Untreated, Both ATTRv and ATTRwt Lead to Death in < 5 Years

Survival studies in patients with ATTRwt-CM coalesce around median survival in the 3.5 to 5-year range; generally, ATTRv progresses even more quickly [1-7]
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  • Transthyretin Amyloid Cohort Study (TRACS): in an early longitudinal multicenter investigation that studied advanced patients, mortality with ATTR-CA was high and was worse in patients with ATTRv Val22Ile vs. ATTRwt [3]
    • Common causes of death included HF, SCD, and sepsis
  • Transthyretin Amyloid Outcome Survey (THAOS): which focused on US ATTR patients, corroborated the above data and reported significantly worse age-adjusted survival from time of enrollment over 3 years in patients with ATTRv-CA Val122Ile vs. ATTRwt-CA [3]
  • A single-center US study also demonstrated significantly worse overall and age-adjusted survival from time of diagnosis in patients with ATTRv-CA Val122Ile compared with ATTRwt-CA (median survival 47 months vs. 59 months, P = .01), with survival diverging well after 24 months from diagnosis [5]
  • A smaller US study also found that survival in 11 V122I ATTRv patients was worse than 18 ATTRwt patients (median survival 25.6 months vs. 43 months, respectively) [6]
Notes: CM = cardiomyopathy; HF = heart failure; SCD = sudden cardiac death
 
  1. Hendren, NS, et al. Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis. Current Heart Failure Reports. 2020;17:77-83. https://doi.org/10.1007/s11897-020-00457-z.
  2. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-2891. doi:10.1016/j.jacc.2019.04.003
  3. Thoracic Key: Cardiac Amyloidosis. https://thoracickey.com/cardiac-amyloidosis-4/. Accessed November 3, 2021.
  4. Yilmaz, A., Bauersachs, J., Bengel, F. et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol. 110, 479–506 (2021). https://doi.org/10.1007/s00392-020-01799-3.
  5. Singh A, Geller HI, Falk RH. Val122Ile mt-ATTR Has a Worse Survival Than wt-ATTR Cardiac Amyloidosis. J Am Coll Cardiol. 2017 Feb 14;69(6):757-758. doi: 10.1016/j.jacc.2016.09.987. PMID: 28183520.
  6. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164(2):222-8 e1.
  7. Lane T, Fontana M, Martinez-Naharro A, Quarta CC, Whelan CJ, Petrie A, et al. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. Circulation. 2019;140(1):16-26.

ATTRwt-CM Mortality in Japan

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There is limited data on mortality and survival in ATTRwt-CM patients in Japan [1], but a recently published study found median survival of ATTRwt-CM at 4.9 years [2]
In a study of 129 consecutive patients with ATTRwt-CM, diagnosed between 2002 and 2019 at Kumamoto University in Japan, median survival was 58.9 months (4.9 years) from diagnosis [2]
  • 3-years survival was 68.7%
  • 5-year-survival was 48.0%
 
•
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Deaths were classified as cardiac or non-cardiac—among 34 deaths during the study period:
  • 27 (79%) were due to cardiac reasons, primarily heart failure
  • Noncardiac deaths included:
    • Pneumonia (4);
    • Sepsis (2); and
    • Lung cancer (1) [2]
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All-cause survival (months) from time of diagnosis
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ATTR mortality studies in Japan
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  1. ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier
  2. Yamada T, Takashio S, Arima Y, Nishi M, Morioka M, Hirakawa K, et al. Clinical characteristics and natural history of wild-type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail. 2020;7(5):2829-37.

ATTR-CM Mortality in the US and UK

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Length of survival is significantly impacted by severity at diagnosis
Gillmore, et al. 2018: NAC staging for ATTR-CA (both ATTRwt-CM and ATTRv) using NT-proBNP (threshold of >3,000 pg/ml) and eGFR (<45 ml/min/1.73 m2) [3]
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Law, et al. studied 945 ATTR-CM patients in the UK NAC (ATTRwt and ATTRv associated with V122I mutation), diagnosed between 2001 and 2019 [1,2]:
Median Survival by NAC ATTR Stage at Time of Diagnosis
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Notes: eGFR = estimated glomerular filtration rate; NAC = National Amyloidosis Centre (UK); NT-proBNP = N-terminal pro b-type natriuretic peptide
  1. ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier.
  2. Law S, Petrie A, Chacko L, Cohen OC, Ravichandran S, Gilbertson JA, et al. Disease progression in cardiac transthyretin amyloidosis is indicated by serial calculation of National Amyloidosis Centre transthyretin amyloidosis stage. ESC Heart Fail. 2020.
  3. Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39(30):2799-806.

Predictors of Disease Progression with Cardiac Involvement

In both ATTRwt and ATTRv, the degree of cardiac involvement is closely associated with prognosis and survival. [1,2] A number of biomarkers have been linked to disease progression, however, an accurate prognostic prediction method has not yet been established. [6]
  • The amyloid deposits can infiltrate all structures of the heart and, in addition to the ventricular and atrial wall, can also affect the conduction system, the heart valves, and the coronaries
  • Thus, the clinical spectrum of cardiovascular involvement is broad, ranging from asymptomatic courses, the occurrence of dizziness and syncope, to the development of restrictive CM and progressive terminal heart failure
  • The cardiac biomarkers NT-proBNP and troponin T are often elevated, but not as pronounced as in patients with AL amyloidosis [5]
In addition to the risk factors used in proposed staging systems (NT-proBNP and troponin T, see treatment section), a few other predictors of mortality have been identified:
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  • In a cohort of ATTR-CM patients (n=869) from the same setting as Law et al., eGFR <45 ml/min/1.73 m2 was an independent predictor of mortality on multivariable analysis [7]
    • Median survival was ~ 2.5 years for those with eGFR below the threshold compared with ~ 5 years for those above the threshold
  • Lane, et al. studied 711 patients with ATTRwt-CM, 205 with V122I-ATTRv-CM, and 118 with non-V122I-ATTRv-CM at the UK NAC between 2000 and 2017 [4]
    • NAC ATTR Disease Stage, calculated according to previously published cutoffs in NT-proBNP (3000 ng/L) and eGFR (45 mL/min) was, as expected, strongly predictive of survival across all genotypes (as well as within each) with a median survival of 68.0, 42.4, and 25.9 months among patients with stage I, stage II, and stage III disease respectively
    • Moreover, Lane, et al. also found that 6MWT was among independent variables to predict all-cause mortality
  • In a small US study by Ruberg, et al. (V1221 ATTRv and ATTRwt patients), predictors of mortality in the entire cohort included increased disease duration, heart rate >=70 beats/min, baseline stroke volume (higher stroke volume protective), LVEF <50%, and presence of V122I mutation [3]
  • The Japanese guidelines note that the following prognostic factors were identified: age, NYHA functional class, biomarkers (e.g., BNP/NT-proBNP, troponin, renal function, uric acid), echocardiographic indices (e.g., LVEF, relative wall thickness, strain), and CMR (e.g., LGE, ECV) [6]
 
* HF survival prediction models using multiple clinical indicators have been reported but it is unclear if they are useful for ATTR. For HF in general, the most consistently reported predictors were age,NYHA functional class, renal function, low blood pressure, low body mass index, malnutrition, and exercise capacity. In addition, in aged patients w ith HF, comorbidities are often the primary determinant of prognosis, rather than HF itself.5
Notes: eGFR = estimated glomerular filtration rate; NAC = National Amyloidosis Centre (UK); NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA = New York Heart Association
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A-fib + independent predictors
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  1. ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier. Citing:
  2. Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-12.
  3. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-91.
  4. Lane T, et al. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. Circulation. 2019;140(1):16-26.
  5. Yilmaz, A., Bauersachs, J., Bengel, F. et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol 110, 479–506 (2021). https://doi.org/10.1007/s00392-020-01799-3
  6. Kitaoka, et al. JCS 2020 Guidelines Dx Tx Cardiac Amyloidosis Circ J 2020.pdf.
  7. Feng KY, Loungani RS, Rao VN, Patel CB, Khouri MG, Felker GM, et al. Best Practices for Prognostic Evaluation of a Patient With Transthyretin Amyloid Cardiomyopathy. JACC: CardioOncology. 2019;1(2):273-9.

ATTRwt Staging to Characterize Severity and Prognosis

ATTR staging has also been used to characterize severity and prognosis in addition to NYHA Functional Class; however, it has not been universally adopted as a prognostic method [1]
Both of the following studies found that ECHO findings were not independent predictors of survival [2]
  • Grogan, et al. 2016: Mayo Clinic staging for ATTRwt-CM based on troponin T and NT-proBNP (>0.05 ng/ml and >3,000 pg/ml, respectively)3
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  • Gillmore, et al. 2018: NAC staging for cardiac ATTR amyloidosis (both ATTRwt-CM and ATTRv) also uses NT-proBNP (same threshold of >3,000 pg/ml) and eGFR (<45 ml/min/1.73 m2)4
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Data from Cheng, et al. (2020) [5] suggests that adding diuretic dose and functional class improves model prediction; scoring parameters:
 
  • Mayo or NAC score (0-2 points)
  • Daily dose of furosemide or equivalent (diuretic):
    • 0mg/kg (0 points); >0-0.5mg/kg (1 point); >0.5-1mg/kg (2 points); >1mg/kg (3 points)
  • NYHA class I-IV (1 to 4 points)
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Incremental Benefit of Adding Diuretic Dose and NYHA Functional Class to Existing ATTR-CM Risk Models for All-Cause Mortality [5]
  • Adding diuretic dose + NYHA functional class to the Mayo Clinic score improved the time-dependent AUC from 0.693 to 0.798
  • Adding diuretic dose + NYHA functional class to the NAC score improved the time-dependent AUC from 0.711 to 0.816
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Notes: AUC = area under the curve; eGFR = estimated glomerular filtration rate; NAC = National Amyloidosis Centre (UK); NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA = New York Heart Association
  1. ALXN: ATTR Amyloidosis: Epidemiology Dossier. Elissa Wilker & Shona Fang. September 2021. 18_ATTR Amyloidosis Epi Dossier. Citing:
  2. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-91.
  3. Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, et al. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016;68(10):1014-20.
  4. Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39(30):2799-806.
  5. Cheng RK, Levy WC, Vasbinder A, Teruya S, De Los Santos J, Leedy D, et al. Diuretic Dose and NYHA Functional Class Are Independent Predictors of Mortality in Patients With Transthyretin Cardiac Amyloidosis. JACC CardioOncol. 2020;2(3):414-24.
  6. Garcia-Pavia P, et al. Diagnosis and Treatment of Cardiac Amyloidosis: A Position Statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2021;42(16):1554-1568. DOI: https://doi.org/10.1093/eurheartj/ehab072.

Prognostic Predictors in Japan

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In Japan, ATTRwt staging and/or prognostic systems have not yet been developed; however, a recent study identified three meaningful prognostic biomarkers
In a small retrospective study of the clinical characteristics and outcomes of 47 ATTRwt patients, 15 patients died within 2 years of diagnosis*
The best predictors of 2-year mortality were**:
  • Low serum albumin (≤3.75 g/dL),
  • Elevated hs-cTnT (>0.086 ng/mL), and
  • Reduced LVEF (<50%)
The combination of these factors may be useful for predicting medium-term mortality in patients with ATTRwt [1]***
Patients were stratified into 4 subgroups according to total number of these 3 risk factors:
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There were no differences in ECG findings between survivors and non-survivors within the 2 years after diagnosis

However, with regard to echocardiographic parameters, survivors had a significantly higher SVI (36.1±10.2 vs. 27.9±5.7 mL/m2, respectively; P=0.015) and lower E/e′ ratio (septal; 21.8±7.6 vs. 28.7±10.5, respectively; P=0.017) than non-survivors
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Notes: ECG = electrocardiography; E/e’ ratio = ratio of the peak early mitral inflow velocity (E) over the early diastolic mitral annular velocity (e′); hs-cTnT = high-sensitivity cardiac troponin T; LVEF = left ventricular ejection fraction; SVI = stroke volume index
Notes: * Retrospective evaluation of 70 consecutive ATTRwt patients diagnosed at Kochi Medical School Hospital between April 2001 and August 2019 for all-cause death. 23 were excluded because their 2-year outcome was unknown.

Notes: ** There were no significant differences in sex, BSA, BMI, severity of HF (ACC/AHA stage, NYHA class, plasma BNP concentration), prevalence of comorbidities, eGFR, serum UA concentration, or medication between the 2 groups.

Notes: *** Several prognostic factors, such as biomarkers and echocardiographic parameters, have been proposed in patients with ATTR amyloidosis. In a large series, Connors et al identified BNP, RWT, LVEF, and UA as factors associated with survival in a prospective cohort study of ATTRwt. The Mayo Clinic presented a staging system for ATTR cardiac amyloidosis, using N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin T, whereas Gillmore et al proposed another staging system using NT-proBNP and eGFR. Conversely, in the present study, serum albumin, hs-cTnT, and LVEF were found to be markers of 2-year mortality in our cohort. However, the authors also noted that these differences in clinical features may result from a bias in patient cohorts from referral tertiary centers or community-based medical facilities. They recently reported that patients with ATTRwt in daily clinical practice presented broad clinical features, unlike patients with classical characteristics. Therefore, previously published prognostic factors of ATTRwt may not be generalizable to these patients.
  1. Ochi Y, et al. Prediction of Medium-Term Mortality in Japanese Patients With Wild-Type Transthyretin Amyloidosis. Circ Rep. 2020 Apr 29;2(6):314-321. DOI: https://doi.org/10.1253/circrep.CR-20-0031.

Conceptual Model of Cardiac ATTR Progression

ATTR is an increasingly recognized cause of restrictive CM related to amyloid fibril deposition in cardiac tissues; as therapies have emerged for ATTR, so has interest in using biomarkers to identify disease prior to advanced presentation [1]
Myocardial amyloid infiltration occurs before clinically manifest changes in ejection fraction, cardiac biomarkers, and renal function.

Thus, most patients with cardiac ATTR likely have a long latency period before declines in functional capacity, which can occur rapidly in the context of multiple hospitalizations for acute decompensated heart failure and arrhythmias.

Transthyretin, retinol binding protein-4, transthyretin kinetic stability, and protein-based peptide probes have potential as biomarkers for earlier diagnosis and prognosis. [1]
ATTR-CM patients typically experience years of relative stability despite advanced disease based on imaging, hemodynamics, and reduced functional capacity; this is followed by significant decline3
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* Biomarker Stage defined by the Mayo Clinic for ATTRwt as cardiac troponin T (< 0.05 ng/mL) and amino-terminal pro-B-type natriuretic peptide (< 3000 pg/mL) with stages I, II, and III defined as having both, one, or neither of the markers below the threshold [1]
Notes: NAC = National Amyloidosis Center (UK); NYHA = New York Heart Association
Notes: ^ Changes in various parameters are shown. The relative scale specific to each factor and time course are not proportional. The ideal emerging therapeutic window for novel therapies is hypothesized to be before significant organ dysfunction has occurred and before rapid and potentially irreversible declines in functional capacity. 
  1. Hendren, NS, et al. Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis. Current Heart Failure Reports. 2020;17:77-83. https://doi.org/10.1007/s11897-020-00457-z.
  2. Image reprinted from: Grodin JL, Maurer MS. The Truth Is Unfolding About Transthyretin Cardiac Amyloidosis. Circulation. 2019;140 (1):27–30.
  3. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(22):2872-91.

Clinical Follow-up in ATTR-CM

Model 1
Experts* with experience in treating amyloidosis and ATTR-CM developed consensus recommendations for monitoring the course of patients with ATTR-CM and proposed meaningful thresholds and frequency for specific parameters
A set of 11 measurable features across 3 separate domains were evaluated; experts recommended at least 1 marker from each of the 3 domains as the minimum requirements for assessing disease progression
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The NAC, Mayo Clinic, and NYHA(+) models use independent measures for estimating prognosis in ATTR-CM, but they are limited by inter-subject variability and were not designed to monitor progression
Notes: 6MWT = 6-min walk test; ECG = electrocardiogram; EQ-5D = EuroQol five dimensions; GLS = global longitudinal strain; HF = heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; LV = left ventricular; LVEF = left ventricular ejection fraction; NAC = UK National Amyloidosis Centre; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; QoL = quality of life
Notes: * A panel of experts from Europe (Austria, France, Germany, Italy, Portugal, Spain and UK), Japan, and the USA were convened in sponsored meetings. No participant was appointed by a national society or by a regulatory authority.​
 

Notes: Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered.

Model 2
In patients with cardiac amyloidosis in general, serial comprehensive follow-up examinations should be performed including the assessment of all involved organs / organ systems [2]
For the assessment of the clinical course of CA and the respective treatment effect, primarily laboratory biomarkers such as NT-proBNP or troponin T (or -I) as well as non-invasive imaging parameters are available [2]
However, further research is urgently indicated
Even though (a) the existing data for serum biomarkers such as NT-proBNP or troponin T (or I) are much more comprehensive than for non-invasive imaging parameters (e.g., CMR parameters) and (b) some staging procedures already account for the level of NT-proBNP or troponin T (or I) levels, a diagnostic “superiority” of these serum parameters in direct comparison to new imaging parameters has not yet been proven
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On the contrary, initial CMR results indicate that a more precise risk stratification, e.g., with the T1 mapping procedure and the determination of the ECV value, is possible
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Simply measuring the LV wall thickness or the LVEF, on the other hand, is insufficient or only of minor importance in assessing treatment success and to risk stratification of CA
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The following monitoring schedules have also been proposed
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a. Measuring of NT-proBNP should be performed in patients in a (re)compensated state (and with a time delay from any cortisone administration)

b. For Vyndaqel, lack of further increase in NT-proBNP has already been interpreted as a Tx success, while, e.g., under Patisiran, a drop of > 30% to the respective prior value was described after 9 and 18 months
Notes: CA = cardiac amyloidosis; CMR = cardiac magnetic resonance; ECHO = echocardiograph; ECV = extracellular volume fraction; LGE = late gadolinium enhancement; LV = left-ventricular; LVEF = LV ejection fraction; NT-proBNP = N-terminal pro b-type natriuretic peptide
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Tracking Disease Progression: Changes in Amyloid Load
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Tracking Disease Progression: Serum TTR Levels
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  1. Garcia-Pavia P, et al. Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy. Eur J of Heart Failure. (2021)23, 895–905. DOI: 10.1002/ejhf.2198.
  2. Yilmaz, A., Bauersachs, J., Bengel, F. et al. Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK). Clin Res Cardiol. 110, 479–506 (2021). https://doi.org/10.1007/s00392-020-01799-3