new england

The
journal of medicine
established in 1812 October 26, 2023 vol. 389 no. 17

Patisiran Treatment in Patients with Transthyretin Cardiac

Amyloidosis
M.S. Maurer, P. Kale, M. Fontana, J.L. Berk, M. Grogan, F. Gustafsson, R.R. Hung, R.L. Gottlieb, T. Damy,
A. González‑Duarte, N. Sarswat, Y. Sekijima, N. Tahara, M.S. Taylor, M. Kubanek, E. Donal, T. Palecek, K. Tsujita,
W.H.W. Tang, W.-C. Yu, L. Obici, M. Simões, F. Fernandes, S.H. Poulsen, I. Diemberger, F. Perfetto, S.D. Solomon,
M. Di Carli, P. Badri, M.T. White, J. Chen, E. Yureneva, M.T. Sweetser, P.Y. Jay, P.P. Garg, J. Vest, and J.D. Gillmore,
for the APOLLO-B Trial Investigators*​​

a bs t r ac t

BACKGROUND
Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with ac- The authors’ full names, academic de-
cumulation of ATTR amyloid deposits in the heart and commonly manifests as grees, and affiliations are listed in the
­Appendix. Dr. Maurer can be contacted
progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, at ­msm10@​­cumc​.­columbia​.­edu or at the
inhibits the production of hepatic transthyretin. Department of Medicine, PH12 Stem Rm.
134, Columbia University Irving Medical
METHODS Center, 622 W. 168th St., New York, NY.
In this phase 3, double-blind, randomized trial, we assigned patients with heredi-
*A complete list of the APOLLO-B trial
tary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, investigators and collaborators is pro-
to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every vided in the Supplementary Appendix,
3 weeks for 12 months. A hierarchical procedure was used to test the primary and available at NEJM.org.
three secondary end points. The primary end point was the change from baseline This article was updated on November 2,
in the distance covered on the 6-minute walk test at 12 months. The first second- 2023, at NEJM.org.
ary end point was the change from baseline to month 12 in the Kansas City Car- N Engl J Med 2023;389:1553-65.
diomyopathy Questionnaire–Overall Summary (KCCQ-OS) score (with higher DOI: 10.1056/NEJMoa2300757
Copyright © 2023 Massachusetts Medical Society.
scores indicating better health status). The second secondary end point was a
composite of death from any cause, cardiovascular events, and change from base- CME
line in the 6-minute walk test distance over 12 months. The third secondary end at NEJM.org
point was a composite of death from any cause, hospitalizations for any cause, and
urgent heart failure visits over 12 months.
RESULTS
A total of 360 patients were randomly assigned to receive patisiran (181 patients)
or placebo (179 patients). At month 12, the decline in the 6-minute walk distance
was lower in the patisiran group than in the placebo group (Hodges–Lehmann
estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69;
P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the
placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2;
P = 0.04). Significant benefits were not observed for the second secondary end
point. Infusion-related reactions, arthralgia, and muscle spasms occurred more
often among patients in the patisiran group than among those in the placebo group.
CONCLUSIONS
In this trial, administration of patisiran over a period of 12 months resulted in
preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded
by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.)

n engl j med 389;17 nejm.org October 26, 2023 1553

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

T
ransthyretin amyloidosis, also the primary efficacy and safety data from the
called ATTR amyloidosis, is a progressive, 12-month double-blind period of the APOLLO-B
debilitating, and fatal disease caused by trial, a phase 3, randomized, placebo-controlled
misfolded transthyretin protein that accumu- trial involving patients with variant or wild-type
A Quick Take
lates as amyloid fibrils in multiple organs, in- ATTR cardiac amyloidosis.
is available at cluding the heart, nerves, gastrointestinal tract,
NEJM.org and musculoskeletal tissues.1-3 Patients with in- Me thods
herited TTR gene variants have hereditary, also
known as variant, ATTR amyloidosis, which can Trial Oversight
manifest as cardiomyopathy, polyneuropathy, or The APOLLO-B trial is an ongoing, internation-
a mixture of the two phenotypes.1,4,5 Patients al, phase 3, multicenter, double-blind, random-
with wild-type ATTR amyloidosis predominantly ized, placebo-controlled trial of patisiran in pa-
have cardiomyopathy, although polyneuropathy tients with variant or wild-type ATTR cardiac
may coexist.2 Ongoing ATTR amyloid deposition amyloidosis. The institutional review board or
in the heart drives the progression of infiltrative independent ethics committee at each center ap-
cardiomyopathy,6-8 leading to worsening heart proved the trial protocol and amendments, avail-
failure, arrhythmias, and conduction disease.9-11 able with the full text of this article at NEJM.org.
The median survival among patients with ATTR All patients provided written informed consent.
cardiac amyloidosis ranges from 2 to 6 years, The trial is being conducted in accordance with
depending on the disease stage at diagnosis.12 all applicable regulatory requirements, the Inter-
Current treatment options for ATTR amyloidosis national Council for Harmonisation Good Clini-
with cardiomyopathy are limited. Tafamidis, cal Practice guidelines, and principles that have
which stabilizes the tetrameric transthyretin pro- their origin in the Declaration of Helsinki. Alny­
tein, was associated with reductions in death lam Pharmaceuticals, the trial sponsor, designed
from any cause and cardiovascular-related hospi- the trial in collaboration with the principal in-
talizations after 30 months as compared with vestigators. The trial investigators collected data,
placebo in the ATTR-ACT trial; however, on aver- which were analyzed by the sponsor and inter-
age, functional capacity and quality of life de- preted jointly by the sponsor and the authors.
clined among patients treated with tafamidis.13 The authors prepared the first draft of the sub-
Patisiran, an RNA interference therapeutic mitted manuscript with editorial assistance from
agent with a lipid nanoparticle delivery system, Adelphi Communications, funded by Alnylam
targets the common 3′ untranslated region of Pharmaceuticals. All the coauthors participated
TTR messenger RNA in the liver to reduce circu- in the interpretation of the data. All the authors,
lating transthyretin protein levels in both variant who had access to the data, vouch for the accu-
and wild-type ATTR amyloidosis.14 Patisiran has racy and completeness of the data and for the
been approved for the treatment of variant ATTR fidelity of the trial to the protocol. All the coau-
amyloidosis in patients with polyneuropathy15,16 on thors contributed to the critical revision of the
the basis of the results of the phase 3 APOLLO manuscript. All the investigators had confiden-
trial, which showed that patisiran halted or re- tiality agreements with the sponsor.
versed the progression of neuropathy and im-
proved quality of life.17,18 Furthermore, in a pre- Patients
specified subgroup of patients in the APOLLO Key eligibility criteria included an age of 18 to 85
trial with evidence of cardiac amyloid involve- years; a diagnosis of ATTR cardiac amyloidosis
ment at baseline, measures of cardiac structure (defined as the presence of transthyretin amy-
and function favored patisiran over placebo at 18 loid deposits on analysis of tissue biopsy speci-
months.19 These data support the hypothesis mens or fulfillment of validated nonbiopsy diag-
that a reduction in amyloidogenic transthyretin nostic criteria for ATTR cardiac amyloidosis20);
protein can provide a therapeutic benefit in pa- evidence of cardiac involvement (confirmed by
tients with ATTR cardiac amyloidosis. Patisiran echocardiography), with an end-diastolic inter-
is currently under investigation for the treatment ventricular septal wall thickness exceeding 12
of ATTR cardiac amyloidosis. Here, we present mm; and a history of heart failure. At baseline,

1554 n engl j med 389;17 nejm.org October 26, 2023

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Patisir an for Tr ansthyretin Cardiac Amyloidosis

some patients were receiving tafamidis, at the Overall Summary (KCCQ-OS) score (scores range
approved dose within each country, and others from 0 to 100, with a score of 0 to 24 indicating
were not receiving it. very poor to poor quality of life, 25 to 49 poor
Key exclusion criteria were a New York Heart to fair, 50 to 74 fair to good, and 75 to 100 good
Association (NYHA) class of III and an ATTR to excellent).21 The second secondary end point
amyloidosis stage of 3 (defined as an N-terminal was a composite of death from any cause, car-
pro–B-type natriuretic peptide [NT-proBNP] level diovascular events, and change from baseline in
of >3000 pg per milliliter occurring concomi- the 6-minute walk test distance at 12 months.
tantly with an estimated glomerular filtration The third secondary end point was a composite
rate [eGFR] of <45 ml per minute per 1.73 m2 of death from any cause, hospitalizations for any
of body surface area),12 an NYHA class of IV, a cause, and urgent visits for heart failure over 12
6-minute walk distance of less than 150 m, a poly- months. Exploratory end points included the
neuropathy disability score greater than II (pos- change in cardiac biomarkers NT-proBNP and
sible scores, 0, I, II, IIIa, IIIb, and IV, with higher troponin I, modified body-mass index (modified
scores indicating more impaired walking ability), BMI, defined as the conventional BMI [weight in
and cardiomyopathy not associated with ATTR kilograms divided by square of height in meters]
amyloidosis (e.g., cardiomyopathy due to ische­ multiplied by the albumin level in grams per
mic or valvular heart disease). Full inclusion and liter, with lower values indicating worse nutri-
exclusion criteria are provided in the Supplemen- tional status), and echocardiographic measures
tary Appendix (available at NEJM.org). of cardiac structure and function, which were
assessed in a core laboratory. The pharmacody-
Trial Design namic effect of transthyretin protein reduction
Patients were randomly assigned (in a 1:1 ratio) was assessed by measurement of the change in
to receive patisiran (at a dose of 0.3 mg per kilo­ serum transthyretin levels from baseline to
gram of body weight; maximum dose, 30 mg) or month 12. Safety was monitored throughout the
placebo intravenously once every 3 weeks for 12 trial and included assessments of adverse events,
months. Randomization was stratified accord- clinical laboratory variables, and vital signs.
ing to the use of tafamidis at baseline (yes vs. Further details on the end points and safety as-
no), genotype (variant vs. wild-type ATTR), and sessments are provided in the Supplementary
NYHA class and age at baseline (NYHA class I or Appendix.
II and age <75 years vs. all others). All patients
received standard premedication to reduce the Statistical Analysis
risk of infusion-related reactions with patisiran Assuming a treatment difference of approxi-
(see the Supplementary Appendix for additional mately 29 m, with a standard deviation of 75 m,
details). Patients were instructed to take the rec- between the patisiran and placebo groups for
ommended daily oral dose of vitamin A during the change from baseline to month 12 in the
the trial. At the end of the 12-month double- distance covered on the 6-minute walk test, we
blind period, patients were eligible to be enrolled estimated that a sample size of 300 patients
in the ongoing open-label extension period would be needed for the trial to have at least
(ClinicalTrials.gov number, NCT03997383). 90% power to detect a between-group treatment
difference at a two-sided alpha level of 0.05. The
End Points primary end point was analyzed with the use of
For all efficacy end points, we assessed the the stratified Wilcoxon rank-sum test and the
change from baseline to month 12 in the pati- stratified Hodges–Lehmann estimate of median
siran group as compared with the placebo difference, with stratification according to base-
group. The primary end point was the change in line use of tafamidis (yes vs. no). To control the
functional capacity, as measured by the distance overall type I error rate, the primary and second-
covered on the 6-minute walk test. The first ary end points were tested in a prespecified
secondary end point was the change in health hierarchical order. The statistical analysis plan
status and quality of life, as measured by the (available with the protocol) includes additional
Kansas City Cardiomyopathy Questionnaire– details on the primary and sensitivity analyses

n engl j med 389;17 nejm.org October 26, 2023 1555

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*

Patisiran Placebo
Characteristic (N = 181) (N = 178)
Median age at screening (range) — yr 76 (47–85) 76 (41–85)
Male sex — no. (%) 161 (89) 160 (90)
Race — no. (%)†
White 138/180 (77) 140/174 (80)
Asian 23/180 (13) 15/174 (9)
Black 16/180 (9) 15/174 (9)
Other 3/180 (2) 4/174 (2)
Wild-type ATTR amyloidosis — no. (%) 144 (80) 144 (81)
Median time since diagnosis of ATTR amyloidosis (range) — yr 0.8 (0.0–6.0) 0.4 (0.0–10.0)
Treatment with tafamidis — no. (%)
At baseline 46 (25) 45 (25)
Started during 12-month double-blind period 5 (3) 3 (2)
ATTR amyloidosis stage — no. (%)‡
Stage 1 124 (69) 120 (67)
Stage 2 46 (25) 45 (25)
Stage 3 11 (6) 13 (7)
Polyneuropathy disability score — no. (%)
0: no impairment 96 (53) 109 (61)
I: preserved walking, sensory disturbances 63 (35) 55 (31)
II: impaired walking without need for a stick or crutches 22 (12) 14 (8)
NYHA class — no. (%)
Class I 10 (6) 15 (8)
Class II 156 (86) 150 (84)
Class III 15 (8) 13 (7)
Median 6-minute walk distance (IQR) — m 358.0 (295.0–420.0) 367.7 (300.0–444.3)
Score on the KCCQ-OS§ 69.8±21.2 70.3±20.7
Laboratory values
Median NT-proBNP level (IQR) — pg/ml 2008.0 (1135.0–2921.0) 1813.0 (952.0–3079.0)
Median high-sensitivity troponin I level (IQR) — pg/ml¶ 64.0 (38.6–92.0) 60.2 (38.2–103.1)
Median mBMI (IQR)‖ 1147.0 (988.4–1273.8) 1134.0 (1018.7–1259.1)
Median eGFR (IQR) — ml/min/1.73 m2 71 (58–83) 67 (51–84)
Median creatinine (IQR) — mg/dl 1.0 (0.9–1.2) 1.0 (0.8–1.4)
Coexisting conditions — no. (%)
Diabetes mellitus 30 (17) 25 (14)
Hypertension 84 (46) 101 (57)
Concomitant medication — no. (%)
Diuretic 168 (93) 164 (92)
Mineralocorticoid receptor antagonist 92 (51) 74 (42)
Beta-blocker 73 (40) 77 (43)
ACEI, ARB, or ARNI 82 (45) 71 (40)
SGLT2 inhibitor 8 (4) 7 (4)

1556 n engl j med 389;17 nejm.org October 26, 2023

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Patisir an for Tr ansthyretin Cardiac Amyloidosis

Table 1. (Continued.)

* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. ACEI denotes angiotensin-
converting–enzyme inhibitor, ARB angiotensin-receptor blocker, ARNI angiotensin receptor–neprilysin inhibitor, ATTR
transthyretin-mediated, eGFR estimated glomerular filtration rate, IQR interquartile range, NT-proBNP N-terminal pro–
B-type natriuretic peptide, NYHA New York Heart Association, and SGLT2 sodium–glucose cotransporter-2.
† Race was reported by the patients.
‡ Risk stratification was based on the levels of the serum biomarkers NT-proBNP and an eGFR. Stage 1 (lower risk) was
defined by an NT-proBNP level of 3000 pg per milliliter or less and eGFR of at least 45 ml per minute per 1.73 m2.
Stage 2 (intermediate risk) included all patients who did not meet the criteria for stages 1 or 3. Stage 3 (higher risk)
was defined by an NT-proBNP greater than 3000 pg per milliliter and an eGFR of less than 45 ml per minute per 1.73 m2.
§ Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) scores range from 0 to 100, with a score of
0 to 24 indicating very poor to poor quality of life, 25 to 49 poor to fair, 50 to 74 fair to good, and 75 to 100 good to
excellent.
¶ Troponin I levels were assessed at baseline in a total of 174 patients in the patisiran group and in 172 patients in the
placebo group.
‖ The modified body-mass index (mBMI) was calculated as the conventional BMI (weight in kilograms divided by the
square of the height in meters) multiplied by the serum albumin level in grams per liter.

for the efficacy end points, the hierarchical test- venous access, was excluded from the efficacy
ing procedure, the analyses for exploratory end and safety analysis. A total of 172 patients
points, and the handling of missing data. The (95.0%) in the patisiran group and 167 patients
reported confidence intervals have not been ad- (93.3%) in the placebo group completed the
justed for multiplicity and may not be used in month 12 visit. The demographic and clinical
place of hypothesis testing. For the analysis of characteristics of the patients at baseline were
deaths (efficacy analysis only), heart transplan- balanced between the two groups and were gen-
tation and the implantation of left ventricular erally representative of the global population
assist devices were counted as deaths. Data for of patients with ATTR cardiac amyloidosis (Ta-
patients who died from coronavirus disease ble 1, and Tables S1 and S2). The median age of
2019 (Covid-19) were censored at the date of the patients was 76 years, most patients were
death, and the deaths were not counted as events men, and 25% of the patients were receiving
in the efficacy analysis. tafamidis at baseline. Approximately 80% of the
Safety data were summarized with the use of patients had wild-type ATTR amyloidosis. Among
descriptive statistics. Efficacy and safety were the patients with variant ATTR amyloidosis, there
analyzed in the full analysis set, which included were 16 different pathogenic transthyretin pro-
all patients who underwent randomization and tein variants; 41% (29 patients) had V122I, which
received any amount of patisiran or placebo. was the most common variant in this subgroup
Pharmacodynamic assessments were conducted (Table S3). The baseline demographic and dis-
in all patients who received at least one complete ease characteristics of patients in this trial with
dose of patisiran or placebo and who had an variant ATTR amyloidosis and evidence of poly-
evaluable measurement of serum transthyretin neuropathy are shown in Table S4. Information
levels at baseline and at least one evaluable mea- about the cardiac medications patients received
surement after baseline. during the trial are provided in Table S5.

Efficacy
R e sult s
Primary End Point
Patients The magnitude of decline from baseline in the
From October 2019 through May 2021, a total of 6-minute walk distance at 12 months was sig-
360 patients at 69 sites in 21 countries were nificantly lower in the patisiran group than in
enrolled in the trial and randomly assigned to the placebo group, with a median change from
receive patisiran (181 patients) or placebo (179 baseline of −8.15 m (95% confidence interval
patients) (Fig. S1 in the Supplementary Appen- [CI], −16.42 to 1.50) in the patisiran group and
dix). One patient, who was randomly assigned to −21.35 m (95% CI, −34.05 to −7.52) in the placebo
the placebo group but did not receive the as- group; the Hodges–Lehmann estimate of the
signed placebo because of difficulty with intra- median difference was 14.69 m (95% CI, 0.69 to

n engl j med 389;17 nejm.org October 26, 2023 1557

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Change from Baseline in 6-Minute Walk Test

−0.81
(95% CI, −8.80
10 −9.83 to 8.00) −8.15
(95% CI, −16.50 (95% CI, −16.42
Better to 0.85) to 1.50)
0
Patisiran

Median Change (m)

−10 −6.75
(95% CI, −13.90 Placebo
Worse −20 to 1.50) −13.20
(95% CI, −19.65 −21.35
to −1.15) (95% CI, −34.05
−30 H−L estimate of median difference at 12 mo, to −7.52)
14.69 (95% CI, 0.69 to 28.69)
P=0.02
−40
0 6 9 12
Months
No. of Patients
Placebo 178 178 178 178
Patisiran 181 181 181 181

B Change from Baseline in Kansas City Cardiomyopathy Questionnaire−Overall Summary

0.7 0.3
4 0.1 (95% CI, −1.6 (95% CI, −2.2
(95% CI, −2.1 to 3.1) to 2.8)
to 2.3)
LS Mean Change (points)

Better 2
Patisiran
0

−1.1
−2 (95% CI, −3.3
to 1.1) Placebo
Worse −2.7
(95% CI, −5.1 −3.4
−4 Least-squares median difference at 12 mo,
to −0.4) (95% CI, −5.9
3.7 (95% CI, 0.2 to 7.2)
to −0.9)
P=0.04
−6
0 6 9 12
Months
No. of Patients
Placebo 178 170 167 164
Patisiran 181 169 170 170

C Change from Baseline in Serum Transthyretin Level

20

0
Mean Change (%)

Placebo
−20

−40

−60

Patisiran
−80

−100
Base- 3 3 6 9 51 12
line Wk Mo Mo Mo Wk Mo
Visit
No. of Patients
Placebo 178 170 153 162 162 151 164
Patisiran 181 169 152 164 167 144 158

1558 n engl j med 389;17 nejm.org October 26, 2023

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Patisir an for Tr ansthyretin Cardiac Amyloidosis

Figure 1 (facing page). Changes over Time between was observed with patisiran as compared with
the Patisiran Group and the Placebo Group. placebo across prespecified subgroups defined
Panel A shows the median change from baseline in the according to baseline demographic and disease
distance covered on the 6-minute walk test (primary characteristics, including variant and wild-type
end point) with 95% confidence intervals. A farther ATTR amyloidosis (Fig. S3A). In a post hoc
­distance walked indicates better function. At baseline,
analysis, the results for 6-minute walk distance
the median distance covered on the 6-minute walk test
was 358.00 m (interquartile range, 295.00 to 420.00) in among 205 patients who did not have walking
the patisiran group and 367.74 m (interquartile range, impairment due to neuropathy (polyneuropathy
300.00 to 444.25) in the placebo group. Missing assess- disability score, 0) at baseline were consistent
ments owing to deaths not caused by coronavirus dis- with those of the primary analysis (Table S7).
ease 2019 [Covid-19] or owing to the inability to walk
because of progression of transthyretin amyloidosis
(also known as ATTR amyloidosis) disease were imput- Secondary End Points
The KCCQ-OS score decreased from baseline in
ed as −115 meters (the worst 10th percentile change
the placebo group (least-squares mean change,
observed across all patients in the double-blind peri-
od). Other missing data (e.g., assessments obtained
−3.4 points [95% CI, −5.9 to −0.9]) and in-
­after a serious adverse event due to Covid-19, which
creased slightly from baseline in the patisiran
were counted as missing) were multiply imputed as-
group (least-squares mean change, 0.3 points
suming that data were missing at random (see the statis-
[95% CI, −2.2 to 2.8]), representing a least-
tical analysis plan, available with the protocol, for details).
squares mean difference of 3.7 points (95% CI,
Missing data were imputed 100 times to create 100
complete data sets. All data sets were analyzed with
0.2 to 7.2; P = 0.04) (Fig. 1B). The between-group
the use of the stratified Wilcoxon rank-sum test and the
difference was consistent across prespecified
stratified Hodges–Lehmann (H–L) estimate, and the
subgroups (Fig. S3B) and across all KCCQ do-
results were combined according to Rubin’s rules. The
mains (Fig. S4).
6-minute walk test assessments were conducted in all
For the composite end point of death from
patients at baseline; 6% and 8% of patients in the pati-
siran and placebo groups, respectively, had missing
any cause, cardiovascular events, and change
­assessments at month 12. Panel B shows the least-
from baseline in the distance covered on the
squares mean change from baseline in the Kansas
6-minute walk test, the win ratio over the
City Cardiomyopathy Questionnaire–Overall Summary
12-month double-blind period was 1.27 (95% CI,
(KCCQ-OS) score (secondary end point), analyzed with
0.99 to 1.61) and was not significant (Table S8).
the use of a mixed model with repeated measures. Low-
er values indicate worse quality of life. The KCCQ-OS
The estimated hazard ratio (patisiran-to-placebo)
assessments were conducted in all patients at baseline;
for the composite end point of death from any
5% and 6% of patients in the patisiran and placebo
cause, hospitalizations for any cause, and urgent
groups, respectively, had missing assessments at month
visits for heart failure was 0.88 (95% CI, 0.58 to
12. Panel C shows the mean percentage change from
1.34) in the overall trial population and 1.0
baseline in serum transthyretin levels (measured with
the use of a proprietary enzyme-linked immunosorbent
(95% CI, 0.62 to 1.60) in the patients who were
assay [ELISA]). At baseline, the mean (±SD) serum trans-
not receiving tafamidis at baseline (Table S8). In
thyretin level was 235.32±68.05 mg per liter in the pati-
the 12-month double-blind period, 4 deaths
siran group and 244.77±73.17 mg per liter in the place-
(2.2%) occurred in the patisiran group and 10
bo group. At month 12, the mean serum transthyretin
deaths (5.6%) occurred in the placebo group.
level was 30.93±33.60 mg per liter in the patisiran group
and 229.40±77.15 mg per liter in the placebo group.
The estimated hazard ratio (patisiran-to-place-
Transthyretin levels were measured in all patients at
bo) was 0.36 (95% CI, 0.11 to 1.14). In the pla-
baseline; 13% and 8% of patients in the patisiran and
cebo group, two patients (1.1%) received heart
placebo groups, respectively, had missing measure-
transplants, which were counted as deaths in the
ments at month 12. The widths of the confidence inter-
efficacy analysis. Data for a patient who died
vals have not been adjusted for multiplicity and may
not be used in place of hypothesis testing. I bars indi-
from Covid-19 (one patient [0.56%] in the pati-
cate confidence intervals.
siran group) were censored at the date of death
and this death was not included as an event in
28.69; P = 0.02) (Fig. 1A). Results from the pre- the efficacy analysis.
specified sensitivity analyses of the 6-minute
walk test were consistent with those of the pri- Exploratory End Points
mary analysis (Fig. S2 and Table S6). A consis- At 12 months, the median change from baseline
tent difference in the 6-minute walk distance in the NT-proBNP level was 131 pg per milliliter

n engl j med 389;17 nejm.org October 26, 2023 1559

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Change from Baseline in NT-proBNP Level

1.38
Change (95% CI, 1.29
1.5 Ratio of adjusted geometric mean to 1.48)
factor increase (patisiran-to-placebo)
Median NT-proBNP Level
1.27
at 12 mo, 0.80 (95% CI, 0.73 to 0.89) (95% CI, 1.18 Change
1.4 from
1.20 Placebo
Geometric Mean Factor

to 1.35)
(95% CI, 1.13 Baseline Month 12 baseline
Change (pg/ml)

1.3 to 1.27) pg/ml (IQR)

Worse 1.06 Placebo 1813 2299 518
1.2 (95% CI, 1.01 (952 to (1180 to (51 to
to 1.12) Patisiran 3079) 4364) 1544)
1.1
Patisiran 2008 1944 131
1.0 (1135 to (1158 to (−280 to
Better 1.01 (95% CI, 0.96 1.07 (95% CI, 1.01 1.07 (95% CI, 1.00 1.11 (95% CI, 1.04 2921) 3726) 817)
to 1.07) to 1.14) to 1.15) to 1.19)
0 3 6 9 12
Months
No. of Patients
Placebo 178 168 165 164 163
Patisiran 181 171 169 169 167

B Change from Baseline in Troponin I Level

1.5 Ratio of adjusted geometric mean 1.30

factor increase (patisiran-to-placebo) (95% CI, 1.22 Median Troponin I Level
1.4 at 12 mo, 0.87 (95% CI, 0.80 to 0.95) to 1.38) Change
1.21
Geometric Mean Factor

1.18 (95% CI, 1.15 from

Baseline Month 12 baseline
Change (pg/ml)

1.3 (95% CI, 1.12 to 1.28) Placebo

Worse to 1.24) pg/ml (IQR)
1.2 Placebo 60.20 72.10 14.50
1.01 Patisiran (38.15 to (45.60 to (0.00 to
1.1 (95% CI, 0.96 103.10) 127.35) 32.20)
to 1.06) 1.13
1.05 1.06 (95% CI, 1.07 Patisiran 64.00 67.75 3.75
1.0
1.02 (95% CI, 1.00 (95% CI, 1.00 to 1.20) (38.60 to (37.40 to (−7.10 to
Better (95% CI, 0.97 to 1.11) to 1.12) 92.00) 114.10) 19.90)
to 1.08)
0 3 6 9 12
Months
No. of Patients
Placebo 172 158 162 156 155
Patisiran 174 161 162 160 158

Figure 2. Change in Cardiac Biomarker Levels (Exploratory End Points).

Panel A shows the adjusted geometric mean factor change from baseline to month 12 in the N-terminal pro–B-type natriuretic peptide
(NT-proBNP) level, a cardiac biomarker, with higher values indicating a greater level of cardiac stress. All patients had an NT-proBNP
measurement obtained at baseline; assessments were missing for 8% of patients in both the patisiran and placebo groups at month 12.
Panel B shows the adjusted geometric mean factor change from baseline in the high-sensitivity troponin I level, a measure of myocardial
wall injury, with higher values indicating a greater level of myocardial injury. Troponin I measurements were missing for 4% of patients
in the patisiran group and 3% of patients in the placebo group at baseline; at month 12, measurements were missing for 9% and 10%
of patients in the patisiran and placebo groups, respectively. The number of patients assessed at each time point is shown for both bio-
markers. The median levels of each cardiac biomarker measured at baseline and 12 months and the change from baseline to month 12
are also shown. I bars indicate confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity and
may not be used in place of hypothesis testing. IQR denotes interquartile range.

(interquartile range, −280 to 817) in the patisir- (interquartile range, −7.1 to 19.9) in the patisiran
an group and 518 pg per milliliter (interquartile group and 14.5 pg per milliliter (interquartile
range, 51 to 1544) in the placebo group. The range, 0.0 to 32.2) in the placebo group. The
median change in the troponin I level from ratios (patisiran-to-placebo) of the adjusted geo-
baseline to month 12 was 3.8 pg per milliliter metric mean factor increase from baseline in the

1560 n engl j med 389;17 nejm.org October 26, 2023

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Patisir an for Tr ansthyretin Cardiac Amyloidosis

Table 2. Safety during the 12-Month Double-Blind Treatment Period.

Patisiran Placebo
Event (N = 181) (N = 178)

no. of patients (%)

Any adverse event 165 (91) 168 (94)
Adverse events occurring in ≥10% of patients in either group
Cardiac failure 54 (30) 68 (38)
Infusion-related reaction 22 (12) 16 (9)
Constipation 20 (11) 19 (11)
Atrial fibrillation 16 (9) 26 (15)
Covid-19* 16 (9) 25 (14)
Adverse events occurring in ≥5% of patients treated with patisiran and at least
3 percentage points more common in the patisiran group
Infusion-related reaction 22 (12) 16 (9)
Arthralgia 14 (8) 8 (4)
Muscle spasm 12 (7) 4 (2)
Any serious adverse event† 61 (34) 63 (35)
Any severe adverse event† 47 (26) 52 (29)
Serious adverse events occurring in ≥2% of patients in either group
Cardiac failure 15 (8) 13 (7)
Atrial fibrillation 5 (3) 4 (2)
Atrioventricular block complete 2 (1) 4 (2)
Amyloidosis‡ 1 (1) 4 (2)
Syncope 2 (1) 4 (2)
Cardiac adverse events§ 82 (45) 100 (56)
Cardiac serious adverse events§ 32 (18) 28 (16)
Any adverse event leading to treatment discontinuation 5 (3) 5 (3)
Death: safety analysis¶ 5 (3) 8 (4)

* Included are all patients with Covid-19 of any severity, including two patients in the patisiran group who had asymp-
tomatic Covid-19.
† Serious adverse events were defined as adverse events that resulted in death, were life-threatening, resulted in inpatient
hospitalization or prolongation of existing hospitalization, resulted in persistent or clinically significant disability or
incapacity, were a congenital anomaly or birth defect, or were important medical events as determined by the investi-
gators. All adverse events (including serious adverse events) were graded for severity. Severe events were defined as
adverse events for which more than minimal, local, or noninvasive intervention was received; which had a severe effect
on limiting self-care activities of daily living; or which had the potential for life-threatening consequences or death.
‡ Amyloidosis includes adverse events that were reported as worsening amyloidosis, ATTR disease progression, worsen-
ing of amyloid polyneuropathy, and amyloidosis in the bladder.
§ Cardiac adverse events and serious adverse events included all events selected according to the Medical Dictionary for
Regulatory Activities, version 23.0, system organ class: Cardiac disorders.
¶ Death in the patisiran group included sudden cardiac death (1 patient) and death from heart failure, pancreatitis,
Covid-19, and undetermined cause (1 patient each). Death in the placebo group included death from heart failure (3 pa-
tients), undetermined cause (2 patients), and cholangitis, infection, and pancreatic cancer (1 patient each). Although
heart transplantation and the implantation of left ventricular assist devices were counted as deaths in the efficacy analysis,
they were not counted as deaths in the safety analysis.

levels of NT-proBNP and troponin I were 0.80 to assess the change from baseline to month 12
(95% CI, 0.73 to 0.89) and 0.87 (95% CI, 0.80 to in left ventricular structure and function. The
0.95), respectively (Fig. 2A and 2B). change in left ventricular mass was −1.00 g
Echocardiographic analyses were performed (95% CI, −7.31 to 5.32) in the patisiran group

n engl j med 389;17 nejm.org October 26, 2023 1561

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

and 8.45 g (95% CI, 2.02 to 14.89) in those who cebo group included infusion-related reactions,
received placebo, with a between-group least- arthralgia, and muscle spasms. All infusion-
squares mean difference of −9.45 g (95% CI, related reactions were mild or moderate in se-
−18.48 to −0.42). The change in left ventricular verity, and one patient in the patisiran group
global longitudinal strain (least-squares mean discontinued the trial regimen owing to a mild
change from baseline) was 0.36 percentage infusion-related reaction. Serious adverse events
points (95% CI, 0.01 to 0.71) in the patisiran reported in at least 2% of patients in either
group and 0.90 percentage points (95% CI, 0.55 group were cardiac failure, atrial fibrillation, com-
to 1.26) in the placebo group, with a between- plete atrioventricular block, amyloidosis, and
group least-squares mean difference of −0.54 syncope (Table 2 and Table S9). Adverse events
percentage points (95% CI, −1.04 to −0.05). The leading to discontinuation of the trial regimen
change in left ventricular stroke volume was 0.48 occurred in five patients (3%) in each group. In
ml (95% CI, −1.19 to 2.15) in the patisiran group the safety analysis, five deaths (3%) occurred in
and −2.52 ml (95% CI, −4.21 to −0.82) in the the patisiran group, and eight deaths (4%) oc-
placebo group, with a between-group least- curred in the placebo group. No clinically rele-
squares mean difference of 3.00 ml (95% CI, vant changes in laboratory measures (including
0.61 to 5.38) (Fig. S5). In addition to the echo- hematologic measures, blood chemical mea-
cardiographic results, investigators observed a sures, liver-function tests, and renal measures),
least-squares mean change from baseline to vital signs, or electrocardiograms were observed
week 48 in the modified BMI (calculated as the in either group during the trial.
BMI × g of albumin per liter) of −34.5 (95% CI,
−50.6 to −18.4) in the patisiran group as com- Discussion
pared with −44.7 (95% CI, −60.9 to −28.6) in the
placebo group, for a least-squares mean differ- ATTR cardiac amyloidosis is characterized by
ence of 10.3 (95% CI, −12.5 to 33.0) (Fig. S6). unrelenting disease progression due to ongoing
amyloid deposition in the heart.6-8,13 The present
Pharmacodynamics trial showed that treatment with patisiran sup-
A rapid and sustained reduction in the serum pressed the level of circulating transthyretin
transthyretin level was observed in the patisiran protein by silencing messenger RNA and result-
group, with a mean (±SD) percent reduction of ed in preserved functional capacity, health sta-
86.8±13.6% at 12 months (Fig. 1C). The reduc- tus, and quality of life, as measured by the
tion in the transthyretin level among patients 6-minute walk test and the KCCQ-OS score after
receiving patisiran was similar across subgroups 12 months of treatment. These results are con-
at month 12, regardless of whether patients had sistent with the effects of transthyretin reduc-
been receiving tafamidis treatment at baseline tion observed in trials of variant ATTR amyloido-
(83.7±16.3% reduction in those who were receiv- sis with polyneuropathy17,22,23 and add to a growing
ing tafamidis and 87.9±12.3% in those who were body of evidence that supports the benefit of the
not) and whether patients had variant ATTR therapeutic reduction of the circulating amy-
amyloidosis (85.2±12.7% reduction) or wild-type loidogenic protein, transthyretin, in ATTR amy-
ATTR amyloidosis (87.2±13.9% reduction). loidosis, a finding previously established in sys-
temic amyloidoses caused by serum amyloid A or
Safety immunoglobulin light chain.24-27
Adverse events occurred in 91% of patients in Over the 12-month double-blind period, dis-
the patisiran group and in 94% of patients in the ease progression was observed more often in the
placebo group (Table 2); the majority of events placebo group than in the patisiran group, as
were mild or moderate in severity. The frequency measured by the 6-minute walk test and the
of severe and serious adverse events was similar KCCQ-OS score. In addition, the patients who
in the two groups. Adverse events that occurred received patisiran showed a stable health status
in at least 5% of patients treated with patisiran and quality of life, as measured by the KCCQ-OS
and that were at least 3 percentage points more score. The magnitude of the differences mea-
common in the patisiran group than in the pla- sured between the trial groups for these end

1562 n engl j med 389;17 nejm.org October 26, 2023

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Patisir an for Tr ansthyretin Cardiac Amyloidosis

points were determined by the rate of disease patient population had disease manifestations
progression in the placebo group, with between- that were predominantly cardiac in nature, it is
group differences starting to appear by 6 to 9 possible for patients with variant ATTR amyloi-
months. dosis to have polyneuropathy. The improvement
The overall incidence and type of adverse or worsening of polyneuropathy can influence
events were similar in the patisiran and placebo performance on the 6-minute walk test. How-
groups, with a small percentage of adverse ever, patients with substantially limited ambula-
events (3% in each group) leading to discontinu- tion owing to neuropathy (patients requiring
ation of the trial regimen. All patients received one or two canes to walk or those who were
premedication before each injection of patisiran wheelchair users) were excluded from the trial,
or placebo to reduce the risk of infusion-related and patients with wild-type ATTR amyloidosis,
reactions. who rarely have such limiting neuropathy, com-
The APOLLO-B trial enrolled patients at 69 prised the majority of the trial population. The
sites in 21 countries, with a trial population that results of a post hoc analysis of the primary end
is generally representative of the global popula- point that was limited to the evaluation of pa-
tion of patients with ATTR cardiac amyloidosis; tients without impaired walking ability due to
however, this trial has certain limitations. The neuropathy (i.e., polyneuropathy disability score,
size of the trial precluded formal assessment of 0) at baseline suggest that the treatment differ-
the efficacy of patisiran in certain subgroups, ence in the 6-minute walk test distance was un-
such as patients receiving tafamidis at baseline. related to an effect of patisiran on neuropathy.
The trial also excluded patients who are the In the context of a disease characterized by
most severely affected by ATTR amyloidosis (i.e., progression, treatment with patisiran in patients
patients with both NYHA class III and ATTR with variant or wild-type ATTR cardiac amyloido-
amyloidosis stage 3 or with NYHA Class IV heart sis over 12 months preserved functional capac-
failure). However, recent studies have shown ity, health status, and quality of life. Studies of
that the clinical phenotype of patients who re- longer duration are needed to determine wheth-
ceive a diagnosis of ATTR cardiac amyloidosis is er the benefits observed with the reduction of
changing, which is likely to be related, in part, transthyretin mediated by RNA interference are
to an increase in disease awareness and im- associated with a reduction in mortality and
provements in diagnostic pathways; patients in improved hospitalization outcomes in patients
whom ATTR cardiac amyloidosis has been diag- with ATTR cardiac amyloidosis.
nosed in recent years have had less severe dis- Supported by Alnylam Pharmaceuticals. During the Covid-19
ease and a shorter duration of symptoms before pandemic, infusions at Columbia University Medical Center
were performed in the Irving Institute for Clinical and Transla-
diagnosis.28 This trial population may be more tional Research, which is supported by the National Center for
representative of the current demographic char- Advancing Translational Sciences, National Institutes of Health
acteristics of patients than the population in (UL1TR001873).
Disclosure forms provided by the authors are available with
previous studies, thus precluding any direct com- the full text of this article at NEJM.org.
parison of outcomes. Another limitation, owing A data sharing statement provided by the authors is available
to the duration of the trial, is that the 12-month with the full text of this article at NEJM.org.
We thank all the patients and their families for their par-
randomized trial period did not provide suffi- ticipation in the APOLLO-B trial, Xingyu Li (Alnylam Pharma-
cient power to assess the effect of treatment on ceuticals), and Juanjuan Li (Alnylam Pharmaceuticals) for their
end points related to mortality and hospitaliza- contributions, and Kristen Brown, Ph.D., of Adelphi Commu-
nications (Macclesfield, United Kingdom) for medical writing
tion. Finally, specific measures of polyneuropa- assistance with an earlier version of the manuscript, funded by
thy were not assessed in this trial. Although the Alnylam Pharmaceuticals.

Appendix
The authors’ full names and academic degrees are as follows: Mathew S. Maurer, M.D., Parag Kale, M.D., Marianna Fontana, M.D.,
Ph.D., John L. Berk, M.D., Martha Grogan, M.D., Finn Gustafsson, M.D., Ph.D., Rebecca R. Hung, M.D., Ph.D., Robert L. Gottlieb,
M.D., Ph.D., Thibaud Damy, M.D., Ph.D., Alejandra González‑Duarte, M.D., Ph.D., Nitasha Sarswat, M.D., Yoshiki Sekijima, M.D.,
Ph.D., Nobuhiro Tahara, M.D., Ph.D., Mark S. Taylor, M.B., B.S., Ph.D., Milos Kubanek, M.D., Ph.D., Erwan Donal, M.D., Ph.D., To-
mas Palecek, M.D., Ph.D., Kenichi Tsujita, M.D., Ph.D., W.H. Wilson Tang, M.D., Wen‑Chung Yu, M.D., Laura Obici, M.D., Marcus
Simões, M.D., Ph.D., Fábio Fernandes, M.D., Ph.D., Steen Hvitfeldt Poulsen, D.M.Sci., Igor Diemberger, M.D., Ph.D., Federico

n engl j med 389;17 nejm.org October 26, 2023 1563

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Perfetto, M.D., Ph.D., Scott D. Solomon, M.D., Marcelo Di Carli, M.D., Prajakta Badri, Ph.D., Matthew T. White, Ph.D., Jihong Chen,
Ph.D., Elena Yureneva, M.D., Marianne T. Sweetser, M.D., Ph.D., Patrick Y. Jay, M.D., Ph.D., Pushkal P. Garg, M.D., John Vest, M.D.,
and Julian D. Gillmore, M.D., Ph.D.
The authors’ affiliations are as follows: Columbia University Irving Medical Center (M.S.M.) and Grossman School of Medicine, NYU
Langone (A.G.-D.) — both in New York; the Center for Advanced Heart and Lung Disease, Baylor University Medical Center (P.K.,
R.L.G.), Baylor Scott & White Research Institute, and Texas A&M Health Science Center, Dallas (R.L.G.), and TCU School of Medicine,
Fort Worth (R.L.G.) — all in Texas; the National Amyloidosis Centre, UCL, Division of Medicine, Royal Free Hospital, London (M.F.,
J.D.G.); Boston University School of Medicine (J.L.B.), the Cardiovascular Division, Brigham and Women’s Hospital (S.D.S., M.D.C.),
and the Division of Nuclear Medicine and Molecular Imaging, Brigham and Women’s Hospital, Harvard Medical School (M.D.C.),
Boston, and Alnylam Pharmaceuticals, Cambridge (P.B., M.T.W., J.C., E.Y., M.T.S., P.Y.J., P.P.G., J.V.) — all in Massachusetts; the
Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN (M.G.); the Department of Cardiology, Rigs­
hospitalet, University of Copenhagen, Copenhagen (F.G.), and the Department of Cardiology, Aarhus University Hospital, Aarhus
(S.H.P.) — both in Denmark; the Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center,
Nashville (R.R.H.); the Cardiology Department and French National Reference Center for Cardiac Amyloidosis, GRC Amyloid Research
Institute and Clinical Investigation Centre 1430 at Hôpitaux Universitaires Henri-Mondor Assistance Publique–Hôpitaux de Paris, and
IMRB, INSERM, Université Paris Est Creteil, Creteil (T.D.), and INSERM, LTSI UMR 1099, Centre Hospitalier Universitaire de Rennes,
Rennes (E.D.) — both in France; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City (A.G.-D.); the De-
partment of Medicine, University of Chicago, Chicago (N.S.); the Department of Medicine (Neurology and Rheumatology), Shinshu
University School of Medicine, Matsumoto (Y.S.), the Division of Cardiovascular Medicine, Department of Medicine, Kurume Univer-
sity School of Medicine, Kurume (N.T.), and the Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kuma-
moto University, Kumamoto (K.T.) — all in Japan; Westmead Amyloidosis Service, Westmead Hospital, Sydney (M.S.T.); the Depart-
ment of Cardiology, Institute for Clinical and Experimental Medicine (M.K.), and the 2nd Department of Medicine, Department of
Cardiovascular Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague (T.P.) —
both in Prague, Czech Republic; the Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland (W.H.W.T.); Taipei Veterans
General Hospital and National Yang Ming Chiao Tung University, Taipei, Taiwan (W.-C.Y.); Amyloidosis Research & Treatment Center,
Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia (L.O.), the Department of Medical and Surgical Sciences, University of
Bologna, and the Cardiology Unit, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna (I.D.), and the Department of Clinical
and Experimental Medicine, Careggi University Hospital, Florence (F.P.) — all in Italy; and Unidade de Pesquisa Clínica–UPC, Hospital
Das Clinicas da Faculdade de Medicina de Ribeirão Preto–USP (M.S.), and Instituto do Coração–HCFMUSP (F.F.) — both in São Paulo.

References
1. Maurer MS, Hanna M, Grogan M, et al. 8. Chacko L, Karia N, Venneri L, et al. 2022 (https://www​.­a lnylam​.­c om/​­sites/​
Genotype and phenotype of transthyretin Progression of echocardiographic param- ­default/​­f iles/​­pdfs/​­ONPATTRO​-­Prescribing​
cardiac amyloidosis: THAOS (transthyre- eters and prognosis in transthyretin car- -­Information​.­pdf).
tin amyloid outcome survey). J Am Coll diac amyloidosis. Eur J Heart Fail 2022;​24:​ 16. European Medicines Agency. Sum-
Cardiol 2016;​68:​161-72. 1700-12. mary of product characteristics. Onpattro
2. Ruberg FL, Grogan M, Hanna M, Kelly 9. Lane T, Fontana M, Martinez-Naharro 2 mg/ml concentrate for solution for infu-
JW, Maurer MS. Transthyretin amyloid A, et al. Natural history, quality of life, sion. 2018 (https://www​.­ema​.­europa​.­eu/​
cardiomyopathy: JACC state-of-the-art re- and outcome in cardiac transthyretin ­documents/​­product​-­information/​­onpattro​
view. J Am Coll Cardiol 2019;​73:​2872-91. amyloidosis. Circulation 2019;​140:​16-26. -­epar​-­product​-­information_en​.­pdf).
3. Adams D, Koike H, Slama M, Coelho 10. Nativi-Nicolau J, Judge DP, Hoffman 17. Adams D, Gonzalez-Duarte A,
T. Hereditary transthyretin amyloidosis: JE, et al. Natural history and progression O’Riordan WD, et al. Patisiran, an RNAi
a model of medical progress for a fatal of transthyretin amyloid cardiomyopathy: therapeutic, for hereditary transthyretin
disease. Nat Rev Neurol 2019;​15:​387-404. insights from ATTR-ACT. ESC Heart Fail amyloidosis. N Engl J Med 2018;​379:​11-
4. Rapezzi C, Quarta CC, Obici L, et al. 2021;​8:​3875-84. 21.
Disease profile and differential diagnosis 11. Gonzalez-Lopez E, Escobar-Lopez L, 18. Obici L, Berk JL, González-Duarte A,
of hereditary transthyretin-related amy- Obici L, et al. Prognosis of transthyretin et al. Quality of life outcomes in APOLLO,
loidosis with exclusively cardiac pheno- cardiac amyloidosis without heart failure the phase 3 trial of the RNAi therapeutic
type: an Italian perspective. Eur Heart J symptoms. JACC CardioOncol 2022;​4:​442- patisiran in patients with hereditary
2013;​34:​520-8. 54. transthyretin-mediated amyloidosis. Amy-
5. Coelho T, Maurer MS, Suhr OB. THAOS 12. Gillmore JD, Damy T, Fontana M, loid 2020;​27:​153-62.
— the Transthyretin Amyloidosis Out- et al. A new staging system for cardiac 19. Solomon SD, Adams D, Kristen A, et al.
comes Survey: initial report on clinical transthyretin amyloidosis. Eur Heart J Effects of patisiran, an RNA interference
manifestations in patients with heredi- 2018;​39:​2799-806. therapeutic, on cardiac parameters in pa-
tary and wild-type transthyretin amyloi- 13. Maurer MS, Schwartz JH, Gundapa- tients with hereditary transthyretin-medi-
dosis. Curr Med Res Opin 2013;​29:​63-76. neni B, et al. Tafamidis treatment for pa- ated amyloidosis. Circulation 2019;​139:​431-
6. Fontana M, Pica S, Reant P, et al. tients with transthyretin amyloid cardio- 43.
Prognostic value of late gadolinium en- myopathy. N Engl J Med 2018;​379:​1007-16. 20. Gillmore JD, Maurer MS, Falk RH, et al.
hancement cardiovascular magnetic reso- 14. Coelho T, Adams D, Silva A, et al. Nonbiopsy diagnosis of cardiac trans-
nance in cardiac amyloidosis. Circulation Safety and efficacy of RNAi therapy for thyretin amyloidosis. Circulation 2016;​
2015;​132:​1570-9. transthyretin amyloidosis. N Engl J Med 133:​2404-12.
7. Martinez-Naharro A, Kotecha T, Nor- 2013;​369:​819-29. 21. Green CP, Porter CB, Bresnahan DR,
rington K, et al. Native T1 and extracel- 15. Alnylam Pharmaceuticals. Prescribing Spertus JA. Development and evaluation
lular volume in transthyretin amyloidosis. information. Onpattro (patisiran) lipid of the Kansas City Cardiomyopathy Ques-
JACC Cardiovasc Imaging 2019;​12:​810-9. complex injection, for intravenous use. tionnaire: a new health status measure

1564 n engl j med 389;17 nejm.org October 26, 2023

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 Patisir an for Tr ansthyretin Cardiac Amyloidosis

for heart failure. J Am Coll Cardiol 2000;​ 24. Lachmann HJ, Goodman HJ, Gilbert- MC, et al. Daratumumab-based treatment
35:​1245-55. son JA, et al. Natural history and outcome for immunoglobulin light-chain amyloido-
22. Benson MD, Waddington-Cruz M, Berk in systemic AA amyloidosis. N Engl J Med sis. N Engl J Med 2021;​385:​46-58.
JL, et al. Inotersen treatment for patients 2007;​356:​2361-71. 27. Martinez-Naharro A, Patel R, Kotecha
with hereditary transthyretin amyloido- 25. Palladini G, Dispenzieri A, Gertz MA, T, et al. Cardiovascular magnetic reso-
sis. N Engl J Med 2018;​379:​22-31. et al. New criteria for response to treat- nance in light-chain amyloidosis to guide
23. Adams D, Tournev IL, Taylor MS, et al. ment in immunoglobulin light chain amy­ treatment. Eur Heart J 2022;​43:​4722-35.
Efficacy and safety of vutrisiran for pa- loidosis based on free light chain mea- 28. Ioannou A, Patel RK, Razvi Y, et al.
tients with hereditary transthyretin-medi- surement and cardiac biomarkers: impact Impact of earlier diagnosis in cardiac
ated amyloidosis with polyneuropathy: a on survival outcomes. J Clin Oncol 2012;​ ATTR amyloidosis over the course of 20
randomized clinical trial. Amyloid 2023;​ 30:​4541-9. years. Circulation 2022;​146:​1657-70.
30:​1-9. 26. Kastritis E, Palladini G, Minnema Copyright © 2023 Massachusetts Medical Society.

TRACK THIS ARTICLE’S IMPACT AND REACH

Visit the article page at NEJM.org and click on Metrics for a dashboard
that logs views, citations, media references, and commentary.
NEJM.org/about-nejm/article-metrics.

n engl j med 389;17 nejm.org October 26, 2023 1565

The New England Journal of Medicine is produced by NEJM Group, a division of the Massachusetts Medical Society.
Downloaded from nejm.org on May 12, 2025. For personal use only.
No other uses without permission. Copyright © 2023 Massachusetts Medical Society. All rights reserved.