論文ID: CJ-21-0965
Background: Tafamidis has emerged as an effective treatment for patients with wild-type transthyretin cardiac amyloidosis (ATTRwt CA). The early experience of tafamidis treatment for Japanese patients with ATTRwt CA is reported here.
Methods and Results: Over the past 2 years, in 82 patients with ATTRwt CA (mean age of 81.7±6.0 years), tafamidis treatment was initiated for 38 patients. The remaining 44 patients were not administered tafamidis. The most frequent reason for non-administration of tafamidis was advanced heart failure and the second most reason was the patient’s frailty. In patients who received tafamidis treatment, there was no discontinuation of tafamidis due to adverse events, the rate of cardiovascular-related hospitalizations per year was 0.19, and the 1-year survival rate was 92%. In the patients who continued tafamidis for 12–18 months, there was no significant deterioration from baseline for high-sensitivity cardiac troponin T level, plasma B-type natriuretic peptide level, left ventricular ejection fraction, inter-ventricular septum wall thickness, or value of left ventricular longitudinal strain.
Conclusions: Tafamidis treatment was introduced for approximately half of the study patients with ATTRwt CA in real-world practice. Tafamidis is likely to be safe and may maintain the status of disease severity in the short-term in selected Japanese patients with ATTRwt CA. Further research is needed to determine appropriate patient selection for tafamidis treatment and efficacy of tafamidis in the long term.
Wild-type transthyretin amyloidosis (ATTRwt) is associated with aging and mainly affects the hearts of elderly people. Transthyretin cardiac amyloidosis (ATTR CA) is a progressive disease that ultimately leads to death.1–8 In patients with ATTRwt in our study cohort, the median survival period was predicted to be 3.80 years.9
In patients with this life-threatening disease, tafamidis as a specific TTR stabilizer was shown to have a substantial benefit for patients with ATTR CA in the phase 3 Transthyretin Amyloid Cardiomyopathy (ATTR-ACT) clinical trial.10 As noted in this trial, a beneficial effect of tafamidis on mortality was seen after 18 months and the effectiveness was not provided to all patients because patients with advanced disease (e.g., New York Heart Association [NYHA] functional class IV) were excluded. In addition, a recent study showed that tafamidis treatment exceeds conventional cost-effectiveness thresholds.11 Therefore, the selection of patients is extremely important in terms of the appropriate use of tafamidis.
In Japan, tafamidis has been approved for the treatment of cardiomyopathy that is caused by both ATTRwt and hereditary transthyretin amyloidosis since March 2019. The guideline and statement were issued by the Japanese Circulation Society (JCS) for the proper use of this drug;6,12 however, there are limited reports about patient selection and the efficacy of tafamidis in real-world practice in Japan.13 The aim of this study is to investigate the early experience of tafamidis treatment for patients with ATTRwt CA in our aged Japanese cohort, and discuss appropriate patient selection.
This study was performed according to the Declaration of Helsinki. The Ethics Committee for Medical Research from the Kochi Medical School approved this retrospective study (reference number: ERB-002528 and ERB-103944).
We retrospectively evaluated a total of 82 consecutive patients with ATTRwt CA who were considered for tafamidis treatment at Kochi Medical School Hospital from June 2019 (at the time when our facility was permitted to start administration of tafamidis treatment by the JCS) to July 2021.
All of the patients who started tafamidis treatment had “Definite” diagnosis of the diagnosis category, as determined by using the JCS 2020 guideline, and met the patient requirements for the administration of tafamidis by the JCS.6,12 Finally, the administration or non-administration of tafamidis was decided at a meeting with several experts and by the informed consent of patients. Patients who were approved to receive tafamidis were administered orally 80 mg once daily.
Diagnosis of Wild-Type Transthyretin Amyloid CardiomyopathyThe diagnosis of ATTR was confirmed by biopsy-proven TTR in at least 1 organ and/or positive uptake of the myocardium on 99 mTc-PYP scintigraphy with an immunoglobulin normal free light chain κ/λ ratio and absence of M protein in serum or urine immunofixation electrophoresis. The subtype of ATTRwt was established by the absence of mutations in the TTR gene shown by a genetic test and /or apparent signs and a family history indicative of hereditary transthyretin amyloidosis. All patients had cardiac amyloidosis based on the following criteria: (1) endomyocardial biopsy (EMB)-proven TTR amyloid deposition; and (2) in the absence of an EMB, biopsy-proven TTR amyloid deposits in ≥1 extracardiac organ with positive uptake of the myocardium on 99 mTc-PYP scintigraphy.14,15
Clinical EvaluationMedical records of all patients at the time of decision for administration or non-administration of tafamidis were retrospectively reviewed. We divided all patients into 2 groups according to the administration or non-administration of tafamidis. We analyzed clinical manifestations and results of laboratory studies, 12-lead electrocardiography, and echocardiography. Clinical parameters were based on database information at the time of a steady state of heart failure (HF). Echocardiographic parameters were measured in a standard fashion, as recommended by the American Society of Echocardiography guidelines.16 Left ventricular (LV) ejection fraction (EF) was calculated using the modified Simpson’s method. LV global longitudinal strain (GLS) was measured from 3 apical views with commercially available speckle-tracking software (2D strain; GE Vingmed Ultrasound). In order to estimate LV longitudinal segmental strain, we averaged the values from the basal, middle and apical segments of the LV wall.
Follow-up data including the number of cardiovascular-related hospitalizations including worsening HF and arrhythmic events (bradycardia requiring pacemaker implantation, atrial/ventricular tachyarrhythmia requiring electrical cardioversion or defibrillation, and appropriate implantable cardioverter-defibrillator therapy) and all-cause death were assessed. In patients who were administered tafamidis, we analyzed the values of parameters as the severity of amyloid cardiomyopathy at baseline (before administration of tafamidis) and at 12 months and at 18 months after the start of tafamidis treatment.
Statistical AnalysisAll data were assessed for normality using the Shapiro-Wilk test. Categorical variables are expressed as numbers (percentages) and continuous variables are presented as means±standard deviation (SD) (normally distributed variables) or medians with interquartile range (IQR) (non-normally distributed variables). The unpaired t-test or Mann-Whitney U-test for continuous variables and the chi-squared test for categorical variables were used to compare differences between the 2 groups. Survival and cardiovascular-related hospitalization event-free rate were assessed by using the Kaplan-Meier method. In 30 patients who continued tafamidis treatment for >12 months, clinical data at baseline and at 12–18 months were compared by using repeated-measures analysis of variance for normally distributed variables or the Friedman test for non-normally distributed variables.
Statistical analysis was performed using IBM SPSS version 21.0 software (IBM Corp., Armonk, NY, USA). Probability values <0.05 were considered statistically significant.
A total of 82 consecutive patients with ATTRwt CA (mean age of 81.7±6.0 years, 86% male) were considered for tafamidis treatment at Kochi Medical School Hospital from June 2019 to July 2021. Twenty-four patients had already been diagnosed with ATTRwt CA and were alive in June 2019, and the remaining 58 patients were newly diagnosed with ATTRwt CA from June 2019 to July 2021. In these 82 patients, 38 patients (mean age of 78.4±5.9 years, 87% male) were administered tafamidis and 44 patients (mean age of 84.3±4.6 years, 86% male) were not administered tafamidis. In the 44 patients who were not administered tafamidis, 13 patients had “Definite” diagnosis of the diagnosis category according to the JCS 2020 guideline, and the remaining 31 patients were clinically diagnosed with ATTRwt without genetic testing; they did not want further detailed examination upon recognizing by informed consent that tafamidis might be available.
The main reasons or factors for the decision not to administer tafamidis are shown in Figure 1. The most frequent reason was advanced HF (American College of Cardiology Foundation/American Heart Association Stage D or NYHA functional class ≥III at a steady state) and the second-most frequent reason was the patient’s frailty. Although there were listed one main reason in Figure 1, in actually, many patients had combing several of these reasons. Figure 2 shows the ages of patients at the time of the decision to administer or not administer tafamidis. All of the patients aged <75 years were administered tafamidis, whereas none of the patients aged >90 years were administered tafamidis. For patients aged between 75 years and 89 years, administration or non-administration of tafamidis was decided depending on the condition of each patient.
Pie chart showing the percentages of patients with wild-type transthyretin cardiac amyloidosis who were administrated and not administrated tafamidis and the main reason or factor influencing the decision for non-administration of tafamidis. *JCS statement.12 ACC/AHA, American College of Cardiology Foundation/American Heart Association; JCS, Japanese Circulation Society; NYHA, New York Heart Association.
Proportions of patients with wild-type transthyretin cardiac amyloidosis who were administered and not administered tafamidis treatment according to age.
Clinical characteristics of patients at baseline are shown in Table 1. Patients who received administration of tafamidis were younger than patients who did not. A larger percentage of patients who received administration of tafamidis had a NYHA class ≤II and used diuretics, and they also had a lower level of high-sensitivity cardiac troponin T (Hs-cTnT) than patients who did not receive tafamidis administration. A larger percentage of patients who were not administered tafamidis had a previous history of unplanned hospitalization for heart failure. In contrast, the percentage of patients who had atrial fibrillation, QRS duration, LVEF, and inter-ventricular septum (IVS) thickness was not different between the 2 groups.
| All patients (N=82) |
Tafamidis | P value | ||
|---|---|---|---|---|
| (+) (N=38) | (−) (N=44) | |||
| Age, years | 81.7±6.0 | 78.4±5.9 | 84.3±4.6 | <0.001 |
| Age at diagnosis, years | 80.9±6.0 | 78.1±6.0 | 83.2±4.9 | <0.001 |
| Sex: male, n (%) | 71 (86) | 33 (87) | 38 (86) | 1 |
| Number of patients who underwent TTR genetic testing, n (%) |
51 (62) | 38 (100) | 13 (30) | <0.001 |
| NYHA functional class ≤II, n (%) | 46 (56) | 33 (92) | 13 (30) | <0.001 |
| ACC/ AHA Stage, n (%) | 0.029 | |||
| Stage B | 4 (5) | 0 | 4 (9) | |
| Stage C | 60 (73) | 34 (89) | 26 (59) | |
| Stage D | 18 (22) | 4 (11) | 14 (32) | |
| Number of patients who had a previous history of unplanned hospitalization for HF, n (%) |
56 (68) | 20 (53) | 36 (82) | 0.008 |
| Atrial fibrillation or atrial flutter, n (%) | 38 (46) | 18 (46) | 20 (46) | 1 |
| QRS duration, ms | 137±116 | 124±26 | 149±157 | 0.872 |
| BNP, pg/mL | 276 [171–427] | 231 [164–353] | 281 [209–516] | 0.090 |
| Hs-cTnT, ng/mL | 0.066 [0.046–0.100] | 0.057 [0.038–0.072] | 0.088 [0.054–0.114] | 0.001 |
| eGFR, mL/min/1.73 m2 | 47.9±17.8 | 50.1±12.8 | 45.0±20.1 | 0.139 |
| Serum Alb, g/dL | 3.80±0.57 | 3.93±0.42 | 3.70±0.63 | 0.081 |
| LVEF, % | 50 [44.5–57.5] | 50 [41–58] | 51 [45.5–57] | 0.837 |
| IVS thickness, mm | 14.6 [13.5–15.6] | 14.6 [13.4–15.7] | 14.6 [13.7–15.1] | 0.996 |
| Baseline medications, n (%) | ||||
| ACE inhibitor or ARB | 24 (29) | 12 (33) | 12 (36) | 0.809 |
| Beta blockers | 4 (5) | 0 | 4 (9) | 0.496 |
| Diuretics | 75 (91) | 38 (100) | 37 (84) | 0.013 |
| Antithrombotic agents | 38 (46) | 18 (46) | 20 (46) | 1 |
Data are shown as mean±SD or median [interquartile range] or number (percentage). Alb, albumin; ACC/AHA, American College of Cardiology Foundation/American Heart Association; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ATTRwt CA, wild-type transthyretin cardiac amyloidosis; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; HF, heart failure; Hs-cTnT, high-sensitivity cardiac troponin T; IVS, interventricular septal; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
Follow-up data are shown in Table 2. The median follow-up period was not different between the 2 groups. In patients who were administered tafamidis, there was no discontinuation of tafamidis treatment due to adverse events, but 3 patients died. Cardiovascular-related hospitalizations and all-cause death were less frequent in patients who were administered tafamidis than in patients who were not administered tafamidis. Hospitalization for HF was the most common cardiovascular event for both groups. In patients who were administered tafamidis, the rate of cardiovascular-related hospitalizations per year was 0.19 and the 1-year survival rate was 92%. The Kaplan-Meier curves show the overall survival and cardiovascular-related hospitalization event-free rate after the time of decision of administration or non-administration of tafamidis in the 2 groups (Figure 3). The curve comparison with the log-rank test revealed significant differences in overall survival (P=0.012) and the cardiovascular-related hospitalization event-free rate (P=0.002).
| All patients (N=82) |
Tafamidis | P value | ||
|---|---|---|---|---|
| (+) (N=38) | (−) (N=44) | |||
| Follow-up period, months | 16.7 [8.8–23.8] | 16.4 [9.6–23.2] | 16.8 [8.0–24.9] | 0.831 |
| Discontinuation of tafamidis | ||||
| Due to treatment-related adverse events |
– | 0 | – | NA |
| Due to death | – | 3 (8) | – | NA |
| Cardiovascular-related hospitalization | 33 (38) | 7 (19) | 26 (59) | <0.001 |
| HF hospitalizations, n (%) | 31 (36) | 6 (16) | 25 (57) | <0.001 |
| Pacemaker implantation, n (%) | 2 (2) | 1 (3) | 1 (2) | 0.898 |
| All-cause death, n (%) | 18 (22) | 3 (8) | 15 (34) | 0.003 |
Data are shown as median [interquartile range] or number (percentage). NA, not available. Other abbreviations as in Table 1.
Kaplan-Meier analysis for overall survival and cardiovascular-related hospitalization event-free rate after the time of decision of administration or non-administration of tafamidis in patients with wild-type transthyretin amyloidosis, stratified by patients who received tafamidis treatment vs. patients who did not receive tafamidis treatment.
Table 3 shows detailed data for the 3 patients who died among the patients who were administrated tafamidis. All of the 3 patients who died were classified with NYHA class ≥III at the time of administration of tafamidis and were hospitalized with HF after starting tafamidis treatment.
| Age, years | Sex | NYHA functional class |
ACC/AHA stage | Hs-cTnT, ng/mL | BNP, pg/mL | eGFR, mL/min/1.73 m2 |
Alb, g/dL | LVEF, % | Comorbidities | Clinical course after starting tafamidis treatment |
|---|---|---|---|---|---|---|---|---|---|---|
| 72 | M | III | C | 0.057 | 165.5 | 44.2 | 3.9 | 45 | Atrial fibrillation, pacemaker implantation for CAVB |
One time HF hospitalization and HF death after 20 months |
| 79 | M | III | D | 0.109 | 334.8 | 40.2 | 3.5 | 35 | Atrial fibrillation, IHD with drug-eluting stent implantation |
One time HF hospitalization and HF death after 6 months |
| 78 | M | III | C | 0.077 | 198.8 | 42.1 | 3.6 | 57 | Atrial fibrillation, Moderate MR, Severe TR | One time HF hospitalization and sudden death after 6 months |
CAVB, complete atrioventricular block; IHD, ischemic heart disease; MR, mitral regurgitation; TR, tricuspid valve regurgitation. Other abbreviations as in Table 1.
Figure 4 shows data from baseline to 12 months and 18 months in the parameters of severity of amyloid cardiomyopathy in patients who were administered tafamidis. There were no significant changes in the hs-cTnT level, B-type natriuretic peptide (BNP) level, LVEF, IVS thickness, value of LV GLS, and value of each segmental longitudinal strain (LS) at base, mid, and apex from baseline to 18 months (P>0.05 for all).
Changes in hs-cTnT level, BNP level, LVEF, IVS thickness, value of GLS, and segmental LS at base, middle, and apex from baseline to 12 months and 18 months after starting tafamidis treatment. Data are shown as mean±standard deviation or median and interquartile ranges. BNP, B-type natriuretic peptide; Hs-cTnT, high-sensitivity cardiac troponin T; IVS, intra-ventricular septum; LS, longitudinal strain; LVEF, left ventricular ejection fraction; LV GLS, left ventricular global longitudinal strain.
We reported the early clinical experience of tafamidis treatment for patients with ATTRwt CA from a regional community-based medical facility in Kochi, Japan. Over the past 2 years, we administered tafamidis to 46% of the patients in our patient cohort who had ATTRwt CA. Although there was a relatively low number of patients and the follow-up duration was short, the data obtained in our cohort would be useful for many other Japanese facilities in their daily clinical practice.
Safety and Efficacy of Tafamidis Treatment for ATTRwt CAIn this study, there were few adverse events during treatment in patients who received tafamidis. The frequency of HF hospitalizations and rate of all-cause deaths were lower in patients who received tafamidis treatment than in patients who did not receive tafamidis treatment. This difference might be due to the baseline patient characteristics and severity of disease rather than the effect of tafamidis because we did not aggressively indicate tafamidis for patients with an advanced stage of ATTRwt CA.
Compared to the results of the ATTR-ACT trial,10 the patients who received tafamidis treatment were relatively older in our Kochi amyloidosis cohort (the mean age of patients who received tafamidis treatment in the ATTR-ACT trial was 74.5±7.2 years and that in this study was 78.4±5.9 years). Regarding medication, the percentage use of diuretics was relatively high in our Kochi amyloidosis cohort. In our facility, we started tafamidis treatment for patients who had a heart failure condition that required treatment with a diuretic for improvement. Therefore, all patients who were administered tafamidis treatment were on diuretics. Although clinical characteristics were not balanced in patients with ATTR-ACT and our Kochi amyloidosis cohort, the rate of cardiovascular-related hospitalizations per year and the 1-year survival rate in our patients who received tafamidis treatment were not poor. The rate of cardiovascular-related hospitalizations per year and the 1-year survival rate in the ATTR-ACT trial were 0.55 and 89%, respectively, whereas they were 0.19 and 92%, respectively, in our patient cohort.
Furthermore, there were no significant changes in the parameters of severity of amyloid cardiomyopathy (hs-cTnT level, BNP level, LVEF, IVS thickness, value of LV GLS, and each value of segmental LS) after starting tafamidis treatment. Recent studies have shown that amyloid infiltration causes significantly reduced GLS, which often precedes significant changes in LVEF.17,18 Apical sparing is a typical finding of CA, in which LS in the basal and mid segments of the LV is more severely impaired compared with the LS in the apical segments.17–19 In our patients who were treated with tafamidis, the apical sparing pattern was consistently observed during follow up; there were no significant changes in each value of basal segmental LS from baseline to 18 months (P>0.05 for all).
Nakamura et al also reported that there were no significant changes in BNP, NT-proBNP, troponin I, QRS duration, IVS thickness, LV mass index, and E/e over a 6-month period of tafamidis treatment.13 These results suggest that tafamidis treatment might maintain the status and halt disease progression in Japanese patients with ATTRwt CA after a short follow-up duration. Further evaluation during a long follow-up period for ATTRwt CA patients receiving tafamidis treatment is required to assess the efficacy of tafamidis treatment.
Consideration of Appropriate Selection of Patients With ATTRwt CA for Tafamidis TreatmentTafamidis treatment is only currently approved as a disease-modifying treatment for patients with ATTRwt CA in Japan. However, tafamidis is remarkably expensive and not very cost-effective.11 In Japan, the JCS statement stipulates the requirements of facilities and physicians for the introduction of tafamidis for patients with ATTR-CM in addition to patient requirements.6,12 The patient requirements are as follows: a history of hospitalization for HF or a HF condition requiring treatment with a diuretic for improvement; presence of amyloid deposits in biopsy tissue (cardiac or non-cardiac); transthyretin precursor protein identification by immunohistochemistry; immunohistochemically confirmed TTR precursor protein; and evidence of cardiac involvement on echocardiography with an end-diastolic IVS thickness of >12 mm. There is no limitation for patient age.
At present in our facility, for each patient with ATTRwt CA, there is discussion among several physicians about whether to start tafamidis treatment with consideration of various factors including patient’s age, disease severity or progression, patient’s willingness, patient’s frailty and comorbidities. Consequently, more than half of patients who had a diagnosis of ATTRwt CA were not actually administered tafamidis treatment in clinical practice.
In consideration of more appropriate patient selection for tafamidis treatment, we focused on the result of the ATTR-ACT trial in which a beneficial effect of tafamidis treatment on mortality was seen after 18 months.10 Therefore, tafamidis treatment would be desirable for patients who are expected survive for at least 2 years. Recently, we reported that a low serum albumin level (≤3.75 g/dL), an elevated hs-cTnT level (>0.086 ng/mL), and reduced LVEF (<50%) were associated with 2-year mortality in patients with ATTRwt CA.9 Patients with these 3 risk factors had a poor prognosis, with an estimated 2-year survival rate of 11%, whereas patients with no more than 2 risk factors had an estimated 2-year survival rate of 86%. In the present study, 3 patients died within 2 years from the start of the tafamidis treatment period and each of them had 1, 2, and 3 of the above 3 risk factors. Further studies on other more accurate predictors of medium-term mortality and predictors for identifying patients with the potential to benefit most from tafamidis treatment are needed in the future.
Study LimitationsThe limitations of the present study include its single-center design, relatively low number of patients and short observation period. More data with a long follow-up duration involving larger patient groups are needed. Second, this study was not a randomized control trial, but a retrospective cohort study; however, this study provides detailed data for clinical physicians and will be useful for managing a treatment plan for patients with ATTRwt CA in Japan. Third, TTR genetic data were not obtained in all cases. In some patients who did not receive tafamidis treatment, instead of excluding patients with hereditary transthyretin amyloidosis by genetic testing, clinical presentation at an advanced age without signs indicative of amyloid polyneuropathy and family history of amyloidosis supported the diagnosis. Finally, in patients who did not receive tafamidis treatment, sufficient follow-up serial data were lacking in this retrospective study.
This study reported the early experience of tafamidis treatment for Japanese patients with ATTRwt CA. Tafamidis treatment seemed to be safe and might maintain the cardiac status in our patient cohort with ATTRwt CA with a short follow-up duration. In contrast, about half of the patients with ATTRwt CA were not administered tafamidis treatment for various reasons in real-world clinical practice. Further examinations are required to establish the standard criteria of patient selection for tafamidis treatment and to evaluate long-term safety and efficacy of this drug.
This work was supported, in part, by a research grant from the Japan Society for the Promotion of Science (18k08078; to H.K.).
T.K., H.K. have received consulting fees or honoraria and remuneration for lectures from Pfizer Japan Inc. The remaining authors have no conflicts of interest to declare.
H.K. is a member of Circulation Journal’s Editorial Team.
This study was approved by the Ethics Committee on Medical Research of Kochi Medical School (Reference no. ERB-002528, ERB-103944).
