Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04765943 |
| Other study ID # |
PI19/0065 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 15, 2020 |
| Est. completion date |
December 31, 2024 |
Study information
| Verified date |
September 2023 |
| Source |
Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Nowadays, Sudden Cardiac Death (SCD) due to malignant arrhythmias is an important cause of
death among acute myocardial infarction (AMI) survivors. Preventive strategies with
implantable cardioverter-defibrillators (ICD) are the best clinical option for patients, but
associated sociosanitary impact in the National Health Systems and the fact that current
implant strategy not always results in benefits for the patient requires to develop further
selection criteria. The TeVeO project aims to study the events that take place early
following an AMI to predict the short- and long-term risk of experiencing a potentially
lethal ventricular tachycardia (VT). The project will carry out an observational and
multicentric study involving 5 different hospitals to: a) qualitative and quantitative
characterize non-sustained VTs (NSVT) that take place during the first 6 months after an AMI
and b) characterize the evolution of the substrate (scar and surrounding tissue) in patients
meeting criteria for ICD implant. Patients included in the study will be implanted with an
implantable loop recorder (ILR) in order to register NSVT and cMRI images will be acquired
prior to hospital discharge and at 6 months after AMI to study the substrate. Further
patients' management will follow the protocols within each entity. Project results will allow
us to stratify patients according to identified risks for developing malignant VT, which will
improve patient selection for ICD implantation and will contribute to tailor patients'
treatment and prevention, improving the cost-effectiveness of these devices and minimizing
their associated problems and sociosanitary burden.
Description:
INTRODUCTION Worldwide, cardiovascular diseases (CVD) are the leading cause of death, being
responsible for nearly one out of three demises, and including pathologies with a huge impact
in patients' and their families' quality of life and a major sociosanitary burden for
national health systems. Among them, ischemic heart diseases including mainly myocardial
infarction are the leading cause of death (12-15% deaths Globally), but with significative
differences among countries. In Spain, and similarly in other European nations, prevention
strategies, early and new therapeutic interventions and social awareness campaigns have
contributed to reduce ischemic heart diseases death rate from 11% in 2001 to 7.6%. However,
its incidence has remained practically unaltered in last decades due to the fact that the
benefit from prevention strategies is being undermined by progressive population ageing.
Since elder patients are at higher risk of developing these cardiovascular diseases, the
impact and burden of heart failure in our society are expected to be increased during the
next decades. Nowadays, approximately 30% of the patients with an acute myocardial infarction
(AMI) die before reaching the hospital. Among survivors, life-threatening sequels are highly
common and account for secondary alterations in heart pacing, mainly ventricular tachycardia
(VT), and contractility leading to heart failure. VT can be also presented as a consequence
of other pathologies, but cardiac alteration following AMI is the underlying cause in most
patients and it is often poorly tolerated leading to sudden cardiac death (SCD) in up to 30%
of AMI survivors. Today SCD represents a relevant problem for national health systems and it
is expected to get worse in the future European society due to population aging.
According to the duration of the episodes, VT can be classified as non-sustained, when the
altered rhythm is selfterminated within 30 seconds, and sustained if it lasts more than 30
secs. While non-sustained VT (NSVT) are frequently asymptomatic, sustained VT (SVT) are
potentially lethal leading to SCD by haemodynamic destabilization, shock or ventricular
fibrillation and usually an intervention is required to stop the arrythmia.
Interventions to avoid SCD following SVT are based on restoring sinus rhythm as soon as
possible. Therefore, preventive strategies with implantable cardioverter-defibrillator (ICD)
are the best clinical option for certain patients at higher risk of developing VT leading to
life-threating events and, in fact, its implantation can rescue them from SCD. Some patients
more prone to suffer STV following AMI are those with prior history of SVT, poorly tolerated
VT or previous aborted SCD. Prevention of further lethal VT by ICD implantation, a strategy
known as secondary prevention, was proved beneficial by through 3 different early clinical
trials, even when compared with antiarrhythmic drugs. The overall evidence clearly
demonstrated that IDC reduce global and arrhythmic death and thus, its implantation is now a
class I recommendation in the international guidelines for patients with aborted SCD, or
potentially lethal VT. On the other hand, despite the fact that NSVT are usually
asymptomatic, they often precede SVT especially when recurrent and monomorphic as an
expression of a significant ventricular dysfunction. These NSVT are the clinical
manifestation of an underlaying arrhythmogenic substrate and of the activation status of
triggering factors. In fact, our group has published that the amount of NSVT is associated
with the risk of medium and long-term clinically relevant events, especially with the risk of
developing poorly tolerated and potentially lethal VT. Several multicentric prospective
clinical studies have demonstrated that ICD implantation improves overall survival of
patients at high risk of developing a first episode of SVT after AMI, a strategy known as
primary prevention. As a general conclusion, mortality is reduced around 20-30% and mainly
due to SCD abortion. Although different approaches have been considered to identify those
patients at higher risk, up to date, scientific evidence only support selection of ICD
candidates for primary prevention according to following criteria: a) left ventricular
ejection fraction (LVEF) and b) functional class by the New York Heart Association (NYHA)
scale, both measured between 1-6 months after the AMI and under optimal pharmacological
treatment with antiarrhythmic drugs. However, different guidelines do not agree on LVEF
threshold to select primary ICD implantation, but it is generally accepted that a benefit is
obtained in patients with functional class I-III and LVEF<35%.
However, ICD devices not always produce benefits. On one hand, the apparition of a lethal SVT
is not prevented, just aborted, and ICD implantation early after AMI is not translated into a
better prognostic outcome for the patient. In fact, in the MADIT-II study, ICDs only produced
a reduced mortality in patients implanted beyond 18 months after AMI. On the other, the
device only responses to treat a VT in one every 10 patients implanted for primary
prevention. Besides, ICD implantation requires an invasive surgery which implies the
possibility of having a surgical complication and post-procedural infections in up to 3% of
the patients, requiring sometimes to remove the IDC and replace it once the infection is
cleared up. IDC malfunction and inappropriate shocks delivered by the device when no
life-threatening arrythmia is present are additional problems that can be presented after the
surgery. Therefore, device implantation and management accounts for a high economic cost,
with a relevant burden for the national health systems and, despite the fact that clear
benefits are observed, patient selection for primary prevention of VT by IDC implantation
should be further studied in order to first maximize the cost-effectiveness of the device and
second minimize as much as possible associated complications and sociosanitary burden.
Implantable loop recorders (ILR) are small devices that are subcutaneously implanted
requiring a minimally invasive procedure and work as a long-term Holter, monitoring for
24-hour a day patient's heart rhythm to detect arrythmias. ILR are compatible with remote
monitoring systems (RMS), allowing the patients to send daily the information registered by
the device to the healthcare center just using a conventional phone landline. This
information can be immediately analyzed by the medical practitioner allowing to quickly adopt
proper measures according to patient's clinical situation, which contributes to reduce the
morbidity and mortality. Due to their safety and effectiveness, ILR are a valuable tool for
the diagnosis of different clinical manifestations suspected to have a cardiac origin.
However, up to date they have not been systematically used to detect NSVT in patients
following an AMI, neither in their prognostic stratification, thus the viability of this
strategy that could result in improving patients selection for ICD implantation need to be
demonstrated. Though ILR monitoring, the TeVeO project aims to qualitative and quantitative
characterize NSVT that take place during the first 6 months after an AMI, stablishing the
relative importance of the two main factors influencing the arrhythmogenic mechanisms that
can originate potentially lethal VT: substrate and triggers, which will allow us to advance
in the proper treatment and prevention of these life-threatening events through patients
stratification. The substrate for VT following AMI is the scar tissue, which extension and
heterogeneity increase the risk. Prior studies have demonstrated that scar characterization
by cardiac magnetic resonance imaging (cMRI) provides additional information to the LVEF and
functional class to identify those patients at higher arrhythmic risk. However, little data
are available regarding the underlying substrate and its evolution in chronic AMI with NSVT.
Therefore, in addition to ILR monitoring, TeVeO study will evaluate the scar tissue by cMRI
trying to identify further predictive markers associated to increased risk of developing SVT
after AMI.
HYPOTHESIS The project is grounded on the main assumption that the unsustained ventricular
tachycardias (NSVT) that spontaneously occur during the first 6 months after an AMI can
predict short and long-term functional outcome, specifically the risk of experiencing a
potentially lethal VT. Therefore, the study of theses arrhythmic events can contribute to
patient stratification and help to develop further improvements for their management.
TeVeO project assume the following further hypothesis for the study of the NSVT following an
AMI:
- The implantable loop recorders (ILRs) are able to accurately detect the NSVTs that
patients submitted to coronary revascularization experiment after the medical discharge
and during the first 6 months after an acute myocardial infarction (AMI).
- There are differences in the arrhythmogenic substrate of patients presenting NSVT in the
6 first months after an AMI with depressed left ventricular ejection fraction (LVEF)
that can be determined by the study of the scar tissue by cardiac MRI (cMRI).
OBJECTIVES The main objective of TeVeO study is to qualitative and quantitative characterize
NSVTs that take place during the first 6 months after an AMI in patients with LVEF ≤40%, and
to discriminate the short- and long-term risks of developing potentially lethal arrhythmic
events, which will contribute to tailor patients' treatment and prevention according to
identified risks and will improve patient selection for implantable
cardioverter-defibrillator (ICD) implantation, improving the cost-effectiveness of these
devices and minimizing its associated problems and sociosanitary burden.
To achieve main purpose, primary and secondary specific objectives have been stablished.
METHODS.
1. Characteristics:
Type: prospective clinical study, multicentric, Observational study. Participating
centres: Hospital Universitario de Salamanca, Complejo Asistencial Universitario de
Burgos, Hospital Universitario San Pedro de Alcántara, Complejo Asistencial
Universitario de Santiago de Compostela and Complejo Asistencial Universitario de Lugo.
Comparing groups: Acquired data within the first 6 months after an AMI will be study in
order to stablish possible associations with the patient outcome in the first 2 years
after an AMI.
Definitions:
- NSVT: Any rhythm with a wide QRS from a ventricular origin that is self-terminated
within 30 second, with a heart rate over 100 bpm and over 5 beats.
- SVT: Any rhythm with a wide QRS from a ventricular origin with a heart rate over
100 bpm, that lasts over 30 seconds or that needs an intervention to be finished.
- Monomorphic VT: All QRS complex present the same morphology
- Polymorphic VT: QRS morphology changes in any heartbeat.
- Appropriate therapy: Any therapy (antitachycardia pacing or discharge) applied by
ICD due to a ventricular tachycarrhythmia.
- Inappropriate therapy: Any ICD therapy that is not due to a ventricular
tachycarrhythmia.
- Ischemic left ventricular dysfunction: The systolic dysfunction due to a previous
coronary artery disease with myocardial necrosis with previous demonstration of at
least one obstructed epicardial coronary artery, and presence of ischemic scar in
MRI with characteristic distribution of late-enhancement of gadolinium.
2. Study population: Unselected patients who have suffered a myocardial infarction and who
have an LVEF equal to or less than 40% (determined by transthoracic echocardiography) on
the fourth day after the event.
Sample size calculation: Study aims to include around 200 AMI patients. Sample size has
been estimated for a confidence level of 95%, defined by a coefficient Za = 1.96 and
taking into account a prevalence (p) of NSVT (< 5 episodes in 6 months) of 15% and a
precision level (d) of 5%. According to the following formula, in which q = 1-p:
n = Z2 * a * p * q / d2 n = 3.84 * 0.15 * 0.85 / 0.0025 = 196 patients to be included.
3. Study design:
- Epidemiological and basic clinical data of all the patients hospitalized in the
participating hospitals after an episode of AMI will be collected.
- Patients accomplishing inclusion and exclusion criteria will be submitted to
continuous electrocardiographic monitoring until medical discharge.
- Before discharge a cMRI (days 6-10 after AMI) will be performed and after an ILR
will be implanted.
- Following medical discharge, enrolled patients will daily transmit the device
register, which will be analyzed by specialized personnel. An intervention will
take place if any arrhythmic event is registered following the current
recommendations of scientific society.
- Patients will be reevaluated 6 months after the coronary revascularization
performed during hospitalization. This clinical evaluation will include, at least,
the clinical and functional status (NYHA scale), pharmacological treatment and LVEF
determination by echocardiography. Besides, ILR will be explanted to cMRI
acquisition. If the patient fulfills current criteria of the European Society of
Cardiology according to LVEF criteria, an ICD will be then implanted without
resynchronization therapy. If the patient does not fulfill ICD criteria, ILR
monitoring will continue for 18 months more (2 years after the AMI event). Periodic
clinical checkup will take place according to the protocols specified by our
center. According to the scientific evidence, 5-10% of subjects with LVEF <40% in
the first week post revascularizated AMI will recover part of the ventricular
function, falling outside of ICD implantation criteria.
- Patients will be followed-up during the first 2 years after the AMI. Periodic
checkups will be programmed according to the protocols of our center. ICD and ILR
implanted patients will daily transmit the device register that will be weekly
reviewed.
- After the 2 years follow-up, the ILR, in those patients without an ILR, will be
explanted and a cMRI will be performed.
ICD programming:
Detection and therapy programming will be standardized and included two zones:
Ventricular Fibrillation (VF) (Cycle Length [CL] < 250 ms) and Ventricular Tachycardia
Zone 1 (CL from 250 to 320 ms). In both cases tachycardia detection will require that 30
of the last 40 R-R intervals had to have a CL bellow the cutoff point. Episodes
classified as VF will receive a sequence of high-energy shocks. Otherwise, episodes
detected in Ventricular Tachycardia Zone 1 will be initially treated by a single ATP
sequence (an 8-pulse-burst train at 88%). Failed ATP will be followed by shock and then
other shocks as necessary. An additional monitoring zone (Ventricular Tachycardia Zone
2) will be programmed for episodes with a CL from 321 to 400 ms. All devices will be
programmed to store the far-field electrograms before the onset of the episodes detected
to aid in rhythm classification.
MRI protocol:
All patients will undergo contrast-enhanced MRI with a 1.5-T or 3 T scanner. All images
will be obtained with electrocardiographic gating and breath-holding. The MRI study will
consist of cine steady-state free precession imaging of left ventricular function and
late enhancement imaging of myocardial scar tissue. Late Enhancement images will be
obtained 10 to 15 min after an injection of 0.2 mmol/kg of gadodiamide. Late-enhanced
images will be used for infarct characterization. Infarct and heterogeneous tissue
(i.e., gray zone) mass will be quantified by 2 methods: 1) the full width at half
maximum; and 2) on the basis of Standard Deviations (SD) of the signal intensity from
the remote mean healthy myocardium (>2SDs defined the total infarct mass,>3SDs the core
infarct and HT between 2 and 3 SDs).
4. Data collection and statistical analysis
Data collection:
No personal data will be collected or processed without prior formal authorization. Once
informed consent has been signed, data will be collected, stored and managed according
to current local, national and EU legislation on this matter. In particular, the
Regulation (EU) 2016/679 of the European Parliament and of the Council on the protection
of natural persons with regard to the processing of personal data and on the free
movement of such data will be carefully fulfilled. Any further ethical issue that may
arise within the project will be properly consulted and addressed by participating
entities.
Clinical variables:
1. Clinical variables from hospitalization phase:
- Date of AMI index.
- AMI location.
- Demographic data: age, gender, profession.
- Weight and height.
- Cardiovascular risk factors: Hypertension, dyslipemia, diabetes, smoking,
obesity, peripheral vascular disease, drug abuse.
- Electrocardiographic variables:
o Atrial rhythm (sinus, atrial fibrillation/flutter, paced).
- Number of Q waves.
- Duration of QRS complex.
- Presence of complete bundle branch block.
- Number of epicardial coronary arteries with stenosis >70%.
- Coronary revascularization: type (percutaneous and surgical) and affected
arteries.
- NSVT incidence during hospitalization.
- LVEF measured 5-7 days following the AMI: %.
- Date of ILR implantation.
- Pharmacological treatment at medical discharge.
2. Clinical variables from ILR monitoring phase:
- Qualitative (heartbeats number, polymorphic/monomorphic) and quantitative (event
number) incidence of NSVT.
- Functional Class (NYHA) and LVEF (by echo) 6 months after revascularization.
- Unplanned medical interventions as a consequence of data collected from the
ILR within the 6 first months post-AMI.
- After six months of ILR monitoring, among non-appropriate patients for ICD
implant, clinical events will be recorded: hospitalization due to cardiac
causes, syncope, pacemaker of ICD implant, aborted SCD, cardiovascular death.
3. Clinical variables from post-ICD implant phase:
- ICD or ICD-TRC implant date.
- Complications related to ICD or ICD-TRC implant.
- Clinical events after ICD implant: appropriate therapies, appropriate
discharges, inappropriate therapies, hospitalization due to heart failure,
cardiovascular death.
Variables from ILR recording:
- Relevant arrhythmias: sinus pause >3 seconds, second- or third-degree AV block,
NSVT, SVT.
- For NSVT:
o Data: day and hour.
o Number of beats.
o Duration, seconds
o Cycle Length.
- Morphology: monomorphic or polymorphic.
- For SVT:
o Data: day and hour.
o Duration, seconds.
o Cycle Length.
o Morphology: monomorphic or polymorphic.
Variables from cMRI studies:
- Left ventricular dimensions.
- LVEF.
- Extension of scar.
- Extension of dense scar.
- Extension of heterogeneous tissue.
Statistical analysis:
Statistical analysis will be performed using the SPSS programme 11.0 or further.
Normal and continuous variables will be described by means and standard deviations,
whereas categorical variables will be summarized by the number of patients and
percentages. Comparison of the categorical variables will be performed with the
Chi-square test (or Fisher's exact test if n<5). Comparison of 2 normal variables
(determined with the Kolgomorov-Smirnov test) and continuous variables will be done
with Student's t test. Comparison of >2 continuous variables will be performed
using the ANOVA test. Multivariate analysis will be accomplished by a logistic
regression or Cox regression tests. To determine the individual mean of proportions
adjusted per multiple episodes per patient, the Generalized Estimating Equations
Method will be used in the calculations and comparisons. A p value <0.05 will be
considered statistically significant.
Machine learning and Deep learning:
Due to the great amount of data to be collected by the ILR during the first 6
months after an AMI and by the ICD/ILR up to 2 years following the AMI, a Machine
Learning analysis will be also performed to determine the association between the
incidence, burden and temporal distribution of NSVTs registered by ILRs with the
occurrence of ICD appropriate therapies.
Machine Learning techniques to be used will consist in supervised since the
response variable is identified. The usual algorithms (random forest, xgboost, SVM,
etc.) will be combined in order to find the balance between bias and variance,
avoiding overfitting the available data, so that the model can be successfully
generalized to further populations. In cases where the response variable is
represented by a few cases, we will use subsampling and oversampling techniques
such as bagging balance. All the Machine Learning analysis will be carried out
using the Python programming language and libraries like scikit-learn, which
include proper algorithms and techniques for the project.
Project will also acquire 2/3 cMRI of ICD/ILR implanted patients. Together with the
abovementioned statistical analysis, cMRI images will be analyzed by deep learning
(neural networks) in order to detect any possible pattern and their evolution. Raw
images could be a reliable predictor of patient's evolution. For the implementation
of deep learning techniques Keras and TensorFlow programs will be used.
