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

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.