Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04587648 |
| Other study ID # |
201906065RINA |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2019 |
| Est. completion date |
December 31, 2023 |
Study information
| Verified date |
May 2023 |
| Source |
National Taiwan University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure
cases with heterogenous cause and variable presentations. The diagnosis of HFpEF required
clinical signs and symptoms of HF, normal left ventricular ejection fraction (LVEF) and
evidence of diastolic dysfunction. No treatment has been shown in recent major clinical
trials having benefits in these patients. One major reason of the poor response to medical
treatment is the heterogeneity of HFpEF, which contains many different underline causes. To
identify the underlying causes of HFpEF may improve the diagnosis and treatment in these
patients.
Age-related amyloid deposition has first been reported in 1876 and the following autopsy
studies showed the prevalence of senile cardiac amyloid is up to 25%. Recently, it has been
recognized that the deposits in senile cardiac amyloid are derived from wild-type
transthyretin (TTR). Transthyretin amyloidosis cardiac amyloidosis (ATTR CA) is caused by
myocardial deposition of misfolded transthyretin protein. There are 2 types of ATTR
classified by genetic mutation including wild-type ATTR (ATTRwt) and familial cardiac amyloid
caused by TTR mutation (ATTRm).
Multimodality techniques have been developed to assist in the diagnosis of the diagnosis of
TTR. Among them, 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy
is a non-invasive test and it can diagnose TTR from other cause diverse form of cardiac
amyloidosis and cardiomyopathy. In the study of Gonzalez-Lopez et al, in 120 HFpEF patients,
16 (13.3%) had positive 99mTc-DPD scan. Four patients with positive 99mTc-DPD scan received
endomyocardial biopsy and confirmed cardiac amyloid deposition.
ATTRwt could be an important cause of HFpEF and it was often under diagnosed. A recent study
in Spain reported that 13% of patents over age of 60 years with HFpEF and left ventricular
wall thickness of 12mm or more had ATTRwt. However, the prevalence of ATTRwt among patients
with HFpEF is not well-established in Taiwan and Asia. The aim of this study is to determine
the prevalence, clinical characteristics, risk factors and outcomes of ATTRwt related HFpEF
patients in Taiwan.
Description:
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical situation
with multiple underlying causes. The diagnosis of HFpEF is challenging which requires
clinical signs/symptoms of HF, a normal or mildly impaired systolic function measured by left
ventricular ejection fraction (LVEF), and evidence of diastolic dysfunction. There are no
significant improvements in treatment of HFpEF in recent years and the results in the major
clinical trials for HFpEF were disappointed. One major reason is the heterogeneity of HFpEF,
which contains several diseases under the same entity.
Small deposits of amyloid are found in the elder hearts in up to 25% of the autopsies. These
deposits are mainly composed by wild-type transthyretin (TTR). Transthyretin amyloidosis
cardiac amyloidosis (ATTR CA) is caused by myocardial deposition of misfolded transthyretin
protein. It is classified into 2 groups by the genetics of Transthyretin amyloidosis (ATTR):
wild-type (ATTRwt) or hereditary (hATTR or ATTRm). ATTR CA, irrespective of genotype, is an
unrecognized mechanism underlying HFpEF. It was reported wild-type TTR might be an
underdiagnosed cause of HFpEF. However, the prevalence of wild-type ATTR among patients with
HFpEF is not well-established in Taiwan and Asia.
One of the most convenient method to detect and diagnosis cardiac amyloidosis is
99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy6. In the study of
Gonzalez-Lopez et al, in 120 HFpEF patients, 16 (13.3%) had positive 99mTc-DPD scan6. Four
patients with positive 99mTc-DPD scan received endomyocardial biopsy and confirmed cardiac
amyloid deposition6. In addition, technetium-99m TC pyrophosphate (PYP) scintigraphy is also
very useful in diagnosis of cardiac amyloidosis.
The propose of this study is to determine the prevalence of ATTRwt among elderly HFpEF
patients in Taiwan. In this study, the investigators will recruit a cohort of HFpEF patients
in Taiwan to define the number of patients who have cardiac amyloidosis by utilizing highly
sensitive heart imaging and blood tests. The investigators will also explore differences in
different risk factors as they relate to heart failure disease progression in cardiac
amyloidosis. According our previous studies, the average age of HFpEF in Taiwan is 65 y/o. In
this study, the investigators set age limitation as 60 y/o. However, because 5% ATTRwt were <
60 y/o9, therefore, the investigators also recruit patients >50y/o with risk factors of
ATTRwt.
Hypothesis HFpEF is a heterogeneous clinical situation with multiple underlying causes.
ATTRwt is an underdiagnosed cause of HFpEF but the prevalence is unknown in Taiwan. ATTRwt
can be diagnosed non-invasively by 99mTc-PYP scintigraphy7. The investigators aimed to
investigate the prevalence and clinical characteristics of ATTRwt among patients with HFpEF.
Primary Objective(s) / Endpoint(s) Percentage of participants with ATTRwt among patients with
HFpEF in Taiwan
Secondary Objective(s) / Endpoint(s) To investigate the clinical and echocardiographic
characters in ATTRwt patients and compare with HFpEF patients without ATTRwt
Trial Population Eligible HFpEF patients with a LVEF of ≧50%, New York Heart Association
(NYHA) class I-IV symptoms: Both in-patients or patients in clinics could be enrolled. These
patients could be newly diagnosed or has been diagnosed. Study subjects will be
pre-stratified according to left ventricular posterior wall thickness (LVPW) ≥12mm or less;
number of subjects with LVPW ≥12mm should account for more than 50% of total subjects
recruited in the final analysis.
Sample Size and Sample Size Justification The study will prospectively evaluate the
prevalence of ATTRwt among patients with HFpEF. Assume the expected 10% prevalence of ATTRwt
in patients with HFpEF, the target recruitment of 260 HFpEF patients would yield 25 ATTRwt
positive result, which would provide the prevalence estimate with associated 90% confidence
interval at the range of +- 3%. The estimated enrolled time is 18 months.
Key Inclusion Criteria
1. Patient is ≥ 60 years old or 50 y/o with carpal tunnel syndrome or spinal stenosis
2. Patient has been diagnosed as HFpEF in their medical history or newly diagnosed as
HFpEF. They have HF symptoms with NYHA Classification of I-IV when diagnosis. The
criteria of HFpEF is according to our previous studies10.
3. More than 50% of them have LVPW ≥12mm (when diagnosis).
4. Written informed consent could be obtained
Key Exclusion Criteria
1. Patients unwilling to join this projects
2. Patients with unstable coronary artery disease, plan to receive coronary intervention
within months.
3. Patients has previous history of heart failure reduced ejection (HFrEF) with a LVEF
<40%.
Method
1. Patients recruitment and study protocol The enrolled and exclusion criteria were
mentioned above. The investigators will enroll 260 HFpEF patients (> 50% with LVPW
thickness >12mm). After receiving informed consent, patients will receive NTproBNP, ECG,
and echocardiography. Then the investigators will arrange 99mTc-PYP scan to detect the
presence of amyloidosis. If patients have these data (ECG, NTproBNP, echocardiogram,
99mTc PYP) within 6 months, the investigators will record and use this data and do not
perform again. In patients with positive 99mTc-PYP scan, the investigators will detect
urinary monoclonal light chain and serum monoclonal light chain. In addition, the
investigators will arrange TTR genetic testing.
2. Data Collection Delegated physicians or study personnel blinded to scintigraphy results
will review the medical records of all patients. Demographic and clinical data will be
collected during outpatient clinic visit.
3. Scintigraphy Protocol Planar and single-photon positive emission computed tomography
(SPECT) imaging with 99mTc-PYP was performed with a dual head Philips Precedence
SPECT/CT camera (Philips Healthcare, Guildford, United Kingdom). Patients received 20 to
25 mCi of 99mTc-PYP intravenously and images were obtained at 2 hours over 8 minutes
duration.
4. Genotype Testing The TTR mutation was confirmed by sequencing of the TTR gene following
National Taiwan University Hospital established protocols. All 4 exons and their
flanking intron regions of the human TTR gene were amplified by polymerase chain
reaction (PCR). The amplicons were purified by the Gel/PCR DNA Fragments Extraction Kit
(Geneaid, Taipei, Taiwan). Sequencing was performed at the corresponding exons by using
the ABI3730 automatic DNA sequencer (Applied Biosystems, Foster City, CA).
