The EPIVER Randomized Controlled Trial (EPIVER)

April 19, 2023 updated by: Tomsk National Research Medical Center of the Russian Academy of Sciences

Intracoronary Administration of Epinephrine and Verapamil in the Refractory No-reflow Phenomenon in Patients With Acute Myocardial Infarction: The EPIVER Randomized Controlled Trial

The trial aims to estimate the efficacy and safety of the intracoronary administration of adrenalin, verapamil, as well as their combination compared to standard treatment in patients with STEMI and refractory coronary no-reflow despite conventional treatment during percutaneous coronary intervention (PPCI)

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for treating acute ST-segment elevation myocardial infarction (STEMI). The main goals are to restore epicardial infarct-related artery patency and to achieve microvascular reperfusion as early as possible. No-reflow is the term used to describe inadequate myocardial perfusion of a given coronary segment without angiographic evidence of persistent mechanical obstruction of epicardial vessels and it refers to the high resistance of microvascular blood flow encountered during opening of the infarct-related coronary artery. Despite optimal evidence-based PPCI, myocardial no-reflow can still occur, negating many of the benefits of restoring culprit vessel patency, and is associated with a worse in-hospital and long-term prognosis.

According to clinical guidelines, nitrates, adenosine, platelet IIb / IIIa receptor inhibitors and thrombus extraction can be used to prevent and treat this complication.These methods have demonstrated the ability to improve coronary blood flow in experiment and small clinical trials, however, limiting the zone of myocardial necrosis and improving disease outcomes have not been achieved.

The search for new methods of influencing the pathogenetic links of this complication is urgent. One of the main potentially reversible factors in the pathogenesis of the no-reflow phenomenon, along with microvascular obstruction, is microvascular arteriolar spasm. Thus, this problem of emergency cardiology remains relevant and requires further research, new methods of prevention and treatment.

Aside from exerting beta-1 agonist properties at higher doses and increasing the inotropic and chronotropic stimulation of the myocardium, epinephrine may, at lower doses, exert potent beta receptor agonist properties that mediate coronary vasodilatation. Another drug with a pronounced coronary vasodilation effect is verapamil.

Based on the pharmacodynamic effects of epinephrine and verapamil, it is expected to increase the vasodilating effect when they are used together, due to the additive type of synergistic interaction, which will improve coronary microcirculation after PCI in patients with acute myocardial infarction and refractory no-reflow phenomenon.

Currently, in clinical practice, there is a possibility of very sensitive diagnosis of microvascular obstruction (MVO) using magnetic resonance imaging (MRI), as well as the area of the coronary reserve according to dynamic perfusion scintigraphy of the myocardium. It is advisable to evaluate the effectiveness of treatment of the no-reflow phenomenon using these methods.

The trial aims to estimate the efficacy and safety of the administration of intracoronary epinephrine, verapamil, as well as their combination versus to standard treatment in patients with STEMI and refractory coronary no-reflow despite conventional treatments during PPCI.

Study Type

Interventional

Enrollment (Actual)

104

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Russian Federation
    • Tomsk Region
      • Tomsk, Tomsk Region, Russian Federation
        • Cardiology Research Institute, Tomsk NRMC

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • patients with ST-elevation myocardial infarction
  • Infarct-related artery TIMI flow grade 0-2 during the interventional procedure after the initial opening of the vessel.
  • Written the informed consent to participate in research

Exclusion Criteria:

  • Unable to undergo or contra-indications for MRI or SPECT

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Sham Comparator: Standard therapy
No intracoronary epinephrine and verapamil
Drug: Standard therapy
Standard therapy as follows: adenosine, nitroglycerine, thrombus aspiration/extraction, and platelet IIb/IIIa receptor inhibitors.
Other Names:
  • Control
Active Comparator: Epinephrine
Intracoronary bolus epinephrine injection requires two ampoules each of 1:1,000 epinephrine (1 μg/mL) diluted into 100 mL of normal saline solution (to 20 μg/mL epinephrine solution); therefore, a 5-mL syringe contains 100 μg of epinephrine. Intracoronary epinephrine will be administered at a dose of 100 μg and at a lower dose of 80 μg in patients with blood pressure >160 mmHg
Drug: Epinephrine
Standard therapy plus epinephrine as follows: epinephrine, adenosine, nitroglycerine, thrombus aspiration/extraction, and platelet IIb/IIIa receptor inhibitors.
Other Names:
  • Epi
Active Comparator: Verapamil
Intracoronary verapamil is administered at a dose of 0.5 mg.
Drug: Verapamil
Standard therapy plus verapamil as follows: verapamil, adenosine, nitroglycerine, thrombus aspiration/extraction, and platelet IIb/IIIa receptor inhibitors.
Other Names:
  • Ver
Active Comparator: Epinephrine + verapamil
Intracoronary administration of epinephrine at a dose of 80-100 μg and verapamil at a dose of 0.5 mg.
Drug: Epinephrine + verapamil
Standard therapy plus epinephrine + verapamil as follows: epinephrine, verapamil, adenosine, nitroglycerine, thrombus aspiration/extraction, and platelet IIb/IIIa receptor inhibitors.
Other Names:
  • Epi+Ver

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: month 1
Mortality rate (percent)
month 1
New onset or worsening acute heart failure
Time Frame: month 1
The rate (percent) of patients experiencing new onset or worsening acute heart failure. Congestion characterized by dyspnea, edema, rales, jugular venous distention and need to increase diuretic doses is a hallmark of acute heart failure prompting hospitalization
month 1

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Thrombolysis in myocardial infarction (TIMI) 3
Time Frame: hour 1
The rate of patients (percent) who achieved TIMI 3 coronary blood flow after percutaneous coronary intervention
hour 1
Change in systolic/diastolic blood pressure
Time Frame: minute 3
Change in systolic/diastolic blood pressure values (mmHg) before and after intracoronary verapamil/epinephrine
minute 3
ST segment resolution
Time Frame: hour 72
Degree of ST segment resolution on ECG (mm)
hour 72
Troponin I release
Time Frame: hour 72
Concentration of troponin I (ng/mL)
hour 72
LV EF
Time Frame: day 10
Left ventricular ejection fraction (LV EF) (percent)
day 10
Myocardial injury
Time Frame: day 2
Total volume (mL) of microvascular obstruction, myocardial necrosis, edema, and hemorrhagic impregnation according to MRI data
day 2
SPECT-based coronary reserve
Time Frame: day 7
Coronary reserve will be measured by cardiac single photon emission computed tomography (SPECT) with technetium-99m-labeled methoxy-isobutyl isonitrile (99mТсMIBI) at rest and during pharmacological stress-test (counts)
day 7
Change in heart rate values
Time Frame: minute 3
Change in heart rate values (beat per minute) before and after intracoronary verapamil/epinephrine
minute 3
LV EDV
Time Frame: 10 days
Left ventricular end-diastolic volume (LV EDV) (mL)
10 days
LV ESV
Time Frame: day 10
Left ventricular end-systolic volume (LV ESV) (mL)
day 10
LV WMSI
Time Frame: day 10
Left ventricular wall motion score index (LV WMSI) (conventional units)
day 10
Arrhythmias
Time Frame: minute 5
Frequency of arrhythmias (atrial fibrillation, atrial flutterу, supraventricular tachycardia, premature ventricular contractions, ventricular tachycardia, conduction disorders and other heart rhythm disorders) after intracoronary administration verapamil and/or epinephrine
minute 5

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tomsk National Research Medical Center of the Russian Academy of Sciences

Investigators

  • Principal Investigator: Vyacheslav V Ryabov, MD, PhD, Cardiology Research Institute, Tomsk NRMC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 30, 2020

Primary Completion (Actual)

January 31, 2023

Study Completion (Anticipated)

January 31, 2024

Study Registration Dates

First Submitted

September 28, 2020

First Submitted That Met QC Criteria

September 28, 2020

First Posted (Actual)

October 5, 2020

Study Record Updates

Last Update Posted (Actual)

April 20, 2023

Last Update Submitted That Met QC Criteria

April 19, 2023

Last Verified

April 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EPIVER

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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