Ranolazine a Potential New Therapeutic Application

NCT02687269 | Withdrawn Phase 4

• 1 other identifier: RAN
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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).

Conditions

Myocardial Stunning

Keywords

myocardial protection; coronary artery bypass grafting

Outcome Measures

Primary Outcomes (4)

• Troponins I variation collected by coronary sinus pre and post clamping of the aorta.

  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.

  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.

  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

  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 Outcomes (3)

• Echocardiographic evaluation to assess significant differences in terms of systolic and diastolic left ventricular function post cardiopulmonary by-pass.

  30 minute after intubation before sternotomy and ten minute after protamin

• Hemodynamic measurements

  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

  Since arrival on intensive care unit and 6, 12, 24, 48 h after unclamping of the aorta

Study Arms (2)

Ranolazine

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Ranolazine DRUG

Patients in this arm receive Ranolazine at a dose of 375 mg twice daily in the three days before surgery

Also known as: Ranexa

Ranolazine

Placebo DRUG

Patients receive Placebo twice daily in the three days before surgery

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

MeSH Terms

Conditions

Myocardial Stunning

Interventions

Ranolazine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Gabriella Arlotta, MD

  Department cardiovascular diseases A. Gemelli Polyclinic , University Sacred Heart in Rome

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, Resident in Anesthesia and Intensive Care Department

Study Record Dates

• First Submitted: February 10, 2016
• First Posted: February 22, 2016
• Study Start: April 10, 2019
• Primary Completion: September 1, 2020
• Study Completion: October 1, 2020
• Last Updated: February 25, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will share