Glutamate for Metabolic Intervention in Coronary Surgery

Brief Summary

Official Title: “Phase III Study of Intravenous Glutamate Infusion for Metabolic Protection of the Heart in Surgery for Unstable Coronary Artery Disease”

The main purpose of this study is to determine whether intravenous glutamate infusion given in association with surgery for unstable coronary artery disease can protect the heart from myocardial injury, postoperative heart failure and death.

  • Study Type: Interventional
  • Study Design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
  • Study Primary Completion Date: December 2009

Detailed Clinical Trial Description

Myocardial preservation in cardiac surgery has mainly focused on the period when the heart is arrested (cross-clamp time). Today the heart can be arrested for up to 2-3 hours without major consequences. However, in spite of comparatively short cross-clamp times approximately 10% of the patients undergoing coronary surgery sustain significant myocardial injury whereas perioperative myocardial infarction is rare in aortic valve surgery despite longer cross-clamp times. The reason for this is that preoperative ischemia, and to some extent postoperative ischemia, remain major risk factors for development of myocardial infarction in patients with ischemic heart disease. In light of this, we suggest that efforts to improve outcome and reduce permanent myocardial damage should focus on the preoperative and the postoperative phase of coronary surgery. Furthermore, efforts should be instituted to reduce reperfusion injury and minimize permanent myocardial damage in long-standing or severe myocardial ischemia.

Metabolic intervention with intravenous glutamate infusion, offers the prospect of addressing the issues above and extending myocardial protection into the pre- and postoperative phase. Glutamate is an important substrate for the intermediary metabolism of the heart, particularly in association with ischemia. The effects of glutamate are partly related to its role in the malate-aspartate shuttle, transporting reducing equivalents across the mitochondrial membrane, regulating the NAD/NADH balance in the cytosol of the cells, and thereby enhancing anaerobic glycolysis during ischemia. Furthermore, glutamate contributes to an alternative anaerobic pathway for regeneration of high-energy phosphates, by substrate level phosphorylation in the Krebs cycle. Glutamate also improves clearance of metabolic waste produced during ischemia such as lactate and NH3, by taking part in the reactions involving transamination of pyruvate to alanine and of glutamate to glutamine. During reperfusion glutamate contributes to the replenishment of Krebs cycle intermediates lost during ischemia, which is essential for recovery of oxidative metabolism.

Administration of glutamate to patients with stable angina pectoris has been found to increase tolerance to stress-induced ischemia. Ischemia before onset of cardiopulmonary bypass has been established as a major risk factor for postoperative myocardial infarction. Patients with unstable coronary artery disease may have critical ischemia at rest and are particularly vulnerable to the increased oxygen demands during the early stages of coronary surgery. In a pilot study on patients operated urgently for unstable angina we found metabolic signs compatible with improved tolerance to ischemia before surgery and improved recovery of oxidative metabolism during early reperfusion. These results warrant further studies to evaluate the potential clinical benefit of preoperative glutamate infusion extended into the early postoperative period.

Comparisons: Intravenous infusion of 0.125 M glutamic acid solution v saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.

Preliminary power analysis (80% power; p<0.05) suggests that 2214 patients will be required with regard to primary end-point assuming 30% reduction of events occurring in 12% of untreated patients.

Stage I of the study comprises 800 patients* and will lead to an interim analysis with report of secondary end-points** and recalculation of sample-size with regard to primary end-point. An adaptive design with regard to primary end-point and analysis performed by external statistician blinded to the investigators will be used to avoid increasing the risk for type I error.

*Patient number 800 is anticipated to be enrolled during the summer of 2009 and for practical reasons all patients enrolled until the end of August 2009 will comprise the interim analysis.

**Secondary end-points include analysis of markers for myocardial injury (CK-MB, troponin-T), markers for hemodynamic adequacy (mixed venous oxygen saturation), renal function (p-creatinine, p-Cystatin C), brain injury (S100B, clinical signs). As a substudy a blinded analysis of the value of NT-pro BNP (obtained immediately before surgery, 24 hours postoperatively and on the 3rd postoperative day) as marker of postoperative heart failure and outcome will be conducted. NT-pro BNP will also be related to treatment with glutamate or placebo. Similar evaluation will involve markers troponin-T, p-Cystatin C and mixed venous oxygen saturation. For further details see outcome measures.

Substudies will involve subgroup analyses of patients with regard to combined CABG + valve procedures, severely unstable patients requiring emergency surgery / intravenous nitrates, preoperative LV-dysfunction and patients with diabetes. For further details see outcome measures.

Interventions Used in this Clinical Trial

  • Drug: Intravenous infusion of saline
    • Intravenous infusion of isotonic saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
  • Other: Intravenous glutamate infusion
    • Intravenous infusion of 0.125 M glutamic acid solution at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.

Arms, Groups and Cohorts in this Clinical Trial

  • Experimental: Intravenous glutamate
    • Intravenous infusion of 0.125 M glutamic acid solution at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
  • Placebo Comparator: Saline infusion
    • Intravenous infusion of saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.

Outcome Measures for this Clinical Trial

Primary Measures

  • Composite of perioperative myocardial infarction, postoperative heart failure or postoperative mortality
    • Time Frame: 30 days
      Safety Issue?: No

Secondary Measures

  • Degree of perioperative myocardial injury: CK-MB postoperative day 1, troponin-T postoperative day 3
    • Time Frame: perioperative
      Safety Issue?: No
  • Postoperative hemodynamic state: Mixed venous oxygen saturation + p-lactate, heart rate, systolic AP, diastolic AP, Pulmonary diastolic AP, CVP (weaning-arrival ICU) and NT-proBNP (24hrs, 3 days)
    • Time Frame: Hours-3days
      Safety Issue?: No
  • Outcome and postoperative hemodynamic state in patients with severely reduced left ventricular ejection fraction (LVEF<0.40)
    • Time Frame: End of surgery
      Safety Issue?: No
  • Postoperative renal function: p-cystatin C (postoperative day 3) and maximal p-creatinine recorded
    • Time Frame: 30 days
      Safety Issue?: No
  • Neurological safety issues: postoperative stroke (CT-scan) and p-S100B (substudy n=70)
    • Time Frame: 24 hours
      Safety Issue?: Yes
  • ICU treatment: duration of stay and ventilator treatment, dialysis, circulatory support (pharmacological / mechanical)
    • Time Frame: ICU-stay
      Safety Issue?: No
  • Atrial fibrillation
    • Time Frame: Hospital stay
      Safety Issue?: No
  • Planned subgroup analyses: Patients requiring emergency surgery/intravenous nitrates, Patients with severely reduced LV-function, Diabetics, type of myocardial protection, OPCAB/ONCAB, combined CABG-valve procedures
    • Time Frame: 30 days
      Safety Issue?: No
  • Late mortality – related to biochemical markers (troponin-T, mixed venous oxygen saturation, NT-proBNP) and intervention
    • Time Frame: 6 months – 5 years
      Safety Issue?: No

Criteria for Participation in this Clinical Trial

Inclusion Criteria

  • surgery for unstable coronary artery disease (unstable angina, non-STEMI)
  • accepted for surgery < 2 weeks after STEMI
  • coronary surgery for indications above performed with or without cardiopulmonary bypass
  • coronary surgery for indications above with or without simultaneous valve procedure

Exclusion Criteria

  • informed consent not possible because of critical condition or other reason
  • preoperative use of inotropes or mechanical circulatory assist
  • preoperative dialysis
  • redo-procedure
  • unexpected intraoperative finding / event that increased the dignity of the procedure to overshadow the originally planned operation
  • body weight > 125 kg
  • food allergy known to have caused flush, rash or asthma

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • University Hospital, Linkoeping
  • Collaborator
    • University Hospital Orebro
  • Provider of Information About this Clinical Study
    • Principal Investigator: Rolf Svedjeholm, Professor – University Hospital, Linkoeping
  • Overall Official(s)
    • Rolf Svedjeholm, MD PhD, Study Director, University Hospital, Linkoeping

References

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