Clinical Effects of Intra-aortic Balloon Support in Early Acute Coronary Syndrome and Non-Acute Coronary Syndrome Related Cardiogenic Shock (IABP ON-TIME)

Clinical Effects of Intra-aortic Balloon Support in Early Acute Coronary Syndrome and Non-Acute Coronary Syndrome Related Cardiogenic Shock: a Multicenter Randomized Controlled Trial

The goal of this randomized controlled trial is to appraise the impact of intra-aortic balloon pump (IABP) in the treatment of early stages of cardiogenic shock, irrespective of etiology. Findings of this randomized trial may enhance clinical decision making regarding the use of MCS in specific subsets of patients in early stages of cardiogenic shock.

The main questions it aims to answer are:

• What are the effects of IABP on a composite of clinical endpoints representing clinical deterioration at 30-days in patients presenting with SCAI stage B or C cardiogenic shock?
• What is the 1-year clinical outcome (including mortality and hospital admissions for cardiovascular causes) of patients treated with vs. without IABP for early cardiogenic shock?
• Is there a difference in efficacy of IABP within the treatment of early cardiogenic shock related to Acute Coronary Syndrome versus non-ischemic causes?
• Is there a difference in efficacy of IABP within the treatment of SCAI stage B versus stage C cardiogenic shock?

Participants will be 1:1 randomized to IABP support or standard of care (a treatment strategy including inotropes and/or vasopressors but no IABP insertion). Patients will be stratified for Acute Coronary Syndrome/non-ischemic etiology and stage B/stage C cardiogenic shock, following stratification to center. Researchers will compare the group who was randomized to IABP to the control group (i.e. standard of care) to see if there is a difference in the primary trial endpoint after 30-days, including 1) all-cause mortality, 2) escalation to invasive mechanical ventilation, 3) escalation of mechanical circulatory support strategy, 4) acute kidney injury and 5) stroke or transient ischemic attack.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiogenic Shock
• Intervention / Treatment: Device: Intra-Aortic Balloon Pump

Detailed Description

Rationale: The scientific underpinning for the use of mechanical circulatory support (MCS) in early cardiogenic shock, especially for the intra-aortic balloon pump (IABP), is scarce and insufficiently clarified for different etiologies of cardiogenic shock. Previous randomized trials limited the inclusion criteria to patients with ischemic cardiogenic shock while observational research suggested favorable effects of timely adoption of IABP in patients with deteriorating myocardial function through ischemic or non-ischemic causes. Early stage of cardiogenic shock is defined by relative hypotension without hypoperfusion, or hypoperfusion still responsive to therapy (Society for Cardiovascular Angiography and Interventions, SCAI, stage B and C, respectively). A tightening of global guidelines with respect to the clinical adoption of IABP overshadowed the potential beneficial effects for specific patient categories within the total spectrum of cardiogenic shock. Patients currently presenting with early stages of cardiogenic shock caused by ischemic or non-ischemic etiology are hypothetically undertreated due to an assumed lack of clinical benefit of IABP in general. The aim of this randomized trial is to appraise the impact of IABP in the treatment of early stages of cardiogenic shock, irrespective of etiology. Findings of this randomized trial may enhance clinical decision making regarding the use of MCS in specific subsets of patients in early stages of cardiogenic shock.

Objective: The primary objective of this trial is to evaluate the 30-day clinical impact of IABP within the treatment of early (SCAI stage B or C) cardiogenic shock. Secondary objectives are

1) To evaluate the 1-year clinical outcome (including mortality and hospital admissions for cardiovascular causes) of patients treated with IABP for early cardiogenic shock; 2) To identify differences in efficacy of IABP in the treatment of early cardiogenic shock related to Acute Coronary Syndrome (ACS) versus non-ischemic causes; 3) To explore differences in efficacy of IABP in the treatment of stage B versus stage C cardiogenic shock.

Trial design: Open-label, multicenter, investigator-initiated, randomized controlled trial.

Trial population: The trial population consists of patients in early cardiogenic shock, defined as SCAI stage B or C, either related or unrelated to ACS.

Intervention: Patients enrolled in this trial will be 1:1 randomized to IABP support or standard of care (i.e. inotropes and/or vasopressors but no IABP insertion). Patients will be stratified for ACS/non-ischemic etiology and stage B/stage C cardiogenic shock following stratification according to center.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Antoon JM van den Enden, MD; Phone Number: +31 10 7038896; Email: a.vandenenden@erasmusmc.nl

Study Locations

• Netherlands
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3000 CA
      • Erasmus University Medical Center
      • Principal Investigator: Nicolas M Van Mieghem, Prof MD PhD
      • Contact: Antoon JM van den Enden; Phone Number: +31 70 308896; Email: a.vandenenden@erasmusmc.nl
      • Sub-Investigator: Christiaan L. Meuwese, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At least 18 years of age;
• Stage B cardiogenic shock (presence of hypotension or tachycardia with signs of venous congestion, in absence of tissue hypoperfusion) OR
• Stage C cardiogenic shock (evidence of tissue hypoperfusion requiring any intervention beyond fluid management, still responsive to therapy) AND
• Must include at least one of the following: 1) lactate levels at least 2.0 mmol/L; 2) creatinine doubling OR >50 percent decline in glomerular filtration rate compared to baseline; 3) laboratory markers indicating liver injury (e.g. high serum transaminase levels) or 4) elevated NT-pro BNP.

A patient is eligible for trial inclusion if, at the time of randomization, no more than 1 inotropic agent has been administered AND when the maximum dose of noradrenaline/norepinephrine has not exceeded 0.2 ug/kg/min in the context of mean arterial pressure >65 mmHg.

Exclusion Criteria:

• The patient is in cardiogenic shock but does not fulfill the definition for stage B or C;
• Administration of at least 2 inotropic or vasopressive agents at study randomization;
• Administration of noradrenaline/norepinephrine exceeding 0.2 ug/kg/min at study randomization;
• Suspected or known mechanical complication contributing to cardiogenic shock, e.g. ventricular septal defect or papillary muscle rupture;
• Cardiogenic shock developing within 72 hours of a surgical procedure (i.e. low cardiac output with an inability to wean cardiopulmonary bypass);
• Inability to provide informed consent. Of not: patients admitted in cardiogenic shock who required cardiopulmonary resuscitation earlier, but are conscious at the time of hospital admission, are eligible for study participation;
• Known or suspected insufficiency of the aortic valve with at least moderate aortic regurgitation;
• Known or suspected peripheral arterial disease preventing safe insertion of IABP;
• Known or suspected thoracic or abdominal aortic disease (including aortic dissection or aortic aneurysm) precluding safe insertion of IABP;
• Suspicion of sepsis or septic shock (including septic cardiomyopathy);
• Pregnancy;
• Predicted life expectancy <6 months because of concomitant disease;
• Concurrent participation in a clinical trial with competing endpoints.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IABP-arm; Patients assigned IABP therapy will undergo IABP insertion as promptly as possible, with a target interval from randomization to insertion of less than 30 minutes. Implantation of the IABP balloon can be established either in the cardiac catheterization laboratory or at bedside in the ICU or cardiac care unit. The steering committee of this trial recommends the use of an appropriate-sized IABP balloon according to the instructions for use. Low-dose vasopressors (noradrenaline/norepinephrine up to 0.2 ug/kg/min) are allowed next to IABP support. The necessity of increasing the noradrenaline/norepinephrine dose with at least 0.2 ug/kg/min or the necessity to initiate de-novo inotropic agents to reach a mean arterial blood pressure of at least 65 mmHg is considered treatment escalation.	Device: Intra-Aortic Balloon Pump; Patients who are randomized to the IABP-arm will be supported with IABP according to local, clinical guidelines (including algorithms for anticoagulation, verification of correct positioning and weaning strategies). The IABP console and disposables should be used according to the instructions for use, including the use of an appropriate-sized IABP balloon alligned with patient length and height.
No Intervention: Standard of care-arm; When a patient is randomized to the standard of care-arm, the definitive treatment strategy is up to the discretion of the treating physician (providing no IABP is inserted). The treatment strategy may include fluid management as well as administration of inotropes and vasopressors. The only imposed difference in treatment is the omission of IABP, as the dose of inotropes and vasopressors is not expected to be high in early cardiogenic shock. The final decision to escalate in the strategy of mechanical circulatory support (including to initiate IABP in the standard of care-arm) is up to the discretion of the treating physician. However, the steering committee feels escalation in MCS strategy is appropriate in case of persistent mean arterial pressure <65 mmHg with incessant lactate levels >5.0 mmol/L when pharmacologic support was already intensified (e.g. the noradrenaline/norepinephrine dose exceeds 0.2 ug/kg/min or inotropic support was already administered).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite primary endpoint (percent)	The primary endpoint of the trial is the composite of the following outcomes: 1) all-cause mortality, 2) escalation to invasive mechanical ventilation, 3) escalation of mechanical circulatory support, 4) acute kidney injury and 5) stroke or transient ischemic attack.	30-days post enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality (i.e. the individual determinants of the composite primary outcome) (percent)	See primary outcome (%) (based on details stated in patient's records)	30-day follow-up
Escalation to invasive mechanical ventilation (i.e. the individual determinants of the composite primary outcome	See primary outcome (%) (based on details stated in patient's records)	30-day follow-up
Escalation to mechanical circulatory support (i.e. the individual determinants of the composite primary outcome)	See primary outcome (%) (based on details stated in patient's records)	30-day follow-up
Acute kidney injury (i.e. the individual determinants of the primary outcome)	See primary outcome (%) (based on details stated in patient's records)	30-day follow-up
Stroke or transient ischemic attack (i.e. the individual determinants of the primary outcome)	See primary outcome (%) (based on details stated in patient's records)	30-day follow-up
Treatment escalation (percent)	Any steps in noradrenaline increase at least 0.2 ug/kg/min, or intensifying inotropic treatment (i.e. dose increasing or initiation of new agents) are considered treatment escalation, irrespective of trial arm. Uptitration of noradrenaline up to 0.2 ug/kg/min is considered standard of care. Treatment escalation also includes the initiation of MCS (including the institution of IABP in the standard of care-arm or escalation to e.g. continuous flow or extracorporeal mechanical circulatory support in the IABP-arm).	30-day follow-up
Deterioration of SCAI stage B to C (percent)	If the patient entered the trial meeting criteria for SCAI stage B	30-day follow-up
Deterioration of cardiogenic shock (percent)	Degradation to SCAI stage D or E	at 7 and 14 days after randomization
Vascular complications defined according to VARC-3 guidelines (percent)	Following randomization to the IABP-arm, specifying major and minor vascular complications as well as major and minor access-related non-vascular complications	30-day follow-up
Major bleeding complications defined according to BARC guidelines (at least type 2) (percent)	Following randomization to the IABP-arm	30-day follow-up
De-novo Acute Coronary Syndrome (percent)	i.e. type 1 myocardial infarction	30-day and 1-year follow-up
Cardiopulmonary resuscitation or defibrillation (percent)	Including an appropriate shock of an Implantable Cardioverter Defibrillator	30-day follow-up
Development of SIRS, sepsis or severe sepsis (percent)	Defined according to the Surviving Sepsis Guidelines	96-hours after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality (percent)	Including presumed cause of death	30-day follow-up and 1-year follow-up
Length of intensive care unit and hospital stay (in days)	Stay after randomization	30-day follow-up
Re-admission to the intensive care unit (percent)	After randomization	30-day follow-up
Implantation of Left Ventricular Assist Device or heart transplant (percent)	After randomization	30-day follow-up
Revascularization attempts (percent)	Including percutaneous coronary intervention or coronary artery bypass graft	30-day follow-up
1-Year composite endpoint (percent)	Including 1) all-cause mortality and 2) hospital admission because of cardiovascular disease	1-year follow-up
All-cause mortality (i.e. the individual determinants of the 1-year composite endpoint)	See 1-Year composite endpoint (percent), including 1) all-cause mortality and 2) hospital admission because of cardiovascular disease. Based on details stated in the patient's record.	1-year follow-up
Hospital admission because of cardiovascular disease (i.e. the individual determinants of the 1-year composite endpoint)	See 1-Year composite endpoint (percent), including 1) all-cause mortality and 2) hospital admission because of cardiovascular disease. Based on details stated in the patient's record.	1-year follow-up
Hospital re-admission (percent)	Including a description of the presumed cause of hospital (re-)admission	1-year follow-up
Visits to the emergency department (percent)	Of note, visits necessitating treatment escalation for heart failure	1-year follow-up
Unplanned revascularization (percent)	Including details concerning the revascularization attempt (i.e. percutaneous coronary intervention or coronary artery bypass graft)	1-year follow-up

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Arrow International LCC (Subsidiary of Teleflex Inc.)
• Investigators: Study Chair: Nicolas M Van Mieghem, Prof MD PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: January 3, 2024
• First Submitted That Met QC Criteria: May 13, 2024
• First Posted (Actual): May 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Acute coronary syndrome; Cardiogenic shock; Intra-aortic balloon pump; Mechanical circulatory support; Decompensated heart failure; Ischemic cardiogenic shock; Non-ischemic cardiogenic shock
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Disease; Myocardial Infarction; Infarction; Syndrome; Shock; Acute Coronary Syndrome; Shock, Cardiogenic
• Other Study ID Numbers: IABP ON-TIME

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No