Systematic review and meta-analysis of prognostic markers in transthyretin amyloid cardiomyopathy

Abstract

BACKGROUND

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and fatal cardiomyopathy resulting from myocardial deposition of misfolded transthyretin protein. The literature on review of prognostic tools in this patient population is limited.

AIM

To determine which parameters are commonly used in prognostication of ATTR-CM.

METHODS

We conducted a systematic review of studies assessing prognostic role in ATTR-CM amyloidosis. Studies published from inception till December 2022 were included in this review. The databases searched were PubMed, EMBASE, Scopus and ACP Journal Club, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register Database, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, National Health Service Economic Evaluation Database.

RESULTS

Of 7272 studies initially identified, 42 studies comprising 13145 transthyretin amyloid (ATTR) patients were included. The median mortality of patients with ATTR was 33.6%. Majority of studies assessed biomarkers [Troponin, B type Natriuretic peptide (BNP), NTpro-BNP, glomerular filtration rate (eGFR)], echocardiographic findings [interventricular septal diameter (IVSd), posterior wall thickness, left ventricle ejection fraction (LVEF)], New York heart association (NYHA) class, Gillmore staging in predicting mortality, they were included in meta-analysis. In meta-analysis, higher Gillmore staging, BNP, N Terminal pro-B Type Natriuretic peptide (NT-proBNP), troponin-T, IVSd, and NYHA were associated with higher risk of mortality. On other hand, higher eGFR, was associated with lower risk of mortality.

CONCLUSION

Most commonly used parameters for prognostication of ATTR-CM studies included Gillmore staging, eGFR, Trop-T, NT pro-BNP and LVEF. Prognostication of ATTR-CM patients can help predict disease severity, survival outcomes and subsequently timely initiation of appropriate treatment strategies.

Key Words: Transthyretin amyloid cardiomyopathy; Prognosis; Gillmore staging; Biomarkers; Echocardiogram; Glomerular filtration rate

Core Tip: We conducted systematic review and meta-analysis assessing prognostic tools in transthyretin amyloid cardiomyopathy (ATTR-CM) amyloidosis. Out of 7272 studies identified, 42 studies (13145 patients) were included. Prognostic factors associated with higher odds of mortality in transthyretin cardiomyopathy included: higher Gillmore staging, B type Natriuretic peptide, NT pro-BNP, troponin-T, interventricular septal thickness, New York heart association class. Prognostication of ATTR-CM patients can significantly aid in predicting disease severity and guide timely initiation of appropriate treatment strategies.

INTRODUCTION

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and fatal cardiomyopathy resulting from myocardial deposition of misfolded transthyretin (TTR) protein[1]. Studies have reported median survival from diagnosis is 3-4 years in ATTR-CM patients[2]. There had been significant transformation in landscape of management of ATTR-CM patients with advent of new medical therapies like TTR protein stabilizers and TTR gene silencers[3,4]. Hence, determining prognostication tools in this population is crucial for not only determining disease severity but also tailoring treatment therapies especially earlier in the disease course. Although, there has been a significant increase in scientific literature regarding prognostication markers in ATTR-CM in recent years including role of biomarkers [NT pro-BNP (N terminal pro brain natriuretic peptide), B type Natriuretic peptide (BNP), troponin], imaging studies [echocardiogram, cardiac magnetic resonance imaging (MRI), technetium pyrophosphate scan (Tc PYP scan)], New York heart association (NYHA) classification, type of genetic mutation and cardiopulmonary exercise testing (CPET); however, there is a lack of systematic review or meta-analysis combining these studies, which is considered the highest level of evidence[5-11]. Therefore, we conducted systematic review and meta-analysis including these studies to provide physicians with predominant parameters studied to determine prognosis in ATTR-CM patients.

MATERIALS AND METHODS

Study design and objectives

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations[12]. The published literature was systematically searched for studies reporting (1) Prognostic role of biomarkers [troponin-T, NT pro-BNP, BNP, estimated glomerular filtration rate (eGFR)], imaging modalities (cardiac MRI, echocardiogram, Tc PYP scan), functional tests that includes CPET, NYHA class, 6 minute walk test; and (2) Clinical outcome that is, all-cause mortality in ATTR-CM patients. The study was registered with PROSPERO (ID: CRD42022332550).

Literature screening and study eligibility

Eligibility criteria for including studies were as follows.

Type of studies: Clinical cohorts (both prospective and retrospective) or randomized control trials (in English language).

Type of participants: Patients with ATTR-CM (either wild type or hereditary type), 18 years and older.

Time definition: The mortality was extracted for median study duration when available.

Type of interventions: Any intervention which included prognostic tools like (biomarkers, imaging and functional test) in patients with ATTR-CM.

Type of outcome measured: The primary outcome measured was all-cause mortality.

We excluded following studies: Animal, pre-clinical or phase I studies, reviews, abstracts, meta-analyses, case reports, case series, notes, comments, editorials, letters, or opinions, studies not in English.

Search strategy and sources of information

An experienced medical librarian developed and conducted the literature search in following databases:

PubMed, EMBASE, Scopus and ACP Journal Club, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register Database, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, National Health Service Economic Evaluation Database from database inception till December 2022. MeSH and keywords search terms included: “Amyloidosis”, “cardiac amyloidosis”, “transthyretin amyloid cardiomyopathy”, “ATTR-CM”, “wild type transthyretin cardiomyopathy”, “prognostic role in transthyretin cardiomyopathy”, “mortality”.

Study selection and data collection

We used Covidence (a standard platform for systematic reviews) for data management and extraction of studies[13]. Two independent reviewers (Joseph Mancuso, Siva Naga S Yarrarapu) screened abstracts and two other independent reviewers (Anureet Malhotra, Varun Kohli) screened full text review to be included in the final list of extracted studies. Two independent reviewers (Amandeep Goyal, Tarun Dalia) reviewed the results and resolved any conflicts. The pertinent data extracted included study first author, publication date, study location, study design, study participants number, baseline characteristics, study interventions, median follow-up and study outcomes.

Assessment of methodological quality

The risk of bias for randomized controlled trials was assessed using the revised Cochrane risk-of-bias tool for randomized trials[14]. For retrospective observational studies and cohort studies, the Newcastle-Ottawa Scale (NOS) for case-control and cohort studies was used, respectively[15]. For the NOS, a score of 6 or more was considered to be suggestive of higher study quality and study credibility. Two authors (Varun Kohli, Siva Naga S Yarrarapu) assessed the risk of bias in the included studies, and the results were reviewed by other authors. Disagreements were resolved by group discussion and consensus. The signaling questions and quality assessment definitions are provided in Supplementary material. The risk of bias is provided in Supplementary Tables 1 and 2. To assess potential publication bias, we examined funnel plot and performed meta-regression and Egger’s regression tests (Supplementary Figure 1). We also performed sensitivity analysis using trim and fill method (Supplementary material).

Statistical analysis

Statistical heterogeneity was assessed using the Cochran Q test and the I² statistic[16]. A P value of ≤ 0.05 and an I² value of 50% or more was considered as evidence of heterogeneity. Pooled hazard ratios (HRs) and corresponding confidence intervals for outcomes of interest were calculated using a random-effects model. All analyses were performed using RevMan 5.3 statistical software (The Cochrane Collaboration, Copenhagen, Denmark).

As majority of studies assessed biomarkers (Troponin, BNP, NT pro-BNP, eGFR), echocardiographic findings [Interventricular septal diameter (IVSd), posterior wall thickness (PWT), left ventricle ejection fraction (LVEF)], NYHA, Gillmore staging in predicting mortality, they were included in meta-analysis. For Troponin, BNP, NT pro-BNP variables: We only included those studies in meta-analysis which reported logarithmic change in these units because per unit change in these variables has none to very minimal clinical value. Similarly, for LVEF: We included those studies in meta-analysis which compared LVEF > 50% to < 50%.

RESULTS

Our search identified 7272 studies, out of which 42 eligible studies were included in the systematic review after applying inclusion and exclusion criteria (Figure 1).

Figure 1 PRISMA diagram showing flowchart of final studies included in this systematic review.

Study characteristics

Most of studies included were retrospective studies (29 studies or 69%), rest were prospective (12 studies or 28.5%) and randomized controlled study (1 study or 2.4%). The majority of studies were from the United States (n = 16, 38%), and the European countries (n = 13, 31%). A total of 13145 transthyretin amyloid (ATTR) patients are included in this review. The median age was 75.5 years, and the majority (82.5%) were male. The median LVEF was 50.05% [interquartile range (IQR): 48%, 53.4%] and the median follow up was 27 months (IQR: 18, 32 months) (Table 1)[1,5-11,17-50].

Table 1 Study characteristics and key features of included studies.

Ref.	Country	Study design	Number of ATTR patients	Wild type ATTR patients (in %)	Mean or median age (years)	Male (%)	Mean or median eGFR	Mean or median NT pro BNP	Mean LV ejection fraction (in %)	Mean or median follow-up (in months)
Donnellan et al[5], 2020	United States	Retrospective study	382	71	76	81	45	7558	46.4	35
Martyn et al[17], 2022	United States	Retrospective study	86	65	78	87	45	3152	50	20
Gagliardi et al[18], 2018	Italy	Retrospective study	67	0	71	78	54	3287	51	43
Gillmore et al[19], 2018	United Kingdom	Retrospective study	869	64	77	85	61	3036	NA	32
Nakashima et al[20], 2022	Japan	Retrospective study	176	100	78	85	50	NA	53.4	21
Siepen et al[6], 2018	Germany	Retrospective study	191	100	73.8	92	67.3	3644	45.8	26.2
Gospodinova et al[21], 2020	Bulgaria	Prospective study	78	0	56	50	81.7	NA	61	30
Cappelli et al[22], 2020	Italy	Retrospective study	175	76	78.4	86	66.3	6791	53.9	27
Law et al[23], 2022	United Kingdom	Retrospective study	432	100	77	95	60	2760	48	12
Ogasawara et al[7], 2022	Japan	Retrospective study	68	100	75	90	55	NA	51	22
Hanson et al[24], 2018	United States	Retrospective study	116	100	76	97.4	NA	NA	50	NA
Yunis et al[10], 2019	United States	Prospective study	56	100	74.8	100	NA	NA	50.2	35
Chacko et al[8], 2020	United Kingdom	Prospective study	1240	62	77.5	78.4	NA	NA	48.5	32
Hirakawa et al[9], 2019	Japan	Retrospective study	90	0	56.7	55.6	87.8	NA	61.6	72
Martinez-Naharro et al[11], 2019	United Kingdom	Prospective study	227	59	72	NA	NA	286	56	32
Hein et al[50], 2021	Germany	Prospective study	121	44.6	63.8	75.2	77.5	3616.5	51.8	13.6
Rubin et al[25], 2018	United States	Retrospective study	530	30	58.4	74	89	6503	60.4	18
Bhuiyan et al[26], 2011	United States	Prospective study	29	62	74	93	NA	NA	56	18
Lai et al[27], 2020	Taiwan	Retrospective study	67	NA	65.1	77.6	NA	7720	63.4	31.2
Lane et al[28], 2019	United Kingdom	Retrospective study	1034	69	74	78	66.3	2803	53.3	NA
Sperry et al[29], 2018	United States	Retrospective study	54	69	78	76	54.5	4252	46.2	21.6
Coutinho et al[30], 2013	Portugal	Prospective study	143	0	42	44.8	NA	NA	NA	66
Ruberg et al[51], 2012	United States	Prospective study	29	62	74	93	NA	4643	59	15.5
Vong et al[31], 2021	Multiple (13 countries)	RCT	441	76	75	90	NA	461.1	47.8	30
Oghina et al[32], 2021	France	Retrospective study	454	70.5	77	82.4	59.2	1980	50.1	14.2
Oike et al[33], 2021	Japan	Retrospective study	113	100	79.8	85	47.6	NA	51	22.3
Hutt et al[34], 2017	United Kingdom	Prospective study	602	62.6	75	86	57	2765	49	29.6
Dalia et al[35], 2021	United States	Retrospective study	33	100	82	79	NA	NA	50	12
Donnellan et al[36], 2020	United States	Retrospective study	369	70.7	75.5	82	44	8152	46	28
Kharoubi et al[37], 2021	France	Prospective study	62	100	78.6	93.5	59.8	4528	46.8	NA
Ochi et al[38], 2020	Japan	Retrospective study	47	100	80.3	87.2	49.9	NA	49.6	28.32
Kristen et al[39], 2014	Germany	Prospective study	70	NA	67.4	75.5	71.1	1950	NA	31.3
Grogan et al[40], 2016	United States	Retrospective study	360	100	75.5	91	NA	2838	51	31.2
Fumagalli et al[41], 2021	United States	Retrospective study	160	87	80	90.6	NA	3275	54	21
Siddiqi et al[42], 2022	United States	Retrospective study	104	100	75.8	97	60.25	NA	49	39
Kristen et al[43], 2017	United States	Retrospective study	1617	10.2	43.9	54.5	104.5	NA	NA	14.4
Connors et al[44], 2016	United States	Prospective study	121	100	75.6	98	NA	NA	48	NA
Cheng et al[45], 2020	United States	Retrospective study	309	66	73.2	84.1	60.1	NA	45.1	23
Law et al[46], 2020	United Kingdom	Retrospective study	945	77.1	78	82.5	57.5	2836	47	24
Miller et al[47], 2021	Canada	Retrospective study	43	NA	79.3	83.7	NA	NA	49	14
Bandera et al[48], 2022	United Kingdom	Retrospective study	906	62.3	75.3	85.2	58.3	3205	47	35
Yamada et al[49], 2020	Japan	Retrospective study	129	100	78.5	85	50.3	NA	53.2	15

ATTR: Transthyretin amyloidosis; eGFR: Glomerular filtration rate; LV: Left ventricle; BNP: Brain natriuretic peptide; NT pro BNP: N-terminal pro BNP; NA: Not available.

Outcomes

The median mortality for the overall study population was 33.6%. The details regarding the independent predictors of mortality in ATTR patients are mentioned in Table 2[5-11,16-49].

Table 2 Table showing which parameters were associated with mortality in transthyretin amyloidosis patients along with results.

Ref.	Positive predictors of mortality	Results	Mortality (in %)
Donnellan et al[5], 2020	Gillmore staging, NYHA class, maintenance of sinus rhythm, tafamidis use	On multivariate analysis, advanced ATTR stage [HR: 1.65 (1.3-2.09); P < 0.0001] and higher NYHA functional class [HR: 1.57 (1.19-2.06); P = 0.001] were associated with increased mortality. Maintenance of normal sinus rhythm [HR: 0.54 (0.31-0.96); P = 0.03] use of Tafamidis (HR: 0.14; 95%CI: 0.06-0.34; P < 0.0001) associated with reduced mortality	60
Martyn et al[17], 2022	Gillmore staging	On multivariate analysis, a H/CL ratio of greater than or less than 1.6 did not impact survival probability (HR: 0.56; 95%CI: 0.21-1.50; P = 0.20). There was significant difference in mortality between Gillmore stages 1 and 3 (P = 0.001; HR: 12.1; 95%CI: 2.7-54). There was no statistical difference between Gillmore stages 2 and 3 (P = 0.084; HR: 2.10; 95%CI: 0.90-4.89)	33.7
Gagliardi et al[18], 2018	Age at diagnosis and NYHA class III/IV	On multivariate analysis, age at diagnosis (for each 1-year increase) HR: 1.07 (1.03-1.11) P = 0.002 and NYHA class III/IV HR 4.01 (1.98-8.16), P = 0.0001 were independent predictors of mortality in patients with Ile68 Leu hATTR patients. The presence of Ile68 Leu mutation was not significantly associated with survival (HR: 0.90, 95%CI: 059-1.38; P = 0.641)	41
Gillmore et al[19], 2017	Gillmore staging, eGFR and NT pro BNP	After adjusting for age, compared with stage I, the HR for death was 2.05 (95%CI: 1.54-2.72, P < 0.001) for stage II and 3.80 (95%CI: 2.73-5.28, P < 0.001) for stage III patients. The HR for death in patients with stage III cardiac ATTR amyloidosis compared with stage II cardiac ATTR amyloidosis was 1.86 (95%CI: 1.38-2.48, P < 0.001)	32
Nakashima et al[20], 2022	Staging using combination of hs-cTnT, BNP and eGFR	Score calculated by adding 1 point if hs-cTnT and BNP levels increased or eGFR decreased by more than the cut-off value. The HR for all-cause mortality adjusted by age and sex, using score 0 as a reference, was 0.44 (95%CI: 0.08-2.49, P = 0.44) for score 1, 3.69 (95%CI: 1.21-11.21, P = 0.02) for score 2, and 5.40 (95%CI: 1.57-18.54, P = 0.007) for score 3	25
Siepen et al[6], 2018	MAPSE (mitral annular plane systolic excursion), NT-proBNP	A comprehensive risk model revealed MAPSE (HR: 0.142; 95%CI: 0.034-0.598; P = 0.008) and NT-proBNP (HR: 1.000; 95%CI: 1.000-1.000; P = 0.018) as the only independent predictors of mortality	25.5
Gospodinova et al[21], 2020	FAP stage (2-3), NYHA class III-IV, ejection fraction (< 50%), restrictive filling, tafamidis treatment	A significant difference in survival with FAP stage (2-3), NYHA class III-IV, ejection fraction (< 50%), restrictive filling predicting worse survival and better survival with Tafamidis treatment	28
Cappelli et al[22], 2020	Gillmore staging (2-3), modified Grogan staging (3)	Age-adjusted HRs for all-cause mortality for the Gillmore staging system in the overall population were as follows: 2.07 (95%CI: 1.15-3.70) for stages 2 vs 1, 7.89 (3.89-16.01) for stages 3 vs 1, and 3.43 (1.84-6.39) for stages 2 vs 3. Age-adjusted HRs for all-cause mortality for the modified Grogan staging system in the overall population were as follows: 1.44 (95%CI: 0.73-2.85) for stages 2 vs 1, 4.04 (2.267.21) for stages 3 vs 1, and 2.68 (1.43-5.02) for stages 2 vs 3	40
Law et al[23], 2022	NT-proBNP, increasing NYHA class	Multivariable analysis showed both ∆ NT-proBNP [HR: 1.04 (95%CI: 1.01 to 1.07) per 500 ng/L increase; P = 0.003] and increasing NYHA class [HR: 1.65 (95%CI: 1.11-2.47); P = 0.014] to be predictive of mortality from the 12-month timepoint, independent of change in other disease- related variables	33.8
Ogasawara et al[7], 2022	hs-cTnT, La/C, age	On multivariate analysis: Hs-cTnT (HR: 1.153; 95%CI: 1.034-1.286; P < 0.01), La/C (HR: 2.091; 95%CI: 1.012-4.322; P = 0.046), and age (HR: 1.116; 95%CI: 1.007-1.238; P = 0.037) were significant independent prognostic factors. La/C > 2.2 and hs-cTnT > 0.0545 were found to be significantly associated with event-free survival (P < 0.004 and P < 0.001, respectively)	10
Hanson et al[24], 2018	TTR < 18 mg/dL, LVEF, cTn-I	Multivariate analysis predictors of shorter overall survival were decreased TTR, left ventricular ejection fraction and elevated cTn-I (cardiac troponin I). TTR values lower than the normal limit, < 18 mg/dL, were associated with shorter survival (2.8 years vs 4.1 years; P = 0.03)	45.7
Yunis et al[10], 2019	CRP, sodium, creatinine, VE/VCO2	CRP [HR: 1.10 (1.03-1.18)], decreased sodium [HR: 0.75 (0.58-0.97)], creatinine [HR: 7.48 (2.44-22.98)] and VE/VCO2 [HR: 1.10 (1.05-1.16)] were significant risk factors for mortality (P < 0.05)	58.7
Chacko et al[8], 2020	SV index, LS, severe AS	A multivariable model combining LAA index, RAA index, IVSd, significant TR, significant MR, longitudinal strain, E/e’ lateral, TAPSE/PASP, SV index, RWT, heart rate, and severe AS at the time of diagnosis revealed that SV index (HR: 0.97, 95%CI: 0.95-0.99; P = 0.004), RAA index (HR: 1.05, 95%CI: 1.01-1.10; P = 0.016), LS (HR: 1.08, 95%CI: 1.04-1.12; P < 0.001), and severe AS (HR: 2.46, 95%CI: 1.29-4.72; P = 0.007) were independently associated with patient survival in the overall population	39
Hirakawa et al[9], 2019	Age, PQ interval, interventricular septum thickness in diastole, non-Val30Met mutation, delayed HM ratio < 1.6	In a multivariate Cox hazard analysis, age (HR: 1.07, 95%CI: 1.01-1.12, P = 0.015), PQ interval (HR: 1.01, 95%CI: 1.00-1.02, P = 0.042), interventricular septum thickness in diastole (HR: 1.25, 95%CI: 1.09-1.42, P = 0.001), and non-Val30Met mutation (HR: 4.31, 95%CI: 1.53-12.16, P = 0.006) were independent predictive factors of clinical outcomes. Also, Kaplan-Meier curve analysis showed that a delayed HM ratio < 1.6 on MIBG scan is associated with a poor prognosis (log-rank test: P = 0.001)	7
Martinez-Naharro et al[11], 2019	Age, ECV, and NT-proBNP	Only age, ECV, and NT-proBNP remained significantly associated with mortality when LGE was added to the multivariate model (ECV: HR: 1.106 for each 3% increase; 95%CI: 1.011 to 1.209; P < 0.05; LGE: HR: 0.868; 95%CI: 0.447-1.973; P = 0.939)	42
Hein et al[50], 2021	None	In the multivariate model, IL-6 did not improve risk stratification	15.7
Rubin et al[25], 2018	Myocardial contraction fraction < 25%, eGFR, SBP, NYHA functional class	In multivariate analysis, myocardial contraction fraction < 25% was independently associated with significantly greater risk of death (HR: 5.4, 95%CI: 1.82 15.86; P = 0.0024), as was eGFR, SBP, NYHA functional class	17
Bhuiyan et al[26], 2011	EF < 50%	Multivariable survival analysis demonstrated that initial ejection fraction (a measure of ventricular-vascular coupling) < 50% was associated with increased mortality (HR: 6.6; 95%CI: 1.1-40.3)	41.3
Lai et al[27], 2020	RALS (in echo)	Using a stepwise regression model, RALS remained significantly associated with survival [HR: 13.0 (95%CI: 1.81-93.45), P = 0.011] after correction for confounding factors	15
Lane et al[28], 2019	Age, NAC ATTR disease stage 2 and 3, LVEF, genotypic subgroup, 6MWT distance	On multivariate analysis: Age (HR: 1.037 per year; 95%CI: 1.008-1.067; P < 0.011), NAC ATTR disease stage (HR: 2.049; 95%CI: 1.352-3.104; P = 0.001 for stage II and HR: 3.705; 95%CI: 2.313-5.933; P < 0.001 for stage III in comparison to stage I), LVEF (HR: 0.978 per 1% increase; 95%CI: 0.963-0.993; P = 0.003), genotypic subgroup (HR: 2.071; 95%CI: 1.415-3.031; P < 0.001 for V122I-hATTR-CM and HR: 2.727; 95%CI: 1.458-5.098; P = 0.002 for non-V122I-hATTR-CM in comparison to ATTRwt-CM), and 6MWT distance (HR: 0.881 per 50-m increase; 95%CI: 0.832-0.933; P < 0.001) were independently associated with patient survival. Among NAC ATTR staging: Even within each category of disease stage, V122I genotype was an independent predictor of death (HR for V122-hATTR-CM vs ATTRwt-CM between 2 and 3, P < 0.002 for all analyses)	N/A
Sperry et al[29], 2018	Diffuse myocardial uptake of TcPYP, LVEF, global LS	A more diffuse myocardial uptake of TcPYP, represented by higher percentages of uptake in apical segments, lower percentage of uptake in basal segments, and a lower ASR, were all associated with age-adjusted mortality (P = 0.013, Harrell’s C-statistic 0.722 for ASR). Age-adjusted ejection fraction and global LS were also associated with mortality (P = 0.041 and P = 0.01, respectively). Other parameters of presumed echocardiographic and nuclear disease severity including the H/CL ratio and total indexed LV counts, were not associated with age-adjusted mortality. A higher ASR of TcPYP uptake was associated with decreased mortality, with decreased risk seen at values above 275	48
Coutinho et al[30], 2013	MIBG: Late H/M < 1.6	Late H/M was identified as an independent prognostic predictor	22
Ruberg et al[51], 2012	Disease duration (from the time of diagnosis to enrollment), heart rate ≥ 70, baseline stroke volume, LVEF < 50%, presence of V122I mutation	Statistically significant univariate predictors of mortality among all measured include increased disease duration (from the time of diagnosis to enrollment), heart rate ≥ 70 beats/minute, baseline stroke volume (higher stroke volume protective), LVEF < 50%, and presence of V122I mutation	38
Vong et al[31], 2021	Genotype (ATTRwt), 6MWT, NT-proBNP, LVEF, BUN	Patient with ATTRwt, a greater 6WMT distance, higher LVEF, and lower BUN and NT-proBNP concentrations would have an increased likelihood of survival. The inclusion of baseline NYHA class strata I/II or III did not improve the predictive model for TTE over the set of baseline covariates discussed	34.9
Oghina et al[32], 2021	NT-proBNP, cTnT-HS	the multivariate analysis, identified: Non-50% relative increased NT-proBNP levels [HR: 0.66 (95%CI: 0.48-0.90); P < 0.01, Wald test], as well as baseline levels of NT-proBNP ≤ 3000 ng/L and cTnT-HS ≤ 50 ng/L to be significantly and independently associated with extended EFS (event free survival included acute heart failure plus death plus heart transplant)	5.5
Oike et al[33], 2021	LASr (LA strain during reservoir phase), age, ln BNP, ln hs troponin	On multivariate analysis, LASr (LA strain during reservoir phase) was still significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (odds ratio: 0.83; 95%CI: 0.70-0.98; P < 0.05). Other independent predictors of mortality were age, ln BNP, ln hs Trop. LASr cut was 6.69%. LASr > 6.69 associated with less mortality	24.8
Hutt et al[34], 2017	Perugini grade 1/2/3, eGFR, ECOG performance 3	Survival was significantly longer (median not reached) in patients with a Perugini grade 0 99mTc-DPD scan compared to those with a Perugini grade 1, Perugini grade 2 or Perugini grade 3 no difference between grade 1, 2, and 3 noted. ECOG performance status [HR for 3 vs 0 of 9.5 (95%CI: 1.9-47.4)], eGFR [HR: 0.98 (95%CI: 0.96-0.99)]	33.5
Dalia et al[35], 2021	Peak VO2, peak CP, peak VO2/HR, exercise duration of less than 5.5 minutes	Peak VO2 (HR: 0.43, 95%CI: 0.23-0.79, P = 0.007), peak CP (HR: 0.98, 95%CI: 0.98-0.99, P = 0.02), peak VO2/HR (HR: 0.62, 95%CI: 0.39-0.97, P = 0.03), and exercise duration of less than 5.5 minutes (HR: 5.82, 95%CI: 1.29-26.2; P = 0.02) independently predicted events during 1-year of follow-up	24
Donnellan et al[36], 2020	Advanced ATTR-CA stage, history of obstructive coronary artery disease	Advanced ATTR-CA stage (HR: 3.32, 95%CI: 2.28 to 4.83, P < 0.001), and a history of obstructive coronary artery disease (HR: 1.82, 95%CI: 1.09 to 3.03, P = 0.02) were associated with increased mortality	62
Kharoubi et al[37], 2021	fESC (electrochemical skin conductance at the feet), NT-proBNP	Multivariate analysis revealed that fESC and NT-proBNP were independent prognostic factors, and Kaplan-Meier estimator evidenced a greater occurrence of cardiac decompensation and death in patients with fESC < 70 μS, P = 0.046	N/A
Ochi et al[38], 2020	Serum albumin, hs-cTnT, LVEF	Low serum albumin, elevated hs-cTnT, and reduced LVEF are associated with a worse prognosis in Japanese patients with ATTRwt	63.8
Kristen et al[39], 2014	Troponin T	By multivariate analysis, troponin T remained the only independent predictor of survival (HR: 4.4, P < 0.05)	35.7
Grogan et al[40], 2016	Age, ejection fraction, NT-proBNP, troponin T, Grogan stage	In a multivariate analysis, age (HR: 1.07; 95%CI: 1.03-1.12), ejection fraction < 50% (HR: 1.76; 95%CI: 1.07-2.88), NT-proBNP > 3000 pg/mL (HR: 1.57; 95%CI: 0.93-2.63), and troponin T ≥ 0.05 ng/mL (HR: 2.27; 95%CI: 1.36-3.77) remained predictive of survival. Stage III subjects were found to be at 3.4-times higher risk than stage I subjects (HR: 3.41; 95%CI: 1.89-6.16), and stage II subjects were not significantly different compared with stage I (HR: 1.24; 95%CI: 0.66-2.33)	66.7
Fumagalli et al[41], 2021	Diagnostic timing, age at diagnosis, coronary artery disease, NYHA class (III/IV vs I/II), ATTR stage II and III, ejection fraction	Diagnostic timing was independently associated with all-cause mortality (HR per additional month, 1.049; 95%CI: 1.017-1.083) together with age at diagnosis (HR per additional year, 1.078; 95%CI: 1.008-1.153), coronary artery disease (HR: 4.291; 95%CI: 1.678-10.979), New York Heart Asso-ciation class (III/IV vs I/II: HR: 4.240; 95%CI: 1.923-9.348), and disease stage (stage II vs I: HR: 2.928; 95%CI: 1.169-7.335; stage III vs I: HR: 9.951; 95%CI: 3.043-32.543)	26.2
Siddiqi et al[42], 2022	Diflunisal administration, troponin	Diflunisal administration and troponin associated with mortality in multivariate analysis	50
Kristen et al[43], 2017	Age, modified BMI, mutation, BNP/NT-proBNP	From Cox proportional hazards model, age, modified body mass index, mutation (Val30Met vs Non-Val30Met) and BNP/NT-proBNP (Q1-Q3 pooled vs Q4) were identified as independent predictors of survival in patients with mutant-type ATTR	7.1
Connors et al[44], 2016	Serum uric acid, BNP, RWT, LVEF	Increased levels of serum uric acid (HR: 1.28; 95%CI: 1.10-1.51; P = 0.003), BNP (HR: 1.002; 95%CI: 1.0015-1.0030; < 0.0001), and RWT (HR: 34.0; 95%CI: 6.41-180.51; P < 0.0001) were related to shorter survival, whereas a decrease in LVEF (HR: 0.94; 95%CI: 0.93-0.97 P = 0.0001) was associated with a worsening prognosis	56
Cheng et al[45], 2020	Diuretic dose, NYHA functional class	Diuretic dose and NYHA functional class are independent predictors of mortality in ATTR-CM patients. Daily mean diuretic dose was 0.6 ± 1.0 mg/kg and significantly associated with all-cause mortality [unadjusted hazard ratio: 2.12 per 1-mg/kg increase, (95%CI: 1.71-2.61)] and fully adjusted HR: 1.43 (95%CI: 1.06-1.93)	33.3
Law et al[46], 2020	ATTR stage	At diagnosis, 436/945 (46%) patients were categorized as ATTR stage I, 350 (37%) stage II, and 159 (17%) stage III, with median survival of 58 months, 41 months, and 30 months, respectively (stage II vs I, HR: 1.95; P < 0.001; stage III vs II, HR: 2.25; P < 0.001)	32.2
Miller et al[47], 2021	None	Perugini score, and H/CL ratio were not associated with the composite clinical outcome (death or HF hospitalization) or its components. CPA was not associated with an increased risk of the combined outcome of cardiovascular death or admission for heart failure (adjusted HR per 100 unit increase 117, 95%CI: 0.98-1.38, P = 0.076) after adjusting for age, sex, and LVEF. However, CPA (adjusted HR per 100 unit increase 129, P = 0.001) and volume of involvement (adjusted HR per 100 cm3 1.81, P < 0.001) were associated with HF hospitalization	18.2
Bandera et al[48], 2022	Three echo variables (LA stiffness, RAA index, significant MR), genotype V122I-ATTR-CM, period of diagnosis before February 9, 2015	Multivariate analysis revealed that ln LA stiffness (HR: 1.23; 95%CI: 1.03-1.49; P = 0.029) remained independently associated with patient survival, together with RAA index (HR: 1.05; 95%CI: 1.01-1.10; P = 0.033), LVLS (HR: 1.07; 95%CI: 1.03-1.12; P = 0.002), significant MR (HR: 1.35; 95%CI: 1.03-1.77; P = 0.032), genotypes (V122I-ATTR-CM vs wtATTR CM; HR: 1.49; 95%CI: 1.12-1.97; P = 0.006) and the period of diagnosis (before vs after February 9, 2015; HR: 1.52; 95%CI: 1.13-2.06; P = 0.006)	40.8
Yamada et al[49], 2020	Age, low serum sodium levels	According to a multivariate Cox hazard analysis, age (HR: 1.14; 95%CI: 1.05-1.23, P = 0.002) and low serum sodium levels (HR: 0.89; 95%CI: 0.79-0.996; P = 0.04) contributed to all-cause mortality	26

ATTR: Amyloid transthyretin cardiomyopathy; AS: Aortic stenosis; BNP: Brain natriuretic peptide; CI: Confidence interval; CRP: C-reactive protein; CPA: Cardiac pyrophosphate activity; ECV: Extra cellular volume; eGFR: Glomerular filtration rate; EKG: Electrocardiogram; E/e’: Mitral inflow velocity to tissue annular velocity ratio; HF: Heart failure; HR: Hazard ratio; HM ratio: Heart mediastinal ratio; LA: Left atrium; H/CL: Heart to contralateral lung ratio; CM: Cardiomyopathy; RWT: Relative wall thickness; SBP: Systolic blood pressure; MIBG scan: MetalodoBenzyl Guanidine scan; MR: Mitral regurgitation; MRI: Magnetic resonance imaging; NYHA: New York Heart Association; peak VO2: Peak oxygen consumption; VE/VCO2: Ventilatory efficiency slope; LASr: LA strain during reservoir phase; LS: Longitudinal strain; RALS: Relative apical sparing of longitudinal strain; RAA: Right atrial area; SV: Stroke volume; MAPSE: Mitral annular plane systolic excursion; 6MWT: 6-minute walk test; hs Tn-T: High sensitivity troponin-T; TAPSE: Tricuspid annular plane systolic excursion; TTR: Transthyretin; PQ: This is ECG interval and no full form available; ASR: Apical sparing; IL-6: Interleukin 6; ECOG: Eastern Cooperative Oncology Group; LVEF: Left ventricle ejection fraction; ATTR-CM: Transthyretin amyloid cardiomyopathy; LVLS: Left ventricular longitudinal strain; wtATTR: Wild-type ATTR amyloidosis.

Out of 42 studies, 25 studies assessed echocardiographic findings, 26 studies assessed biomarkers including eGFR and BNP, 5 studies assessed functional capacity via CPET, or 6-minute walk test, and 4 studies assessed special imaging modalities like Tc PYP or cardiac MRI for predictors of mortality. As mentioned above following parameters were included in meta-analysis: Biomarkers (Troponin, BNP, NT pro-BNP, eGFR), echocardiographic findings (IVSd, PWT, LVEF), NYHA, Gillmore staging for determining their effect on mortality.

In meta-analysis, the HR for the Gillmore stage 2 patients was two times higher for mortality (HR: 2.02, 95%CI: 1.76-2.32, P ≤ 0.001) compared to stage 1; Gillmore stage 3 patients had five times higher risk of mortality (HR: 5.37, 95%CI: 3.9-7.40, P ≤ 0.001) as compared to stage 1, and Gillmore stage 3 patients had two times higher risk of mortality (HR: 2.21, 95%CI: 1.7-2.87, P ≤ 0.0001) as compared to stage 2.

For biomarkers; every logarithmic unit increase in BNP (HR: 2.49, 95%CI: 1.90-3.26, P < 0.001), N Terminal pro-B Type Natriuretic peptide (NT-proBNP) (HR: 1.59, 95%CI: 1.37-1.84, P ≤ 0.001) and Troponin-T (HR: 3.97, 95%CI: 2.22-7.08, P ≤ 0.001) lead to significantly higher risk of mortality. Every unit increase in eGFR leads to numerically significant lower risk of mortality (HR: 0.97, 95%CI: 0.97-0.98, P ≤ 0.001).

For echocardiographic parameters, every unit increase in IVSd leads to statistically significant increased risk of mortality (HR: 1.09, 95%CI: 1.06-1.13, P ≤ 0.001). Whereas every unit increase in PWT (HR: 1.04 95%CI: 0.99-1.09, P = 0.16) and LVEF < 50% compared to LVEF > 50% (HR: 1.64, 95%CI: 0.66-4.11, P = 0.29) did not lead to statistically significant change in mortality.

For functional parameters; increase in NYHA class had 1.7 times higher risk of mortality (HR: 1.66, 95%CI: 1.23-2.24, P ≤ 0.001) (Figure 2). Increased heterogeneity noted in few of the parameters assessed is probably due to varied baseline demographics and characteristics of patients of the included studies. Due to heterogeneity of studies, we applied trim and fill sensitivity analysis and found that effect size stayed highly statistically significant despite heterogeneity.

Figure 2 Forrest plot. A: Gillmore stage 2 vs 1; B: Gillmore stage 3 vs 1; C: Gillmore stage 3 vs 2; D: B type Natriuretic peptide; E: N Terminal pro-B Type Natriuretic peptide; F: Estimated glomerular filtration rate; G: Troponin T; H: Left ventricular ejection fraction; I: Interventricular septal diameter; J: Posterior wall thickness; K: New York Heart Association class. BNP: B type Natriuretic peptide; NT-proBNP: N Terminal pro-B Type Natriuretic peptide; eGFR: Estimated glomerular filtration rate; LVEF: Left ventricular ejection fraction; IVSd: Interventricular septal diameter; PWT: Posterior wall thickness; NYHA: New York Heart Association.

DISCUSSION

To the best of our knowledge this is the first systematic review and metanalysis to combine the prognostic role of different biomarkers, imaging studies, and functional studies among TTR amyloidosis patients. In this study we provide systematic evidence summarizing the various predictors of mortality to aid clinicians in identifying high risk ATTR patients.

The ATTR cardiomyopathy patients have significant mortality with some studies suggesting median survival of 30 months from diagnosis[51,52]. A recent systematic review suggested pooled 2-year mortality of approximately 27%[53]. In THAOS registry the 30 months mortality was reported approximately 16% in Tafamidis treated and approximately 30% in Tafamidis untreated group[54]. In our review with median follow up of 27 months, pooled median mortality was 33.6%. The prognosis of ATTR cardiomyopathy is poor without treatment.

Gillmore staging which includes NT-proBNP and eGFR was used predominantly in multiple studies for prognosticating ATTR cardiomyopathy patients. Stage I was defined as NT-proBNP ≤ 3000 ng/L and eGFR ≥ 45 mL/minute/1.73 m², stage III was defined as NT-proBNP > 3000 ng/L and eGFR < 45 mL/minute/1.73 m², and the remainder were stage II[19]. Multiple studies in our review suggested Gillmore staging to be an independent predictor of mortality. In our metanalysis, Gillmore staging II and III had worse prognosis compared to stage I. Several studies have also reported NT-proBNP, BNP, Troponin-T as independent predictors of mortality[7,23,39,43]. In our metanalysis, higher NT-proBNP, BNP and Troponin-T were associated with higher mortality.

In metanalysis of included studies, increase in interventricular septal thickness was associated with significant mortality which has been shown in prior studies[28,55]. Interestingly, increase in PWT and LVEF < 50% did not lead to significant increase in mortality. Studies have shown LVEF < 50% had been associated with worse prognosis, but these studies have been inconsistent[56]. Other echocardiogram parameters like left atrial (LA) strain during reservoir phase, relative wall thickness, relative apical sparing of longitudinal strain, right atrial area index, severe aortic stenosis, LA stiffness have been reported as independent predictors of mortality in some studies[8,27,33]. But they could not be included in our metanalysis as only few studies (n = 6, or 14%) evaluated this association. Likewise, only one assessed role of cardiac MRI in prognostication and hence could not be included in meta-analysis[11].

Only two studies assessed the role of CPET in prognosticating ATTR patients[10,35]. In these studies, Peak V02, VE/VC02, and exercise time were independently associated with mortality. Because of limited studies assessing its role in prognostication, CPET variables could not be included in metanalysis. Further studies needed to explore its utility in prediction of mortality[57].

There have been significant advancements in the treatment of amyloidosis over the past decade, with availability of newer therapeutic options including stabilizers, silencers and heart transplant[58]. The latest addition to United States Food and Drug Administration approved medications for ATTR-CM was Vutrisiran in March 2025[59]. There are also ongoing studies for drugs that can lead to elimination or removal of deposited amyloid fibrils[58]. As the number of available treatments continue to grow, knowing about available prognostic tools will be helpful in predicting survival outcomes, initiation of appropriate treatment, close clinical monitoring, advanced care planning, and patient counselling.

Despite its strengths, this study is subject to limitations. A key limitation of this review is that the majority of included studies were observational in nature — either retrospective or prospective cohorts — which inherently carry a higher risk of bias due to unmeasured confounders, selection bias, and variability in data collection methods. This limits the ability to infer causal relationships and may affect the reliability of pooled estimates. Second, the studies had highly heterogeneous patient subgroups, thus suggesting a difference in demographics characteristics of the enrolled population, which could be the reason for different outcomes differences between the studies. Despite the heterogeneity, trim and fill sensitivity analysis suggests our effect estimate was statistically significant. Third, we included studies with both type of TTR amyloidosis (wild type and hereditary) in metanalysis which makes generalizing our results to one type of TTR cardiomyopathy difficult. Fourth, we were unable to include all predictors of mortality for TTR patients (like arrhythmias/atrial fibrillation, CPET parameters, cardiac MRI findings etc.) in meta-analysis given small number of studies evaluating them.

CONCLUSION

Our systematic review showed that most commonly used prognostic tools in ATTR-CM studies were Gillmore staging, eGFR, Trop-T, NT pro-BNP and LVEF. Very few studies have explored role of CPET, cardiac MRI in prognostication of ATTR-CM patients and further studies are needed to explore this. Meta-analysis of included studies highlighted higher Gillmore staging, BNP, NT-proBNP, troponin-T, IVSd, and NYHA were associated with higher risk of mortality.