Glutamics - a randomized clinical trial on glutamate infusion in patients operated for acute coronary syndrome

BACKGROUND

Glutamate is an important substrate for the intermediary metabolism of the heart, particularly in association with ischemia. In animal models glutamate has been shown to protect the heart from ischemia and to facilitate metabolic and hemodynamic recovery after ischemia.

Adverse outcome in CABG is closely related to postoperative heart failure precipitated by ischemia and myocardial infarction. Based on encouraging clinical experience with intravenous glutamate infusion in high-risk CABG the GLUTAMICS-trial was initiated.
(ClinicalTrials.gov Identifier: NCT00489827)

 

AIMS

To investigate if intravenous glutamate infusion given in association with CABG for acute coronary syndrome can reduce mortality and prevent or mitigate myocardial injury and postoperative heart failure.

GLUTAMICS - TRIAL:

GLUTAMICS - GLUTAmate for Metabolic Intervention in Coronary Surgery

Investigator initiated clinical phase III trial on 861 patients undergoing CABG for acute coronary syndrome between October 4, 2005 and November 12, 2009 in three Swedish Cardiac Surgery Centers.
External monitoring and reporting of adverse events according to Good Clinical Practice standard.
Power analysis (80% power; p<0.05) suggested that 2214 patients would be required with regard to primary endpoint assuming 30% reduction of events occurring in 12% of untreated patients. Interim analysis was planned to occur after inclusion of 800 patients. The trial was terminated after interim analysis as prespecified stopping criteria per protocol were fulfilled.

Intervention: intravenous infusion of 0.125M glutamate solution or saline at a rate of 1.65 mL/kg and hour commencing at the induction of anesthesia and discontinued 2.5 hours after declamping the aorta or when a total of 500 mL had been infused.

Condition: CABG for acute coronary syndrome.

Exclusion criteria:  informed consent not possible because of critical condition or other reason, preoperative use of inotropic drugs or mechanical circulatory assist, preoperative dialysis, redo-procedure, unexpected intraoperative finding or event that increased the dignity of the procedure to overshadow the originally planned operation, age > 85 years, body weight > 125 kg and food allergy known to have caused flush, rash or asthma.

Study design: prospective, randomized, placebo controlled, double-blind.

Primary endpoint: composite of postoperative mortality (≤30 days), perioperative myocardial infarction and left ventricular heart failure in association with weaning from cardiopulmonary bypass.

Secondary endpoints: neurological safety issues, degree of myocardial injury, postoperative hemodynamic state, use of inotropic drugs and mechanical circulatory support, severe circulatory failure1, atrial fibrillation, renal function, ICU-treatment, cardiac mortality and late mortality.

Subgroup analysis: CCS class IV angina.

Disclosures: Investigator initiated trial. No other disclosures.

RESULTS

GLUTAMICS-trial (n=861)
There was no difference in the primary endpoint between the groups. Significantly fewer patients in the glutamate group were hemodynamically unstable or in need of intra-aortic balloon pump at completion of surgery (Table 2).
No significant differences were found regarding stroke, renal function, atrial fibrillation or markers of myocardial injury.
No significant differences were found regarding serious or non-serious adverse events.

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CCS class IV angina undergoing isolated CABG (n=458)
There was no difference in the primary endpoint between the groups. The incidence of severe circulatory failure according to prespecified criteria1 was significantly lower in the glutamate group (Table 4).
Glutamate infusion was independently associated with a reduced risk of severe circulatory failure1 (Table 5).
No significant differences were found regarding stroke, renal function, atrial fibrillation and markers of myocardial injury.

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CONCLUSION

The results are compatible with a beneficial effect of glutamate on myocardial recovery.
Intravenous glutamate infusion could provide a novel and important way of promoting myocardial recovery after ischemic injury.

ACRONYMS AND DEFINITIONS

GLUTAMICS- GLUTAmate for Metabolic Intervention in Coronary Surgery

1. Severe circulatory failure was defined as heart failure leading to death or requiring ICU stay ≥ 48 hours with inotropic drugs in prespecified dosages for ≥24 hours or IABP3 for ≥24 hours.
2. Unstable hemodynamic state despite inotropic drugs or in need of  IABP3
3. IABP- Intra aortic balloon pump
4. LITA- Left Interior Thoracic Artery
5. CPB- Cardiopulmonary Bypass