Glutamate for Metabolic Intervention in Coronary Surgery II
Condition: Coronary Artery Bypass Surgery; Postoperative Complications; Heart Failure
MeSH terms: Heart Failure; Postoperative Complications
Study type: Interventional
Phase: Phase 3

Summary: 
      The aim of GLUTAMICS II is to evaluate whether intravenous glutamate infusion surgery reduces
      the risk of postoperative heart failure as measured by plasma NT-proBNP in patients
      undergoing moderate to high-risk coronary artery bypass graft surgery. Patients accepted for
      coronary artery bypass surgery of at least two vessel disease or left main stenosis with or
      without concomitant procedure and considered to be at moderate to high surgical risk
      preoperatively with regard to postoperative heart failure will be studied. The primary
      endpoint is postoperative increase of NT-proBNP from the day before surgery to the third
      postoperative day.
    

Detailed description: 
      In spite of the progress in cardiac surgery and perioperative management postoperative heart
      failure remains the leading cause of death and organ failure. Although acknowledged as a
      major problem in cardiac surgery there are no generally accepted criteria for the diagnosis
      of postoperative heart failure. This in turn could explain why treatment for postoperative
      heart failure is poorly documented with regard to clinical outcome.

      Ischemia prior to cardiopulmonary bypass is the main cause of myocardial infarction after
      CABG. Available data demonstrate that ischemia and evolving myocardial infarction account for
      a large proportion of patients with postoperative heart failure after CABG.

      Conventional treatment of postoperative heart failure presents a therapeutic dilemma as
      inotropic drugs not only aggravate ischemia and increase the size of evolving myocardial
      infarction, but also stimulate apoptotic processes that may have adverse long-term
      consequences.

      The role of inotropes in cardiac surgery is therefore controversial. Some authors claim that
      liberal use of inotropes and goal-directed haemodynamic therapy can improve outcome whereas
      other report that liberal use of inotropes is associated with increased morbidity and
      mortality.

      Alternative measures that can enhance myocardial recovery and function without putting
      further strain on the heart are therefore desirable.

      Glutamate could influence outcome after myocardial ischemia by two different biochemical
      mechanisms. First, glutamate improves myocardial tolerance to ischemia by facilitated
      anaerobic metabolism and substrate level phosphorylation during ischemia. The second
      mechanism is related to the anaplerotic role of glutamate. Glutamate plays a key role for
      replenishment of Krebs cycle intermediates lost during ischemia, which enhances post-ischemic
      recovery of myocardial oxidative metabolism and function.

      Promoting metabolic and functional recovery with metabolic support represents a novel concept
      in the treatment of heart failure after acute ischemia. Animal experiments suggest that
      glutamate increases myocardial tolerance to ischemia and that glutamate promotes
      post-ischemic recovery. Intravenous glutamate improved metabolic and hemodynamic recovery in
      humans early after CABG. Early clinical experience with intravenous metabolic support showed
      that the need for inotropes could be substantially reduced while clinical outcomes with
      regard to postoperative mortality, postoperative renal dysfunction and long-term survival
      compared favourably with the literature. This encouraging experience contributed to the
      initiation of the first GLUTAMICS-trial.

      The first GLUTAMICS-trial investigated if intravenous glutamate infusion given in association
      with surgery for acute coronary syndrome could prevent myocardial injury, postoperative heart
      failure and reduce mortality. The study was negative with regard to the primary endpoint,
      which was a composite of postoperative mortality, perioperative myocardial infarction and
      left ventricular failure at weaning from cardiopulmonary bypass.

      However, the study included a high proportion of low risk patients. Furthermore, the design
      of the primary endpoint suffered from liberal preemptive use of inotropes in patients
      anticipated to have weaning problems. It became evident at clinical endpoint committee
      meetings that preemptive use of inotropes prevented detection of weaning problems in patients
      who later developed severe heart failure. The secondary endpoint severe circulatory failure
      discriminated mild short-lasting heart failure at weaning from cardiopulmonary bypass from
      clinically significant heart failure requiring substantial circulatory support and leading to
      prolonged ICU stay or death. In the glutamate treated patients the relative risk of
      developing severe circulatory failure was reduced by more than 50% in most risk groups
      undergoing isolated CABG.

      The first GLUTAMICS trial also included a substudy consisting of a blinded evaluation of
      NT-proBNP as a marker for postoperative heart failure.

      Due to the lack of generally accepted criteria for postoperative heart failure, the
      evaluation of treatment is difficult. Consequently, comparative studies on different
      treatment strategies of heart failure after cardiac surgery are sparse given the magnitude of
      the problem.

      Natriuretic peptides have been extensively studied in cardiology. In patients with chronic
      heart failure markedly increased BNP and NT-pro BNP levels are associated with poor
      prognosis. The response of natriuretic peptides to heart failure treatment has significant
      prognostic implications, and non-responders have a poor prognosis.

      In cardiac surgery NT-proBNP increase was more pronounced in patients requiring inotropes.
      High postoperative levels of BNP and NT-proBNP were associated with worse outcome, both in
      the short- and long-term.

      The first GLUTAMICS-trial permitted a blinded prospective evaluation of NT-proBNP by a
      clinical end-points committee relying on strict prespecified criteria with regard to
      postoperative heart failure. Data to be published demonstrate that postoperative NT-proBNP
      (day 1 and day 3) levels were strong predictors for severe heart failure associated with
      extended ICU stay or death. This implies that postoperative NT-proBNP could serve as a
      measure to assess efficacy of treatment and preventive strategies for postoperative heart
      failure. Albeit, a surrogate marker for postoperative heart failure it provides the advantage
      of a standardized and objective analysis, which makes the study reproducible.

      AIM

      The aim is to confirm findings in subgroups from the first GLUTAMICS-trial that intravenous
      glutamate infusion reduces the risk of postoperative heart failure in moderate to high risk
      patients undergoing coronary artery surgery by showing a reduced increase of NT-proBNP
      postoperatively.

      PATIENTS

      Patients accepted for coronary artery bypass surgery of at least two vessel disease or left
      main stenosis with or without concomitant procedure considered to be at moderate to high
      surgical risk preoperatively with regard to postoperative heart failure.

      310 patients are planned to be included after informed written consent.

      Exclusion criteria: patients with ambiguous food allergies that trigger shortness of breath,
      headache or flushing; patients> 85 years, previous cardiac surgery, patients who are in such
      bad condition that they cannot be asked to participate, patients who for linguistic or other
      reasons are unable to provide informed consent, severe renal failure with preoperative
      dialysis or calculated GFR <30 mL / min, patients requiring inotropic drugs or mechanical
      circulatory support (intra-aortic balloon pump) due to circulatory failure even before they
      enrolled in the study, patients who undergo surgery without the heart-lung machine
      (off-pump), patients who undergo concomitant Maze-procedure or surgery of ascending aorta.

      STUDY DESIGN

      The GLUTAMICS II is an investigator initiated prospective, randomized, placebo controlled,
      double-blind trial with parallel assignment to glutamate or placebo (saline). The trial is
      externally randomized and randomization is stratified for patients undergoing isolated CABG
      and for those having CABG with concomitant procedure.

      INTERVENTION

      Patients are randomly allocated to blinded intravenous infusion of 0.125M L-glutamic acid
      solution or saline at a rate of 1.65 ml/kg and hour commencing at or up to 20 minutes before
      the release of aortic cross-clamp. The infusion is continued for two hours after declamping
      the aorta after which an additional 50 ml is given at a halved infusion rate.

      PRIMARY ENDPOINT

      The primary endpoint is a postoperative increase of NT-proBNP from the day before surgery to
      the third postoperative day.

      SECONDARY ENDPOINTS

      Secondary endpoints are the absolute postoperative plasma levels of NT-proBNP day 1 and day
      3.

      SAFETY VARIABLES

      Postoperative mortality (30 days + hospitals), stroke within 24 hours and SUSARs

      SAMPLE SIZE

      Sample size is based on available results from the first GLUTAMICS study. In that study, the
      following increase of NT-proBNP from the preoperative value to third postoperative day (mean
      ± SD) were observed in patients with LVEF ≤ 0.30 or EuroSCORE II ≥ 3.0 undergoing coronary
      artery surgery for with or without concomitant procedure.

      Glutamate (n=71): 5261 ± 4409

      Placebo (n=62): 7112 ± 6454

      Sample size assessment by external statistical expertise (80% power, 5% risk level; two-sided
      test) suggests 141 patients in each group. To account for failed sampling and other loss we
      plan a total of 310 patients.

      INTERIM ANALYSIS

      Interim analysis will be performed by an external independent statistician after 160 patients
      by an adaptive design as reported in detail to the Swedish Medical Product Agency.

      Update August 30, 2020: Interim analysis in December 2017 supported the original sample size
      assessment and the aim was set to reach 300 patients with complete data for the primary
      endpoint. The original goal of 280 patients with complete data has been reached and the study
      is approaching 300 but as study solutions will expire September 30, 2020 this will be the
      last date for inclusion of patients into the trial.

      ETHICAL CONSIDERATIONS

      A concern with the use of glutamate is that it may act as an excitotoxin under certain
      conditions and participate in events leading to neurological damage. However, brain tissue
      concentrations of glutamate are more than fifty-fold higher than in blood whereas the dosage
      used only elevates blood levels three-fold. Neurological outcome has been carefully monitored
      when intravenous infusions have been used in clinical practice without evidence of adverse
      effects. No evidence of subclinical neurological injury associated with intravenous glutamate
      infusion could be detected by the S-100B measurements and no differences in neurological
      outcome or other adverse events were found in the GLUTAMICS trial.

      After written informed consent eligible patients will be enrolled in the study. The study
      will be performed according to the Helsinki Declaration of Human Rights and is approved by
      the Regional Ethical Review Board in Linköping (Dnr 2011/498-31; Dnr 2015/333-32).

      The Swedish Medical Products Agency requests surveillance and unblinding in cases of
      CT-verified stroke within 24 hours of surgery, mortality and suspected unexpected serious
      adverse reactions (SUSAR). External monitoring of all key data, written informed consent and
      unblinding procedures will be done.
    

Intervention name(s): glutamate infusion; saline infusion
Intervention type(s): Drug; Drug
Intervention description(s): Intravenous infusion of 0.125M L-glutamic acid solution at a rate of 1.65 ml/kg BW and hour commencing at or up to 20 minutes before the release of aortic cross-clamp. The infusion is continued for two hours after declamping the aorta after which an additional 50 ml is given at a halved infusion rate.; Intravenous infusion of saline at a rate of 1.65 ml/kg BW and hour commencing at or up to 20 minutes before the release of aortic cross-clamp. The infusion is continued for two hours after declamping the aorta after which an additional 50 ml is given at a halved infusion rate.
Other intervention name(s): glutamate; saline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: glutamate, heart failure, coronary artery bypass surgery