Highlights
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A minority of post-MI patients with LVEF ≤ 35% ever need their primary prevention ICD.
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Pharmacotherapy has advanced since previous trials for primary prevention ICD.
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This trial will reassess the role of primary prevention ICD in contemporary practice.
ABSTRACT
Background
Randomized clinical trials from over 20 years ago demonstrated that an implantable cardioverter defibrillator (ICD) improved survival for patients with severely reduced left ventricular ejection fraction (LVEF) after myocardial infarction (MI) compared with optimal medical therapy (OMT) alone. Since then advances in therapy have led to the reduction in the incidence of sudden cardiac death (SCD) in this population, whilst complication rates from ICD implantation are still substantial.
Objectives
To determine whether OMT without ICD implantation is not inferior to OMT with ICD implantation with respect to all-cause mortality.
Design
The PROFID EHRA trial is an investigator-driven, prospective, parallel-group, randomized, open-label, blinded outcome assessment (PROBE), multi-center, noninferiority trial without dedicated investigational medical device (Proof of Strategy Trial) with 2 groups with 1:1 randomization. PROFID-EHRA will recruit approximately 3,595 patients with documented history of MI at least 3 months prior, LVEF ≤35%, on OMT for at least 3 months, and with New York Heart Association class II or III, who will be randomized to OMT or OMT plus ICD, to collect 374 first primary outcome events within a median observation period of around 28 months from about 180 clinical sites in an estimated 13 countries. The primary outcome is time from randomization to the occurrence of all-cause death. Secondary outcomes include time from randomization to death from cardiovascular causes, to SCD, to first hospital readmission for cardiovascular causes after date of randomization, the average length of hospital stay during follow-up, and quality of life trajectories.
Clinical Trial
Trials.gov NCT05665608
Patients who have survived a myocardial infarction (MI) are at increased risk for sudden cardiac death (SCD), mostly caused by life-threatening ventricular tachyarrhythmia such as ventricular tachycardia and ventricular fibrillation. A severely reduced left ventricular ejection fraction (LVEF) after MI indicates a higher risk for SCD. Two landmark randomized clinical trials (RCTs), MADIT II and SCD-HeFT, , were conducted between end of the 1990s and early 2000s, and demonstrated that receipt of an implantable cardioverter defibrillator (ICD) in addition to optimal medical therapy (OMT) led to significantly better survival than optimal medical therapy alone for patients with severely reduced LVEF, either after MI or due to other causes of heart failure. These results led to international guideline recommendations for routine implantation of ICDs in survivors of MI with severely impaired LVEF as a means for primary prevention of SCD.
In these trials, therapies delivered by the defibrillators were reported in a substantial portion of patients. However OMT of patients with severely reduced LVEF has changed dramatically in the last 2 decades with the advent of a series of novel drug classes, resulting in current guidelines for treatment of patients with heart failure to recommend the administration of 4 different drug classes for reduction of mortality in heart failure patients- beta blockers, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor-neprilysin inhibitors, mineralocorticoid antagonists and sodium glucose sodium glucose transporter-2 (SGLT-2) inhibitors. When the MADIT II and SCD-HeFT trials were conducted utilization of beta blockers and ACE inhibitors was sub-optimal, and use of mineralocorticoid receptor antagonists not reported. , Importantly, each of these 4 drug classes reduce not only total mortality but specifically SCD, ,,, and contemporary data suggests therapies delivered by ICDs has declined to 1%-3% per year. In addition, the number of patients who undergo coronary revascularization after MI has significantly increased. Thus, the benefit derived in contemporary practice from ICDs is expected to have decreased.
ICDs have a substantial complication rate including peri‑procedural complications (eg, pneumothorax, cardiac perforation) and long-term complications (eg, lead dislodgement, device infection), which appears to remain relatively stable over time. By contrast many advances in the programming of ICD has occurred which may also contribute to the reduction in mortality and ICD therapies. , Therefore the risk-benefit assessment of defibrillator therapy has most likely changed since the landmark RCTs that influenced current guidelines.
Accordingly, a novel randomized adequately powered assessment of the benefit or harm of the ICD in survivors of MI with reduced LVEF with contemporary OMT is required. The PROFID EHRA trial, which is part of the PROFID project, seeks to address this evidence gap.
Methods and design
Objectives
The primary objective of the PRevention Of sudden cardiac death aFter myocardial Infarction by Defibrillator Implantation European Heart Rhythm Association (PROFID EHRA) trial is to determine whether, in post-MI patients with symptomatic heart failure who receive OMT for this condition, and with reduced LVEF ≤ 35%, OMT without ICD implantation is not inferior to OMT with ICD implantation with respect to all-cause mortality ( Figure ).
Study flow chart. ICD, implantable cardioverter defibrillator; i/e, inclusion/exclusion; OMT, optimal medical therapy; R x , randomization.
A secondary objective of the trial is to explore the potential of novel and promising risk markers for personalized risk prediction of SCD. For this purpose, 2 sub-studies will be conducted: a cardiac Magnetic Resonance Imaging (CMR) sub-study and a genomics sub-study, each of them in a subset of participating study sites with adequate potential.
Trial design
This publication describes V2.0 of the PROFID EHRA protocol, dated March 21, 2024.
PROFID EHRA is a noncommercial, investigator-driven, prospective, parallel-group, randomized, open-label, blinded outcome assessment (PROBE), multi-center, noninferiority trial without dedicated investigational medical device (Proof of Strategy Trial) with 2 groups with 1:1 randomization ( Figure ). The randomization to one of the treatment strategy groups is the only study intervention, all medical treatment (drugs, devices, procedures) used within this trial is at the discretion of the treating physicians and represent clinical routine practice. It will be conducted in about 13 countries with about 180 clinical sites actively participating.
Eligibility criteria
Participants with documented history of MI at least 3 months prior, left ventricular ejection fraction ≤35%, on optimal medical therapy for at least 3 months, and with symptomatic heart failure (New York Heart Association class II or III) will be recruited. The full eligibility criteria are reported in Table .
Table
Inclusion and exclusion criteria
| Inclusion criteria |
| • Age ≥18 years. |
| • Naïve to implantation of any pacemaker or defibrillator. |
| • Documented history of MI either as ST segment elevation myocardial infarction (STEMI) or as non-ST segment elevation myocardial infarction (NSTEMI) at least 3 months prior to enrolment. MI is defined according to the 2018 European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation Fourth Universal Definition of MI. |
| • Symptomatic heart failure with New York Heart Association (NYHA) class II or III. |
| • On OMT for at least 3 months prior to enrolment. |
| • LVEF ≤35% (at transthoracic echocardiography (TTE or CMR at least 3 months after MI). |
| • Signed informed consent. |
| Exclusion criteria |
| Cardiac condition |
| • Class I or IIa indication for implantation of an ICD for secondary prevention of SCD and ventricular tachycardia according to the European Society of Cardiology guidelines. |
| • Ventricular tachycardia induced in an electrophysiologic study. |
| • Unexplained syncope when ventricular arrhythmia is suspected as the cause of syncope. |
| • Class I or IIa indication for Cardiac Resynchronization Therapy (CRT) according to the European Society of Cardiology guidelines. |
| • Acute coronary syndrome or coronary angioplasty or coronary artery bypass grafting surgery performed within 6 weeks prior to enrolment. |
| • Cardiac valve surgery or percutaneous cardiac valvular intervention performed within 6 weeks prior to enrolment. |
| • On the waiting list for heart transplantation. |
| General exclusion criteria |
| • Any known disease that limits life expectancy to less than 1 year. |
| • Participation in another randomized clinical trial if study-specific treatment is still active at enrolment into PROFID EHRA. |
| • Previous participation in PROFID EHRA. |
Informed consent
A signed informed consent form, written in accordance with applicable laws for research using medical devices, country-specific applicable data privacy acts and the Declaration of Helsinki, and approved by the responsible Ethics Committee (EC), will be obtained from every patient prior to any study-related procedure. Additional informed consent will be obtained in case of participation of patients in optional sub-studies.
Randomization
Successfully enrolled and screened study patients are randomized to 1 of 2 parallel study groups in a 1:1 design. Randomization is done per study site in blocks of variable size to allow for minimizing potential confounders related to different healthcare practice using the integrated randomization server of the e-CTMS ‘Marvin’ (by XClinical GmbH). With a planned recruitment of over 3,000 patients the overall distribution of sex and myocardial infarction subtype is expected to be balanced due to the large sample size.
Intervention
PROFID EHRA compares 2 treatment strategies in post-MI patients with symptomatic heart failure with reduced LVEF ≤35%: implantation of an ICD device versus no ICD implantation. OMT for heart failure with reduced ejection fraction is defined as baseline treatment in both groups and is not affected by randomization. As such, OMT, as defined by the European Society of Cardiology (ESC) guideline recommendations published in 2021, has to be confirmed for all study patients as well as receipt of care for chronic coronary syndromes as per ESC guideline recommendations. Assignment to the intervention group means that the patient continues to receive OMT without implantation of an ICD.
Control
Assignment to ICD implantation whereby the participant receives OMT and an ICD is considered the control group. In the case of being assigned to the control group the implantation of the ICD device for the participant should be performed as soon as possible after the date of randomization, preferably within the same hospital stay, and with the aim of latest 3 months after the date of randomization. The type of device (including whether subcutaneous or transvenous) is at the discretion of the investigator, and all aspects of device implantation and care should follow local routine clinical practice.
Outcome measures
The primary endpoint is time from randomization to the occurrence of all-cause death. Secondary endpoints are:
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Time from randomization to death from cardiovascular causes.
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Time from randomization to SCD.
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Time from randomization to first hospital readmission for cardiovascular causes after date of randomization.
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Average length of stay in hospital during the study period.
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Quality of life (EQ-5D-5L) trajectories assessed at baseline and 12-month intervals thereafter.
Secondary endpoints will be adjudicated by the independent Endpoint Review Committee (ERC) using standardized definitions provided in the ERC charter. Members of the ERC will be blinded to the assignment of the participant to the intervention or control arm.
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