The EPIVER Randomized Controlled Trial

Sponsor

Tomsk National Research Medical Center of the Russian Academy of Sciences (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04573751

Collaborator

(none)

104

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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)

Condition or Disease	Intervention/Treatment	Phase
ST Elevation Myocardial Infarction Percutaneous Coronary Intervention No-Reflow Phenomenon	Drug: Standard therapy Drug: Epinephrine Drug: Verapamil Drug: Epinephrine + verapamil	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

104 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 30, 2020

Actual Primary Completion Date :

Mar 31, 2022

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Mortality [month 1]
Mortality rate (percent)
New onset or worsening acute heart failure [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

Secondary Outcome Measures

Thrombolysis in myocardial infarction (TIMI) 3 [hour 1]
The rate of patients (percent) who achieved TIMI 3 coronary blood flow after percutaneous coronary intervention
Change in systolic/diastolic blood pressure [minute 3]
Change in systolic/diastolic blood pressure values (mmHg) before and after intracoronary verapamil/epinephrine
ST segment resolution [hour 72]
Degree of ST segment resolution on ECG (mm)
Troponin I release [hour 72]
Concentration of troponin I (ng/mL)
LV EF [day 10]
Left ventricular ejection fraction (LV EF) (percent)
Myocardial injury [day 2]
Total volume (mL) of microvascular obstruction, myocardial necrosis, edema, and hemorrhagic impregnation according to MRI data
SPECT-based coronary reserve [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)
Change in heart rate values [minute 3]
Change in heart rate values (beat per minute) before and after intracoronary verapamil/epinephrine
LV EDV [10 days]
Left ventricular end-diastolic volume (LV EDV) (mL)
LV ESV [day 10]
Left ventricular end-systolic volume (LV ESV) (mL)
LV WMSI [day 10]
Left ventricular wall motion score index (LV WMSI) (conventional units)
Arrhythmias [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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