Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction (PROTECT-ICD)
Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction (PROTECT-ICD)
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.
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.