min/1.73 m
2
,or
as Stage III, defined as NT‐proBNP >3000 ng/L and
eGFR <45 mL/min/1.73 m
2
; with the remainder categorized
as Stage II.
13
NAC ATTR stage was calculated at baseline and
again at each follow‐up attendance within the 6,12, and
24 month window.
Biomarker analysis
N‐terminal pro‐B‐type natriuretic peptide was measured with
an electrochemiluminescence sandwich immunoassay on the
Elecsys system 2010 (Roche Diagnostics, Basel, Switzerland);
eGFR was calculated by standard Modification of Diet in
Renal Disease study equation.
Statistical methods
Date of diagnosis (baseline) was defined as date of first re-
view at NAC. Mortality date was obtained from central Na-
tional Health Service care records. Patients were
categorized into NAC ATTR Stage I, II, and III and further strat-
ified by genotype into wtATTR‐CM and V122I‐hATTR‐CM.
Kaplan–Meier (KM) plots were used to illustrate survival
stratified by NAC ATTR stage, and Cox proportional hazard re-
gression analysis was used to estimate hazard ratios for mor-
tality in patient subgroups.
Patients with attendances at 6±1,12 ±3, and
24 ±3months were then restaged based on eGFR and
NT‐proBNP at the relevant time point. Landmark KM analyses
provided survival curves from the relevant time point strati-
fied by NAC ATTR stage recalculated at the relevant time
point. Cox proportional hazard regression analysis was used
to estimate hazard ratios for mortality from each attendance
stratified by NAC ATTR stage, and further subgroup analyses
were conducted for both genotypes.
Landmark KM analyses in the subgroup of patients with
NAC ATTR Stage I at diagnosis, stratified by whether the
Disease progression in ATTR 3943
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DOI: 10.1002/ehf2.12989

NAC ATTR stage was stable or had increased since diagnosis,
were performed at each time point. Cox proportional hazard
regression analysis was also used in this patient subgroup to
compare mortality from each follow‐up time point among
those in whom NAC ATTR stage was stable (i.e. still Stage I)
and those in whom NAC ATTR stage had increased since
diagnosis.
Data are presented as median (inter‐quartile range) or
number (percentage) unless otherwise stated. A P‐value of
<0.05 was deemed significant unless otherwise stated.
Figure 1 Consort diagram showing evaluable patients at each follow‐up time point.
Table 1 Baseline characteristics in patients with wtATTR‐CM and V122I‐hATTR‐CM
wtATTR‐CM (n= 727) V122I‐hATTR‐CM (n= 218) P‐value
Age at diagnosis (years) 79 (73–83) 77 (72–81) 0.056
Male gender 683 (94%) 154 (71%) <0.001
Caucasian ancestry 678 (94%) 30 (14%) <0.001
NAC ATTR Stage I 330 (45%) 106 (49%) 0.464
NAC ATTR Stage II 277 (38%) 73 (34%)
NAC ATTR Stage III 120 (17%) 39 (18%)
NT‐proBNP (ng/L) 3036 (1717–5310) 2636 (1581–5193) 0.254
eGFR (MDRD, mL/min) 58 (47–71) 57 (46–69) 0.721
CKD Stage I 38 (5%) 13 (6%)
CKD Stage II 305 (42%) 79 (36%)
CKD Stage IIIa 235 (32%) 76 (35%)
CKD Stage IIIb 120 (17%) 34 (16%)
CKD Stage IV 29 (4%) 16 (7%)
CKD Stage V 0 (0%) 0 (0%)
NYHA heart failure class (n= 596, 189) <0.001
I 54 (9%) 10 (5%)
II 416 (69%) 112 (59%)
III 126 (21%) 66 (35%)
IV 3 (1%) 3 (2%)
Systolic blood pressure (mmHg) 123 (113–137) 121 (110–135) 0.480
Diastolic blood pressure (mmHg) 74 (68–80) 74 (66–82) 0.612
IVSd (mm) 17 (16–18) 17 (16–18) 0.300
LVPWd (mm) 16 (15–18) 17 (15–18) 0.896
Left ventricular ejection fraction (%) 49 (41–56) 45 (35–51) <0.001
6MWT distance (m) 363 (274–439) 272 (184–368) <0.001
Perugini grade on Tc‐DPD scan (n= 639, 170) <0.001
Grade 2 597 (93%) 109 (64%)
Grade 3 42 (7%) 60 (36%)
Follow‐up (months) 26 (15–39) 24 (15–34) 0.195
Deaths 225 (31%) 114 (52%) <0.001
6MWT, 6 min walk test; ATTR, transthyretin amyloidosis; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IVSd, in-
terventricular septum in diastole; LVPWd, left ventricular posterior wall in diastole; MDRD, Modification of Diet in Renal Disease; NAC, Na-
tional Amyloidosis Centre; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; Tc‐DPD,
99m
technetium‐labelled 3,3‐diphosphono‐1,2‐propanodicarboxylic acid; V122I‐hATTR‐CM, hereditary cardiac transthyretin amyloidosis
associated with the V122I variant; wtATTR‐CM, wild‐type cardiac transthyretin amyloidosis.
Results were displayed as number (percentage) or median (inter‐quartile range).
3944 S. Law et al.
ESC Heart Failure 2020;7:3942–3949
DOI: 10.1002/ehf2.12989

Summary statistics were obtained using SPSS (IBM Corp.,
2017), and all other analyses were performed using Stata
(Stata Corp., 2019, New York, United States).
Results
Baseline characteristics
Baseline characteristics of 945 patients (727 wtATTR‐CM
and 218 V122I‐hATTR‐CM) diagnosed at NAC are shown
in Table
1
. At diagnosis, patients with wtATTR‐CM were
more commonly male (P<0.001) and had less severe
New York Heart Association class heart failure (P<0.001),
better left ventricular ejection fraction (P<0.001), higher
6min walk test distance (P<0.001), and fewer Perugini
Grade 3
99m
technetium‐labelled 3,3‐diphosphono‐1,2‐
propanodicarboxylic acid scans (P<0.001)comparedwith
patients with V122I‐hATTR‐CM (Table
1
).
Survival by National Amyloidosis Centre
transthyretin amyloidosis stage throughout the
disease course
At diagnosis, 436/945 (46%) patients were categorized as
NAC ATTR Stage I, 350 (37%) Stage II, and 159 (17%) Stage
III, with median survival of 58,41, and 30 months, respec-
tively [Stage II vs. I, hazard ratio (HR) 1.95;P<0.001; Stage
III vs. II, HR 2.25;P<0.001]. In wtATTR‐CM, 330 (45%) pa-
tients were categorized as Stage I, 277 (38%) Stage II, and
120 (17%) Stage III, with median survival of 63,46, and
33 months, respectively (Stage II vs. I, HR 2.41;P<0.001;
Stage III vs. II, HR 2.46;P<0.001). In V122I‐hATTR‐CM,
106 (49%) patients were categorized as Stage I, 73 (34%)
Stage II, and 39 (18%) Stage III, with median survival of 39,
35, and 26 months (Stage II vs. I, HR 1.62;P=0.030; Stage
III vs. II, HR 1.63;P=0.062;Figure
2
A,Table
2
, and
Supporting Information, Table S
1
).
At 6months of follow‐up, 186/432 (43%) patients were
categorized as Stage I, 147 (34%) Stage II, and 99 (23%) Stage
III, with median survival from this time point of 56,36, and
28 months, respectively (Stage II vs. I, HR 2.45;P<0.001;
Stage III vs. II, HR 1.86;P=0.001;Figure
2
B,Table
2
, and
Supporting Information, Table S
1
).
At 12 months of follow‐up, 216/562 (38%) patients were
categorized as Stage I, 211 (38%) Stage II, and 135 (24%)
Stage III, with median survival from this time point of 51,
32, and 23 months, respectively (Stage II vs. I, HR 2.45;
P<0.001; Stage III vs. II, HR 1.75;P<0.001;Figure
2
C,Table
2
, and Supporting Information, Table S
1
).
At 24 months of follow‐up, 105/316 (33%) patients were
categorized as Stage I, 119 (38%) Stage II, and 92 (29%) Stage
III, with median survival from this time point of 43,28, and
Figure 2 Landmark Kaplan–Meier analyses showing survival percentages in cardiac transthyretin amyloidosis stratified by National Amyloidosis Centre
(NAC) transthyretin amyloidosis stage calculated at the following follow‐up time points: (A) diagnosis (P<0.001, log‐rank test), (B) 6 month follow‐up
time point (P<0.001, log‐rank test), (C) 12 month follow‐up time point (P<0.001, log‐rank test), and (D) 24 month follow‐up time point (P<0.001,
log‐rank test). The numbers at risk are displayed below each figure.
Disease progression in ATTR 3945
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DOI: 10.1002/ehf2.12989

19 months, respectively (Stage II vs. I, HR 2.67;P<0.001;
Stage III vs. II, HR 1.64;P=0.013;Figure
2
D,Table
2
, and
Supporting Information, Table S
1
).
Change in National Amyloidosis Centre
transthyretin amyloidosis stage in patients with
National Amyloidosis Centre Transthyretin
Amyloidosis Stage I disease at diagnosis
Among 436 (46%) patients with NAC ATTR Stage I disease at
baseline, 204 were evaluated at 6months, 2had died, 2were
censored prior to the 6month time point, and 228 were alive
but not evaluated within the 6month time point window. Of
the 204 evaluable patients, 43 (21%) had an increase in NAC
ATTR stage, and the remaining 161 (79%) were still at NAC
ATTR Stage I at this time point. Cox regression analysis
showed a highly significant increase in ongoing mortality risk
among patients with an increase in NAC ATTR stage com-
pared with stable NAC ATTR stage {HR 3.19 [95% confidence
interval (CI) 1.76–5.77]; P<0.001}, with consistent results
across both genotypes (Table
3
). Landmark KM survival anal-
ysis stratified by stable or increased NAC ATTR stage at
6months is shown in Figure
3
A.
Among 436 patients with NAC ATTR Stage I disease at
baseline, 283 were evaluated at 12 months, 4had died, 46
were censored prior to the 12 month time point, and 103
were alive but not evaluated within the 12 month time point
window. Of the 283 evaluable patients, 90 (32%) had an in-
crease in NAC ATTR stage, and the remaining 193 (68%) were
still at NAC ATTR Stage I at this time point. Cox regression
analyses showed a highly significant increase in ongoing mor-
tality risk among patients with an increase in NAC ATTR stage
compared with stable NAC ATTR stage [HR 2.58 (95%CI1.67–
3.99); P<0.001] with consistent results across both geno-
types (Table
3
). Landmark KM survival analysis stratified by
stable or increased NAC ATTR stage at 12 months is shown
in Figure
3
B.
Among 436 patients with NAC ATTR Stage I disease at
baseline, 166 were evaluated at 24 months, 34 had died,
148 were censored prior to the 24 month time point, and
88 were alive but not evaluated within the 24 month time
point window. Of the 166 evaluable patients, 73 (44%) had
an increase in NAC ATTR stage, and the remaining 93 (56%)
were still at NAC ATTR Stage I at this time point. Cox regres-
sion analyses showed a highly significant increase in ongoing
mortality risk among patients with an increase in NAC ATTR
stage compared with stable NAC ATTR stage [HR 3.22 (95%
CI 1.87–5.52); P<0.001] with consistent results across both
genotypes (Table
3
). Landmark KM survival analysis stratified
by stable or increased NAC ATTR stage at 24 months is shown
in Figure
3
C.
Increase in NAC ATTR stage or death occurred in a signifi-
cantly higher proportion of NAC ATTR Stage I patients with
Table 2 Cox regression analyses showing risk of mortality from different follow‐up time points in relation to NAC ATTR disease stage calculated at the relevant time point
All patients wtATTR‐CM V122I‐hATTR‐CM
HR P‐value HR P‐value HR P‐value
At diagnosis (N= 945) N= 727 N= 218
Stage II vs. I 1.95 (1.52–2.49) <0.001 Stage II vs. I 2.41 (1.77–3.29) <0.001 Stage II vs. I 1.62 (1.05–2.49) 0.030
Stage III vs. I 4.38 (3.27–5.87) <0.001 Stage III vs. I 5.92 (4.09–8.56) <0.001 Stage III vs. I 2.63 (1.59–4.34) <0.001
Stage III vs. II 2.25 (1.70–2.98) <0.001 Stage III vs. II 2.46 (1.76–3.42) <0.001 Stage III vs. II 1.63 (0.97–2.72) 0.062
At 6 month time point (N= 432) N= 336 N=96
Stage II vs. I 2.45 (1.67–3.58) <0.001 Stage II vs. I 2.96 (1.85–4.74) <0.001 Stage II vs. I 1.90 (0.96–3.74) 0.065
Stage III vs. I 4.55 (2.98–6.96) <0.001 Stage III vs. I 5.32 (3.11–9.11) <0.001 Stage III vs. I 2.71 (1.34–5.47) 0.006
Stage III vs. II 1.86 (1.27–2.72) 0.001 Stage III vs. II 1.80 (1.13–2.87) 0.014 Stage III vs. II 1.43 (0.71–2.85) 0.313
At 12 month time point (N= 562) N= 432 N= 130
Stage II vs. I 2.45 (1.74–3.45) <0.001 Stage II vs. I 2.36 (1.56–3.55) <0.001 Stage II vs. I 2.29 (1.21–4.31) 0.011
Stage III vs. I 4.29 (2.99–6.16) <0.001 Stage III vs. I 4.07 (2.64–6.27) <0.001 Stage III vs. I 4.32 (2.19–8.53) <0.001
Stage III vs. II 1.75 (1.28–2.40) <0.001 Stage III vs. II 1.73 (1.17–2.55) 0.006 Stage III vs. II 1.89 (1.10–3.24) 0.020
At 24 month time point (N= 316) N= 251 N=65
Stage II vs. I 2.67 (1.68–4.23) <0.001 Stage II vs. I 2.53 (1.51–4.24) <0.001 Stage II vs. I 3.91 (1.29–11.6) 0.016
Stage III vs. I 4.36 (2.66–7.16) <0.001 Stage III vs. I 3.73 (2.08–6.68) <0.001 Stage III vs. I 6.48 (2.07–20.3) 0.001
Stage III vs. II 1.64 (1.11–2.42) 0.013 Stage III vs. II 1.47 (0.91–2.38) 0.112 Stage III vs. II 1.66 (0.79–3.48) 0.182
HR, hazard ratio; V122I‐hATTR‐CM, hereditary cardiac transthyretin amyloidosis associated with the V122I variant; wtATTR‐CM, wild‐type cardiac transthyretin amyloidosis.
3946 S. Law et al.
ESC Heart Failure 2020;7:3942–3949
DOI: 10.1002/ehf2.12989

V122I‐hATTR‐CM than wtATTR‐CM at the 12 (P=0.01)and
24 month (P=0.001) follow‐up time points (Supporting
Information, Table S
2
). Among 397 wtATTR‐CM patients with
NAC ATTR Stage II or III disease at diagnosis, 2(1%), 10 (3%),
and 70 (17%) had died at 6,12, and 24 months of follow‐up,
respectively. Among 112 V122I‐hATTR‐CM patients with NAC
ATTR Stage II or III disease at diagnosis, 1(1%), 10 (9%), and
31 (27%) had died at 6,12, and 24 months of follow‐up,
respectively.
Discussion
This study shows that NAC ATTR stage, which has been val-
idated as a prognostic tool for ATTR‐CM at the time of
diagnosis,
13
is applicable throughout the disease course
with patients tending to increase their NAC ATTR stage as
the condition progresses. The natural history of ATTR‐CM
is one of relentless progression and eventual death, al-
though the rate of clinical decline varies between individ-
uals. Furthermore, there is often substantial delay in
diagnosis of ATTR‐CM such that the diagnosis may be made
at any time during its natural history.
8,9
Our study shows
that patients tend to increase their NAC ATTR stage by 1
point every ~2years, which is entirely consistent with the
published median survival associated with each of the three
diagnostic NAC ATTR stages, which differs by about 2years
per stage,
13
and that the prognostic significance of NAC
ATTR stage holds up throughout the disease course. Nota-
bly, however, the proportion of patients who increased
their NAC ATTR stage during follow‐up was higher in
V122I‐hATTR‐CM than in wtATTR‐CM and, taken together
with the higher mortality rate in V122I‐hATTR‐CM, provides
further evidence of a more aggressive phenotype in the he-
reditary condition.
8,16
Table 3 Cox regression analyses showing risk of ongoing mortality among patients who were at NAC ATTR Stage I at diagnosis according
to whether the recalculated NAC ATTR stage was stable or had increased at the relevant time point
All patients wtATTR‐CM V122I‐hATTR‐CM
NHR (95% CI) P‐value NHR (95% CI) P‐value NHR (95% CI) P‐value
6 month FU time point 204 152 52
Stable NAC ATTR Stage I 161 1 123 1 38 1
Increased NAC ATTR stage 43 3.19 (1.76–5.77) <0.001 29 2.77 (1.16–6.70) 0.024 14 3.28 (1.37–7.87) 0.008
12 month FU time point 283 210 73
Stable NAC ATTR Stage I 193 1 152 1 41 1
Increased NAC ATTR stage 90 2.58 (1.67–3.99) <0.001 58 1.86 (1.01–3.43) 0.048 32 2.52 (1.28–4.95) 0.007
24 month FU time point 166 134 32
Stable NAC ATTR Stage I 93 1 78 1 15 1
Increased NAC ATTR stage 73 3.22 (1.87–5.52) <0.001 56 2.98 (1.58–5.64) 0.001 17 4.38 (1.38–13.95) 0.012
CI, confidence interval; FU, follow‐up; HR, hazard ratio; NAC ATTR, National Amyloidosis Centre transthyretin amyloidosis; V122I‐hATTR‐
CM, hereditary cardiac transthyretin amyloidosis associated with the V122I variant; wtATTR‐CM, wild‐type cardiac transthyretin
amyloidosis.
Figure 3 Landmark Kaplan–Meier survival analyses in patients with National Amyloidosis Centre transthyretin amyloidosis (NAC ATTR) Stage I cardiac
transthyretin amyloidosis at diagnosis stratified by whether the recalculated NAC ATTR stage was stable or had increased at each time point. (A) At
6 month follow‐up time point, patients with stable NAC ATTR Stage I disease had median ongoing survival of 57 months, and patients with increased
NAC ATTR stage had median ongoing survival of 36 months (P<0.001, log‐rank test). (B) At 12 month follow‐up time point, patients with stable NAC
ATTR Stage I disease had median ongoing survival of 51 months, and patients with increased NAC ATTR stage had median ongoing survival of 31 months
(P<0.001, log‐rank test). (C) At 24 month follow‐up time point, patients with stable NAC ATTR Stage I disease had median ongoing survival of
43 months, and patients with increased NAC ATTR stage had median ongoing survival of 26 months (P<0.001, log‐rank test). The numbers at risk
are displayed below each figure.
Disease progression in ATTR 3947
ESC Heart Failure 2020;7:3942–3949
DOI: 10.1002/ehf2.12989

Despite the diagnostic delays highlighted earlier, there is
evidence that the recent development and validation of
non‐invasive diagnosis of ATTR‐CM,
6,7
coupled with an in-
crease in disease awareness among cardiologists, partly as a
result of therapeutic advances,
12,17
is leading to earlier
diagnosis.
8
It seems highly probable that the proportion of
patients who are diagnosed with NAC ATTR Stage I will rise
to >50% within the next decade. Furthermore, NAC ATTR
Stage I encompasses a broad range of disease severity from
virtually asymptomatic imaging or histological abnormalities
to very significant clinical disease. Our demonstration of the
fact that progression from NAC ATTR Stage I to a higher
NAC ATTR stage during follow‐up is prognostically important
is therefore likely to have very substantial clinical relevance.
One might even postulate that the absence of an increase
in NAC ATTR stage could be used to demonstrate efficacy of
novel therapeutic agents in ATTR‐CM, although this hypothe-
sis needs further study.
Limitations of our study include the variation in patient
numbers, in part as a result of evaluations occurring outside
the specified time point windows; however, it is not antici-
pated that this will introduce bias because appointment de-
lays in our centre almost invariably occur because of issues
of capacity rather than on clinical grounds. We maintain that
the consistency of the findings across the studied time points
indicates that the NAC ATTR stage is applicable at any time
during the disease natural history. A further limitation is the
relatively small number of patients with V122I‐hATTR‐CM
compared with wtATTR‐CM, particularly among those evalu-
ated at later time points.
In summary, we demonstrate for the first time that NAC
ATTR stage predicts survival in ATTR‐CM throughout
follow‐up and that an increase in NAC ATTR stage from a di-
agnostic stage of I predicts mortality throughout the disease
natural history.
Acknowledgements
We thank our many physician colleagues for referring the
patients.
Conflict of interest
S.L., A.P., L.C., O.C.C., S.R., J.A.G., D.R., A.M.‐N., H.J.L., C.J.W.,
P.N.H., and M.F. declare that they have no conflict of interest.
A.W. and D.F.H. report personal fees from Akcea outside of
the submitted work. J.D.G. is an expert advisory board mem-
ber for Akcea, Alnylam, and Eidos.
Funding
This work was funded by the UK Department of Health.
Author contributions
S.L., A.P., M.F., and J.D.G. were responsible for conceiving the
study, interpreting the results, and drafting the manuscript. L.
C., O.C.C., S.R., J.A.G., D.R., A.W., A.M.‐N., H.J.L., C.J.W., D.F.
H., and P.N.H. were responsible for the data collection and
interpretation.
Supporting information
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
Table S1.Median survival in months from each follow up
timepoint according to NAC ATTR Stage calculated at the rel-
evant timepoint.
Table S2.Comparison of change in NAC ATTR Stage and mor-
tality between patients with wtATTR‐CM and V122I‐hATTR‐
CM at different timepoints among those with NAC ATTR
Stage I at diagnosis.
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