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TTR (Transthyretin) Stabilizers Are Associated With Improved Survival in Patients With TTR Cardiac Amyloidosis

Originally publishedhttps://doi.org/10.1161/CIRCHEARTFAILURE.117.004769Circulation: Heart Failure. 2018;11:e004769

    Abstract

    Background:

    TTR (transthyretin) cardiac amyloidosis is caused by dissociation of TTR into monomers, which misassemble into amyloid fibrils. TTR stabilizers act at the dimer–dimer interface to prevent dissociation. We investigated differences in survival among patients with TTR cardiac amyloidosis on stabilizer medications compared with those not on stabilizers.

    Methods AND RESULTS:

    A retrospective study of patients with TTR cardiac amyloidosis presenting to a single center was conducted. Baseline characteristics were compared between those treated with stabilizers and those not treated with stabilizers. Cox proportional hazards modeling assessed for univariate predictors of the composite outcome of death or orthotopic heart transplant (OHT). Multivariable Cox proportional hazards assessed whether stabilizer treatment was independently associated with improved death or OHT after controlling for significant univariate predictors. One hundred twenty patients (mean age, 75±8, 88% male) were included: 29 patients who received stabilizers and 91 patients who did not. Stabilizer use was associated with a lower risk of the combined end point of death or OHT (hazard ratio, 0.32; 95% confidence interval, 0.18–0.58; P<0.0001). Subjects treated with stabilizers were more likely to be of White race (93% versus 55%; P<0.001), classified as New York Heart Association classes I and II (79% versus 38%; P=0.002), less likely to have a mutation (10% versus 36%; P=0.010), have lower troponin I (median 0.06 versus 0.12 ng/mL; P=0.002), and higher left ventricular ejection fraction (49% versus 40%; P=0.011), suggesting earlier stage of disease. In multivariable Cox analysis, the association between stabilizer and death or OHT persisted when adjusted for all noncollinear univariate predictors with P<0.05 (hazard ratio, 0.37; 95% confidence interval, 0.19–0.75; P=0.003).

    Conclusions:

    TTR stabilizers are associated with decreased death and OHT in TTR cardiac amyloidosis. These results need to be confirmed by ongoing randomized clinical trials.

    Introduction

    WHAT IS NEW?

    • The study shows an independent association of TTR (transthyretin) stabilizer medications (tafamidis and diflunisal) in patients with TTR cardiac amyloidosis with the composite outcome of survival and orthotopic heart transplant.

    WHAT ARE THE CLINICAL IMPLICATIONS?
    • The results from this retrospective single-center study demonstrate for the first time an association between TTR tetrameter stabilizer use and improved survival.

    • These data highlight the potential value of TTR stabilizers for patients with TTR cardiac amyloidosis, which are being evaluated in an ongoing randomized, placebo-controlled trials.

    • If these findings are confirmed, future trials should be performed to determine whether TTR stabilizers are equally effective.

    Transthyretin (TTR) cardiac amyloidosis (CA) is a significant cause of progressive heart failure with preserved ejection fraction (EF).1 TTR is a 127-amino acid protein produced by the liver that circulates as a homotetramer. However, destabilization of the TTR protein from either inherited mutations (hereditary transthyretin amyloidosis [ATTRh]) or the aging process in wild-type disease (wild type transthyretin amyloidosis [ATTRwt]) promotes its dissociation into monomers, which misassemble into amyloid fibrils and deposit in tissues and organs. In the heart, deposition of amyloid fibrils in the extracellular space leads to diastolic dysfunction, progressing to heart failure with a restrictive physiology and eventual death.1,2

    More than 120 mutations in the TTR gene affect people of all ages with ATTRh. The most common allele in the United States, caused by a substitution of valine to isoleucine at position 122 (Val122Ile), is found in 3.4% of African Americans.25 ATTRwt predominantly affects older adult men6 and has been detected at autopsy in 32% of patients with heart failure with preserved EF >75 years of age without antemortem suspicion of amyloid deposition7,8 and in 13.3% of hospitalized patients with heart failure with preserved EF and left ventricular (LV) wall thickness of ≥12 mm.1

    Previously, treatment options for TTR-CA were limited to supportive care with a minority receiving heart transplant,9 an option that often is not feasible in elderly patients with advanced disease. Stabilization of the TTR homotetramer has become a target for novel therapies to prevent progression of TTR amyloidosis.2,10,11 The approach was first considered after the discovery that a benign polymorphism in the TTR protein, Thr119Met, effectively stabilized the protein in the context of a transdestabilizing mutation.12 Multiple TTR kinetic stabilizer structures have been studied. Diflunisal, a nonsteroidal anti-inflammatory drug, and tafamidis, an analog of diflunisal without nonsteroidal anti-inflammatory drug properties, are the only 2 small molecule stabilizers of the TTR tetramer that have been shown to date to be safe in animal studies and human clinical trials.1324

    Long-term effects of stabilizers in TTR-CA have yet to be demonstrated in large cohorts. In heart failure patients, where chronic nonsteroidal anti-inflammatory drug use may lead to worsening renal dysfunction and precipitate heart failure, diflunisal, at low doses, has been shown to be safe in both ATTRwt and ATTRh patients over the short to intermediate term, and potentially slow disease progression.18,25 Phase II trials of tafamidis demonstrate a high degree of stabilization of the TTR tetramer and the absence of clinically significant changes in most clinical, biochemical, electrocardiographic, and echocardiographic parameters, consistent with the potential for tafamidis to slow cardiac disease progression.2628 A phase III double-blind, placebo-controlled, randomized trial evaluating the efficacy, safety, and tolerability of tafamidis is anticipated to report results in 2018.29 We conducted a retrospective analysis of patients with TTR-CA seen at the Center for Advanced Cardiac Care at Columbia University Medical Center to evaluate for differences in survival in patients treated with stabilizer medications compared with those not on stabilizers.

    Methods

    The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. The study was approved by the Columbia University Medical Center Institutional Review Board.

    Study Population and Study Design

    We conducted a retrospective analysis of 160 patients with TTR-CA presenting to Center for Advanced Cardiac Care between 2001 and 2016 (Figure 1). Cardiac amyloidosis was defined by (1) endomyocardial biopsy-proven congophilic deposits, (2) histological documentation of congophilic deposition in at least 1 noncardiac organ and echocardiographic evidence of infiltrative cardiomyopathy without another cause of LV hypertrophy, and/or (3) positive Tc99 pyrophosphate scan with grade 2 or 3 myocardial uptake or a heart to contralateral ratio of >1.5.30 Evidence for TTR as the precursor protein causing amyloid was confirmed by histochemical analysis or mass spectroscopy. Both ATTRwt and ATTRh patients were included. TTR-CA patients were subdivided into 2 groups: those treated with stabilizers (tafamidis or diflunisal) and those not treated with stabilizers.

    Figure 1.

    Figure 1. Study population and breakdown by treatment strategy. TTR-CA indicates transthyretin cardiac amyloidosis.

    Among the 160 patients, 40 patients were excluded from further analysis for the following reasons: if they received a medication other than tafamidis or diflunisal for treatment of TTR-CA (n=10; Revusiran [n=9], Doxycycline [n=1]) or were part of a randomized blinded clinical study of either tafamidis (n=29)29 or Ionis TTR-Rx (n=1). In the remaining 120 patients, 13 were on diflunisal and 16 were on tafamidis (including 9 in the open-label tafamidis trial, Unique identifier: NCT00935012; https://clinicaltrials.gov/ct2/show/NCT00935012).26 Baseline characteristics were assessed and included cardiac biomarkers (troponin I and brain natriuretic peptide [BNP]), estimated glomerular filtration rate, modified body mass index (mBMI; serum albumin multiplied by BMI), and functional status by New York Heart Association (NYHA) class. Echocardiography was used to assess the LV structure and function as described by the American Heart Association guidelines.31 Electrocardiography at the time of TTR-CA diagnosis analyzed for the presence of arrhythmias, conduction abnormalities, low QRS voltage, and pseudoinfarct (anterior or lateral) pattern. Right heart catheterization data from time of diagnosis were obtained. Patients were followed for a combined primary outcome of all-cause mortality or orthotopic heart transplant (OHT) from time of first diagnosis until March 30, 2017, ascertained from the electronic medical record, contacting primary physicians, and by cross-referencing the social security death index. We include OHT as a death equivalent because patients who underwent OHT would have otherwise died without transplant.

    Statistical Analysis

    Analyses were performed using Statistical Analysis Software version 9.4 (SAS Institute, Inc). Continuous variables were presented as mean±SD or median (interquartile range) if highly skewed, and categorical variables were summarized as counts (percentages). The χ2 test or the Fisher exact test (when cell counts were small) was used to compare categorical variables, and the Wilcoxon rank-sum test was used to compare continuous variables, between patients who were treated and patients who were not treated with stabilizers. Univariate Cox proportional hazards models were created to identify factors associated with death or OHT. Troponin and BNP were log transformed to adjust for skewness. Multivariable Cox proportional hazards modeling was subsequently performed to determine whether stabilizer treatment was independently associated with reduced death or OHT after controlling for all noncollinear univariate predictors of death or OHT with P<0.05: race, presence of mutation, NYHA class, Log10 BNP, and LVEF by 1% increase. Kaplan–Meier survival analysis using log-rank test was performed to compare patients treated with a stabilizer to those not treated with a stabilizer for the composite end point of death or OHT. Supplemental analyses for the outcome of death alone were similarly conducted. Finally, Kaplan–Meier survival analysis using log-rank test was performed to compare outcomes between patients treated with tafamidis and diflunisal (Figure III in the Data Supplement).

    Results

    Baseline Characteristics

    The study cohort included 120 patients (mean age 75±8 years) with TTR-CA of which 84 (70%) were ATTRwt and 36 (30%) were ATTRh with the following mutations (Table 1): Val122Ile (N=33), Thr60Ala (N=2), and Phe64Leu (N=1). The cohort was predominantly male (88%), with NYHA class II or III symptoms (89%). There were 29 (24%) patients who received stabilizer treatment (either tafamidis 16 patients, or diflunisal 13 patients) and 96 (76%) patients who did not receive stabilizer treatment. Compared with patients who were not on a stabilizer, patients who were treated with a stabilizer were more likely to be of White race (93% versus 55%; P<0.001), classified as NYHA classes I and II (79% versus 39%; P=0.002), less likely to have a mutation (10% versus 36%; P=0.010), had a lower troponin I (median 0.06 versus 0.12 ng/mL; P=0.002), higher modified BMI (118 versus 108 kg·g/dL·m2; P=0.039), higher LVEF (49% versus 40%; P=0.0011), and less low voltage on ECG (17% versus 39%; P=0.041). There was no difference between the 2 groups with respect to baseline systolic or diastolic blood pressure, BNP, albumin, estimated glomerular filtration rate, left atrial size, interventricular septal wall thickness, poor R-wave progression or pseudoinfarct pattern on ECG, or cardiac output or pulmonary vascular resistance on right heart catheterization.

    Table 1. Demographic and Clinical Variables Among Patients With TTR-CA Comparing on Stabilizer vs Not on Stabilizer

    DemographicOverall(N=120)Not on Stabilizer (N=91)On Stabilizer (N=29)P Value
    Age, y75±875±875±90.704
    Male sex, N (%)105 (87.5)77 (84.6)28 (96.6)0.114
    Race, N (%)<0.001
     White77 (64.2)50 (55.0)27 (93.0)
     Black35 (29.2)34 (37.3)1 (3.5)
     Other8 (6.6)7 (7.7)1 (3.5)
    NYHA class, N (%)0.002
     I6 (5.0)4 (4.4)2 (6.9)
     II53 (44.2)32 (35.1)21 (72.4)
     III54 (45.0)48 (52.8)6 (20.7)
     IV7 (5.8)7 (7.7)0 (0)
    Era diagnosed<0.001
     Early (2001–2010)40 (33%)24 (26%)16 (55%)
     Middle (2010–2014)40 (33%)36 (40%)4 (14%)
     Late (2014–2016)40 (33%)31 (34%)9 (31%)
    ATTR mutation, N (%)36 (30.0)33 (36.3)3 (10.3)0.010
    SBP, mm Hg113±15113±16115±150.317
    DBP, mm Hg68±1068±970±110.306
    Biochemistry
     Troponin I, ng/mL (median, IQR)0.10 (0.06–0.17)0.12 (0.07–0.18)0.06 (0.05–0.10)0.002
     BNP, pg/mL (median, IQR)592 (278–1216)685 (302–1411)494 (269–736)0.123
     Albumin, g/dL4.1±0.44.1±0.34.3±0.30.072
     Creatinine, mg/dL1.5±0.51.5±0.51.5±0.50.750
     eGFR, mL/min56±1955±1956±200.993
     Modified BMI, kg·g/dL·m2110±21108±20118±250.039
    Echocardiography
     LVEF, %42±1640±1649±150.011
     LA size, cm4.6±0.64.6±0.64.8±0.70.222
     LVPW, mm16±416±416±40.531
     IVS, mm17±417±417±40.819
    Electrocardiogram
     Atrial fibrillation or flutter, N (%)35 (30.4)27 (31.4)8 (27.6)0.817
     Low voltage any lead, N (%)38 (33.3)33 (38.8)5 (17.2)0.041
     PRWP, N (%)58 (54.7)44 (55.0)14 (53.9)0.918
     Pseudoinfarct pattern, N (%)8 (7.25 (6.0)3 (10.7)0.414
    RHC
     CO, L/min3.6±1.03.5±1.03.8±1.10.385
     CI, L min−1 m−21.8±0.51.8±0.51.9±0.50.617
     PVR, Woods U3.6±1.93.8±1.93.0±1.40.300

    BMI indicates body mass index; BNP, brain natriuretic peptide; CI, cardiac index; CO, cardiac output; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; IQR, interquartile range; IVS, interventricular septal thickness; LA, left atrial; LVEF, left ventricular ejection fraction; LVPW, left ventricular posterior wall; NYHA, New York Heart Association; PRWP, poor R wave progression; PVR, pulmonary vascular resistance; RHC, right heart catheterization; SBP, systolic blood pressure; and TTR-CA, transthyretin cardiac amyloidosis.

    Predictors of Death or OHT

    Subjects were followed for median 1.9 years (interquartile range, 1.0–2.8 years) from time of amyloid diagnosis (Table 2). Over this time period, 78 subjects met the primary end point of death (n=67) or OHT (n=11). Probability of death or OHT at 1 and 5 years comparing stabilizer versus not on stabilizer was 7% versus 21% and 41% versus 86%, respectively. In Cox proportional hazards modeling, patients on a stabilizer had a lower risk of the combined end point of mortality or OHT (hazard ratio, 0.32; 95% confidence interval, 0.18–0.58; P<0.0001). Other univariate predictors of death or OHT included black race (P=0.029), presence of any mutation (P=0.033), higher NYHA class (P=0.005), log10 BNP (P=0.037), and lower LVEF (P=0.041). Modified BMI, male sex, log10 troponin I, estimated glomerular filtration rate, era diagnosed, left atrial size, interventricular septal wall thickness, pseudoinfarct pattern or low voltage on ECG, and cardiac output did not significantly predict death or OHT in this cohort. In multivariable Cox analysis, the association between stabilizer and death or OHT persisted when adjusted by all noncollinear univariate predictors with P<0.05: black race, presence of any mutation, NYHA class, log10 BNP, and lower EF (hazard ratio, 0.37; 95% confidence interval, 0.19–0.75; P=0.003).

    Table 2. Cox Proportional Hazards Univariate and Multivariable Predictors of Death or OHT Among Patients With TTR Cardiac Amyloidosis

    PredictorNHazard Ratio95% CIP Value
    Univariate
     Age, per 1 y increase1201.000.97–1.030.843
     Modified BMI, per 1 U increase1160.990.98–1.010.331
     Male sex1201.360.55–3.390.487
     Black race1201.721.07–2.760.029
     Presence of any mutation1201.671.05–2.640.033
     NYHA classes I–IV, per 1 class increase1201.581.15–2.170.005
     Era diagnosed1200.840.60–1.170.303
     Stabilizer1200.320.18–0.58<0.0001
     Log10 Troponin I1151.200.98–1.470.084
     Log10 BNP1181.301.02–1.650.037
     eGFR<60 mL/min1190.960.60–1.520.850
     LVEF, per 1% increase1160.980.97–0.990.041
     LA size, per 1 cm increase1080.920.62–1.350.660
     IVS, per 1 mm increase1151.010.96–1.070.691
     Pseudoinfarct pattern, yes vs no1111.010.44–2.350.978
     Low voltage, yes vs no1141.070.66–1.760.780
     CO, per 1 L/min decrease770.910.70–1.190.492
     CI, per 1 L min−1 m−2 decrease770.840.48–1.450.525
     PVR, per 1 woods unit increase551.020.87–1.200.836
    Full multivariable model with all univariate predictors with P<0.05
     Stabilizer1120.370.19–0.750.003
     Black race1121.200.56–2.540.643
     NYHA class1121.19081-1.740.387
     Presence of any mutation1121.010.46–2.200.981
     Log10 BNP1121.090.81–1.460.562
     LVEF, by 1% increase1121.000.98–1.020.909

    BMI indicates body mass index; BNP, brain natriuretic peptide; CI, cardiac index; CO, cardiac output; eGFR, estimated glomerular filtration rate; IVS, interventricular septal thickness; LA left atrial; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; OHT, orthotopic heart transplant; PVR, pulmonary vascular resistance; and TTR-CA, transthyretin cardiac amyloidosis.

    Propensity scores were constructed using logistic regression modeling with observed treatment groups as the outcome (Figure I in the Data Supplement). In Cox proportional hazards model for death or OHT adjusting for likelihood of treatment, stabilizer use alone remains significant (hazard ratio, 0.355; 95% confidence interval, 0.19–0.66; P=0.0012). These results are consistent with our findings in the full multivariable model, suggesting an effect of treatment after accounting for nonrandom treatment assignment.

    In Kaplan–Meier analysis (Figure 2) among patients with TTR-CA, median time to the combined outcome of death or OHT was significantly worse if patients were not on a stabilizer, 2.2 versus 5.4 years, log-rank P<0.0001. Similar results were found for the end point of survival (Table I in the Data Supplement and Figure II in the Data Supplement). The association of type of stabilizer (diflunisal versus tafamidis) with the composite outcome of death or OHT did not differ (Figure III in the Data Supplement).

    Figure 2.

    Figure 2. Kaplan–Meier analysis among 120 patients with TTR (transthyretin) cardiac amyloidosis over the 1.9-year median follow-up for the outcome of death or orthotopic heart transplant, stratified by use of stabilizer.

    Discussion

    This retrospective review of a cohort of 120 patients with TTR-CA demonstrates that treatment with TTR stabilizers is associated with improved outcome of survival or OHT. Compared with patients who were not treated with a stabilizer, those treated with a stabilizer were more likely to have lower NYHA class, lower baseline troponin I, higher modified BMI, and higher LVEF, suggesting a less severe phenotype of disease at baseline. However, after accounting for univariate predictors of death or OHT, which include presence of mutation, higher NYHA class, higher troponin I, and lower EF that account for severity of disease, the benefit of TTR stabilizers persists in multivariate modeling.

    Mechanism of TTR Stabilization

    TTR stabilizers block tetramer dissociation, the rate-limiting step in the amyloidogenic process, and reduce de novo deposition of amyloid.19 Negative cooperative binding of stabilizers to the 2 L-thyroxine binding sites in the TTR tetramer stabilizes the native state over the dissociative state and inhibits amyloid fibril formation in vitro.15,3234 Phase I/II studies demonstrated effective binding of tafamidis and diflunisal to the thyroxine binding site, kinetically stabilizing circulating TTR tetramers, and inhibiting release of TTR monomers required for amyloidogenesis.13,14,23,26,35 TTR tetramer stabilization is a critical first step to slowing cardiac disease progression, but the impact of stabilizers on hard outcomes such as survival or OHT has not been previously delineated.

    Stabilizers in TTR Familial Amyloid Polyneuropathy

    TTR stabilizers inhibit progression of polyneuropathy and preserve quality of life in patients with TTR familial amyloid polyneuropathy (TTR-FAP). In a clinical trial of 130 patients with TTR-FAP, diflunisal reduced the rate of progression of neurological impairment (Neurologic Impairment Score+7 score increased 25 points in placebo versus 8.7 in the diflunisal group; P<0.001) and preserved quality of life during 2 year follow-up. At 2 years, the diflunisal group exhibited neurological stability compared with placebo, defined as <2-point increase in Neurologic Impairment Score+7 score (29.7% versus 9.4%; P=0.007).24 In a subsequent study of Japanese subjects with ATTRh with neuropathy, treatment with 12 months of diflunisal significantly increased serum TTR concentrations (21.8±5.2 to 28.1±6.8 mg/dL; P<0.0001) and stabilized TTR structure. Clinical FAP score increased by 1.0/y (P=0.79) at 24 months compared with the previously described natural history of FAP at about 7.0/y, suggesting longitudinal benefits of diflunisal.18

    Data from phase II trials in TTR-FAP have demonstrated long-term efficacy and safety of tafamidis.20,36 In a randomized placebo-controlled trial in patients with TTR-FAP, those in the intent-to-treat population who received tafamidis demonstrated 52% less neurological deterioration after 18 months of treatment than patients who received placebo, with a sustained response in a 12-month extension study.23,37 The long-term safety and efficacy of tafamidis for delaying disease progression in TTR-FAP for up to 5.5 years was also recently demonstrated.21 Among ATTRh patients, those who continuously received tafamidis experienced numerically less deterioration of neurological function from baseline compared with those initially treated with placebo and then switched to tafamidis 18 months later. In fact, patients who received tafamidis from the start of the pivotal study were less likely to progress to the next ambulatory stage by 6 years than patients who started tafamidis later.21,36

    Phase II Studies of Stabilizers in TTR-CA

    Prior phase II studies of both tafamidis26,27 and diflunisal13,18,25 have demonstrated adequate stabilization of the TTR homotetramer and potential clinical stabilization of disease progression in TTR-CA. Two recent open-label studies evaluated the safety and preliminary effects of diflunisal demonstrated stabilization of cardiac structure and function in addition to preservation of renal function. In a single-arm, small open-label study (n=13, 85% male, 69 years old) in TTR-CA, Castaño et al25 report no change in cardiac structure (LV mass) or function (EF), with only nonsignificant uptrend in Troponin I and BNP, suggestive of stabilization of disease. Likewise, in 40 subjects (70% male, 60.7 years old) with ATTRh with both cardiac and neurological manifestations, Sekijima et al18 reported a nonsignificant decrease in cardiac wall thickness by 0.2 mm/y and an increase in EF by 0.4%/y after 24 months of treatment accompanied by increased levels of serum TTR. In our experience, diflunisal at a dose of 250 mg orally twice a day is generally well tolerated by patients with TTR-CA who are not acutely decompensated, have estimated glomerular filtration rate >45 mL min−1 m−2, and are not on high-dose diuretics. Among such patients, ≈10% of subjects do not tolerate diflunisal.

    Two recent phase II, open-label single treatment arm studies of tafamidis demonstrated safety and stabilization of TTR tetramer in TTR-CA. In a study of 21 patients with non-Val30Met TTR amyloid (13 with cardiac involvement) followed over 12 months, 18 patients demonstrated TTR stabilization at week 6. There was maintenance of quality of life, modified BMI, echocardiographic parameters, and stabilization of biomarkers over the follow-up period.27 In a phase II, open-label, multicenter 12-month study evaluating safety and efficacy on TTR stability of oral tafamidis with ATTRwt or ATTRh (V122I), 30 of 31 patients were stabilized at week 6 using a nonphysiological assay and no clinically relevant changes in echocardiographic parameters were observed during the follow-up period. Cardiac biomarkers including NT-proBNP (N-terminal pro-B-type natriuretic peptide), troponin I, and troponin T increased from baseline to 12-month follow-up, but there was minimal decrease of 8 m in six minute walk test and subjects had stable quality of life assessments. Tafamidis treatment was generally well tolerated, although 7 of 31 patients had bouts of diarrhea.26 In a recent post hoc analysis, survival of patients from the TRACS (Transthyretin Amyloidosis Cardiac Study) natural history study was compared with those in the Fx1B-201 tafamidis open-label study and was restricted to include only NYHA class I/II and ATTRwt in attempts to provide a comparable cohort of patients. In time-to-mortality analysis, there was a significant difference in survival for patients treated with tafamidis compared with untreated patients over the long-term follow-up (P=0.0004 for NYHA I/II patients, P=0.0262 for ATTRh patients).27

    Furthermore, a phase III trial evaluating the safety and efficacy of tafamidis on the primary outcome of a composite of all-cause mortality and cardiovascular disease–related hospitalization is anticipated to report results in 2018.29

    Survival in TTR-CA

    TTR-CA is progressive disorder, often undiagnosed until symptoms of heart failure are apparent in the presence of significant ventricular wall thickening and advanced diastolic dysfunction. In the largest and most recent databases of TTR-CA, median survival from the time of diagnosis usually ranges between 25 and 41 months, with longer survival in patients with ATTRwt.8,38,39 In this retrospective analysis, median survival in patients on stabilizers was 65 months, whereas for those not on stabilizers, median survival was only 26 months. In a prospective longitudinal investigation of TTR-CA, the TRACS followed both 29 ATTRwt and ATTRh (V122I) subjects for progression of disease,40 median survival after diagnosis was 26 and 43 months for ATTRh (V122I) and ATTRwt, respectively. Similarly, Connors et al39,41 demonstrated a median survival of 27 months in 26 patients with ATTRh (V122I) and separately report survival in 82 patients with ATTRwt to be 52 months. Notably, although stabilizer use was associated with longer survival in our data, long-term survival (eg, >8–10 years) was rare. Whether study of a larger cohort, higher doses of tafamidis (80 mg), the use of other agents such as TTR silencers, or treatment with multiple agents will translate into long-term survival benefit in early stages of disease requires further study.

    Study Limitations

    Significant limitations to this investigation are worth noting. This was a retrospective case–control cohort study and not a randomized control trial. As such, there were inherent baseline differences between patients who received treatment with TTR stabilizers and those who did not, including a potential selection bias for patients having a less severe disease phenotype. For example, patients without baseline renal dysfunction were more likely to receive TTR stabilizers, especially diflunisal, a nonsteroidal anti-inflammatory drug. Despite differences in baseline characteristics, in multivariable modeling, the hazard ratio for the association of TTR stabilizers with improved survival remained significant with a similar point estimate. Second, this study represents data from a single amyloid center with a relatively small cohort and a low percentage of African American patients with Val122Ile mutation treated with TTR stabilizers, which may limit the generalizability of these results. A prospective, multicenter, randomized, double-blinded, placebo-controlled study with sufficient power to detect differences in clinical outcomes among hereditary and wild-type forms of TTR-CA with tafamidis 20 or 80 mg compared with placebo is now completed with results anticipated in 2018.29 If effective, future trials might study whether multiple agents result in further reduced disease progression and survival in patients with TTR-CA. Finally, the comparison of type of stabilizer (tafamidis and diflunisal) association with the composite outcome of death or OHT is limited by a small sample size and should be considered hypothesis generating.

    Conclusions

    In conclusion, TTR stabilizers, tafamidis and diflunisal, are associated with a lower risk of the combined end point of death or OHT in a small, retrospective analysis among patients treated at a single center. Randomized, placebo-controlled trials are required to confirm these findings.

    Footnotes

    http://circheartfailure.ahajournals.org

    The Data Supplement is available at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.117.004769/-/DC1.

    Mathew S. Maurer, MD, Columbia University Medical Center, Clinical Cardiovascular Research Laboratory for the Elderly, Allen Hospital of New York Presbyterian, 5141 Broadway, 3 Field W Room 035, New York, NY 10034. E-mail

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