Clinical trial NCT03588286: Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction (PROTECT-ICD)
Official title: Programmed Ventricular Stimulation to Risk Stratify for Early Cardioverter-Defibrillator (ICD) Implantation to Prevent Tachyarrhythmias Following Acute Myocardial Infarction (PROTECT-ICD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Sudden Cardiac Death
Keywords: Myocardial Infarction (MI), Sudden Cardiac Death (SCD), Electrophysiological Study (EPS), Ventricular Tachycardia (VT)
Lead sponsor: Western Sydney Local Health District
Sponsor class: OTHER
First posted: 2018-07-17
Enrollment: 1058
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Sudden cardiac death
timeFrame: 2 years after randomisation
measure: Non-fatal arrhythmia
timeFrame: 2 years after randomisation
Secondary outcomes:
measure: All-cause mortality
timeFrame: 2 years after randomisation
measure: Non-sudden cardiovascular death
timeFrame: 2 years after randomisation
measure: Non-fatal repeat MI
timeFrame: 2 years after randomisation
measure: Heart failure
timeFrame: 2 years after randomisation
measure: Inappropriate ICD denial
timeFrame: 2 years after randomisation
measure: Appropriate ICD activations (in patients with ICD)
timeFrame: 2 years after randomisation
measure: Inappropriate ICD activations (in patients with ICD)
timeFrame: 2 years after randomisation
measure: Complications or re-hospitalisation associated with ICD implantation (in patients with ICD)
timeFrame: 2 years after randomisation
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Cairns
country: Australia
facility: Carins Hospital
state: Queensland
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Douglas
country: Australia
facility: The Townsville Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Clayton
country: Australia
facility: MonashHeart
state: Victoria
city: Epping
country: Australia
facility: Northern Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Western Health, Sunshine and Footscray Hospitals
state: Victoria
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine
city: Bad Neustadt An Der Saale
country: Germany
facility: Cardiovascular Center Bad Neustadt
city: Brandenburg
country: Germany
facility: Klinikum Brandenburg
city: Göttingen
country: Germany
facility: Universitaetsmedizin Gittingen (University of Göttingen Medical Center)
city: Leipzig
country: Germany
facility: Leipzig Heart Center
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Athens
country: Greece
facility: General Hospital of Athens Giorgios Gennimatas
city: Athens
country: Greece
facility: General Hospital of Athens Ippokrateio
city: Iraklio
country: Greece
facility: University Hospital of Heraklion Crete
city: Budapest
country: Hungary
facility: Semmelweis University Heart and Vascular Center
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Pécs
country: Hungary
facility: University of Pécs
city: Jerusalem
country: Israel
facility: Sharee Zadek Medical Centre
city: Riga
country: Latvia
facility: Paul Stradins University Clinic
city: Kuala Lumpur
country: Malaysia
facility: Institut Jantung Negara Sdn Bhd
city: Kuala Lumpur
country: Malaysia
facility: Pusat Jantung Sarawak (PJS)(Sarawak Heart Centre)
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital
state: Auckland
city: Hamilton W.
country: New Zealand
facility: Waikato Hospital
state: Hamilton
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Warszawa
country: Poland
facility: National Institute of Cardiology Warsaw
city: Łódź
country: Poland
facility: Medical University of Łódź - Biegański Provincial Specialist Hospital
city: Łódź
country: Poland
facility: Medical University of Łódź - WAM Hospital
city: Łódź
country: Poland
facility: Medical University of Łódź
city: Saint Petersburg
country: Russian Federation
facility: Almazov National Medical Research Centre
city: Samara
country: Russian Federation
facility: Samara State Medical University
city: Singapore
country: Singapore
facility: National University Heart Centre, Singapore (NUHCS)
city: Bratislava
country: Slovakia
facility: The National Institute of Cardiovascular Diseases
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Lausanne
country: Switzerland
facility: Lausanne University Hospital
Study officials:
affiliation: Western Sydney Local Health District
name: Study Principal Investigator Study Principal Investigator
role: PRINCIPAL_INVESTIGATOR
References: