Glutamate for Metabolic Intervention in Coronary Surgery II

NCT02592824 | Completed Phase 3 Results DMC

• 2 other identifiers: EudraCT 2011-006241-15Dnr 5.1-2015-77379
• Study Type: interventional
• Target: 321
• Locations: 1 country
• Sites: 4

Brief 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.

Conditions

Coronary Artery Bypass Surgery; Postoperative Complications; Heart Failure

Keywords

glutamate, heart failure, coronary artery bypass surgery

Outcome Measures

Primary Outcomes (1)

• Postoperative Increase of Plasma NT-proBNP

  Postoperative increase of NT-proBNP reflects postoperative myocardial dysfunction sustained in association with surgery. NT-proBNP usually peaks on the third to fourth postoperative day after coronary artery bypass surgery. In the first GLUTAMICS trial a good agreement between hemodynamic criteria for postoperative heart failure and postoperative NT-proBNP was found.

  from the day before surgery to the third postoperative day

Secondary Outcomes (5)

• Postoperative Plasma Level of NT-proBNP

  first postoperative day

• Postoperative Plasma Level of NT-proBNP

  third postoperative day

• Number of Participants With Incidence of Stroke

  within 24 hours from surgery

• Incidence of Mortality

  up to 30 days

• Incidence of Unexpected Adverse Events

  within 24 hours from infusion

Other Outcomes (1)

• Copeptin Substudy

  preoperative, first and third postoperative day

Study Arms (2)

Intravenous glutamate infusion

ACTIVE COMPARATOR

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.

Drug: glutamate infusion

Intravenous saline infusion

PLACEBO COMPARATOR

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.

Drug: saline infusion

Interventions

glutamate infusion DRUG

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.

Also known as: glutamate

Intravenous glutamate infusion

saline infusion DRUG

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.

Also known as: saline

Intravenous saline infusion

Eligibility Criteria

• Age: 20 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 due to:
• EuroSCORE II ≥ 3.0 with at least one of the following cardiac or procedure related risk factors:
• LVEF ≤ 0.50
• CCS class IV
• Recent Myocardial Infarct (≤ 90 days)
• Emergency / Urgent procedure (as defined in EuroSCORE II)
• CABG with aortic or mitral valve procedure
• LVEF ≤ 0.30 regardless of EuroSCORE II

You may not qualify if:

• age \> 85 years
• ambiguous food allergies that trigger shortness of breath, headache or flushing
• previous cardiac surgery
• patients who are in such bad condition that they cannot be asked to participate
• patients who because of linguistic or other reasons are unable to provide informed consent
• severe renal failure with preoperative dialysis or calculated GFR \<30 mL / min
• patients requiring mechanical circulatory support (intra-aortic balloon pump) due to circulatory failure before they are enrolled in the study
• surgery without heart-lung machine (off-pump)
• concomitant Maze-procedure
• surgery of ascending aorta
• surgery of both aortic and mitral valve

Sponsors & Collaborators

• University Hospital, Linkoeping: lead
• Region Örebro County: collaborator
• University Hospital, Umeå: collaborator
• Sahlgrenska University Hospital: collaborator

Study Sites (4)

Sahlgrenska University Hospital

Gothenburg, SE41345, Sweden

Location

University Hospital Linköping

Linköping, SE58185, Sweden

Location

University Hospital Örebro

Örebro, SE 70185, Sweden

Location

University Hospital Umeå

Umeå, SE90185, Sweden

Location

Related Publications (36)

• O'Connor GT, Birkmeyer JD, Dacey LJ, Quinton HB, Marrin CA, Birkmeyer NJ, Morton JR, Leavitt BJ, Maloney CT, Hernandez F, Clough RA, Nugent WC, Olmstead EM, Charlesworth DC, Plume SK. Results of a regional study of modes of death associated with coronary artery bypass grafting. Northern New England Cardiovascular Disease Study Group. Ann Thorac Surg. 1998 Oct;66(4):1323-8. doi: 10.1016/s0003-4975(98)00762-0.

  PMID: 9800828 BACKGROUND

• Fellahi JL, Parienti JJ, Hanouz JL, Plaud B, Riou B, Ouattara A. Perioperative use of dobutamine in cardiac surgery and adverse cardiac outcome: propensity-adjusted analyses. Anesthesiology. 2008 Jun;108(6):979-87. doi: 10.1097/ALN.0b013e318173026f.

  PMID: 18497597 BACKGROUND

• Gillies M, Bellomo R, Doolan L, Buxton B. Bench-to-bedside review: Inotropic drug therapy after adult cardiac surgery -- a systematic literature review. Crit Care. 2005 Jun;9(3):266-79. doi: 10.1186/cc3024. Epub 2004 Dec 16.

  PMID: 15987381 BACKGROUND

• Mebazaa A, Pitsis AA, Rudiger A, Toller W, Longrois D, Ricksten SE, Bobek I, De Hert S, Wieselthaler G, Schirmer U, von Segesser LK, Sander M, Poldermans D, Ranucci M, Karpati PC, Wouters P, Seeberger M, Schmid ER, Weder W, Follath F. Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery. Crit Care. 2010;14(2):201. doi: 10.1186/cc8153. Epub 2010 Apr 28.

  PMID: 20497611 BACKGROUND

• Slogoff S, Keats AS. Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology. 1985 Feb;62(2):107-14. doi: 10.1097/00000542-198502000-00002.

  PMID: 3970360 BACKGROUND

• Vanky F, Hakanson E, Maros T, Svedjeholm R. Different characteristics of postoperative heart failure after surgery for aortic stenosis and coronary disease. Scand Cardiovasc J. 2004 Jun;38(3):152-8. doi: 10.1080/14017430410029734.

  PMID: 15223713 BACKGROUND

• Vanky FB, Hakanson E, Svedjeholm R. Long-term consequences of postoperative heart failure after surgery for aortic stenosis compared with coronary surgery. Ann Thorac Surg. 2007 Jun;83(6):2036-43. doi: 10.1016/j.athoracsur.2007.01.031.

  PMID: 17532392 BACKGROUND

• Dahlin LG, Olin C, Svedjeholm R. Perioperative myocardial infarction in cardiac surgery--risk factors and consequences. A case control study. Scand Cardiovasc J. 2000 Oct;34(5):522-7. doi: 10.1080/140174300750064710.

  PMID: 11191945 BACKGROUND

• Khoynezhad A, Jalali Z, Tortolani AJ. Apoptosis: pathophysiology and therapeutic implications for the cardiac surgeon. Ann Thorac Surg. 2004 Sep;78(3):1109-18. doi: 10.1016/j.athoracsur.2003.06.034.

  PMID: 15337071 BACKGROUND

• Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E. Factors influencing infarct size following experimental coronary artery occlusions. Circulation. 1971 Jan;43(1):67-82. doi: 10.1161/01.cir.43.1.67. No abstract available.

  PMID: 5540853 BACKGROUND

• Lazar HL, Buckberg GD, Foglia RP, Manganaro AJ, Maloney JV Jr. Detrimental effects of premature use of inotropic drugs to discontinue cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1981 Jul;82(1):18-25.

  PMID: 7242127 BACKGROUND

• Thackray S, Easthaugh J, Freemantle N, Cleland JG. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure-a meta-regression analysis. Eur J Heart Fail. 2002 Aug;4(4):515-29. doi: 10.1016/s1388-9842(02)00041-7.

  PMID: 12167393 BACKGROUND

• Aya HD, Cecconi M, Hamilton M, Rhodes A. Goal-directed therapy in cardiac surgery: a systematic review and meta-analysis. Br J Anaesth. 2013 Apr;110(4):510-7. doi: 10.1093/bja/aet020. Epub 2013 Feb 27.

  PMID: 23447502 BACKGROUND

• Giglio M, Dalfino L, Puntillo F, Rubino G, Marucci M, Brienza N. Haemodynamic goal-directed therapy in cardiac and vascular surgery. A systematic review and meta-analysis. Interact Cardiovasc Thorac Surg. 2012 Nov;15(5):878-87. doi: 10.1093/icvts/ivs323. Epub 2012 Jul 24.

  PMID: 22833509 BACKGROUND

• Shahin J, DeVarennes B, Tse CW, Amarica DA, Dial S. The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery. Crit Care. 2011 Jul 7;15(4):R162. doi: 10.1186/cc10302.

  PMID: 21736726 BACKGROUND

• Lazar HL, Buckberg GD, Manganaro AJ, Becker H, Maloney JV Jr. Reversal of ischemic damage with amino acid substrate enhancement during reperfusion. Surgery. 1980 Nov;88(5):702-9.

  PMID: 7434210 BACKGROUND

• Pisarenko OI. Mechanisms of myocardial protection by amino acids: facts and hypotheses. Clin Exp Pharmacol Physiol. 1996 Aug;23(8):627-33. doi: 10.1111/j.1440-1681.1996.tb01748.x.

  PMID: 8886480 BACKGROUND

• Rau EE, Shine KI, Gervais A, Douglas AM, Amos EC 3rd. Enhanced mechanical recovery of anoxic and ischemic myocardium by amino acid perfusion. Am J Physiol. 1979 Jun;236(6):H873-9. doi: 10.1152/ajpheart.1979.236.6.H873. No abstract available.

  PMID: 443452 BACKGROUND

• Safer B. The Metabolic Significance of the Malate-Aspartate Cycle in Heart. Circ Res. 1975 Nov;37(5):527-33. doi: 10.1161/01.res.37.5.527. No abstract available.

  PMID: 172258 BACKGROUND

• Peuhkurinen KJ. Regulation of the tricarboxylic acid cycle pool size in heart muscle. J Mol Cell Cardiol. 1984 Jun;16(6):487-95. doi: 10.1016/s0022-2828(84)80637-9.

  PMID: 6748086 BACKGROUND

• Pisarenko OI, Novikova EB, Serebryakova LI, Tskitishvili OV, Ivanov VE, Studneva IM. Function and metabolism of dog heart in ischemia and in subsequent reperfusion: effect of exogenous glutamic acid. Pflugers Arch. 1985 Dec;405(4):377-83. doi: 10.1007/BF00595691.

  PMID: 2867519 BACKGROUND

• Haas GS, DeBoer LW, O'Keefe DD, Bodenhamer RM, Geffin GA, Drop LJ, Teplick RS, Daggett WM. Reduction of postischemic myocardial dysfunction by substrate repletion during reperfusion. Circulation. 1984 Sep;70(3 Pt 2):I65-74.

  PMID: 6430593 BACKGROUND

• Engelman RM, Rousou JA, Flack JE 3rd, Iyengar J, Kimura Y, Das DK. Reduction of infarct size by systemic amino acid supplementation during reperfusion. J Thorac Cardiovasc Surg. 1991 May;101(5):855-9.

  PMID: 1673733 BACKGROUND

• Pisarenko OI, Lepilin MG, Ivanov VE. Cardiac metabolism and performance during L-glutamic acid infusion in postoperative cardiac failure. Clin Sci (Lond). 1986 Jan;70(1):7-12. doi: 10.1042/cs0700007.

  PMID: 2867848 BACKGROUND

• Svedjeholm R, Vanhanen I, Hakanson E, Joachimsson PO, Jorfeldt L, Nilsson L. Metabolic and hemodynamic effects of intravenous glutamate infusion early after coronary operations. J Thorac Cardiovasc Surg. 1996 Dec;112(6):1468-77. doi: 10.1016/S0022-5223(96)70005-3.

  PMID: 8975838 BACKGROUND

• Svedjeholm R, Huljebrant I, Hakanson E, Vanhanen I. Glutamate and high-dose glucose-insulin-potassium (GIK) in the treatment of severe cardiac failure after cardiac operations. Ann Thorac Surg. 1995 Feb;59(2 Suppl):S23-30. doi: 10.1016/0003-4975(94)00918-w.

  PMID: 7840695 BACKGROUND

• Svedjeholm R, Vidlund M, Vanhanen I, Hakanson E. A metabolic protective strategy could improve long-term survival in patients with LV-dysfunction undergoing CABG. Scand Cardiovasc J. 2010 Feb;44(1):45-58. doi: 10.3109/14017430903531008.

  PMID: 20141344 BACKGROUND

• Vidlund M, Hakanson E, Friberg O, Juhl-Andersen S, Holm J, Vanky F, Sunnermalm L, Borg JO, Sharma R, Svedjeholm R. GLUTAMICS--a randomized clinical trial on glutamate infusion in 861 patients undergoing surgery for acute coronary syndrome. J Thorac Cardiovasc Surg. 2012 Oct;144(4):922-930.e7. doi: 10.1016/j.jtcvs.2012.05.066. Epub 2012 Jun 19.

  PMID: 22721612 BACKGROUND

• de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet. 2003 Jul 26;362(9380):316-22. doi: 10.1016/S0140-6736(03)13976-1.

  PMID: 12892964 BACKGROUND

• Karlstrom P, Alehagen U, Boman K, Dahlstrom U; UPSTEP-study group. Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome. Eur J Heart Fail. 2011 Oct;13(10):1096-103. doi: 10.1093/eurjhf/hfr078. Epub 2011 Jun 29.

  PMID: 21715446 BACKGROUND

• Reyes G, Fores G, Rodriguez-Abella RH, Cuerpo G, Vallejo JL, Romero C, Pinto A. NT-proBNP in cardiac surgery: a new tool for the management of our patients? Interact Cardiovasc Thorac Surg. 2005 Jun;4(3):242-7. doi: 10.1510/icvts.2004.101576. Epub 2005 Mar 30.

  PMID: 17670401 BACKGROUND

• Nozohoor S, Nilsson J, Algotsson L, Sjogren J. Postoperative increase in B-type natriuretic peptide levels predicts adverse outcome after cardiac surgery. J Cardiothorac Vasc Anesth. 2011 Jun;25(3):469-75. doi: 10.1053/j.jvca.2010.07.002. Epub 2010 Sep 9.

  PMID: 20829070 BACKGROUND

• Fox AA, Nascimben L, Body SC, Collard CD, Mitani AA, Liu KY, Muehlschlegel JD, Shernan SK, Marcantonio ER. Increased perioperative b-type natriuretic peptide associates with heart failure hospitalization or heart failure death after coronary artery bypass graft surgery. Anesthesiology. 2013 Aug;119(2):284-94. doi: 10.1097/ALN.0b013e318299969c.

  PMID: 23695172 BACKGROUND

• Holm J, Vanky F, Svedjeholm R. Association of Glutamate Infusion With Risk of Acute Kidney Injury After Coronary Artery Bypass Surgery: A Pooled Analysis of 2 Randomized Clinical Trials. JAMA Netw Open. 2024 Jan 2;7(1):e2351743. doi: 10.1001/jamanetworkopen.2023.51743.

  PMID: 38252440 DERIVED

• Holm J, Vanky F, Svedjeholm R. Glutamate Infusion Reduces Myocardial Dysfunction after Coronary Artery Bypass Grafting According to NT-proBNP: Summary of 2 Randomized Controlled Trials (GLUTAmate for Metabolic Intervention in Coronary Surgery [GLUTAMICS I-II]). Am J Clin Nutr. 2023 Nov;118(5):930-937. doi: 10.1016/j.ajcnut.2023.08.012. Epub 2023 Aug 30.

  PMID: 37657522 DERIVED

• Holm J, Ferrari G, Holmgren A, Vanky F, Friberg O, Vidlund M, Svedjeholm R. Effect of glutamate infusion on NT-proBNP after coronary artery bypass grafting in high-risk patients (GLUTAMICS II): A randomized controlled trial. PLoS Med. 2022 May 9;19(5):e1003997. doi: 10.1371/journal.pmed.1003997. eCollection 2022 May.

  PMID: 35533197 DERIVED

MeSH Terms

Conditions

Postoperative Complications; Heart Failure

Interventions

Glutamic Acid; Sodium Chloride

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Excitatory Amino Acids; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

The main limitations of the study are: (i) it relies on a surrogate marker for heart failure (ii) the proportion of patients with diabetes had almost doubled compared to the cohort used for the sample size estimation

Results Point of Contact

• Title: Dr Jonas Holm
• Organization: Linköping University Hospital

jonas.holm@regionostergotland.se

+46101034498

Study Officials

• Rolf Svedjeholm, Professor

  University Hospital, Linkoeping

  STUDY CHAIR

• Farkas Vanky, MD, PhD

  University Hospital, Linkoeping

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, MD

Study Record Dates

• First Submitted: October 28, 2015
• First Posted: October 30, 2015
• Study Start: November 15, 2015
• Primary Completion: October 30, 2020
• Study Completion: October 30, 2020
• Last Updated: December 4, 2023
• Results First Posted: December 4, 2023

Record last verified: 2023-02

Locations

SE (4)