Journal of the American Heart Association
SYSTEMATIC REVIEW AND META-ANALYSIS
Specific Therapy for Transthyretin Cardiac
Amyloidosis: A Systematic Literature Review
and Evidence-Based Recommendations
Nuno Marques , MD; Olga Azevedo , MD; Ana Rita Almeida, MD; Dina Bento, MD; Inês Cruz, MD; Emanuel Correia, MD; Carolina Lourenço, MD; Luís Rocha Lopes, PhD
BACKGROUND: The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a system-atic review of the literature.
METHODS AND RESULTS: A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was performed on MEDLINE, PubMed, and Embase databases on November 29, 2019. Studies were selected based on the following predefined eligibility criteria: English-language randomized controlled trials (RCTs), non-RCTs, or observational studies, which included adult patients with variant/wild-type transthyretin-CA, assessed specific therapies for transthyretin-CA, and reported cardiovascular outcomes. Relevant data were extracted to a predefined template. Quality assessment was based on National Institute for Health and Care Excellence recommendations (RCTs) or a checklist by Downs and Black (non-RCTs). From 1203 records, 24 publications were selected, describing 4 RCTs (6 publications) and 16 non-RCTs (18 publications). Tafamidis was shown to significantly improve all-cause mortality and cardiovascular hospitalizations and reduce worsening in 6-minute walk test, Kansas City Cardiomyopathy Questionnaire—Overall Summary score, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in vari-ant/wild-type transthyretin-CA. Patisiran showed promising results in a subgroup analysis of patients with variant transthyre-tin-CA, which have to be confirmed in RCTs. Inotersen showed conflicting results on cardiac imaging parameters. The one study on AG10 had only a 1-month duration and cardiovascular end points were exploratory and limited to cardiac biomarkers. Limited evidence from noncomparative single-arm small non-RCTs existed for diflunisal, epigallocatechin-3-gallate (green tea extract), and doxycycline+tauroursodeoxycholic acid/ursodeoxycholic acid.
CONCLUSIONS: This systematic review of the literature supports the use of tafamidis in wild-type and variant transthyretin-CA. Novel therapeutic targets including transthyretin gene silencers are currently under investigation.
Key Words: amyloid ■ cardiac amyloidosis ■ therapy ■ transthyretin ■ transthyretin-related amyloidosis
T
ransthyretin-related amyloidosis (ATTR) results from the tissue deposition of amyloid fibers that are composed of transthyretin, a protein that is mainly produced by the liver and acts as a carrier of thyroxine and retinol-binding protein bound to retinol.1Fibrillogenesis requires the dissociation of transthyretin tetramers into misfolded monomers that self-assem-ble in soluself-assem-ble oligomeric species. Oligomers aggregate into protofibrils and finally mature amyloid fibers, which then deposit within tissues leading to the development
of ATTR.1 ATTR can result from the deposition of either
variant ATTR (ATTRv) or wild-type ATTR (ATTRwt).2
ATTRv is an autosomal dominant disease and >120 pathogenic variants, mostly missense, have been de-scribed in the transthyretin gene. The phenotype is variable, ranging from pure polyneuropathy to selec-tive cardiac involvement.2 Accurate statistics on the
prevalence of ATTRv are difficult to obtain. Among Americans of European descent, the estimated in-cidence of ATTRv is 0.4 per million people per year; Correspondence to: Nuno Marques, MD, Algarve Biomedical Center, Edifício da Medicina, Campus de Gambelas, Universidade do Algarve, 8005-139 Faro, Portugal. E-mail: marqns@gmail.com
For Sources of Funding and Disclosures, see page 24.
© 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
JAHA is available at: www.ahajournals.org/journal/jaha
however, this condition is believed to be more common among people with African ancestry and in specific geographic areas, such as northern Portugal, Sweden, Japan, or some regions of West Africa.2 In Portugal,
endemic ATTRv is caused by the Val30Met mutation and familial amyloidotic polyneuropathy is the predom-inant feature of the phenotype.
ATTRwt is characteristically associated with almost exclusive cardiac involvement, with carpal tunnel syn-drome being one of the few extracardiac red flags. The true prevalence of ATTRwt is unknown, but it may be relatively high compared with the prevalence of ATTRv.3
It affects the elderly and, in autopsy studies, nearly
25% of the hearts of individuals aged 80 years or older contained wild-type transthyretin fibrils, regardless of the presence of symptoms.3 Studies using nonbiopsy
approaches to diagnose ATTRwt reported prevalence rates of 16% among patients undergoing percutane-ous aortic valve replacement for severe aortic stenosis, 13% among patients with heart failure with preserved ejection fraction, 5% among patients with presumed hypertrophic cardiomyopathy, and 7% to 8% among patients with carpal tunnel syndrome on biopsy of the tenosynovial tissue. Furthermore, 1% to 3% of individ-uals older than 75 years showed myocardial retention of diphosphono-1,2-propanodicarboxylic acid, which is indicative of TTR-related cardiac amyloidosis (CA).3
Cardiac involvement is common in ATTR and is associated with a particularly poor life expectancy of 2 to 6 years after diagnosis. Transthyretin CA is a progressive disorder and patients ultimately develop heart failure, dysrhythmias, and cardiac conduction disturbances, which result in decreased functional capacity, diminished quality of life, and eventually death.3 Moreover, treatment of transthyretin CA was,
until recently, limited to the treatment of symptoms and complications.
However, the emergence of new therapeutic op-tions and the results of recent randomized controlled trials in patients with transthyretin CA warrant the need for a systematic review of the literature.
The aim of the systematic review was to identify and synthesize the available evidence on specific therapies for transthyretin CA and, based on this, to provide ev-idence-based recommendations for the use of these therapies. This systematic review will focus on spe-cific therapies targeting the inhibition of transthyretin synthesis (inotersen or patisiran); tetramer stabilization (diflunisal, tafamidis, or AG10); inhibition of oligomer aggregation and disruption (epigallocatechin-3-gal-late); and degradation and reabsorption of amyloid fi-bers (doxycycline-tauroursodeoxycholic [TUDCA] acid or doxycycline-ursodeoxycholic acid [UDCA]).4
METHODS
The authors declare that all supporting data are avail-able within the article.
This systematic review of the literature was con-ducted using the methodology suggested by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.5 It was conducted in
3 stages: a comprehensive and systematic search of the published literature to identify all potentially relevant studies; systematic selection of relevant studies based on explicit inclusion and exclusion criteria; and ex-traction of relevant data from eligible studies to assess the effects of therapy in patients with transthyretin CA.
CLINICAL PERSPECTIVE
What Is New?
• As novel therapies emerge in the field of tran-sthyretin-related amyloidosis, this systematic review of the literature examines and presents the existing evidence regarding specific thera-pies for transthyretin cardiac amyloidosis.
• This systematic review supports the use of tafamidis in patients with transthyretin cardiac amyloidosis, either variant transthyretin-related amyloidosis or wild-type transthyretin-related amyloidosis, but does not support the use of di-flunisal, AG10, doxycycline, or epigallocatechin-3-gallate in these patients.
What Are the Clinical Implications?
• Novel therapies, including transthyretin gene silencers, are currently under investigation in dedicated randomized controlled trials.
Nonstandard Abbreviations and Acronyms
ATTR transthyretin-related amyloidosis
ATTRv variant transthyretin-related
amyloidosis
ATTRwt wild-type transthyretin-related
amyloidosis
CA cardiac amyloidosis
EMA European Medicines Agency
FDA Food and Drug Administration
KCCQ-OS Kansas City Cardiomyopathy Questionnaire—Overall Summary
NYHA New York Heart Association
TRACS Transthyretin Amyloidosis Cardiac
Study
TUDCA tauroursodeoxycholic acid
UDCA ursodeoxycholic acid
Search Strategy
A systematic search was performed on November 29, 2019, in the following databases: MEDLINE, PubMed, and Embase. The search was performed in the English-language literature using the follow-ing keywords: “transthyretin amyloidosis treatment”; “transthyretin amyloidosis therapy”; “AG10 transthyre-tin amyloidosis”; “diflunisal transthyretransthyre-tin amyloidosis”; “tafamidis”; “oligonucleotides transthyretin amyloido-sis”; “inotersen”; “patisiran”; “green tea transthyretin amyloidosis”; and “doxycycline transthyretin amyloido-sis.” A deduplication step was performed to remove studies that overlapped among the databases.
Selection Criteria
To be included in this review, studies had to meet the predefined eligibility criteria listed in Table 1. In sum-mary, studies included in this review were RCTs, non-RCTs, or observational studies, including adult patients diagnosed with transthyretin CA, assessing at least 1 of the specific therapies for transthyretin CA and re-porting cardiovascular outcomes (Table 1).
Primary screening was performed by 2 authors who independently reviewed each reference (title and abstract) identified by the literature search, applied the inclusion and exclusion criteria listed in Table 1, and de-cided on whether to include or exclude the publication at that stage. Disagreement regarding the inclusion of studies was solved by a third author. The full-text articles were obtained for potentially relevant studies identified by primary screening of titles and abstracts. These were independently reviewed by 2 reviewers against each el-igibility criteria. Disagreement regarding the inclusion of studies was solved by a third author.
Data Extraction
The data regarding the cardiovascular outcomes of patients under specific therapies for transthyretin CA were extracted. Safety data on these therapies were also extracted.
The data extraction process was performed by one author to a predefined extraction data template (Tables 2 and 3) and independently checked for errors against the original study report by another author.
Multiple publications regarding the same patient population and reporting data for the same intervention were linked together and extracted as a single reference.
Quality Assessment
Quality assessment of the included RCTs was per-formed using comprehensive assessment criteria based on recommendations in the National Institute for Health and Care Excellence template30 (Figure 1).
Quality assessment of the included non-RCTs was
performed using a checklist by Downs and Black31
(Figure 2).
RESULTS
Literature Selection
Database searches identified 1203 records, of which 495 studies were identified as duplicates and ex-cluded. The screening of the remaining 708 studies
Table 1. Inclusion and Exclusion Criteria of the Studies for
Systematic Review
Category Inclusion Criteria Exclusion Criteria Population • Patients with
transthyretin CA • Familial or mutant/ variant transthyretin CA • Wild-type transthyretin CA • Any ethnicity • Age ≥18 y • Healthy volunteers only • Pediatric population (<18 y)
• Disease other than transthyretin CA
Interventions Studies assessing specific therapies for ATTR, namely: • AG10 • Diflunisal • Tafamidis • Inotersen • Patisiran • Doxycycline plus tauroursodeoxycholic acid or ursodeoxycholic acid
• Green tea extract (epigallocatechin-3-gallate)
• Nonspecific therapies for ATTR such as diuretics and other nondisease-modifying therapies. • Liver transplantation • Studies assessing interventions not included on the list
Comparators • No restrictions • None Outcomes • Cardiovascular outcomes ◦ Biomarkers ◦ ECG or Holter parameters ◦ Imaging parameters ◦ Functional tests ◦ Quality of life ◦ Arrhythmias ◦ Hospital admissions ◦ Death • Only noncardiovascular outcomes
Study design • RCTs irrespective of blinding status • Non-RCTs
• Observational studies • Single-arm studies • Cohort studies (both
prospective and retrospective) • Systematic reviews and
meta-analyses of RCTs*/ non-RCTs*
• Case reports, case series
• Pharmacokinetic and economic studies • Preclinical studies • Reviews, letters, and
comment articles
Language • English • Other than English ATTR indicates transthyretin-related amyloidosis; CA, cardiac amyloidosis; and RCT, randomized controlled trials.
*Systematic reviews and meta-analyses of RCTs and non-RCTs were included and flagged. Bibliographies of these systematic reviews were screened to check whether literature searches missed any potentially relevant studies.
Ta b le 2 . R C Ts In c lu d e d S tud y/ R ef er en ce S tu d y Ph as e B lin d in g S tu d y D u rati o n , mo Tr eatm en t N o . o f P ati en ts M ea n A g e, y A T T R Ty p e, n P ri m ar y O u tcome R es u lt s on C ar d io va sc u la r a nd S af et y O u tcome s Ino te rse n N E UR O -T TR B en so n e t a l, 20 18 6 P ha se II I D ouble -bl in d 16 .5 Ino te rse n 30 0 m g N =1 12 59. 0 AT TR v N =1 12 CA N=75 • m N IS +7 • N or fol k Q oL -DN C A s ubpop ula tion E cho ca rdio gr ap hic m ea su re s • IV S t hi ck ne ss ( m m ) In ote rs en v s p la ce b o − 0. 57 ( 95 % C I, − 1. 16 t o 0. 45 ), P = 0. 27 0 • LV P W t hi ck ne ss ( m m ) In ote rs en v s p la ce b o − 0. 26 ( 95 % C I, − 1. 32 t o 0. 80 ), P = 0. 621 • LV E F ( % ) In ote rs en v s p la ce b o −1 .9 9 ( 95 % C I, − 5. 49 t o 1 .5 0) , P = 0. 26 0 • LV m as s ( g) In ote rs en v s p la ce b o − 2. 8 ( 95 % C I, − 22 .1 t o 1 6. 4) , P = 0.7 68 • E /E m l ate ra l r at io In ote rs en v s p la ce b o −1 .4 1 ( 95 % C I, − 4. 22 t o 1 .3 9) , P = 0. 317 • G LS ( % ) In ote rs en v s p la ce b o + 0. 20 ( 95 % C I, − 1. 17 t o 1 .5 6) , P = 0. 771 G lob al s tud y pop ula tion sa fet y o ut co m es • A E ( % ) P la ce bo =1 0 0% In ot er sen =9 9% • S er io us A E ( % ) P la ce bo = 22 % Ino te rse n= 32 % • S tu d y d is co nt in ua tio n b ec au se o f a n A E ( % ) P la ce bo = 2% Ino te rse n= 14 % • M or ta lit y c au se d b y a n A E ( % )P la ce b o= 0% Ino te rse n= 1% P la ce bo N = 60 59. 5 AT TR v N = 60 CA N=3 0 (C on tinu es
S tud y/ R ef er en ce S tu d y Ph as e B lin d in g S tu d y D u rati o n , mo Tr eatm en t N o . o f P ati en ts M ea n A g e, y A T T R Ty p e, n P ri m ar y O u tcome R es u lt s on C ar d io va sc u la r a nd S af et y O u tcome s P at is ira n A P O LL O A d am s e t a l, 20 18 7 S ol om on e t a l, 20 19 8 M in am is aw a e t al , 2 019 9 P ha se II I D ouble bl in d 18 P at is ira n 0. 3 m g/ kg N =1 48 62 AT TR v N =1 48 CA N=90 • m N IS +7 C A s ubpop ula tion • A ll-cau se h os p ita liz at io n+ m or ta lit y P at isi ra n v s pla ce bo H R , 0. 49 ( 95 % C I, 0. 30 –0. 79 ) • C ar d iac h os p ita liz at io ns + m or ta lit y P at isi ra n v s pla ce bo H R , 0. 54 ( 95 % C I, 0. 25 –1 .1 6) • N T-p ro B N P ( ra tio o f f ol d -c ha ng e) P at isi ra n v s pla ce bo + 0. 45 ( 95 % C I, 0. 34 –0. 59 ), P < 0. 0 01 • 10 -m w al k te st ( m /s ) P at isi ra n v s pla ce bo + 0. 35 ( 95 % C I, 0. 24 –0. 47 ) E cho ca rdio gr ap hic m ea su re s • LV W th ick ne ss (l eas t-sq ua re s me an ) P at isi ra n v s pla ce bo − 0. 9 ( ± 0. 4) , P = 0. 017 • LV E F ( % ) P at isi ra n v s pla ce bo + 0. 43 ( ±1 .5 7) , P = 0.7 85 • C ar d ia c o ut p ut ( L /m in ) P at isi ra n v s pla ce bo + 0. 38 ( ± 0. 19 ), P = 0. 044 • LV E DV ( m L) P at isi ra n v s pla ce bo + 8. 3 ( ± 3. 9) , P = 0.0 36 • LV E S V ( m L) P at isi ra n v s pla ce bo +2. 7 ( ± 2. 1) , P = 0. 21 1 • Le ft a tr ia l v ol um e ( m L) P at isi ra n v s pla ce bo −1 .0 ( ± 2. 7) , P = 0.7 31 • LV m as s ( g) P at isi ra n v s pla ce bo −1 5. 8 ( ±1 0. 9) , P = 0. 15 0 • G LS ( % ) P at isi ra n v s pla ce bo −1 .4 ( 95 % C I, − 2. 5 t o − 0. 3) , P = 0.0 20 G lob al s tud y pop ula tion sa fet y o ut co m es • A E ( % ) P la ce bo = 97 % P at is ira n= 97 % • S er io us A E ( % ) P la ce bo = 40 % P at is ira n= 36 % • S tu d y d is co nt in ua tio n b ec au se o f a n A E ( % ) P la ce bo =1 2% P at is ira n= 5% • M or ta lit y c au se d b y a n A E ( % )P la ce b o= 0% P at is ira n= 0% P la ce bo N =7 7 63 AT TR v N =7 7 CA N=3 6 (C on tinu es ) Ta b le 2 . C o n tinu ed
(C on tinu es ) S tud y/ R ef er en ce S tu d y Ph as e B lin d in g S tu d y D u rati o n , mo Tr eatm en t N o . o f P ati en ts M ea n A g e, y A T T R Ty p e, n P ri m ar y O u tcome R es u lt s on C ar d io va sc u la r a nd S af et y O u tcome s Ta fa m idi s AT TR -A C T M au re r e t a l, 20 18 10 P ha se II I D ouble -bl in d 30 Ta fa m idi s 80 m g 20 m g N =2 64 74 .5 AT TR v N = 63 AT TR w t N = 201 • A ll-ca us e m or ta lit y • C ar dio va sc ul ar ho sp ita liz at io ns • A ll-cau se m or ta lit y Ta fa mi d is v s pla ce bo H R , 0. 70 ( 95 % C I, 0. 51 –0. 96 ) • C ar d iac h os p ita liz at io ns Ta fa mi d is v s pla ce bo H R , 0. 68 ( 95 % C I, 0. 56 –0. 81 ) • 6-m in w al k te st ( m ) Ta fa mi d is v s pla ce bo +7 5. 7 ( ± 9. 2) , P < 0. 0 01 • K C C Q -O S s co re Ta fa mi d is v s pla ce bo +1 3. 7 ( ± 2. 1) , P < 0. 0 01 • N T-pr oB NP (pg /mL ) Ta fa mi d is v s pla ce bo − 21 80 ( 95 % C I, − 33 26 t o − 10 35 ), P < 0. 0 01 E cho ca rdio gr ap hic m ea su re s • IV S t hi ck ne ss ( m m ) Ta fa mi d is v s pla ce bo − 0. 44 ( 95 % C I, − 1. 11 t o 0. 23 ) • LV P W t hi ck ne ss ( m m ) Ta fa mi d is v s pla ce bo − 0. 27 ( 95 % C I, − 1. 55 t o 1 .0 1) • LV E F ( % ) Ta fa mi d is v s pla ce bo +1 .5 1 ( 95 % C I, − 0. 57 t o 3 .6 0) • LV s tr ok e v ol um e ( m L) Ta fa mi d is v s pla ce bo + 6. 28 ( 95 % C I, 1 .9 6 –1 0. 59 ) • C irc um fe re nt ia l g lo b al s tr ai n ( % ) Ta fa mi d is v s pla ce bo − 2. 67 ( 95 % C I, − 4. 20 t o − 1 .1 5) • R ad ia l g lo b al s tr ai n ( % ) Ta fa mi d is v s pla ce bo + 3. 53 ( 95 % C I, 1 .0 0 –6 .0 6) • G LS ( % ) Ta fa mi d is v s pla ce bo − 0. 70 ( 95 % C I, − 1. 43 t o 0.0 2) S af et y o ut co m es • A E ( % ) P la ce bo = 98 .9 % Ta fa m idi s= 98 .5 % • S er io us A E ( % ) P la ce bo =7 9. 1% Ta fa m idi s= 75 .4 % • S tu d y d is co nt in ua tio n b ec au se o f a n A E ( % ) P la ce bo = 28 .8 % Ta fa m id is = 21 .2 % • M or ta lit y c au se d b y a n A E ( % )P la ce b o= 0% Ta fa m idi s= 0% P la ce bo N =17 7 74 .1 AT TR v N = 43 AT TR w t N =1 34 Ta b le 2 . C o n tinu ed
S tud y/ R ef er en ce S tu d y Ph as e B lin d in g S tu d y D u rati o n , mo Tr eatm en t N o . o f P ati en ts M ea n A g e, y A T T R Ty p e, n P ri m ar y O u tcome R es u lt s on C ar d io va sc u la r a nd S af et y O u tcome s A G 10 NC T0 34 58 13 0 Ju d ge e t a l, 20 19 11 P ha se I I D ouble -bl in d 1 A G 10 40 0 m g 80 0 m g N=3 2 N =1 6 N =1 6 73 .8 75 .4 AT TR v N =1 1 AT TR w t N = 21 S af et y a nd to le ra b ili ty • N T-p ro B N P ( % c ha ng e f ro m b as el in e) P la ce bo = − 4± 36 A G 10 40 0 = +3 ± 33 A G 10 8 0 0 = −1 4±1 6 N o sta tist ic al te st a p p lie d • Tr op on in I ( % c ha ng e f ro m b as el in e) P la ce bo = −7 ±1 5 A G 10 4 0 0 = − 4± 22 A G 10 8 0 0=0 ±1 7 N o sta tist ic al te st a p p lie d S af et y o ut co m es • A E ( % ) P la ce bo = 88 % A G 10 4 0 0 = 63 % A G 10 8 0 0 = 60 % • S er io us A E ( % ) P la ce bo =1 2% A G 10 4 0 0 = 6% A G 10 8 0 0=0 % • S tu d y d is co nt in ua tio n b ec au se o f a n A E ( % )P la ce b o= 0% A G 10 4 0 0=0 % A G 10 8 0 0=0 % P la ce bo N =17 73 .2 AT TR v N=3 AT TR w t N =1 4 A E i nd ica te s a dv er se e ve nt ; A T TR , t ran st hyr et in -r el at ed a m yl oi d os is ; A T TR v, v ari an t t ran st hyr et in -r el at ed a m yl oi d os is ; A T TR w t, w ild -t yp e t ran st hyr et in -r el at ed a m yl oi d os is ; C A , ca rd ia c a m yl oi d os is ; G LS , g lo ba l lo ng itu d in al s tr ai n; H R , h az ar d r at io ; I V S , i nt er ve nt ric ul ar s ep tu m ; K C C Q -O S , K an sa s C ity C ar d io m yo pa th y Q ue st io nn ai re — O ve ra ll S um m ar y; L V, l ef t v en tr ic ul ar ; L V E D V, l ef t v en tr ic ul ar e nd -d ia st ol ic v ol um e; L V E F, l ef t ve nt ric ula r e je ct ion fr act ion ; L V E S V, le ft v en tr ic ula r e nd -s ys to lic v ol um e; L V PW , l ef t v en tr ic ula r po st er ior w al l; L V W , l ef t v en tr ic ula r w al l; mN IS , M od ifi ed N eur op at hy Imp ai rm en t Sc or e; N T-pr oB NP , N-te rmi na l pr o-B -t yp e na tr iu re tic p ep tid e; Q oL -D N , Q ua lit y o f L ife -D ia b et ic N eu ro pa th y; a nd R C T, r an d om iz ed c on tr ol le d t ria l. Ta b le 2 . C o n tinu ed
Ta b le 3 . L is t o f N on -R C Ts In c lu d e d S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es In ot er se n B en so n e t a l, 20 17 12 D as gu pt a e t a l, 20 20 13 P ro sp ec tiv e S ing le -c en te r 36 In ot er se n 30 0 m g S C we ek ly N = 33 63 .4 AT TR v N =1 0 AT TR w t N =2 3 • C ha ng es i n c ar d ia c pa ra m et er s E ch oc ar dio gr aphic p ar am et er • IV S t hi ck ne ss (m m ) ( vs b as el in e) 12 m o 0 .0 24 m o 1 .4 36 m o 3 .0 P = 0. 019 • LV m as s ( g) (m o 1 2 v s b as el in e) N =1 5 AT TR v 36 3± 27 v s 3 52 ± 28 AT TR w t 50 7± 29 v s 4 70 ± 40 • G LS (m o 1 2 v s b as el in e) ( N =1 5) AT TR v 12 .7 v s 1 3.6 AT TR w t 10 .2 v s 8 .6 • G LS (m o 3 6 v s b as el in e) + 0. 3± 0. 9 MR I me as ur es • LV m as s ( % ) 12 m o v s b as el in e 0. 54 % 24 m o v s b as el in e 8. 5% 36 m o v s b as el in e 11 .5 % • 6-m in w al k t es t (m ) ( vs b as el in e) 12 m o +1 0. 6 24 m o +2 2. 2 36 m o +1 6.5 P = NS • B N P ( p g/ m L) ( vs b as el in e) 12 m o 32 1. 7 v s 3 53 .8 24 m o 31 9. 4 v s 3 53 .8 36 m o 26 0. 8 v s 3 53 .8 P = NS • N Y H A c la ss (m o 1 2 v s b as el in e) ( N =1 5) 6 p at ie nt s i m p ro ve d 6 pa tie nt s sta b iliz ed 3 p at ie nt s w or se ne d Sa fe ty o ut co me s • O ne p at ie nt d is co nt in ue d t he ra py b ec au se o f a n A E • Th er e w as a n 1 1% d ec re as e i n p la te le t c ou nt i n 1 5 p at ie nt s ( 45 % ) • The o the r s af et y p ar ame te rs r ema ine d s ta b le (C on tinu es )
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es P at is ira n A d am s e t a l, 20 17 14 P ro sp ec tiv e M ult ic en te r 24 P at is ira n 0. 3 g /k g I V ev er y 3 w k N = 27 64. 0 AT TR v N = 27 C ar diom yop at hy N =11 • S af et y a nd tole ra b ili ty C A s ub p op ul at io n ( 24 m o v s b as el in e) • N T-pr oB NP (n g/ L) − 49 .6 ±1 70 .8 • Tr op on in I ( ng /m L) − 0.1 ± 0.1 E ch oc ar dio gr aphic m ea su re s • LV m as s ( g) −1 6.7 ±1 1.7 • LV w al l t hi ck ne ss (m m ) − 0.8± 1 • LV E F ( % ) + 0. 6±1 .4 • G LS ( % ) + 0. 9± 0. 9 • 10 -m in w al k t es t (m /s ) + 0.0 3± 0.0 5 Sa fe ty o ut co me s • 26% p at ie nt s w ith a s er io us A E • O ne p at ie nt d is co nt in ue d t he ra py b ec au se o f a n A E D iflu nis al C as ta ño e t a l, 20 12 15 P ro sp ec tiv e S ing le -c en te r 10 .8 D iflu nis al 25 0 m g b id N =1 3 69 AT TR v N= 6 AT TR w t N =7 • S af et y a nd e ff ic ac y • B NP (pg /mL ) Ba se lin e= 38 8± 92 Fol lo w -up = 48 1± 10 2 P = 0. 52 • Tr op on in I ( ng /m L) B as el ine = 0. 04 ± 0. 01 Fo llo w -u p = 0.0 7± 0.0 2 P = 0.0 8 E ch oc ar dio gr aphic m ea su re s • IV S t hi ck ne ss (m m ) B as el ine =1 8± 1 Fol lo w -up =1 6± 1 P = 0. 25 • LV P W t hi ck ne ss (m m ) B as el ine =1 6± 1 Fol lo w -up =1 5± 2 P = 0. 50 • LV m as s ( g/ m 2) B as el ine = 384 ± 37 Fo llo w -u p = 33 1± 65 P = 0. 36 • LV E F ( % ) B as el ine = 50 ± 3 Fo llo w -u p = 48± 6 P = 0. 61 • LV E D D (m m ) Ba se lin e= 44 ±1 Fol lo w -up = 45 ±1 P = 0. 33 • L A d ia m et er (m m ) B as el in e= 46± 2 Fol lo w -up = 45 ± 2 P = 0. 80 Sa fe ty o ut co me s • O ne p at ie nt d is co nt in ue d t he ra py b ec au se o f a n A E • W el l t ol er at ed f ro m h em at ol og ic a nd r en al s ta nd p oi nt Ta b le 3 . C o n tinu ed
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es S ek iji m a e t a l, 20 15 16 P ro sp ec tiv e S ing le -c en te r 38 .0 D iflu nis al 25 0 m g b id N = 40 60 .7 AT TR v N = 40 C ar diom yop at hy N = 34 • S af et y a nd e ff ic ac y • B N P ( % v ar ia tio n f ro m b as el in e) +1 1. 7± 42 .5 P = 0. 96 • hA N P ( % v ar ia tio n f ro m b as el in e) +1 1.7 ± 32 .7 P = 0. 96 E ch oc ar dio gr aphic m ea su re s • IV S +L V P W t hi ck ne ss (m m , v ar ia tio n f ro m b as el in e) + 0. 25 ±1 .74 P = 0. 30 • LV E F ( % v ar ia tio n f ro m b as el in e) − 0. 21± 3. 76 P = 0. 23 Sa fe ty o ut co me s • Th re e p at ie nt s d is co nt in ue d t he ra py b ec au se o f a n A E • D et er io ra tion o f r en al fun ct ion a nd th ro mb oc yt op en ia R os en b lu m e t a l, 20 18 17 R et ro sp ec tiv e S ing le -c en te r 22. 8 D iflu nis al Ta fa mi di s W ith ou t S ta b iliz er N =1 20 D iflu nis alN =1 3 Ta fa mi di sN =1 6 C on tr ol s N = 91 75 AT TR v N = 36 AT TR w t N = 84 • A ll-ca us e m or ta lit y o r he ar t tr an sp la nt at ion • M or ta lit y o r he ar t t ra ns p la nt at ion S ta b ili ze r v s w ith ou t sta b iliz er H R 0 .3 2 ( 95 % C I, 0 .1 8 –0 .5 8) , P < 0. 0 01 Mu lti va ria b le a dj us te d H R H R , 0 .3 7 ( 95 % C I, 0 .1 9 –0 .7 5) , P = 0.0 03 Th e a ss oc ia tio n o f t yp e o f s ta b ili ze r w ith t he o ut co m e d id n ot d iff er W ix ne r e t a l, 20 19 18 P ro sp ec tiv e M ult ic en te r 24 D iflu nis al 50 0 m g/ d N = 54 68 AT TR v N = 54 • K uma m ot o s ca le • P ro B N P ( b as el in e v s F ol lo w -u p ( ng /L )) 53 2 v s 4 57 , P = 0.1 9 • IV S t hi ck ne ss ( b as el in e v s f ol lo w -u p [ m m ]) 16 .5 v s 1 8; P = 0. 01 S afe ty • 19 % o f p at ie nt s d is co nt in ue d t he ra py b ec au se o f a n A E • M os t c om m on s id e e ffe ct s w er e d ys p ep si a ( 12 % ), d ia rr he a ( 9% ), a nd inc re as e in c re at in in e (7 % ). Ta b le 3 . C o n tinu ed (C on tinu es )
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es TA FA M ID IS M er lin i e t a l, 20 13 19 D am y e t a l, 20 15 20 P ro sp ec tiv e P ha se II M ult ic en te r 12 Ta fa mi di s 20 m g Q D N = 21 63 .1 AT TR v N = 21 CA N=12 • Tra nst hy re tin sta b ili ty • N T-pr oB NP (v ar ia tio n a t 1 2 mo — pg /mL ) +7 5. 5 • Tr op on in I ( ng /m L) R ema ine d s ta b le E C G a b no rm al iti es ( 12 m o v s b as el in e) • A ny 72.2% v s 7 6. 2% • R hy th m 33 .3% v s 1 4. 3% • C on d uc tion 50 .0 % v s 6 1. 9% • M or p hol og y 5.6% v s 4 .8 % • P at ho lo gi ca l Q w av es 11 .1 % v s 1 4. 3% • A b no rm al T w av e 11 .1 % v s 1 4. 3% H ol te r a b no rma lit ie s ( 12 m o v s b as el ine ) • A ny 72.2% v s 6 6. 7% • A tr ia l f ib rill at io n/ flu tt er 11 .8% v s 4 .8% • A tr ia l t ac hy ca rd ia 66 .7 % v s 5 2. 4% • N S V T 16 .7 % v s 3 8. 1% • S us ta in ed V T 0% v s 0 % • Si nus p aus e 0% v s 4 .8 % E ch oc ar dio gr aphic m ea su re s ( va ria tio n a t 1 2 mo ) • IV S t hi ck ne ss (m m ) +1 .0 ± 2.0 • LV P W t hi ck ne ss (m m ) + 0.7 ±1 .7 • L A d ia m et er (m m ) +1 .6 ± 3. 5 • LV m as s ( g) +2 0. 9± 35. 1 • LV E F ( % ) − 2. 2± 5. 4 Sa fe ty o ut co me s • 86% o f p at ie nt s w ith a n A E • 38 % p at ie nt s w ith a s er io us A E • 14 % o f p at ie nt s d is co nt in ue d t he ra py b ec au se o f a n A E N o sta tist ic al te st a p p lie d Ta b le 3 . C o n tinu ed (C on tinu es )
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es M au re r e t a l, 20 15 21 P ro sp ec tiv e P ha se II M ult ic en te r 12 Ta fa mi di s 20 m g Q D N = 31 76 .7 AT TR w t N = 31 • Tra nst hy re tin sta b ili ty • D ea th 2 p at ie nt s (6.5 % ) • C ar d io va scu la r hos p ita liz at io ns 7 p at ie nt s ( 22 .6% ) • W or se ni ng h ea rt f ai lu re 8 p at ie nt s ( 25 .8 % ) • N T-p ro B N P ( va ria tio n a t 1 2 m o) ( p g/ m L) + 60 1± 92 6 • Tr op on in I ( va ria tio n a t 1 2 m o) ( ng /m L) + 0.0 37 ± 0.0 20 ; P < 0.0 05 • Tr op on in T ( va ria tio n a t 1 2 m o) ( ng /m L) + 0. 0 05 ± 0. 0 06; P > 0.0 5 • 6-m in w al k t es t ( va ria tio n a t 1 2 m o) ( ng /m L) + 8. 9 m E ch oc ar dio gr aphic m ea su re s ( va ria tio n a t 1 2 mo ) • IV S t hi ck ne ss (m m ) +1 .0 ( 95 % C I, − 8. 0 t o 4 .0 ) • LV P W t hi ck ne ss (m m ) +1 .0 ( 95 % C I, − 5. 0 t o 3 .0 ) • R V t hi ck ne ss (m m ) 0. 0 ( 95 % C I, − 4. 0 t o 5 .0 ) • L A d ia m et er (m m ) +1 .0 ( 95 % C I, − 10 .0 t o 9 .0 ) • LV E F ( % ) − 4. 0 ( 95 % C I, − 29 t o 2 0) • S tr ok e v ol um e (m L) −1 .5 ( 95 % C I, − 19 t o 1 3) • P S A P (m m H g) +1 .0 ( 95 % C I, − 19 t o 3 2) • E /E ´ l at er al r at io −1 .3 ( 95 % C I, − 13 .1 t o 1 1. 9) • E /A r at io + 0.6 ( 95 % C I, 0 .0 –1 .4 ) • Is ov ol um ic r el ax at io n t im e (m s) +7 .5 ( 95 % C I, − 29 t o 2 8) H ol te r da ta (ne w -on se t) • A tr ia l f ib rill at io n/ flu tt er 44 .4 % ( 8 o f 1 8 p at ie nt s) • N S V T 36 .4 % ( 4 o f 1 1 p at ie nt s) • S us ta in ed V T 3. 8% ( 1 o f 2 6 p at ie nt s) • Si nus p aus e 20 .8 % ( 5 o f 2 4 p at ie nt s) Sa fe ty o ut co me s • 10 0% o f p at ie nt s w ith a n A E • 42 % o f p at ie nt s w ith a s er io us A E • 3% o f p at ie nt s d is co nt in ue d t he ra py b ec au se o f a n A E Ta b le 3 . C o n tinu ed (C on tinu es )
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es C or te se e t a l, 20 16 22 P ro sp ec tiv e M ult ic en te r 36 Ta fa mi di s N = 61 62. 0 AT TR v N = 61 CA N=34 • S af et y • E xp lo ra to ry e ff ic ac y on n er ve a nd h ea rt fun ct ion E ch oc ar dio gr aphic m ea su re s • IV S t hi ck ne ss (m m ) 12 m o v s b as al + 0. 6± 1. 6 24 m o v s b as al +1 .0 5± 2.0 • C ar dia c di se ase pr ogr es sio n By e ch oc ar d iog ra p hy 15 % a t 3 0 m o B y e ch oc ar dio gr aph y+ N T-pr oB NP 3 p at ie nt s N ew d ev el op m en t o f C A 35% (8 /2 3) N Y H A cl as s p ro gr es si on 12 p at ie nt s P ac ema ke r i mp la nt at ion 1 p at ie nt Sa fe ty o ut co me s • 13 % o f p at ie nt s w ith a n A E • 5% o f p at ie nt s w ith a s er io us A E • N o c as es o f s tu d y d is co nt in ua tio n c au se d b y a n A E A nd o e t a l, 20 16 23 P ro sp ec tiv e M ult ic en te r 19 .5 Ta fa mi di s 20 m g Q D N =1 0 60 .1 AT TR v N =1 0 • Tra nst hy re tin sta b ili ty E ch oc ar dio gr aphic m ea su re s • IV S t hi ck ne ss (m m ) W ee k 5 2 v s b as el in e −1 .3 ± 2. 7 W ee k 7 8 v s b as el in e − 3.7 ± 3.7 • S tr ok e v ol um e (m L) W ee k 5 2 v s b as el in e +1 .1 ± 5. 0 W ee k 7 8 v s b as el in e + 6.0 ±1 3.0 Sa fe ty o ut co me s • 10 0% o f p at ie nt s w ith a n A E • 30 % o f p at ie nt s w ith a s er io us A E • N o c as es o f s tu d y d is co nt in ua tio n c au se d b y a n A E S ul ta n e t a l, 20 17 24 Co m p ar at iv e an al ys is o f ta fa m id is st ud y w ith h is to ric al coh or t M ult ic en te r Ta fa mi di s Fx 1B -2 01 12 m TRAC S 24 m Ta fa mi di s 20 m g Q D N o tre atm en t N = 35 Fx 1B -2 01 N =2 9 TR AC S Un cle ar Tr ea t AT TR w t N = 31 AT TR v N= 4 H is to ric al c oh or t AT TR w t N =1 8 AT TR v N =11 • S ur vi va l • Ti m e t o d ea th ( N Y H A I o r I I a t b as el in e) AT TR w t+ AT TR v H ig he r w ith t af ami di s P = 0. 000 4 AT TR w t H ig he r w ith t af ami di s P = 0.0 26 2 Ta b le 3 . C o n tinu ed (C on tinu es )
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es E pig al lo ca te chi n- 3-ga lla te K ris te n e t a l, 20 12 25 P ro sp ec tiv e S ing le -c en te r 12 50 0 –7 0 0 m g epig al lo ca te chi n- 3-ga lla te (1 .5 –2 L g re en te a o r c ap su le s o f gr een tea e xt ra ct ) M ea n d os e 54 7± 49 m g N =1 9 66. 3 AT TR v N =1 0 AT TR w t N =9 • E ch oc ar dio gr aphic or MR I p ar ame te rs E ch oc ar dio gr aphic m ea su re s D at a a t 1 2 m o ( 14 p at ie nt s) • IV S thic kn es s − 6.5 % , P = 0. 0 081 D ec re as ed i n 8 6% ( 12 /1 4) S ta b le i n 7 % ( 1/ 14 ) In cr ea se d i n 7 % ( 1/ 14 ) • LV P W t hi ck ne ss D ec re as ed i n 7 1% ( 10 /1 4) In cr ea se d i n 2 9% ( 4/ 14 ) • LV m as s D ec re as ed i n 6 4% ( 9/ 14 ) S ta b le i n 1 4% ( 2/ 14 ) In cr ea se d i n 2 1% ( 3/ 14 ) • S ys tol ic v el oci ty o f l at er al m itr al a nn ul us In cr ea se d i n 7 1% ( 10 /1 4) D ec re as ed i n 2 9% ( 4/ 14 ) MR I me as ur es D at a a t 1 2 m o ( 9 p at ie nt s) • LV m as s ( % v ar ia tio n) −1 2. 5% , P = 0.0 03 9 D ec re as ed o r s ta b le i n a ll • LV E F ( % ) U nc ha ng ed , P = NS Sa fe ty o ut co me s • N o s er io us A E (C on tinu es ) Ta b le 3 . C o n tinu ed
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es A us D em S ie p en et a l, 2 01 5 26 P ro sp ec tiv e S ing le -c en te r 12 60 0 m g epig al lo ca te chi n- 3-ga lla te ca p su le s o f g re en te a e xt rac t N =7 72 AT TR w t N =7 • E C V D at a a t 1 2 m o v s b as el in e ( 7 p at ie nt s) • Tr op on in T ( μ g/ L) 26 ( 20 –3 9) v s 2 1 ( 14 –3 6) P = NS • N T-pr oB NP (n g/ L) 39 20 ( 20 79 –6 43 7) v s 2 31 3 ( 76 3 –5 66 4) P = 0.11 • N Y H A c la ss O ne c la ss I v s 2 c la ss I Th re e c la ss I I v s 2 c la ss I I Th re e c la ss I II v s 3 c la ss I II P = NS E ch oc ar dio gr aphic p ar am et er s • E /A r at io 1. 5 ( 0. 96 –2 .0 ) v s 1 .1 5 ( 0.6 7– 1. 53 ) P = NS • E /E ´ r at io 10 ( 7– 21 ) v s 9 ( 7– 15 ) P = NS E C G find ing s • R BBB 2 vs 2 P=NS • LBBB 2 v s 2 P = NS • L A FB 3 v s 3 P = NS • A F 3 vs 3 P=NS CMR pa ra m et er s • LV m as s ( g) M ed ia n de cr ea se — 6% 16 6 ( 12 6 –2 07 ) v s 1 79 ( 15 0 –2 17 ) P = 0.0 46 • LV E F ( % ) 55 ( 47 –6 4) v s 5 7 ( 48 –6 5) P = 0. 3 • N at iv e T 1 (m s) M ed ia n de cr ea se — 4% 10 80 (9 70 –11 20 ) v s 111 0 ( 10 42 –11 74 ) P = 0. 031 • P os t-co nt ra st T 1 (m s) 16 6 ( 12 6 –2 07 ) v s 1 79 ( 15 0 –2 14 ) P = ns • E C V ( % )4 1. 9 ( 38 .4 –4 4. 4) v s 4 2. 9 ( 36 .0 –4 7. 3) P = 0. 47 (C on tinu es ) Ta b le 3 . C o n tinu ed
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es A us D em S ie p en et a l, 2 01 5 27 P ro sp ec tiv e S ing le -c en te r 12 60 0 m g epig al lo ca te chi n- 3-ga lla te ca p su le s o f g re en te a e xt rac t N = 25 71 AT TR w t N = 25 • E ch oc ar dio gr aphic or MR I p ar ame te rs • N T-pr oB NP (n g/ L) 36 81 v s 3 61 7 E ch oc ar dio gr aphic m ea su re s 12 m o v s b as el in e • IV S t hi ck ne ss (m m ) 18 ( 14 –2 5) v s 1 7 ( 13 –2 8) P = NS • LV P W t hi ck ne ss (m m ) 17 ( 12 –1 9) v s 1 6 ( 11 –2 4) P = NS • LV m as s ( g) 33 5 ( 22 8 –5 01 ) v s 3 40 ( 17 3 –5 23 ) P = NS • LV E D D (m m ) 42 ( 33 –5 4) v s 4 4 ( 36 –5 3) P = NS • LV E S D (m m ) 32 ( 24 –4 9) v s 3 3 ( 23 –4 5) P = ns • M A P S E (m m ) 8 ( 4 –1 3) v s 1 0 ( 5 –2 3) P = 0. 3 • TA P S E (m m ) 15 ( 2– 20 ) v s 1 4 ( 8 –2 3) P = 0.4 • E /E ´ 14 ( 4 –3 1) v s 1 1 ( 7– 28 ) P = 0. 8 MR I me as ur es 12 m o v s b as el in e ( 14 p at ie nt s) • LV m as s ( g) − 5. 9% ,P = 0.0 3 18 0 ( 85 –2 37 ) v s 1 96 ( 10 0 –2 47 ) • LV E F ( % ) 54 ( 28 –7 1) v s 5 3 ( 33 –6 9) P = 0.7 5 • LV E D V (m L) 16 2 ( 10 2– 28 9) v s 1 61 ( 87 –2 78 ) P = NS • LV E S V (m L) 76 ( 40 –2 07 ) v s 6 9 ( 40 –1 85 ) P = ns • M A P S E (m m ) 6 ( 3 –9 ) v s 7 ( 3 –1 0) P = 0.0 8 • TA P S E (m m )1 1 ( 5 –1 6) v s 1 2 ( 4 –1 7) P = 0. 28 Sa fe ty o ut co me s N o s er io us A E (C on tinu es ) Ta b le 3 . C o n tinu ed
S tu dy /R ef er en ce S tu dy D es ign S tu d y S et ti ng S tu d y D u ra ti o n , mo Tr ea tm en ts N o . o f P atie nt s M ea n A g e, y A T T R Ty p e P ri ma ry O u tcom e R es u lts o n C ar d io va sc u la r O u tc o m es D ox yc yc lin e O b ic i e t a l, 2 01 2 28 P ro sp ec tiv e P ha se II M ult ic en te r 12 D ox yc yc lin e 10 0 m g B ID TU D CA 25 0 m g 3 t im es p er d N =2 0 64. 0 AT TR v N =17 AT TR w t N =3 ca rdiom yop at hy N =17 • R es po nse r at e a < 2-p oi nt i nc re as e in N eu ro p at hy Imp ai rme nt S co re -Lo we r L im b b <1 0% d ec re as e i n modi fie d B M I c < 30 % o r < 30 0 p g/ m L i nc re as e i n N T-pr oB NP D at a a t 1 2 m o ( 7 p at ie nt s) • N T-pr oB NP In cr ea se > 30 % i n 3 p at ie nt s S ta b le i n 4 p at ie nt s • IV S thic kn es s S ta b le i n 5 p at ie nt s D ec re as e > 2 m m i n 2 p at ie nt s • N Y H A c la ss S ta b le i n a ll p at ie nt s Sa fe ty o ut co me s • N o s er io us A E • Tr ea tm en t w as d is co nt in ue d i n 2 p at ie nt s b ec au se o f a n A E ( ga st ro in te st in al A E ) W ix ne r e t a l, 20 17 29 P ro sp ec tiv e P ha se II M ult ic en te r 18 12 m o D ox yc yc lin e 20 0 m g d /4 w k w ith 2 w k w ith ou t d ox yc ycl ine U D CA 75 0 m g/ d 6 m o W ith d raw al N = 28 72 AT TR v N = 27 AT TR w t N =1 • P roB NP • To ta l K um am ot o sc or e D at a a t 1 2 m o ( 10 p at ie nt s) • P roB NP In cr ea se a t 1 2 m o P < 0.0 05 • IV S thic kn es s S ta b le a t 1 2 m o 13 v s 1 5 m m , P = 0.7 0 Sa fe ty o ut co me s • Tr ea tm en t w as d is co nt in ue d i n 1 4% o f p at ie nt s b ec au se of a n A E A E i nd ica te s a dv er se e ve nt ; A F, a tri al f ib ril la tio n; A T TR , t ran st hyr et in -r el at ed a m yl oi d os is ; A T TR v, v ari an t t ran st hyr et in -r el at ed a m yl oi d os is ; A T TR w t, w ild -t yp e t ran st hyr et in -r el at ed a m yl oi d os is ; B M I, b ody m ass in d ex ; C A , c ar d ia c a m yl oi d os is ; E C V, e xt ra ce llu la r v ol um e; G LS , g lo ba l l on gi tu d in al s tr ai n; I V S , i nt er ve nt ric ul ar s ep tu m ; L A , l ef t a tr ia l; L A FB , l ef t a nt er io r f as ci cu la r b lo ck ; L B B B , l ef t b un d le b ra nc h b lo ck ; L V, l ef t ve nt ric ul ar ; L V E D D , l ef t v en tr ic ul ar e nd -di as to lic di am et er ; L V E D V, le ft v en tr ic ul ar e nd -di as to lic v ol um e; L V E F, le ft v en tr ic ul ar e je ct io n f ra ct io n; L V E S D , l ef t v en tr ic ul ar e nd -s ys to lic di am et er ; L V E S V, le ft v en tr ic ul ar e nd -sy st ol ic v ol um e; L V P W , l ef t v en tr ic ul ar p os te rio r w al l; M A P S E, m itr al a nn ul ar p la ne s ys to lic e xc ur si on ; N S V T, n on su st ai ne d v en tr ic ul ar t ac hy ca rd ia ; N Y H A , N ew Y or k H ea rt A ss oc ia tio n; P A S P, p ul m on ar y a rt er y s ys to lic pr es sur e; R B B B , r igh t b un d le br an ch bl oc k; R C T, r an domi ze d c on tr ol le d t ria l; T A P S E, t ric us pi d a nn ula r pla ne s ys to lic e xc ur si on ; T R A CS , T ra ns th yr et in A m yl oi do si s C ar d ia c S tud y; T U DC A , t aur our sod eo xy ch ol ic a ci d; U D C A , u rso d eo xy cho lic a cid ; a nd V T, v en tr ic ul ar ta ch yc ar di a. Ta b le 3 . C o n tinu ed
led to the exclusion of 644 records, mainly because they were review or opinion articles, natural history studies, or in vitro or animal research studies. The re-maining 64 records were further assessed for their eligibility for this review by full-text screening, which resulted in the additional exclusion of 40 publications, mainly because of the absence of reported cardiovas-cular outcomes. Relevant data were then extracted from 24 publications, namely 4 RCTs reported in 6 publications and 16 non-RCTs reported in 18 arti-cles. Figure 3 presents the PRISMA flow diagram of the studies identified in this systematic review of the literature.
Included Studies and Quality Assessment
A total of 4 RCTs were included in this review. The study characteristics of these trials are presented in Table 2 and their quality assessment in Figure 1.
The 4 RCTs included in this review were the following: 1. a phase III study (NEURO-TTR ) assessing inot-ersen versus placebo and including 172 patients, all with ATTRv, 105 of them with CA;
2. a phase III study (APOLLO) assessing patisiran ver-sus placebo and including 225 patients, all with ATTRv, 126 of them with CA7–9;
3. a phase III study (ATTR-ACT) assessing tafamidis versus placebo and including 441 patients with CA, 106 with ATTRv and 335 ATTRwt10; and
4. a phase II study (NCT03458130) assessing AG10 versus placebo and including 49 patients with CA, 14 with ATTRv and 35 ATTRwt.11
A total of 16 non-RCTs were included in this review. The study characteristics of these trials are presented in Table 3 and their quality assessment in Figure 2.
The 16 non-RCTs included in this review were the following:
1. one study on inotersen, single-arm, assessing 33 patients, 10 with ATTRv and 23 with ATTRwt12,13;
2. one study on patisiran, single-arm, assessing 27 pa-tients, all with ATTRv14;
3. four studies on diflunisal, including 3 single-arm and 1 comparative study of stabilizer therapy (diflunisal or tafamidis), assessing a total of 120 patients, with individualized data available from 100 patients with ATTRv and 7 patients with ATTRwt 15–18;
4. five studies on tafamidis, including 4 single-arm and 1 comparative study of tafamidis with a historical cohort, assessing a total of 127 patients, 96 with ATTRv and 31 ATTRwt19–24;
5. three studies on epigallocatechin-3-gallate (green tea extract), all single-arm, assessing 51 patients, 10 with ATTRv and 41 with ATTRwt25–27; and
6. two studies on doxycycline, both single-arm, as-sessing 48 patients, 44 with ATTRv and 4 with ATTRwt.28,29
Results of Cardiovascular and Safety
Outcomes
The data on the cardiovascular and safety outcomes that were extracted from the studies included in this re-view are detailed in Tables 2 and 3. In this section, we present the main results of the studies on each specific therapy for transthyretin CA.
Inhibition of Transthyretin Synthesis
Inotersen
Inotersen was assessed in 1 non-RCT12,13 and 1 RCT.6
Figure 1. Quality assessment of randomized controlled trials (RCTs).
Questi ons Benson2018(8) Adams 2018(9) Maurer 2018(12) Judge 2019(13)
1 Yes Yes Yes Unclear
2 Yes Yes Yes Unclear
3 Yes Yes Yes No
4 Yes Yes Yes Unclear
5 Yes No Yes No
6 No No No No
7 Yes Yes Yes Yes
1. Was randomization carried out appropriately? 2. Was the concealment of treatment allocation adequate?
3. Were the groups similar at the outset of the study in terms of prognostic factors? 4. Were the care providers, participants and outcome assessors blind to treatment allocation? 5. Were there any unexpected imbalances in drop-outs between groups?
6. Is there any evidence to suggest that the authors measured more outcomes than they reported?
7. Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data?
Figure 2. Quality assessment of non-randomized controlled trials (RCTs).
NA indicates not applicable; and U, unable to determine.
Question No. Benson 2017 (14) A dams 2017 (16) Castaño 2012 (17) Sekijima 2015 (18) Rosenbl um 2018 (19) Wixner 2019 (20) Merlini 2013 (21) Maurer 2015 (23) Cortese 2016 (24) A ndo 2016 (25) Sultan 2017 (26) Kristen 2012 (27) A us Dem Sie pen 2015 (28) A us Dem Sie pen 2015 (29) Obici 201 2 (30) Wixner 2016 (31)
1 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 2 Yes Yes Yes No Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes 3 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 4 Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes 5 No Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 6 No Yes Yes U U No Yes Yes No Yes Yes No Yes Yes No No 7 No No Yes Yes Yes No No Yes Yes Yes No No Yes Yes No No 8 Yes Yes No Yes No No Yes No Yes Yes Yes No No No No No 9 Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10 No No Yes Yes Yes Yes No No Yes No Yes No No No No No 11 Yes Yes No No Yes No No No Yes No No Yes Yes Yes No No 12 Yes Yes Yes No Yes No No No No No No Yes Yes Yes No No 13 No Yes No No No No Yes No Yes No No No No No U U 14 No No No No No No No No No No No No No No No No 15 No No No No No No No No No No No No Yes Yes No No 16 U U U U No U Yes U No No U No U U U No 17 No No No Yes Yes Yes No No No No Yes No No No No No 18 No No Yes U Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No
Question No. Benson 2017 (14) Adams 2017 (16) Castaño 2012 (17) Sekijima 2015 (18) Rosenb lu m 2018 (19) Wixner 2019 (20) Merlini 2013 (21) Maurer 2015 (23) Cortese 2016 (24) A ndo 2016 (25) Sultan 2017 (26) Kristen 2012 (27) Aus De m Si ep en 2015 (28) A us Dem Si ep en 2015 (29) Obici 201 2 (30) Wixner 2016 (31) 19 U Yes U U U U U U U U U Yes U U U U 20 Yes Yes Yes U Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 21 NA NA NA NA Yes NA NA NA NA NA Yes NA NA NA NA NA 22 NA NA NA NA Yes NA NA NA NA NA No NA NA NA NA NA 23 No No No No No No No No No No No No No No No No 24 No No No No No No No No No No No No No No No No 25 No No No No Yes No No No No No No No No No No No 26 No No U Yes U No No No No No U No No No No No
1. Is the hypothesis/aim/objective of the study clearly described?
2. Are the main outcomes to be measured clearly described in the introduction or methods section? 3. Are the characteristics of the patients included in the study clearly described?
4. Are the interventions of interest clearly described?
5. Are the distributions of principal confounders in each group of patients to be compared clearly described? 6. Are the main findings of the study clearly described?
7. Does the study provide estimates of the random variability in the data for the main outcomes? 8. Have all important adverse events that may be a consequence of the intervention been reported? 9. Have the characteristics of patients lost to follow-up been described?
10. Have actual probability values been reported (e.g. 0.035 rather than <0.05) for the main outcomes except where the probability value is less than 0.001? 11. Were the subjects asked to participate in the study representative of the entire population from which they were recruited?
12. Were those subjects who were prepared to participate representative of the entire population from which they were recruited? 13. Were the staff, places, and facilities where the patients were treated representative of the treatment the majority of patients receive?
Question No. Benson 2017 (14) Adams 2017 (16) Castaño 2012 (17) Seki jima 2015 (18) Rosenblu m 2018 (19) Wixner 2019 (20) Merlini 2013 (21) Maurer 2015 (23) Cortese 2016 (24) Ando 2016 (25) Sultan 2017 (26) Kristen 2012 (27) Aus De m Si ep en 2015 (28) Aus De m Sie pen 2015 (29) Obici 201 2 (30) Wixner 2016 (31)
14. Was an attempt made to blind study subjects to the intervention they have received? 15. Was an attempt made to blind those measuring the main outcomes of the intervention? 16. If any of the results of the study were based on ‘data dredging’, was this made clear?
17. In trials and cohort studies, do the analyses adjust for different lengths of follow-up of patients, or in case-control studies, is the time period between the intervention and outcome the same for cases and controls?
18. Were the statistical tests used to assess the main outcomes appropriate? 19. Was compliance with the intervention(s) reliable?
20. Were the main outcome measures used accurate (valid and reliable)?
21. Were the patients in different intervention groups (trials and cohort studies) or were the cases and controls (case-control studies) recruited from the same population? 22. Were study subjects in different intervention groups (trials and cohort studies) or were the cases and controls (case-control studies) recruited over the same period of time?
23. Were study subjects randomised to intervention groups?
24. Was the randomised intervention assignment concealed from both patients and health care staff until recruitment was complete and irrevocable? 25. Was there adequate adjustment for confounding in the analyses from which the main findings were drawn?
26. Were losses of patients to follow-up taken into account?
The non-RCT was a prospective single-arm study, with a duration of 36 months, which included 33 pa-tients treated with inotersen, 10 with ATTRv and 23 with ATTRwt, and reported results on cardiovascular bio-markers (BNP), echocardiographic and CMR param-eters, and clinical data (6-minute walk test and New York Heart Association [NYHA] class). The study com-pared data at the end of the study or at 12-month fol-low-up with baseline data. The interventricular septum thickness measured by echocardiography was lower at study end/12-month follow-up than at baseline, but no significant statistical difference was found on BNP, 6-minute walk test, or other parameters (Table 3).12,13
The phase III double-blind RCT, NEURO-TTR, in-cluded 172 patients with ATTRv, 105 of whom had CA, and compared inotersen with placebo, for a du-ration of 16.5 months, reporting echocardiographic
parameters as exploratory outcomes. In the subset of patients with CA, inotersen did not show a significant effect on the echocardiographic parameters that were evaluated (Table 2).6 Moreover, in patients taking
inot-ersen, there was a higher frequency of serious adverse events (placebo 22% versus inotersen 32%) and study discontinuation caused by adverse events (placebo 2% versus inotersen 14%); and one death occurred related to adverse events (placebo 0% versus inot-ersen 1%) (Table 2). The main serious adverse events associated with inotersen therapy were the occur-rence of glomerulonephritis and thrombocytopenia.6
Patisiran
Patisiran was assessed in 1 non-RCT14 and 1 RCT.7–9
The non-RCT was a prospective single-arm study, with a duration of 24 months, which included
Figure 3. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow
diagram.
CV indicates cardiovascular; RCT, randomized controlled trial.
noi
tac
ifit
ne
dI
Records idenfied through database searching (n=1203) gni ne erc S
Number of duplicates removed (n=495) Records screened (n=708) Records excluded (n=644) • Language (n=27) • Clinical case (n=49)
• Natural history studies (n=179) • Studies on liver transplantaon (n=57) • Animal/in vitro basic research (n=59) • Review/Opinion arcles (n=273)
ytili
bigi
lE
Full-text arcles assessed for eligibility
(n=64)
Arcles excluded (n=40)
• Natural history studies (n=2) • Phase I studies (n=3)
• Review/Opinion arcles (n=10) • Studies without CV outcomes (n=25)
Arcles included in qualitave evaluaon
(n=24)
noi
sul
cnI The evidence represents
• 4 RCTs (6 arcles) • 16 non-RCTs (18 arcles)
27 patients with ATTRv treated with patisiran, 11 of whom had CA, and reported exploratory data on car-diovascular biomarkers (natriuretic peptide and tro-ponin), echocardiographic parameters, and 10-meter walk test. In the subgroup of patients with CA, data at 24 months of follow-up were compared with base-line data, although without applying any statistical test (Table 3).14
The phase III double-blind RCT, APOLLO, com-paring patisiran and placebo, with a duration of 18 months, included 225 patients with ATTRv, 126 of whom had CA, and reported data for a prespecified analysis of the subpopulation with CA. Outcomes in-cluded mortality and hospitalization, mortality and cardiac hospitalization, 10-meter walk test, cardiovas-cular biomarkers (natriuretic peptide), and echocardio-graphic parameters. This subgroup analysis of patients with CA showed that patisiran, in comparison with pla-cebo, appeared to be associated with lower mortality and hospitalization rate with an hazard ratio (HR) of 0.49 (95% CI, 0.30–0.79), higher velocity in 10-meter walk test with a mean difference of 0.35 m/s (95% CI, 0.24–0.47), lower NT-proBNP (N-terminal pro-B-type natriuretic peptide), with a ratio of fold-change of 0.45 (95% CI, 0.34–0.59), lower left ventricular wall thick-ness, and a better cardiac output and global longitudi-nal strain. The results of the other parameters did not reach statistical significance (Table 2).7–9
No significant safety issues related to patisiran were found in these studies (Table 2 and Table 3).7–9,14
Tetramer Stabilization
Diflunisal
Diflunisal was assessed in 4 non-RCTs, with a small number of patients included in each study (between 13 and 54 patients).15–18 Three of these studies were
noncomparative single-arm prospective treated co-horts, reporting cardiovascular biomarkers (natriu-retic peptides and troponin) and echocardiographic parameters as exploratory end points.15,16,18 These
studies compared data at the end of the study with the baseline data (follow-up of 10.8–38.0 months) and suggested stabilization of biomarkers and echo-cardiographic parameters (Table 3).15,16,18 The other
non-RCT was a retrospective study comparing pa-tients on stabilizer therapy, diflunisal (n=13), or tafa-midis (n=16), with patients without stabilizer therapy.17
In this study, the stabilizer therapy was associated with significantly lower all-cause mortality or heart transplantation, although individualized data for each type of stabilizer was not reported (Table 3).17
Notably, the available data for diflunisal refers mainly to patients with ATTRv (n=100) and less to patients with ATTRwt (n=7).
Studies have reported intolerance to diflunisal in some patients, mainly related to gastrointestinal, renal, and hematological adverse events (Table 3).15–18
Tafamidis
Tafamidis was assessed in 5 non-RCTs19–24 and 1
RCT.10
Three of the non-RCTs were prospective noncom-parative single-arm studies in patients with ATTRv, which included a small number of treated patients (between 10 and 61 patients) and reported cardio-vascular outcomes, namely cardiac biomarkers (natriuretic peptides and troponin), ECG and echo-cardiographic parameters, and, in 1 of the studies, NYHA class progression. These studies compared the data at the end of the study with the baseline data (follow-up of 12–36 months), and suggested stabilization of biomarkers, ECG and echocardio-graphic parameters, and NYHA class in patients with ATTRv (Table 3). However, either no statistical test was applied or the outcomes were only explor-atory.19,20,22,23 One prospective noncomparative
sin-gle-arm non-RCT in patients with ATTRwt, including 31 patients, reported clinical outcomes (death, car-diovascular hospitalizations, worsening heart failure, and 6-minute walk test), cardiovascular biomarkers (natriuretic peptides and troponin), and echocardio-graphic and Holter parameters. This study compared data at the end of the study with baseline (follow-up of 12 months) regarding 6-minute walk test, car-diovascular biomarkers, and echocardiographic parameters, suggesting stabilization of all of the an-alyzed parameters with the exception of NT-proBNP, which showed a mean increment of 601 pg/mL in the 12 months (Table 3). This study also reported the occurrence of clinical events and new-onset brad-yarrhythmias or tachbrad-yarrhythmias, although without providing any comparative analysis.21
One non-RCT compared mortality data of a pro-spective study including 31 patients with ATTRwt and 4 patients with ATTRv treated with tafamidis with an untreated historical cohort from the TRACS (Transthyretin Amyloidosis Cardiac Study) registry, including 18 patients with ATTRwt and 11 patients with ATTRv. This study suggested a significantly higher survival in patients treated with tafamidis, both in the total cohort of patients and in patients with ATTRwt.24
The phase III double-blind RCT, ATTR-ACT, in-cluding 441 patients, 106 with ATTRv and 335 with ATTRwt (76.0%), compared tafamidis 20 or 80 mg with placebo, for a duration of 30 months. It reported data on all-cause mortality and cardiovascular hos-pitalizations as the primary outcomes and, also, clin-ical outcomes (6-minute walk test and Kansas City
Cardiomyopathy Questionnaire—Overall Summary [KCCQ-OS] score), cardiovascular biomarkers (na-triuretic peptide), and echocardiographic parameters as secondary outcomes. This study demonstrated a significant reduction in all-cause mortality with an HR of 0.70 (95% CI, 0.51–0.96) and cardiovascular hospitalizations with an HR of 0.68 (95% CI, 0.56– 0.81) in patients treated with tafamidis. Tafamidis also reduced the decline in 6-minute walk test and KCCQ-OS score and was associated with a smaller increase of NT-proBNP. A smaller decrease of left ventricular stroke volume and less worsening of cir-cumferential and radial global strain were also noted in patients treated with tafamidis, but no effect was detected in the other echocardiographic parameters that were evaluated (Table 2).10
The non-RCTs reported the occurrence of some adverse events,19–23 but the RCT ATTR-ACT has not
identified significant safety problems associated with tafamidis therapy in comparison to placebo (Tables 2 and 3).10
AG10
A phase II double-blind RCT, with a duration of 1 month, comparing AG10 and placebo and includ-ing 49 patients, 14 with ATTRv and 35 with ATTRwt, reported safety outcomes and exploratory data of cardiovascular biomarkers. However, no compara-tive statistic test was applied (Table 2). In this study there were no safety issues associated with AG10 therapy (Table 2).11
Inhibition of Oligomer Aggregation and Disruption
Epigallocatechin-3-gallate (green tea extract)
Epigallocatechin-3-gallate (green tea extract) was as-sessed in 3 non-RCTs,25–27 which were
noncompara-tive prospecnoncompara-tive single-arm studies, including a total of 51 patients, 10 with ATTRv and 41 with ATTRwt, with a 12-month follow-up, but in which data were only available for a small number of patients (from 7 to 25 patients). Cardiovascular outcomes of these stud-ies were cardiac biomarkers (natriuretic peptides and troponin) and ECG, echocardiographic, and CMR parameters. One study (n=14) showed that interven-tricular septum thickness, measured by echocar-diography, was lower at follow-up than at baseline, but this result was not supported by another study (n=25). In all studies, left ventricular mass, measured by CMR, was also significantly lower at follow-up than at baseline, although the difference was small. One study reported a significantly lower native T1 time (n=7) at 12 months, although the difference was small and without a significant change in extracellular
volume. All of the other analyzed parameters re-mained stable at 12 months (Table 3).25–27
These studies have not identified significant safety problems associated with green tea extract therapy (Table 3).25–27
Degradation and Reabsorption of Amyloid Fibers
Doxycycline+TUDCA or UDCA
Doxycycline was assessed in 2 non-RCTs28,29 (1 study
in association with TUDCA28 and 1 study in association
with UDCA29
The 2 non-RCTs were noncomparative pro-spective single-arm studies, including 48 patients, 44 with ATTRv and 4 with ATTRwt.28,29 In the study
with doxycycline and TUDCA, a stabilization of natri-uretic peptide, interventricular septum thickness, and NYHA class was reported in 7 patients at 12-month follow-up.28 In the other study with doxycycline and
UDCA, interventricular septum thickness remained stable, but proBNP levels were significantly higher at 12 months in 14 patients (Table 3).29 Notably, data were
available from only 21 patients.28,29
Studies have reported intolerance to doxycycline in some patients leading to treatment discontinuation (Table 3).28,29
DISCUSSION
This systematic review of the literature showed a clini-cal benefit in cardiovascular outcomes of patients with transthyretin CA, either ATTRv or ATTRwt, treated with tafamidis. The potential benefit of patisiran in patients with variant transthyretin CA needs to be confirmed in RCTs. Further studies are needed to evaluate the clinical efficacy and safety of other therapies in patients with transthyretin CA.
This systematic review allows us to recommend, with a high degree of certainty, the use of tafa-midis in transthyretin CA, both ATTRv and ATTRwt (Class of Recommendation I, Level of Evidence B). This recommendation is mainly based on the results of a large and well-designed phase III RCT, ATTR-ACT.10 In this study, tafamidis significantly improved
all-cause mortality and cardiovascular hospitaliza-tions, reduced the decline in 6-minute walk test and KCCQ-OS score, and was associated with a smaller increase of NT-proBNP, smaller decrease of left ven-tricular stroke volume, and less worsening of radial and circumferential global strain in patients with CA, caused by ATTRv or ATTRwt. Of note, in the sub-group analysis of ATTR-ACT, the occurrence of car-diovascular hospitalizations was not significantly different between tafamidis and placebo in the sub-group of patients with ATTRv. However, it should be
noted that the study had no statistical power to draw conclusions from the subgroups and the P interac-tion was not significant. In ATTR-ACT,10 tafamidis
use was safe. Based on the available evidence, the use of tafamidis was approved in adults with trans-thyretin CA (ATTRwt and ATTRv) by the Food and Drug Administration (FDA) in 2019 and the European Medicines Agency (EMA) in February 2020.
This systematic review of the literature also sug-gests that patisiran is a promising drug for patients with variant transthyretin CA.
This hypothesis is mainly based on a subgroup anal-ysis of a phase III double-blind RCT, APOLLO,7–9 which
suggested that treatment with patisiran in these pa-tients was associated with a reduction in mortality and hospitalization, as well as a reduction in NT-proBNP and left ventricular wall thickness and less worsening in cardiac output, global longitudinal strain, and 10-meter walk test. In APOLLO,7–9 patisiran use was safe,
without significant adverse events. The potential bene-fit of patisiran in patients with variant transthyretin CA is currently under investigation in the APOLLO-B phase 3 RCT. Moreover, there are no available data so far to support the use of patisiran in patients with CA caused by ATTRwt and results on these patients will also be provided by the ongoing APOLLO-B trial. Patisiran is currently only approved by the EMA and FDA in adults with ATTRv-related polyneuropathy.
Further studies will be needed to evaluate the effect of inotersen in patients with transthyretin CA, as data in the only 2 studies were contradictory, with 1 non-RCT12,13 showing an improvement of the exploratory
outcome of interventricular septum thickness mea-sured by echocardiography, and 1 RCT, the NEURO-TTR trial,6 showing an absence of significant effect on
the echocardiographic parameters in the subgroup of patients with CA caused by ATTRv. Inotersen, in the NEURO-TTR trial,6 was also associated with the
oc-currence of severe adverse events, namely glomerulo-nephritis and thrombocytopenia. Inotersen is currently only approved by the EMA and FDA in adults with ATTRv-related polyneuropathy.
Similarly, the use of diflunisal cannot be recom-mended at the present time in patients with trans-thyretin CA, because the studies on diflunisal15,16,18
are all noncomparative small non-RCTs, including almost exclusively patients with ATTRv, with explor-atory cardiovascular end points limited to cardiovas-cular biomarkers and echocardiographic parameters. Furthermore, intolerance to diflunisal has been re-ported in some patients, mainly related to gastroin-testinal, renal, and hematological adverse events. The use of diflunisal in transthyretin CA is not currently ap-proved by the EMA or FDA.
Similarly, AG10 cannot be recommended at the present time for transthyretin CA, as the only study of
AG1011 had a short duration of 1 month and the
cardio-vascular end points are merely exploratory and limited to cardiac biomarkers. Accordingly, the use of AG10 in transthyretin CA is not currently approved by the EMA or FDA.
Although a small but significant benefit was found on cardiac MRI parameters such as left ventricular mass and native T1 in patients with transthyretin CA treated with epigallocatechin-3-gallate (green tea ex-tract), these results should be interpreted carefully, as they are based on noncomparative single-arm small non-RCTs.25–27 Therefore, the use of
epigallocate-chin-3-gallate cannot be recommended at the present time, in transthyretin CA. The EMA and FDA also did not approve the use of epigallocatechin-3-gallate in transthyretin CA.
Similarly, results on doxycycline+TUDCA or UDCA are contradictory and based on 2 noncomparative28,29
single-arm small non-RCTs. Doxycycline+TUDCA or UDCA are currently not approved by the EMA or FDA in transthyretin CA.
Further studies, preferentially large double-blinded RCTs, evaluating not only cardiac biomarkers or imag-ing parameters but also hard clinical end points, such as all-cause mortality, cardiovascular mortality, and cardiovascular hospitalizations, will be needed to bet-ter evaluate the efficacy of patisiran, inobet-tersen, difluni-sal, AG10, epigallocatechin-3-gallate, and doxycycline in patients with transthyretin CA.
This is an enthusiastic field of investigation. Many randomized, double-blind, placebo-controlled phase 3 studies are currently underway and their results may change the paradigm of treatment of ATTR cardiomyopathy in the coming years. APOLLO B is evaluating patisiran in patients with ATTR cardiomy-opathy (ATTRwt or ATTRv), considering 6-minute walk test as the primary end point and death and hospitalization outcomes as secondary end points at 12 months. The HELIOS-B study is evaluating another RNA interference agent, vutrisiran, with the advantage of a subcutaneous administration every 3 months. This study will also include patients with ATTR cardiomyopathy, either ATTRwt or ATTRv, but the primary end point is the composite outcome of all-cause mortality and recurrent cardiovascular hos-pitalizations at 30 months. The CARDIO-TTRansform trial is evaluating another antisense oligonucleotide, AKCEA-TTR-LRX, with the advantage of a lower fre-quency of administration (every 4 weeks) and pos-sibly of side effects compared with inotersen. This study will also include patients with ATTR cardiomy-opathy, either ATTRwt or ATTRv, and the primary end point is cardiovascular mortality and clinical events at 120 weeks. The ATTRIBUTE-CM study is evaluating AG10 in patients with ATTR cardiomyopathy (ATTRwt or ATTRv) and the primary end points are 6-minute
