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

Обзор

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.

Вмешательства

• Процедура Electrophysiology study (EPS)
  EPS will be performed in all patients in the intervention arm with programmed ventricular stimulation with a drive train of 8 beats at 400 ms with up to 4 extrastimuli and stimulation from the right ventricular apex with current delivered at twice pacing threshold. The end point for stimulation will be sustained monomorphic ventricular tachycardia (VT) lasting \> 10 seconds. If sustained monomorphic VT with cycle length (CL) ≥200ms is induced by ≤4 extra stimuli the EPS result will be considered
• Другое Standard Care
  The control group receive ongoing standard care according to the practise of their institution. This includes discharge from hospital as per their treating physician and follow up as usual in the community. Participants in this group would be eligible to receive an ICD according to the standard practise of their cardiologist (guideline recommendations are after 40 days following myocardial infarction or 90 days following revascularisation only in patients with left ventricular ejection fraction
• Процедура Cardiac Magnetic Resonance (CMR)
  CMR will be performed on either a 1.5-T or 3-T scanner. Gadolinium contrast (Gd-BOPTA, MultihanceTM) will be administered for quantification myocardial perfusion imaging with subsequent late gadolinium enhanced imaging after a total dose of 0.1mmol/kg. Exclusion criteria specific for CMR will include pregnancy, renal insufficiency defined as glomerular filtration rate (GFR) \<30 mL/min, contraindication to MRI (including non-MRI compatible pacemaker/ICD or metal implants, non-MR safe prosthetic

Первичные конечные точки

• Sudden cardiac death [Срок оценки: 2 years after randomisation]
• Non-fatal arrhythmia [Срок оценки: 2 years after randomisation]

Вторичные конечные точки (8)

• All-cause mortality [Срок оценки: 2 years after randomisation]
• Non-sudden cardiovascular death [Срок оценки: 2 years after randomisation]
• Non-fatal repeat MI [Срок оценки: 2 years after randomisation]
• Heart failure [Срок оценки: 2 years after randomisation]
• Inappropriate ICD denial [Срок оценки: 2 years after randomisation]
• Appropriate ICD activations (in patients with ICD) [Срок оценки: 2 years after randomisation]
• Inappropriate ICD activations (in patients with ICD) [Срок оценки: 2 years after randomisation]
• Complications or re-hospitalisation associated with ICD implantation (in patients with ICD) [Срок оценки: 2 years after randomisation]

Критерии участия

Критерии включения

• 2-40 days (inclusive) following a myocardial infarct
• Impaired left ventricular systolic function (LVEF≤40% or at least moderately impaired)

Критерии исключения

• Age <18 or >85;
• Pregnancy;
• Nursing home resident dependent on one or more activities of daily living;
• Significant non-cardiac co-morbidity with high likelihood of death within 1 year (this would include any metastatic malignancy, or other terminal disease);
• Significant psychiatric illnesses that may be aggravated by device implantation or that may preclude regular follow up;
• Intravenous drug abuse (ongoing);
• Unresolved infection associated with risk for hematogenous seeding;
• Pre-existing implantable cardioverter-defibrillator (ICD);
• 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));
• On the heart transplant list;
• 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);\*\*
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Профилактика

Центры проведения

Австралия · 19 центров

• Canberra Hospital — Garran
• Nepean Hospital — Kingswood
• John Hunter Hospital — New Lambton Heights
• Prince of Wales Hospital — Randwick
• Royal North Shore Hospital — Saint Leonards
• Westmead Hospital — Westmead
• Wollongong Hospital — Wollongong
• Sunshine Coast University Hospital — Birtinya
• … и ещё 11 центров

Германия · 5 центров

• Cardiovascular Center Bad Neustadt — Bad Neustadt an der Saale
• Klinikum Brandenburg — Brandenburg
• Universitaetsmedizin Gittingen (University of Göttingen Medical Center) — Göttingen
• Leipzig Heart Center — Leipzig
• Universitätsklinikum Leipzig — Leipzig

Новая Зеландия · 5 центров

• Auckland City Hospital — Grafton
• Middlemore Hospital — Otahuhu
• Waikato Hospital — Hamilton W.
• Christchurch Hospital — Christchurch
• Wellington Hospital — Wellington

Польша · 4 центра

• Medical University of Łódź - Biegański Provincial Specialist Hospital — Lodz
• Medical University of Łódź - WAM Hospital — Lodz
• Medical University of Łódź — Lodz
• National Institute of Cardiology Warsaw — Warsaw

Греция · 3 центра

• General Hospital of Athens Giorgios Gennimatas — Athens
• General Hospital of Athens Ippokrateio — Athens
• University Hospital of Heraklion Crete — Heraklion

Венгрия · 3 центра

• Semmelweis University Heart and Vascular Center — Budapest
• University of Debrecen — Debrecen
• University of Pécs — Pécs

Швейцария · 3 центра

• University Hospital Basel — Basel
• University Hospital Bern — Bern
• Lausanne University Hospital — Lausanne

Малайзия · 2 центра

• Institut Jantung Negara Sdn Bhd — Kuala Lumpur
• Pusat Jantung Sarawak (PJS)(Sarawak Heart Centre) — Kuala Lumpur

Россия · 2 центра

• Almazov National Medical Research Centre — Saint Petersburg
• Samara State Medical University — Samara

США · 1 центр

• Beth Israel Deaconess Medical Center — Boston

Чехия · 1 центр

• Institute for Clinical and Experimental Medicine — Prague

Израиль · 1 центр

• Sharee Zadek Medical Centre — Jerusalem

Латвия · 1 центр

• Paul Stradins University Clinic — Riga

Сингапур · 1 центр

• National University Heart Centre, Singapore (NUHCS) — Singapore

Словакия · 1 центр

• The National Institute of Cardiovascular Diseases — Bratislava

Идентификаторы

NCT: NCT03588286 · PROTECT-ICD, Version 5 · ACTRN12614000042640

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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