Abstract
Background
Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease. A97S (p.Ala117Ser) is the most common transthyretin genetic mutation in Taiwan. Tafamidis is a transthyretin stabilizer, and it has been shown to improve outcomes. However, its effect on A97S ATTR-CM subtypes remains unknown.
Objectives
This study aimed to investigate the efficacy of tafamidis in patients with hereditary A97S ATTR-CM after 6 months of treatment.
Methods
We retrospectively analyzed ATTR-CM patients who received tafamidis (61 mg/day) treatment at National Taiwan University Hospital. Functional status, biochemistry and echocardiography were measured at baseline and after 6 months of tafamidis treatment. The outcome measure was to compare the N-terminal pro-brain natriuretic peptide (NT-proBNP) level at baseline and after 6 months of tafamidis treatment.
Results
Twenty patients were enrolled in this study. Their mean age was 63.0 ± 5.8 years and 75% were men. The baseline left ventricular (LV) mass index was 200.9 ± 63.9 g/m2, and the baseline LV ejection fraction was 58.9 ± 13.5%. After 6 months of treatment, the log NT-proBNP level significantly improved from 2.9 ± 0.6 to 2.7 ± 0.5 (p = 0.036). Subgroup analysis showed that the LV posterior wall thickness and left atrial diameter were significantly higher in the patients with improved NT-proBNP, suggesting the benefits of tafamidis for ATTR-CM patients with severe cardiac involvement.
Conclusions
The patients with hereditary A97S ATTR-CM in this study had decreased levels of NT-proBNP after 6 months of tafamidis treatment, and this reduction was especially pronounced in those with more severe cardiac involvement.
Keywords: Cardiomyopathy, Hereditary transthyretin amyloidosis, NT-proBNP, Tafamidis
Abbreviations
ATTR-ACT, Transthyretin Amyloidosis Cardiomyopathy Clinical Trial
ATTR-CM, Transthyretin amyloid cardiomyopathy
IVSD, Interventricular septal diameter
KCCQ-OS, Kansas City Cardiomyopathy Questionnaire Overall Summary
LA, Left atrial
LV, Left ventricular
LVEF, LV ejection fraction
LVM, LV mass
LVPWD, Left ventricular posterior wall diameter
NT-proBNP, N-terminal pro-brain natriuretic peptide
NYHA, New York Heart Association
PYP, Tc99m-pyrophosphate
INTRODUCTION
Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the accumulation of transthyretin amyloid fibrils in the myocardium resulting in restrictive cardiomyopathy.1,2 It is a progressive and life-threatening disease, as the accumulation of misfolded transthyretin in the myocardium can lead to conduction disturbance, heart failure and sudden cardiac death.3 Among these factors, heart failure is the most common cause of cardiovascular hospitalization and death in patients with ATTR-CM.4
The transthyretin gene is found on chromosome 18, and more than 120 different transthyretin mutations have been identified, leading to a variable phenotypic presentation.5 The regional prevalence of transthyretin mutations is highly variable. The V30M mutation is the most common ATTR variant worldwide, and Val122Ile is the most common mutation in the United States.5 In Taiwan, A97S (p.Ala117Ser) is the most common ATTR variant, and it is associated with a relatively late onset compared with the V30M transthyretin mutation.6 Interestingly, different transthyretin variants are associated with varying levels of cardiac involvement.7 In Taiwan, up to 82.1% of patients with hereditary A97S ATTR amyloidosis have cardiac involvement, and refractory heart failure is the major cause of death in these patients.8
Treatment of ATTR-CM has traditionally been limited to the alleviation of symptoms. Tafamidis, a transthyretin stabilizer, is an effective treatment for transthyretin amyloid cardiomyopathy. Tafamidis can stabilize both wild-type and hereditary transthyretin, and inhibit the formation of misfolded and misassembled transthyretin amyloid fibrils. In the Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy clinical trial (ATTR-ACT), tafamidis was shown to decrease all-cause mortality and cardiovascular-related hospitalizations in ATTR-CM patients. However, A97S hereditary ATTR-CM patients were not included in the ATTR-ACT trial, and the therapeutic effects of tafamidis on A97S hereditary ATTR-CM and the timing of clinical improvement after tafamidis treatment remain unclear. In this study, we aimed to investigate the efficacy of tafamidis in patients with hereditary A97S ATTR-CM.
METHODS
Patients
We retrospectively analyzed the ATTR-CM patients who received tafamidis (61 mg/day) treatment at National Taiwan University Hospital. The inclusion criteria were patients: (1) with heart failure symptoms; (2) with cardiac amyloidosis confirmed by 99mTc-pyrophosphate (PYP) scintigraphy and in whom light chain disease was excluded;9,10 (3) with the A97S mutation and the genetic tests were performed using either Sanger sequencing or restriction enzyme specific for the A97S transthyretin mutation;8,11 and (4) who completed 6 months of tafamidis treatment and who had available clinical and N-terminal pro-brain natriuretic peptide (NT-proBNP) data at baseline and after 6 months of follow-up. The exclusion criteria were patients: (1) who died or were lost to follow-up within 6 months; (2) who could not tolerate tafamidis or had poor drug compliance; (3) with wild-type ATTR-CM or non-A97S hereditary ATTR-CM; and (4) without complete baseline and post-treatment NT-proBNP data.
A total of 25 A97S hereditary ATTR-CM patients who received tafamidis were identified. Of these 25 patients, one expired due to pneumonia (non-cardiovascular death) within 6 months. The other 24 patients tolerated tafamidis well and completed 6 months of follow-up. Of these 24 patients, four were excluded (one did not have baseline NT-proBNP data and 3 did not have follow-up NT-proBNP data at 6 months). Finally, 20 A97S hereditary ATTR-CM patients were enrolled in this study for further analysis (Figure 1). Of these 20 patients, 10 were participating in an ongoing clinical trial (NCT02791230) and 10 were receiving tafamidis as compassionate use.
Figure 1.
Study flow chart. ATTR-CM, transthyretin amyloid cardiomyopathy; NT-proBNP, N-terminal pro-brain natriuretic peptide.
The primary outcome measure was to compare the NT-proBNP level at baseline and after 6 months of tafamidis treatment. NT-proBNP has been associated with the clinical outcomes of ATTR-CM.12,13 Comprehensive evaluations including baseline characteristics, biochemistry studies, 99mTc-PYP scintigraphy, and echocardiography were performed at enrollment. The follow-up data at 6 months including functional status, quality of life, biochemistry studies and echocardiography were collected for further analysis. Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores were used to evaluate the effects of tafamidis on the quality of life.14 This study was approved by the Institutional Review Board of National Taiwan University Hospital and was performed in accordance with relevant guidelines and regulations. Informed consent was obtained from all patients before enrollment.
99mTc-PYP scintigraphy
99mTc-PYP scintigraphy was performed with planar and single-photon emission computed tomography imaging of the chest 3 hours after the intravenous injection of 20 mCi of technetium pyrophosphate (99mTc-PYP).15 The images were analyzed visually and semi-quantitatively by visual score and heart to contralateral lung ratio, respectively. The imaging acquisition and analysis were performed according to the guidelines.16-18
Echocardiography
All subjects received standard transthoracic echocardiography using an IE33 system (Philips Medical Systems; Andover, Massachusetts, USA), and data were stored digitally for offline analysis. The echocardiographic measurements were performed in accordance with the recommendations of the American Society of Echocardiography.19 Interventricular septal diameter (IVSD), left ventricular (LV) posterior wall diameter (LVPWD), LV end-diastolic and end-systolic diameters, and LV ejection fraction (LVEF) were obtained. The LV mass (LVM) was calculated using the formula reported by Devereux and Reichek: LVM = 1.04 × [(IVSD + LV end-diastolic diameter + LVPWD)3 – (LV end-diastolic diameter)3] – 13.6, and normalized by body surface area to provide the LV mass index.
Statistical analysis
Data were expressed as mean ± standard deviation and median (25th and 75th percentiles) for normally distributed and non-normally distributed continuous variables, respectively, and number (%) for categorical variables. Normality of continuous data was tested using the Kolmogorov-Smirnov test. Comparisons of data between baseline and after tafamidis treatment were performed using the paired sample t test (normally distributed data), Wilcoxon signed-rank test (non-normally distributed data), and McNemar’s test (categorical data). All statistical analyses were performed using SPSS for Windows, version 25.0 (SPSS, Inc, Chicago, IL).
RESULTS
Patient characteristics
The baseline characteristics of all patients are shown in Table 1. Their mean age was 63.0 ± 5.8 years and 75% were men. All patients underwent positive 99mTc-PYP scintigraphy; 80% had a visual score of 3, and 20% had a visual score of 2. The heart to contralateral lung ratio was 1.63 ± 0.20, and the baseline log NT-proBNP level was 2.9 ± 0.6. Nineteen patients (95%) were New York Heart Association (NYHA) functional class II, and one patient (5%) was NYHA functional class I. Baseline echocardiography showed cardiac remodeling with severe LV hypertrophy. The mean IVSD, LVPWD and LV mass index were 15.2 ± 3.4 mm, 14.0 ± 2.3 mm, and 200.9 ± 63.9 g/m2, respectively. The LVEF was 58.9 ± 13.5%. Thirty percent of the patients received loop diuretics and 5% received spironolactone at baseline and during follow-up, and the dosage of the medications remained the same (Table 2).
Table 1. Baseline characteristics.
| A97S ATTR-CM (N = 20) | |
| Age, years | 63.0 ± 5.8 |
| Gender, male | 15 (75%) |
| Body height, cm | 163.8 ± 8.5 |
| Body weight, kg | 56.5 ± 135.7 |
| Body mass index, kg/m2 | 21.0 ± 5.0 |
| NYHA Fc I | 1 (5%) |
| NYHA Fc II | 19 (95%) |
| Biochemistry | |
| Creatinine, mg/dL | 0.7 ± 0.2 |
| Triglyceride, mg/dL | 74.3 ± 18.4 |
| Total cholesterol, mg/dL | 193.2 ± 36.9 |
| Fasting blood glucose, mg/dL | 85.7 ± 16.5 |
| Uric acid, mg/dL | 4.6 ± 1.8 |
| Albumin, g/dL | 3.8 ± 0.7 |
| Prealbumin, mg/dL | 22.8 ± 10.8 |
| NT-ProBNP, pg/ml | 595.1 (352.5-1788.5) |
| LogNT-proBNP | 2.9 ± 0.6 |
| 99mTc-PYP scintigraphy | |
| Visual score 1 | 0 (0%) |
| Visual score 2 | 4 (20%) |
| Visual score 3 | 16 (80%) |
| Heart-lung ratio | 1.63 ± 0.20 |
Data were presented as mean ± standard deviation, median (25th-75th percentile) or number (percentage).
ATTR-CM, transthyretin amyloid cardiomyopathy; NT-ProBNP, N-terminal pro-brain natriuretic peptide; NYHA Fc, New York Heart Association Functional Classification.
Table 2. Treatment response of tafamidis in A97S hereditary ATTR-CM.
| Pre tafamidis (N = 20) | 6m tafamidis (N = 20) | p value | |
| Functional status | |||
| NYHA Fc I | 1 (5%) | 4 (20%) | 0.083 |
| NYHA Fc II | 19 (95%) | 16 (80%) | |
| Change of NYHA Fc | Improved (3/20) | ||
| Stationary (17/20) | |||
| Worse (0/20) | |||
| KCCQ-OS score (N = 10) | 63.3 ± 18.7 | 73.5 ± 20.4 | 0.080 |
| Biochemistry | |||
| Creatinine, mg/dL | 0.74 ± 0.23 | 0.65 ± 0.22 | 0.006 |
| Triglyceride, mg/dL | 74.3 ± 18.4 | 77.1 ± 21.3 | 0.426 |
| Total cholesterol, mg/dL | 193.2 ± 36.9 | 192.2 ± 40.0 | 0.936 |
| Fasting blood glucose, mg/dL | 85.7 ± 16.5 | 88.3 ± 11.4 | 0.408 |
| Uric acid, mg/dL | 4.6 ± 1.8 | 5.2 ± 1.7 | 0.107 |
| Albumin, g/dL | 3.8 ± 0.7 | 4.2 ± 0.3 | 0.041 |
| Prealbumin (N = 9), mg/dL | 22.8 ± 10.8 | 29.4 ± 5.4 | 0.029 |
| LogNT-proBNP | 2.9 ± 0.6 | 2.7 ± 0.5 | 0.036 |
| Echocardiography (N = 19) | |||
| IVSD, mm | 15.2 ± 3.4 | 14.8 ± 2.5 | 0.414 |
| LVPWD, mm | 14.0 ± 2.3 | 14.0 ± 2.5 | 0.399 |
| LVEDD, mm | 43.6 ± 3.5 | 43.6 ± 4.4 | 1.000 |
| LVESD, mm | 29.8 ± 5.5 | 30.1 ± 6.8 | 0.735 |
| LV mass, g | 312.3 ± 111.3 | 295.8 ± 94.3 | 0.066 |
| LV mass index, g/m2 | 200.9 ± 63.9 | 190.5 ± 55.7 | 0.055 |
| LVEF, % | 58.9 ± 13.5 | 55.2 ± 16.8 | 0.147 |
| LA diameter, mm | 39.6 ± 5.5 | 38.1 ± 6.4 | 0.182 |
| Heart failure medication | |||
| Loop diuretic | 6 (30%) | 6 (30%) | 1.000 |
| Spironolactone | 1 (5%) | 1 (5%) | 1.000 |
| ACEI/ARB | 0 (0%) | 0 (0%) | 1.000 |
| Beta blocker | 0 (0%) | 0 (0%) | 1.000 |
Data were presented as mean ± standard deviation or number (percentage).
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ATTR-CM, transthyretin amyloid cardiomyopathy; IVSD, interventricular septal diameter; KCCQ-OS score, The Kansas City Cardiomyopathy Questionnaire Overall Summary Score; LA, left atrial; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricle end-systolic diameter; LVPWD, left ventricular posterior wall diameter; NT-ProBNP, N-terminal pro-brain natriuretic peptide; NYHA Fc, New York Heart Association Functional Classification.
* The data were analyzed with Wilcoxon signed-rank test.
Treatment response to tafamidis
The treatment response to tafamidis with regards to functional status, biochemistry, LV geometry and function are shown in Table 2. After 6 months of tafamidis treatment, three patients had an improvement in NYHA functional class from II to I, and no patient experienced functional decline (p = 0.083). KCCQ-OS scores were obtained in 10 patients, which showed a numerical improvement but without statistical significance (from 63.3 ± 18.7 to 73.5 ± 20.4, p = 0.080, Figure 2A). The log NT-proBNP level also significantly improved after 6 months of tafamidis treatment from 2.9 ± 0.6 to 2.7 ± 0.5, p = 0.036 (Figure 2B). The creatinine level significantly decreased from 0.74 ± 0.23 to 0.65 ± 0.22 mg/dL (p = 0.006), and the albumin level significantly increased from 3.8 ± 0.7 to 4.2 ± 0.3 g/dL (p = 0.041). The prealbumin level, also known as transthyretin, was available in nine patients, and the results showed a significant increase after tafamidis treatment from 22.8 ± 10.8 to 29.4 ± 5.4 mg/dL (p = 0.029, Figure 2C). The LV mass index did not significantly change during the study period (200.9 ± 63.9 to 190.5 ± 55.7 g/m2; p = 0.055, Figure 2D).
Figure 2.
Quality of life, NT-proBNP, prealbumin and LV mass index before and after tafamidis treatment. (A) KCCQ-OS scores, (B) Log-NT-proBNP, (C) Prealbumin, (D) LV mass index. There were 2 patients had same baseline and follow-up KCCQ-OS scores. KCCQ-OS score, The Kansas City Cardiomyopathy Questionnaire Overall Summary Score; LV, left ventricular; NT-ProBNP, N-terminal pro-brain natriuretic peptide.
Characteristics of the patients with or without an improvement in NT-proBNP
Subgroup analysis was performed based on the patients with or without an improvement in NT-proBNP (Table 3). Of the 20 patients enrolled in this study, 14 had an improvement in NT-proBNP level and six did not. The patients with NT-proBNP improvement had a significantly higher LVPWD (14.9 ± 2.4 vs. 12.5 ± 2.2 mm; p = 0.049) and left atrial (LA) diameter (41.8 ± 3.9 vs. 34.2 ± 4.3 mm; p = 0.001) than those without an improvement. The LV mass index and baseline NT-proBNP were numerical higher in the patients with NT-proBNP improvement compared to those without an improvement, but without statistical significance.
Table 3. Characteristics in patients with or without NT-proBNP improvement.
| NT-proBNP improved (N = 14) | NT-proBNP deteriorated (N = 6) | p value | |
| Age, years | 61.9 ± 4.5 | 65.7 ± 7.9 | 0.282 |
| Gender, male | 11 | 4 | 0.613 |
| BMI, kg/m2 | 21.5 ± 4.3 | 20.0 ± 6.6 | 0.322 |
| Functional status | |||
| NYHA Fc I | 1 (7%) | 0 (0%) | 1.000 |
| NYHA Fc II | 13 (93%) | 6 (100%) | |
| KCCQ-OS score (N = 10) | 58.9 ± 17.7 | 73.7 ± 20.1 | 0.359 |
| Biochemistry | |||
| Creatinine, mg/dL | 0.72 ± 0.22 | 0.77 ± 0.23 | 0.692 |
| Triglyceride, mg/dL | 69.7 ± 14.0 | 84.4 ± 24.5 | 0.265 |
| Total cholesterol, mg/dL | 194.4 ± 42.7 | 190.2 ± 20.1 | 0.838 |
| Fasting blood glucose, mg/dL | 83.6 ± 18.1 | 91.6 ± 9.9 | 0.369 |
| Uric acid, mg/dL | 5.1 ± 1.9 | 3.3 ± 1.0 | 0.102 |
| Albumin, g/dL | 4.0 ± 0.3 | 3.5 ± 1.1 | 0.368 |
| Baseline NT-proBNP, pg/ml | 1071.8 (387.3-2258.8) | 452.0 (255.9-614.7) | 0.109 |
| 99mTc-PYP scintigraphy | |||
| Visual score 1 | 0 (0%) | 0 (0%) | 0.549 |
| Visual score 2 | 2 (14%) | 2 (33%) | |
| Visual score 3 | 12 (86%) | 4 (67%) | |
| Heart-lung ratio | 1.7 ± 0.2 | 1.5 ± 0.2 | 0.050 |
| Echocardiography | |||
| IVSD, mm | 15.9 ± 3.4 | 13.8 ± 3.1 | 0.209 |
| LVPWD, mm | 14.9 ± 2.4 | 12.5 ± 2.2 | 0.049 |
| LVEDD, mm | 44.2 ± 2.7 | 42.7 ± 4.9 | 0.495 |
| LVESD, mm | 30.9 ± 5.8 | 27.3 ± 3.2 | 0.174 |
| LV mass, g | 344.9 ± 109.1 | 252.5 ± 91.3 | 0.087 |
| LV mass index, g/m2 | 217.6 ± 62.3 | 165.9 ± 49.8 | 0.089 |
| LVEF, % | 56.7 ± 15.0 | 64.8 ± 4.6 | 0.083 |
| LA diameter, mm | 41.8 ± 3.9 | 34.2 ± 4.3 | 0.001 |
Data were presented as mean ± standard deviation, median (25th-75th percentile) or number (percentage).
BMI, body mass index; IVSD, interventricular septal diameter; KCCQ-OS score, The Kansas City Cardiomyopathy Questionnaire Overall Summary Score; LA, left atrial; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricle end-systolic diameter; LVPWD, left ventricular posterior wall diameter; NT-ProBNP, N-terminal pro-brain natriuretic peptide; NYHA Fc, New York Heart Association Functional Classification.
DISCUSSION
This study is the first to demonstrate the short-term treatment effects of tafamidis in patients with A97S hereditary ATTR-CM. Our results showed that the NT-proBNP level significantly improved after 6 months of tafamidis treatment, and that tafamidis treatment delayed the progression of LV remodeling. In addition, the level of prealbumin, also known as transthyretin, significantly increased after tafamidis treatment, suggesting that tafamidis stabilized the level of transthyretin in the patients with A97S ATTR-CM.
ATTR-CM is a progressive and fatal disease caused by the destabilization of transthyretin. The disease is classified according to the presence or absence of transthyretin gene mutations. Patients without transthyretin mutations are classified as having wild-type ATTR-CM, and those with transthyretin mutations are classified as having hereditary ATTR-CM.1,20 Deposition of amyloid in the myocardium leads to cardiac stiffness, dysfunction and eventually refractory heart failure. In this study, we focused on hereditary ATTR-CM. The natural course of hereditary ATTR-CM, fibril types, and cardiac or neurologic involvement vary among different transthyretin mutations.7 A97S is the most common type of hereditary ATTR-CM in Taiwan, and refractory heart failure is the major cause of death in these patients.8 However, traditional heart failure management has limited benefits for these patients, and may be harmful due to hypotension and concomitant autonomic dysfunction.6,8
In recent years, several therapies targeting transthyretin have been developed.21 Among them, tafamidis is the first to be approved by the US Food and Drug Administration for the treatment of wild-type or hereditary ATTR-CM. In the ATTR-ACT trial, tafamidis was shown to significantly reduce all-cause mortality and the frequency of cardiovascular-related hospitalizations compared to placebo in patients with ATTR-CM. In addition, the patients who received tafamidis also had significantly less deterioration in 6-minute walk test distance and quality of life than the placebo group over the 30-month treatment period. Moreover, most deaths in the ATTR-ACT trial (about 80%) were cardiovascular-related.22 Further subgroup analysis showed that the untreated hereditary ATTR-CM patients had a worse prognosis than those with wild-type ATTR-CM, but that the effects of tafamidis treatment were similar in both disease subtypes.23 Hence, timely management is especially crucial for patients with hereditary ATTR-CM to improve outcomes. However, in the ATTR-ACT trial, most of the randomized patients had wild-type ATTR-CM, and only 24% of those who received tafamidis had hereditary ATTR-CM. In addition, the most common transthyretin genetic mutations in the ATTR-ACT trial were Val122Ile, Thr60Ala and Ile68Leu, and the predominant hereditary ATTR-CM mutation in Taiwan, A97S, was not investigated.22
The current study provides valuable data on the use of tafamidis in patients with A97S hereditary ATTR-CM. The NT-proBNP level improved after 6 months of tafamidis treatment, and there were also trends of improvements in the quality of life (KCCQ-OS score), NYHA functional class, and LV remodeling (LV mass index). Although none of these improvements reached statistical significance, this may be due to the small number of cases. In the ATTR-ACT trial, tafamidis significantly reduced the decline in KCCQ-OS score.22 In addition, a greater proportion of the patients had improved KCCQ-OS scores after tafamidis treatment (41.8%) compared with placebo (21.4%) at 30 months.24 However, KCCQ-OS scores are self-evaluated scores which can be affected by many factors, including a placebo effect. In addition, the present study is single arm only and the number of cases is small, so the KCCQ-OS score results should be interpreted with caution.
Interestingly, the prealbumin (serum transthyretin) level significantly increased after tafamidis treatment in our study. A previous study demonstrated similar results in 72 ATTR-CM patients (67 wild-type and 5 hereditary).25 These findings suggest that tafamidis can increase serum transthyretin levels in patients with ATTR-CM, consistent with its effect on stabilizing transthyretin.25 In addition, we found that the patients with more severe cardiac involvement were more likely to have an improvement in NT-proBNP level. The patients who had an improvement in NT-proBNP had significantly higher LV wall thickness and LA diameter, which suggested worse diastolic dysfunction. There was also a trend of lower LVEF and higher baseline NT-proBNP and LV mass index in those who had an improvement in NT-proBNP. This finding suggests the short-term benefit of tafamidis in the patients with worse cardiac involvement, possibly because these patients had higher baseline NT-proBNP. A longer duration of tafamidis treatment may be needed to demonstrate the therapeutic effects in patients with lower baseline NT-proBNP and less cardiac involvement of amyloidosis. Further larger studies with longer follow-up are needed to confirm this finding.
There were several limitations to this study. First, this was a small, single-arm, retrospective study. Further larger studies with longer follow-up are needed to verify our findings. However, we still provide valuable data of the treatment effects of tafamidis on patients with A97S ATTR-CM. Second, selection bias is possible in this retrospective cohort study, which may have interfered with the results, and therefore the results should be interpreted carefully. Third, not all of the patients had complete prealbumin data, echocardiography, and quality of life assessments, which may have affected the results. Fourth, the nature of KCCQ-OS scores and study design limited the interpretation of the KCCQ-OS score results. Fifth, this study only provided 6 months of follow-up data. Consequently, the long-term effects of tafamidis on patients with A97S ATTR-CM cannot be demonstrated, and further studies with longer follow-up are needed.
CONCLUSIONS
In this real-world study, the patients with hereditary A97S ATTR-CM had decreased NT-proBNP levels after 6 months of tafamidis treatment, especially in those with more severe cardiac involvement (Central Illustration).
Central Illustration.
Efficacy of tafamidis in patients with A97S transthyretin amyloid cardiomyopathy clinical trial (ATTR-CM).
DECLARATION OF CONFLICT OF INTEREST
The authors have no conflicts of interest relevant to this article.
Acknowledgments
We thank Yih-Hwen Huang, Yi-Chieh Chen and Ting-Yen Lee for technical support during the study.
FUNDING
None.
REFERENCES
- 1.Ruberg FL, Grogan M, Hanna M, et al. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73:2872–2891. doi: 10.1016/j.jacc.2019.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2020;142:e7–e22. doi: 10.1161/CIR.0000000000000792. [DOI] [PubMed] [Google Scholar]
- 3.Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120:1203–1212. doi: 10.1161/CIRCULATIONAHA.108.843334. [DOI] [PubMed] [Google Scholar]
- 4.Miller AB, Januzzi JL, O'Neill BJ, et al. Causes of cardiovascular hospitalization and death in patients with transthyretin amyloid cardiomyopathy (from the tafamidis in transthyretin cardiomyopathy clinical trial [ATTR-ACT]). Am J Cardiol. 2021;148:146–150. doi: 10.1016/j.amjcard.2021.02.035. [DOI] [PubMed] [Google Scholar]
- 5.Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (transthyretin amyloid outcome survey). J Am Coll Cardiol. 2016;68:161–172. doi: 10.1016/j.jacc.2016.03.596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Hsueh HW, Chao CC, Chang K, et al. Unique phenotypes with corresponding pathology in late-onset hereditary transthyretin amyloidosis of A97S vs. V30M. Front Aging Neurosci. 2021;13:786322. doi: 10.3389/fnagi.2021.786322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Pilebro B, Suhr OB, Naslund U, et al. (99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis. Ups J Med Sci. 2016;121:17–24. doi: 10.3109/03009734.2015.1122687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Lai HJ, Huang KC, Liang YC, et al. Cardiac manifestations and prognostic implications of hereditary transthyretin amyloidosis associated with transthyretin Ala97Ser. J Formos Med Assoc. 2020;119:693–700. doi: 10.1016/j.jfma.2019.08.027. [DOI] [PubMed] [Google Scholar]
- 9.Kitaoka H, Izumi C, Izumiya Y, et al. JCS 2020 Guideline on diagnosis and treatment of cardiac amyloidosis. Circ J. 2020;84:1610–1671. doi: 10.1253/circj.CJ-20-0110. [DOI] [PubMed] [Google Scholar]
- 10.Maurer MS, Elliott P, Comenzo R, et al. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135:1357–1377. doi: 10.1161/CIRCULATIONAHA.116.024438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Yang NC, Lee MJ, Chao CC, et al. Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser. Neurology. 2010;75:532–538. doi: 10.1212/WNL.0b013e3181ec7fda. [DOI] [PubMed] [Google Scholar]
- 12.Oghina S, Josse C, Bezard M, et al. Prognostic value of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin T levels in the natural history of transthyretin amyloid cardiomyopathy and their evolution after tafamidis treatment. J Clin Med. 2021;10 doi: 10.3390/jcm10214868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68:1014–1020. doi: 10.1016/j.jacc.2016.06.033. [DOI] [PubMed] [Google Scholar]
- 14.Green CP, Porter CB, Bresnahan DR, et al. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol. 2000;35:1245–1255. doi: 10.1016/s0735-1097(00)00531-3. [DOI] [PubMed] [Google Scholar]
- 15.Bokhari S, Castano A, Pozniakoff T, et al. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging. 2013;6:195–201. doi: 10.1161/CIRCIMAGING.112.000132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Huang YH, Lin YH, Yen RF, et al. 2021 advocacy statements for the role of (99m)Tc-pyrophosphate scintigraphy in the diagnosis of transthyretin cardiac amyloidosis: a report of the Taiwan Society of Cardiology and the Society of Nuclear Medicine of the Republic of China. Acta Cardiol Sin. 2021;37:221–231. doi: 10.6515/ACS.202105_37(3).20210420A. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging. Circ Cardiovasc Imaging. 2021;14:e000029. doi: 10.1161/HCI.0000000000000029. [DOI] [PubMed] [Google Scholar]
- 18.Dorbala S, Ando Y, Bokhari S, et al. Addendum to ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging. J Nucl Cardiol. 2021;28:1769–1774. doi: 10.1007/s12350-020-02455-z. [DOI] [PubMed] [Google Scholar]
- 19.Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1–39 e14. doi: 10.1016/j.echo.2014.10.003. [DOI] [PubMed] [Google Scholar]
- 20.Tseng H, Tsai CH, Jong CB, et al. Transthyretin amyloid cardiomyopathy associated with Ala81Val transthyretin mutation: a case report. Acta Cardiol Sin. 2021;37:549–553. doi: 10.6515/ACS.202109_37(5).20210422A. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Yadav JD, Othee H, Chan KA, et al. Transthyretin amyloid cardiomyopathy-current and future therapies. Ann Pharmacother. 2021;55:1502–1514. doi: 10.1177/10600280211000351. [DOI] [PubMed] [Google Scholar]
- 22.Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379:1007–1016. doi: 10.1056/NEJMoa1805689. [DOI] [PubMed] [Google Scholar]
- 23.Rapezzi C, Elliott P, Damy T, et al. Efficacy of tafamidis in patients with hereditary and wild-type transthyretin amyloid cardiomyopathy: further analyses from ATTR-ACT. JACC Heart Fail. 2021;9:115–123. doi: 10.1016/j.jchf.2020.09.011. [DOI] [PubMed] [Google Scholar]
- 24.Hanna M, Damy T, Grogan M, et al. Impact of tafamidis on health-related quality of life in patients with transthyretin amyloid cardiomyopathy (from the tafamidis in transthyretin cardiomyopathy clinical trial). Am J Cardiol. 2021;141:98–105. doi: 10.1016/j.amjcard.2020.10.066. [DOI] [PubMed] [Google Scholar]
- 25.Falk RH, Haddad M, Walker CR, et al. Effect of tafamidis on serum transthyretin levels in non-trial patients with transthyretin amyloid cardiomyopathy. JACC CardioOncol. 2021;3:580–586. doi: 10.1016/j.jaccao.2021.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]