Clinical trial NCT04876222: Direct or Subacute Coronary Angiography in Patients With Out of Hospital Cardiac Arrest Without Coma.
Official title: Direct or Subacute Coronary Angiography in Patients With Out of Hospital Cardiac Arrest Without Coma. A Prospective Randomized Study.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cardiac Arrest, Out-Of-Hospital
Angiography
Percutaneous Coronary Intervention
Coma
Lead sponsor: Aarhus University Hospital Skejby
Sponsor class: OTHER
Collaborators: name: Aalborg University Hospital
name: Odense University Hospital
name: Rigshospitalet, Denmark
First posted: 2021-05-06
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized
Primary purpose: TREATMENT

Brief summary: In patients with Out-of-Hospital Cardiac arrest who achieves Return Of Spontaneous Circulation (ROSC) The investigators want to evaluate whether there is a benefit from acute Angiography compared to subacute (12-24 hours) Angiography

Detailed description: Background: The majority of patients with out-of-hospital cardiac arrest (OHCA) have ischemic heart disease (IHD). If signs of ST-elevation myocardial infarction (STEMI) acute coronary angiography (CAG) and primary percutaneous coronary intervention (PPCI) is recommended. In most cases, patients with OHCA who does not achieve Return Of Spontaneous Circulation (ROSC) are also triaged directly to a tertiary center with the possibility to establish mechanical circulatory support, e.g. Extracorporeal Cardiopulmonary Resuscitation (eCPR) (Figure 1). For the remaining group of patients with OHCA who achieves ROSC and have no signs of STEMI it is unsettled whether there is a benefit of acute CAG.

A large international study (Direct or Subacute COronary angiography in out-of-hospital cardiac arrest - DISCO) from Uppsala, Sweden, will study the role of acute CAG in 1006 patients with OHCA who are comatose after achieving ROSC (2). In the Swedish study they only include comatose patients, and randomize patients to either acute CAG or CAG after 3 days.

Three of four Danish tertiary centers have decided to join the Swedish DISCO-study (From now on named DISCO-MAIN).

However, many OHCA patients are not comatose, and without signs of STEMI, thus not eligible for DISCO-MAIN. The investigators also want to investigate the role of acute CAG in these patients, which is the purpose of the current study, named DISCO-no-COMA (Direct or subacute coronary angiography in patients with out-of-hospital-cardiac arrest who are not comatose). This study will include patients in parallel with the DISCO-MAIN-study. This means that all patients with OHCA who receive ROSC and do not fulfill the criteria for acute CAG (STEMI) can be randomized in either DISCO-MAIN (if comatose) or DISCO-no-COMA (if not comatose).

This means that a patient with OHCA without obvious non-cardiac cause, should be triaged as follows (See figure 1):

1. ROSC not achieved (ongoing CardioPulmonary Resuscitation (CPR)): These patients are triaged directly to the catheterization laboratory with the possibility to establish ECPR treatment (5) and perform CAG/PCI (percutaneous coronary intervention) and implant pacemaker if indicated.
2. Signs of STEMI: These patients are triaged directly for acute CAG according to guidelines (6).
3. ROSC, COMA (Glasgow coma scale \<=8), not STEMI: Should be included in the DISCO-MAIN trial.
4. ROSC, Glasgow coma scale \>8, not STEMI: Should be included in the DISCO-no-COMA trial.

Purpose:

To randomize non-comatose (Glasgow coma scale \>8) OHCA survivors for acute CAG or subacute CAG (after 12-24 hours).

Study period: 1.5.2021 to 1.5.2026.

Centers eligible for participation: Danish and European centers. The investigators will primarily contact centers already participating in the DISCO-MAIN trial. Currently all four Danish Tertiary centers participate and up to 8 centers from the Netherlands have agreed to participate.

Patients are randomized to:

Group A: Acute CAG: The patient is triaged directly to the catheterization laboratory for acute evaluation including Echocardiography (ECHO), acute CAG and PCI if indicated according to guidelines.

Group B: Subacute CAG: The patient is triaged to the coronary care unit (CCU) for rhythm surveillance, and additional diagnostics, and in case there is found indication for CAG, it is planned for the coming day in daytime (12-24 hours after cardiac arrest). Revascularization is performed if indicated according to guidelines.

Revascularization in group A and B:

The goal is to perform revascularization of the culprit lesion. Additional lesions will be scheduled for an elective procedure, typically after 3-4 weeks. If Coronary Artery Bypass Grafting (CABG) is indicated, it will be scheduled according to the centers local routine.

Cross-over:

A patient randomized to group B will be scheduled for acute CAG if:

1. Signs of STEMI (acute CAG mandatory).
2. Persistent hemodynamic instability of more than 1 hour after randomization, defined as: need of increased dose of vasopressor/inotropic, low Left ventricular ejection fraction (LVEF), no clearance of lactate (Acute CAG should be considered)
3. Recurrent cardiac arrest (Acute CAG should be considered)
4. Patients who after admission is judged to have NSTEMI can cross-over to acute CAG if they are not stabilized medically.

Statistics: Data is analysed according to intention-to-treat. Continuous data will be presented as mean ± standard deviation, and comparison made using t-test if normally distributed. Non-normal distributed data will be presented as median \[interquartile range\], and compared using Mann Whitney U-test. Categorical variables are compared using Fischers exact test or Chi square test as appropriate, and presented as numbers and per centages. Significans level is p\< 0.05 (two-sided).

Data management: Data will be collected and stored according to the Danish Privacy Law. The E-CRF (Electronic Case Report Form) is computer-based (TrialPartner). Patient and procedure information will be entered in the E-CRF by the study nurses at each site. Date is also collected from the CPR-register, the Danish National Patient Register (LPR-register), as well as the invasive registries covering procedure related data for all patients who have CAG or PCI performed. TrialPartner is approved according to Danish regulative, and all access and data-entry are logged. When the study is finalized and data from the various registries have been merged, the personal identification number is removed, and all cases are assigned a key. A separate key file is store. Data is then made anonymous.

Inclusion of patients and consent:

All patients with OHCA without obvious non-cardiac cause are triaged to the invasive centers. The physician on call ensures that any patient with STEMI or ongoing CPR are triaged directly to the catheterization laboratory. Remaining patients are included in the DISCO-MAIN study if comatose. Non-comatose patients are included in the present DISCO-no-COMA study. They are included according to the paragraph "Research in acute situations", and are randomized when they are still in the prehospital phase if possible, en route to the hospital. After arrival to the hospital, the investigators will inform the patient further, to achieve written informed consent also.

Ethical aspects:

The investigators believe it is legitimate to randomize patients to acute or subacute CAG because Denmark nationally have centers that adhere to both strategies, and it is uncertain whether there is a benefit from acute CAG in OHCA patients who have achieved ROSC and are without signs of obvious STEMI.

Furthermore, there are clear recommendations when to cross-over if randomized to a conservative strategy.

Withdrawal from the study: The patients can at any point, and without any reason, decide not to participate in the study. The patient will be asked if data collected from randomization and until withdrawal may be used. Otherwise data will be deleted. Reason for withdrawal, and the patient's decision whether data can be used or not, will be filled in the electronic health record.

Biobank / biological material: No biobank is collected at present.

Blinding: The study is not blinded, which seems impossible to do.

Personal data:

The national Privacy Law will be followed. The trial will be filed to the Central Denmark Region (Instead of the Danish Data Protection Agency, according to current practice), to the Ethical Committee in the Central Denmark Region and to Clinicaltrials.gov. The National Board of Health will be aplied for access to data from the CPR-register and the National Patient Register.

Access to data: Data will be stored in TrialPartner. Any access or attempt to access will be logged. Investigator/institution will grant access for monitoring and audit also from the ethical committee. Investigator will be responsible and ensure that any patient has given written consent, or a deputy consent has been achieved according to the rules for research in acute situations.

Endpoint committee: An endpoint committee will be established consisting of a cardiologist and an anesthesiologist who validates all clinical endpoints, and establish the final diagnosis (cause of cardiac arrest) for the patient. They will have access to all study material as well as information from patient health records if necessary.

Coordinating center: The research department at the Department of cardiology, Aarhus University hospital, will be the coordinating center, and responsible for establishing the eCRF, collecting data, coordinating safety and endpoint committee meetings, and publish data.

Monitoring: Aarhus University hospital will be responsible for trial monitoring. Study nurses will visit each hospital when initiating the trial, and then approximately two times during the study. The monitoring visits will as in the DISCO-MAIN trial focus on: a) That the study adheres to the protocol, b) that inclusion of patients is according to protocol and inclusion criteria, c) that the correct data is entered in the ECRF, and d) that necessary resources are available locally to perform the study.

Economy: The investigators will apply private funds for support to the study. The responsible physicians will receive no honorarium.

Publications: All results, positive and negative or inconclusive will be published.

Power calculation:

There are limited data on mortality, and risk of recurrent cardiac arrest or cardiogenic shock, in patients without coma who have achieved ROSC after OHCA and just waits for CAG. In previous studies the 30-day mortality was 34% in patients with Acute Myocardial Infarction (AMI) who had Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) (7), the risk of cardiogenic shock was 9% in patients with VT and 27% in patients with VF (8), and the risk of recurrent cardiac arrest was 7% within 48 hours (8). In the light of competing risks, and in the light of a general reduction in case-fatality during the years, it is assumed that the risk of the combined endpoint (MACE) is approximately 30% within 30 days of randomization. With an alfa of 0.05, and power of 80%, it will be possible to document a difference in MACE of 25% if 1080 patients are included. With an expected drop-out of 10% the aim is to include 1200 patients.

Eligibility criteria: Inclusion Criteria:

* Witnessed Cardiac Arrest
* ROSC
* CAG possible within 120 minutes
* Glasgow coma scale \>8

Exclusion Criteria:

* Age \< 18 years
* Obvious non-cardiac cause for the arrest
* Terminal illness
* STEMI

Primary outcomes:
measure: Major Adverse Cardiovascular Events
timeFrame: 30-day
Secondary outcomes:
measure: Mortality
timeFrame: 30-day and 1-year and 5-year
measure: Cardiogenic shock
timeFrame: 30-day and 1-year
measure: Recurrent cardiac arrest
timeFrame: 30-day and 5-year
measure: Revascularization
timeFrame: 30-day and 1-year
measure: Cerebral Performance Category score
timeFrame: 30-day and 6-month
measure: modified Ranking Scale score
timeFrame: 30-day and 6-month
measure: EQ-5D-5L score
timeFrame: 30-day and 6-month
measure: Glasgow Outcome Scale Extended
timeFrame: 6-month
measure: Montreal Cognitive Assessment
timeFrame: 6-month
measure: AMPS
timeFrame: 6-month
measure: ADL-1 score
timeFrame: 6-month
measure: Shock from ICD
timeFrame: After randomization and within 30-day and 5-year
measure: AMI
timeFrame: 1-year
measure: Readmission with CHF
timeFrame: 1-year
measure: Treatment with ICD
timeFrame: 1-year
measure: Bleeding
timeFrame: 30-day
measure: Increase in creatinin
timeFrame: 30-day
measure: Dialysis
timeFrame: 30-day
measure: Vascular surgery
timeFrame: 30-day
measure: Cross-over rate
timeFrame: During admission, 30-day
measure: Admission time
timeFrame: 30-day
measure: MWA index
timeFrame: 1-day and 3-day
measure: Renal resistive index
timeFrame: 1-day and 3-day
measure: Renal and liver flow
timeFrame: 1-day, 3-day, 6-month
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Christian Juhl Terkelsen
city: Aarhus
country: Denmark
facility: Department of cardiology, Aarhus University Hospital in Skejby
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
city: Eindhoven
country: Netherlands
facility: Catharina Zeikenhuis
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
Study officials:
References: