Ranolazine a Potential New Therapeutic Application

February 23, 2021 updated by: Temistocle Taccheri, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Ranolazine Myocardial Protection in Complete Coronary Artery Bypass Grafting: A Randomized-controlled Trial

Despite surgical and medical innovation have reduced mortality rates in cardiac surgery, the disease severity and operative procedural complexity have increased and morbidity rate is still high. Ischemia-reperfusion (I/R) injury, redefined in cardiac surgery "post-cardioplegic injury" (2) as a whole of ischemia-reperfusion, cardiopulmonary bypass and surgical trauma, has been recognized as a significant contributor to mortality and morbidity. I/R injury is classified as reversible or irreversible. Reversible injury includes arrhythmias, edema, vascular dysfunction and contractile stunning expressed as low output syndrome without cell death and without apparent signs of infarction or other serum injury markers. Irreversible reperfusion injury includes apoptosis and necrosis. I/R injury is a complex process associated with increase of radical, oxidant and cytokines production, complement and neutrophil activation and endothelial activation leading to microvascular dysfunction and deterioration of coronary flow reserve. In the hypoxic heart increase anaerobic lactate production, K+ efflux and membrane depolarization. The intracellular Na+ concentration rises as a consequence of slow Na+ channels inactivation and the induction of voltage-gated Na+ channel late current component (late INA). Intracellular Na++ accumulation enhanced activity of reversed-mode Na+-Ca++ exchanger causing intracellular Ca++ overload and ventricular dysfunction. Therefore inhibition of late INA has been shown to be cardioprotective. Ranolazine, an FDA-approval antianginal and anti-ischemic agent, high selective blocker of late INA, inhibits the late sodium current in myocardial ischemia, decreases Na+ and Ca2+ overload and improves left ventricular function in experimental animal models. For this reason it was also adjuncted to cardioplegia improving diastolic function in isolate Langerdoff-perfused rat hearts. The authors test the hypothesis that ranolazine improve myocardical protection in patients undergoing coronary artery surgery with cardiopulmonary by-pass (CPB).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

We aim to perform a prospective, single-center, investigator-initiated, randomized (1:1), blinded, placebo-controlled study. The patients undergoing elective and complete CABG revascularization performed by the same surgeon, will be randomized in two different groups to receive, in the three days before surgery, Ranolazine at a dose of 375 mg twice daily or placebo. After the enrollement in the research according the inclusion and exclusion criteria, the randomization list will be computer-generated. The study participants, the reserchers responsible for data reporting and analysis and the ecocardiographers will be blinded to the treatment that each patient will receive. In a previous phase all data for the recruitment will be considered and registered before surgery: basic clinical parameters (age, gender, height, weight, body surface, systolic blood pressure and diastolic blood pressure, mean heart rate); medical history (diabetes mellitus type I or II, smoking status, chronic obstructive pulmonary desease, systemic arterial hypertension, dyslipidemia, family history of cardiovascular events, angina, percutaneous coronary interventions (PCI), acute myocardial infarction (AMI), previous cardiac surgery, chronic peripheral arterial disease, cerebral ischemia, bleeding and chronic renal failure); basic hematologic parameters (creatinine, glucose, hemoglobin, hematocrit, white blood cell counts and equation, platelets number, aPTT, INR); baseline transthoracic echocardiographic (TTE) parameters (left ventricular ejection function (LVEF), left ventricular volumes, left ventricular regional wall motion, diastolic function (mitral inflow velocities as Early diastolic velocity (E), late diastolic velocity with atrial contraction (A), and deceleration time (DT), early diastolic velocity (e') and late diastolic velocity with atrial contraction (a') using tissue Doppler imaging, pulmonary artery systolic pressure (PASP), valvulopathy and aortic desease); assestment of risk stratification according to different scores (New York Heart Association (NYHA) classes, Canadian Cardiovascular Society (CCS) Angina grading scale, EUROSCORE II, American Society og Anesthesiologists (ASA) physical status classification system); preoperative patient therapy. In a following phase laboratory, hemodynamic and imaging evaluation will be carried out during and subsequent to CABG surgery. Through a coronary sinus inserted catheter will be dosed Troponine I (TnI) immediately before CPB and after the release of aortic cross clamp, about 10 minutes after the end of reperfusion. TnI will be also dosed at arrival on intensive care unit and 6, 12, 24, 48 h after unclamping of the aorta. Blood samples will be collected simultaneously from the radial artery and the coronary sinus before starting CPB and after removal of aortic cross clamp to evaluate lactates extraction, oxygen consumption (VO2) and oxygen extraction (O2ER), and C-reactive protein (CRP) pre and post-CPB. Hemodynamic measurements will be obtained by an arterial and a pulmonary artery catheter (PAC) inserted before surgery, and will include arterial pressure (systolic, diastolic and mean pressure), pulmonary artery pressure (PAP), right atrial pressure (RAP), pulmonary artery wedge pressure (PAWP), cardiac output (CO) and cardiac index (CI), systemic vascular resistance (SVR), left ventricular stroke work (LVSW), left stroke volume variaton (LSVV) and coronary artery perfusion pressure (CPP); these measurements will be conducted 30 min after intubation, after sternotomy, 10 min after protamin, after sternosynthesis, at arrival in the intensive care unit, 6, 12, 24, 36, 48 h after CPB. Lastly a transesophageal echocardiographic study will be performed by two expert echocardiographers following the protocols of the Society of Cardiovascular Anesthesiologists (21) and American Society of Echocardiography (22). Left ventricle myocardial performance index, LVEF, left ventricular regional wall motion, E/A ratio, E', E/E' and deceleration time (DT) of mitral inflow velocity will be measured; these measurements will be obteined 30 minute after intubation before sternotomy and ten minute after protamin. All collected data will be entered into a database in Excel format.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • age ≥ 18 years
  • sinus rhythm, heart rate (FC) ≥ 50 bpm at rest;
  • NYHA class I, II, III (CCS I, II, III);

Exclusion Criteria:

  • drugs intolerance or hypersensitivity;
  • cardiogenic shock;ejection fraction (FE ) ≤ 50 % ;
  • NYHA class IV (CCS IV);
  • II or III atrioventricular block;
  • a resting heart rate (HR) < 50 bpm or sick sinus syndrome;
  • rate-corrected QT interval (QTc) greater than 500 ms;
  • age <18 years;
  • symptomatic hypotension or uncontrolled hypertension (systolic blood pressure at rest ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg);
  • severe liver disease
  • severe renal impairment (creatinine clearance ≤ 30 ml/min);
  • from moderate to severe electrolyte disorders (potassium concentration < 2,5 or > 6 mmol/L; calcium concentration < 8 or > 11 mg/dl; magnesium < 1,8 or > 2,5 mg/dl);
  • pregnancy;
  • concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone)
  • concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol) antiarrhythmics other than amiodarone;
  • previous cardiac interventions

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: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Ranolazine
The patients undergoing elective and complete CABG revascularization performed by the same surgeon, will be randomized in two different groups to receive, in the three days before surgery, Ranolazine at a dose of 375 mg twice daily.
Drug: Ranolazine
Patients in this arm receive Ranolazine at a dose of 375 mg twice daily in the three days before surgery
Other Names:
  • Ranexa
Placebo Comparator: Placebo
The patients undergoing elective and complete CABG revascularization performed by the same surgeon, will be randomized in two different groups to receive, in the three days before surgery, placebo twice daily.
Drug: Placebo
Patients receive Placebo twice daily in the three days before surgery

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Troponins I variation collected by coronary sinus pre and post clamping of the aorta.
Time Frame: Before cardiopulmonary by-pass and 10 minutes after the end of reperfusion
A blood sample will be collected by coronary sinus and the sample sent by our laboratories to assess the concentration in µg/l of cardiac troponins directly in venous blood before cardiopulmonary by-pass and after the release of aortic cross clamp, about 10 minutes after the end of reperfusion.
Before cardiopulmonary by-pass and 10 minutes after the end of reperfusion
Myocardial VO2 and O2 extraction variation collected by radial artery and coronary sinus pre and post clamping of the aorta.
Time Frame: Before cardiopulmonary by-pass and 10 minutes after the end of reperfusion
Earlobe arterialized blood sample will be collected by radial artery coronary sinus and the sample sent by our laboratories to assess the concentration of VO2 and O2ER in ml/min in venous blood before cardiopulmonary by-pass and after the release of aortic cross clamp, about 10 minutes after the end of reperfusion.
Before cardiopulmonary by-pass and 10 minutes after the end of reperfusion
Lactates variation collected by the radial artery and coronary sinus pre and post clamping of the aorta.
Time Frame: Before cardiopulmonary by-pass and 10 minutes after the end of reperfusion
Earlobe arterialized blood sample will be collected by radial artery and coronary sinus and the sample sent by our laboratories to assess the concentration of lactates in mmol/L in venous blood before cardiopulmonary by-pass and after the release of aortic cross clamp, about 10 minutes after the end of reperfusion.
Before cardiopulmonary by-pass and 10 minutes after the end of reperfusion
Troponins I variation collected by blood sample
Time Frame: Since arrival on intensive care unit and 6, 12, 24, 48 h after unclamping of the aorta
A blood sample will be collected by peripheral vein and the sample sent by our laboratories to assess the concentration in µg/l of cardiac troponins Since arrival on intensive care unit and 6, 12, 24, 48 h after unclamping of the aorta.
Since arrival on intensive care unit and 6, 12, 24, 48 h after unclamping of the aorta

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Echocardiographic evaluation to assess significant differences in terms of systolic and diastolic left ventricular function post cardiopulmonary by-pass.
Time Frame: 30 minute after intubation before sternotomy and ten minute after protamin
Transesophageal echocardiographic study will be performed by two expert echocardiographers following the protocols of the Society of Cardiovascular Anesthesiologists and American Society of Echocardiography. Left ventricle myocardial performance index, LVEF (%), left ventricular regional wall motion, E/A ratio, E', E/E' and deceleration time (DT) of mitral inflow velocity will be measured; these measurements will be obteined.
30 minute after intubation before sternotomy and ten minute after protamin
Hemodynamic measurements
Time Frame: 30 min after intubation, after sternotomy, 10 min after protamin, after sternosynthesis, at arrival in the intensive care unit, 6, 12, 24, 36, 48 h after CPB
Hemodynamic measurements will be obtained by an arterial and a pulmonary artery catheter (PAC) inserted before surgery, and will include arterial pressure (systolic, diastolic and mean pressure), pulmonary artery pressure (PAP), right atrial pressure (RAP), pulmonary artery wedge pressure (PAWP), cardiac output (CO) and cardiac index (CI), systemic vascular resistance (SVR), left ventricular stroke work (LVSW), left stroke volume variaton (LSVV) and coronary artery perfusion pressure (CPP).
30 min after intubation, after sternotomy, 10 min after protamin, after sternosynthesis, at arrival in the intensive care unit, 6, 12, 24, 36, 48 h after CPB
Cardiac Complications
Time Frame: Since arrival on intensive care unit and 6, 12, 24, 48 h after unclamping of the aorta
New-onset atrial fibrillation, ventricular arrhythmia, low cardiac output syndrome (LCOS), inotropic support and/or intraaortic balloon pump >24 hours, myocardial infarction) and intensive care unit and hospital length of stay between two groups.
Since arrival on intensive care unit and 6, 12, 24, 48 h after unclamping of the aorta

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Gabriella Arlotta, MD, Department cardiovascular diseases A. Gemelli Polyclinic , University Sacred Heart in Rome

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 (Anticipated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 10, 2019

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2020

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 10, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 16, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 22, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 25, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 23, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • RAN

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

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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