Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction (PROTECT-ICD)
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology, Cardiology, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 85 |
| Updated: | 7/22/2018 |
| Start Date: | February 27, 2014 |
| End Date: | June 30, 2023 |
| Contact: | Pramesh Kovoor |
| Email: | pramesh.kovoor@sydney.edu.au |
| Phone: | +61 2 8890 6030 |
The PROTECT-ICD trial is a physician-led, multi-centre randomised controlled trial targeting
prevention of sudden cardiac death in patients who have poor cardiac function following a
myocardial infarct (MI). The trial aims to assess the role of electrophysiology study (EPS)
in guiding implantable cardioverter-defibrillator (ICD) implantation, in patients early
following MI (first 40 days). The secondary aim is to assess the utility of cardiac MRI (CMR)
in analysing cardiac function and viability as well as predicting inducible and spontaneous
ventricular tachyarrhythmia when performed early post MI.
Following a MI patients are at high risk of sudden cardiac death (SCD). The risk is highest
in the first 40 days; however, current guidelines exclude patients from receiving an ICD
during this time. This limitation is based largely on a single study, The Defibrillator in
Acute Myocardial Infarction Trial (DINAMIT), which failed to demonstrate a benefit of early
ICD implantation. However, this study was underpowered and used non-invasive tests to
identify patients at high risk. EPS identifies patients with the substrate for re-entrant
tachyarrhythmia, and has been found in multiple studies to predict patients at risk of SCD.
Contrast-enhanced CMR is a non-invasive test without radiation exposure which can be used to
assess left ventricular function. In addition, it provides information on myocardial
viability, scar size and tissue heterogeneity. It has an emerging role as a predictor of
mortality and spontaneous ventricular arrhythmia in patients with a previous MI.
A total of 1,058 patients who are at high risk of SCD based on poor cardiac function (left
ventricular ejection fraction (LVEF) ≤40%) following a ST-elevation or non-STE myocardial
infarct will be enrolled in the trial. Patients will be randomised 1:1 to either the
intervention or control arm.
In the intervention arm all patients undergo early EPS. Patients with a positive study
(inducible ventricular tachycardia cycle length ≥200ms) receive an ICD, while patients with a
negative study (inducible ventricular fibrillation or no inducible VT) are discharged without
an ICD, regardless of the LVEF.
In the control arm patients are treated according to standard local practice. This involves
early discharge and repeat assessment of cardiac function after 40 days or after 90 days
following revascularisation (PCI or CABG). ICD implantation after 40 days according to
current guidelines (LVEF≤30%, or ≤35% with New York Heart Association (NYHA) class II/III
symptoms) could be considered, if part of local standard practice, however the ICD is not
funded by the trial.
A proportion of trial patients from both the intervention and control arms at >48 hours
following MI will undergo CMR to enable correlation with (1) inducible VT at EPS and (2) SCD
and non-fatal arrhythmia on follow up. It will be used to simultaneously assess left
ventricular function, ventricular strain, myocardial infarction size, and peri-infarction
injury. The size of the infarct core, infarct gray zone (as a measure of tissue
heterogeneity) and total infarct size will be quantified for each patient.
All patients will be followed for 2 years with a combined primary endpoint of non-fatal
arrhythmia and SCD. Non-fatal arrhythmia includes resuscitated cardiac arrest, sustained
ventricular tachycardia (VT) and ventricular fibrillation (VF) in participants without an
ICD. Secondary endpoints will include all-cause mortality, non-sudden cardiovascular death,
non-fatal repeat MI, heart failure and inappropriate ICD denial. Secondary endpoints for CMR
correlation will include (1) the presence or absence of inducible VT at EP study, and (2)
combined endpoint of appropriate ICD activation or SCD at follow up.
It is anticipated that the intervention arm will reduce the primary endpoint as a result of
prevention of a) early sudden cardiac deaths/cardiac arrest, and b) sudden cardiac
death/cardiac arrest in patients with a LVEF of 31-40%. It is expected that the 2-year
primary endpoint rate will be reduced from 6.7% in the control arm to 2.8% in the
intervention arm with a relative risk reduction (RRR) of 68%. A two-group chi-squared test
with a 0.05 two-sided significance level will have 80% power to detect the difference between
a Group 1 proportion of 0.028 experiencing the primary endpoint and a Group 2 proportion of
0.067 experiencing the primary endpoint when the sample size in each group is 470. Assuming
1% crossover and 10% loss to follow up the required sample size is 1,058 (n=529 patients per
arm). To test the hypothesis that tissue heterogeneity at CMR predicts both inducible and
spontaneous ventricular tachyarrhythmias will require a sample size of 400 patients to
undergo CMR.
It is anticipated that the use of EPS will select a group of patients who will benefit from
an ICD soon after a MI. This has the potential to change clinical guidelines and save a large
number of lives.
prevention of sudden cardiac death in patients who have poor cardiac function following a
myocardial infarct (MI). The trial aims to assess the role of electrophysiology study (EPS)
in guiding implantable cardioverter-defibrillator (ICD) implantation, in patients early
following MI (first 40 days). The secondary aim is to assess the utility of cardiac MRI (CMR)
in analysing cardiac function and viability as well as predicting inducible and spontaneous
ventricular tachyarrhythmia when performed early post MI.
Following a MI patients are at high risk of sudden cardiac death (SCD). The risk is highest
in the first 40 days; however, current guidelines exclude patients from receiving an ICD
during this time. This limitation is based largely on a single study, The Defibrillator in
Acute Myocardial Infarction Trial (DINAMIT), which failed to demonstrate a benefit of early
ICD implantation. However, this study was underpowered and used non-invasive tests to
identify patients at high risk. EPS identifies patients with the substrate for re-entrant
tachyarrhythmia, and has been found in multiple studies to predict patients at risk of SCD.
Contrast-enhanced CMR is a non-invasive test without radiation exposure which can be used to
assess left ventricular function. In addition, it provides information on myocardial
viability, scar size and tissue heterogeneity. It has an emerging role as a predictor of
mortality and spontaneous ventricular arrhythmia in patients with a previous MI.
A total of 1,058 patients who are at high risk of SCD based on poor cardiac function (left
ventricular ejection fraction (LVEF) ≤40%) following a ST-elevation or non-STE myocardial
infarct will be enrolled in the trial. Patients will be randomised 1:1 to either the
intervention or control arm.
In the intervention arm all patients undergo early EPS. Patients with a positive study
(inducible ventricular tachycardia cycle length ≥200ms) receive an ICD, while patients with a
negative study (inducible ventricular fibrillation or no inducible VT) are discharged without
an ICD, regardless of the LVEF.
In the control arm patients are treated according to standard local practice. This involves
early discharge and repeat assessment of cardiac function after 40 days or after 90 days
following revascularisation (PCI or CABG). ICD implantation after 40 days according to
current guidelines (LVEF≤30%, or ≤35% with New York Heart Association (NYHA) class II/III
symptoms) could be considered, if part of local standard practice, however the ICD is not
funded by the trial.
A proportion of trial patients from both the intervention and control arms at >48 hours
following MI will undergo CMR to enable correlation with (1) inducible VT at EPS and (2) SCD
and non-fatal arrhythmia on follow up. It will be used to simultaneously assess left
ventricular function, ventricular strain, myocardial infarction size, and peri-infarction
injury. The size of the infarct core, infarct gray zone (as a measure of tissue
heterogeneity) and total infarct size will be quantified for each patient.
All patients will be followed for 2 years with a combined primary endpoint of non-fatal
arrhythmia and SCD. Non-fatal arrhythmia includes resuscitated cardiac arrest, sustained
ventricular tachycardia (VT) and ventricular fibrillation (VF) in participants without an
ICD. Secondary endpoints will include all-cause mortality, non-sudden cardiovascular death,
non-fatal repeat MI, heart failure and inappropriate ICD denial. Secondary endpoints for CMR
correlation will include (1) the presence or absence of inducible VT at EP study, and (2)
combined endpoint of appropriate ICD activation or SCD at follow up.
It is anticipated that the intervention arm will reduce the primary endpoint as a result of
prevention of a) early sudden cardiac deaths/cardiac arrest, and b) sudden cardiac
death/cardiac arrest in patients with a LVEF of 31-40%. It is expected that the 2-year
primary endpoint rate will be reduced from 6.7% in the control arm to 2.8% in the
intervention arm with a relative risk reduction (RRR) of 68%. A two-group chi-squared test
with a 0.05 two-sided significance level will have 80% power to detect the difference between
a Group 1 proportion of 0.028 experiencing the primary endpoint and a Group 2 proportion of
0.067 experiencing the primary endpoint when the sample size in each group is 470. Assuming
1% crossover and 10% loss to follow up the required sample size is 1,058 (n=529 patients per
arm). To test the hypothesis that tissue heterogeneity at CMR predicts both inducible and
spontaneous ventricular tachyarrhythmias will require a sample size of 400 patients to
undergo CMR.
It is anticipated that the use of EPS will select a group of patients who will benefit from
an ICD soon after a MI. This has the potential to change clinical guidelines and save a large
number of lives.
Inclusion Criteria:
- 2-40 days (inclusive) following a myocardial infarct
- Impaired left ventricular systolic function (LVEF≤40% or at least moderately impaired)
Exclusion Criteria:
1. Age <18 or >85;
2. Pregnancy;
3. Nursing home resident dependent on one or more activities of daily living;
4. Significant non-cardiac co-morbidity with high likelihood of death within 1 year (this
would include any metastatic malignancy, or other terminal disease);
5. Significant psychiatric illnesses that may be aggravated by device implantation or
that may preclude regular follow up;
6. Intravenous drug abuse (ongoing);
7. Unresolved infection associated with risk for hematogenous seeding;
8. Pre-existing implantable cardioverter-defibrillator (ICD);
9. Secondary prevention indication for an ICD (i.e. sustained ventricular arrhythmias
occurring more than 48 hours after qualifying myocardial infarction (patients with
ventricular arrhythmias occurring ≤48 hours of myocardial infarction, or with
non-sustained ventricular tachycardia at any time, are not excluded));
10. On the heart transplant list;
11. Recurrent unstable angina despite revascularisation (defined as ongoing chest pain or
ischemic symptoms at rest or with minimal exertion despite adequate treatment with
anti-anginal medications);**
12. Congestive heart failure New York Heart Association class IV, defined as shortness of
breath at rest, which is refractory to medical treatment (not responding to
treatment)** **NOTE: patients who meet exclusion based on (11) or (12) can be reviewed
again in 2-3 days and if symptoms have resolved or treatment performed can be
re-considered for inclusion.
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