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Infusion of glucose, insulin, and potassium was feasible and effective in preventing in-hospital events in patients with acute MI
ET IO L OG Y
Infusion of glucose, insulin, and potassium was feasible and effective in preventing in-hospital events in patients with acute MI DmH az R, Paolasso EA, Piegas LS et al. on behalf of the ECLA (Estudios CardioloH gicos LatinoameH rica) Collaborative Group. Metabolic Modulation of Acute Myocardial Infarction. The ECLA GlucosedInsulindPotassium Pilot Trial. Circulation 1998;98:2227d2234
OBJECTIVE To evaluate the feasibility of infusing glucose, insulin and potassium (GIK) in patients with acute MI, and to assess its efficacy on defined clinical end-points.
MAIN OUTCOME MEASURES Mortal and major morbid in-hospital events.
allocated to GIK. There were no statistically significant differences in any in-hospital event between GIK groups (all P for nine events '0.153). When both groups receiving GIK were combined, there was a trend toward reduced mortality in the GIK group compared with the control group (6.7 vs 11.5%; RR 0.58; 95% CI 0.30–1.10). When limited to patients who received reperfusion strategies, the association was strengthened (5.2 vs 15.2%; RR 0.34; CI 0.15–0.77; P"0.01). The test of heterogeneity was significant (P"0.03), indicating that GIK may have different effects in patients who do and do not undergo reperfusion. There was also a significant risk reduction for electromechanical dissociation (RR 0.25; CI 0.07–0.84; P"0.02). Patients receiving GIK had a significantly lower risk of mortal and major morbid events, including non-fatal severe heart failure (Killip class '2), and ventricular fibrillation (11.9 vs 20.1%; RR 0.59; CI 0.37–0.94; P"0.03). The risk reduction was borderline significant in the subset of reperfused patients. In post hoc analyses of patients in whom the infusion was completed, there was a large risk reduction in overall mortality (RR 0.44; CI 0.21–0.90) and mortality in reperfused patients (RR 0.21; CI 0.08–0.58).
MAIN RESULTS The mean infused volumes were 2422 and 1795 mL over 24 hours in the high- and low-dose groups, respectively. GIK infusion was completed in 88.8% of patients
CONCLUSION Infusion of glucose, insulin and potassium was feasible and effective in preventing in-hospital mortal and major morbid events in patients with acute MI.
Commentary
suggests that GIK can plausibly reduce in-hospital acute MI mortality by a fifth to a quarter, a treatment benefit comparable to some of the widely used therapies, such as thrombolytics.1 The finding that reperfused patients appear to derive a greater mortality benefit is important since this suggests that concomitant use of thrombolytic and GIK are compatible and may be synergistic. These mechanistic and clinical trial data suggest that a large, well-designed clinical trial to evaluate GIK in acute MI is timely. The mechanisms of benefit are convincing, the trial data are highly suggestive and such a trial appears feasible in the modern era. The potential synergy with thrombolysis will be an attraction for the clinician. Much needs to be thought and worked out. For example, details such as the GIK regimen, duration of infusion and time after onset of the acute MI may profoundly affect the trial outcome. If shown to be safe and efficacious, GIK treatment in acute MI, a cheap and commonly available therapy, will benefit many patients worldwide.
DESIGN Multi-center, randomized, controlled pilot study. SETTING 29 hospitals in six Latin American countries. PATIENTS 407 patients (mean age 59 years, 74% men) with suspected AMI presenting within 24 hours of onset of symptoms. Patients with severe renal impairment or hyperkalemia were excluded. INTERVENTION Patients were randomized to one of the three treatment arms: high-dose GIK (25% glucose, 50 IU/L insulin and 80 mmol/L KCl at an infusion rate of 1.5 mL/kg per hour over 24 hours); low-dose GIK (10% glucose, 20 IU/L insulin and 40 mmol/L KCl at an infusion rate of 1.0 mL/kg per hour over 24 hours); or usual care. Physicians were free to use any additional therapies considered necessary.
This feasibility pilot clinical trial by DmH az et al. showed that a trial of glucosedinsulindpotassium (GIK) infusion in acute MI is feasible and that the treatment has potential benefits in reducing mortality and major morbidity in acute MI. While it is not clear why it took the 29 participating hospitals 14 months to recruit 407 patients (only 1 patient per hospital per month), the treatment appeared safe. The mechanisms of benefit from GIK are known. The high sympathetic activity during acute MI increases free fatty acid levels which in turn increase myocardial oxygen demand and depress myocardial mechanical activity and contraction. In this situation, exogenous glucose is a more efficient fuel than free fatty acid or glycogen and is thought to be more likely to prevent ischemic myocardial injury. The individual components of GIK are also thought to be cardioprotective during this acute phase. Insulin lowers the plasma concentration of free fatty acid by inhibiting lipolysis. Other mechanisms include prevention of ischemic contracture, protection of ischemic coronary vasculature, restoration of intracellular potassium and facilitating spontaneous thrombolysis.1 This concept of modulating energy metabolism in the myocardial tissue at risk of undergoing necrosis has been widely studied but has yet to be applied in human subjects. The treatment has been evaluated by small trials in the 1960s and 1970s with inconclusive results. An overview of these trials
^ 1999 Harcourt Brace & Co. Ltd
Koon K. Teo, MD, PhD University of Alberta, Edmonton, Alberta, Canada
Literature cited 1. Fath-Ordoubadi F, Beatt KJ. Circulation 1997; 96: 1152d1156
Evidence-based Cardiovascular Medicine (1999) 3, 37
37
Infusion of glucose, insulin, and potassium was feasible and effective in preventing in-hospital events in patients with acute MI DmH az R, Paolasso EA, Piegas LS et al. on behalf of the ECLA (Estudios CardioloH gicos LatinoameH rica) Collaborative Group. Metabolic Modulation of Acute Myocardial Infarction. The ECLA GlucosedInsulindPotassium Pilot Trial. Circulation 1998;98:2227d2234
OBJECTIVE To evaluate the feasibility of infusing glucose, insulin and potassium (GIK) in patients with acute MI, and to assess its efficacy on defined clinical end-points.
MAIN OUTCOME MEASURES Mortal and major morbid in-hospital events.
allocated to GIK. There were no statistically significant differences in any in-hospital event between GIK groups (all P for nine events '0.153). When both groups receiving GIK were combined, there was a trend toward reduced mortality in the GIK group compared with the control group (6.7 vs 11.5%; RR 0.58; 95% CI 0.30–1.10). When limited to patients who received reperfusion strategies, the association was strengthened (5.2 vs 15.2%; RR 0.34; CI 0.15–0.77; P"0.01). The test of heterogeneity was significant (P"0.03), indicating that GIK may have different effects in patients who do and do not undergo reperfusion. There was also a significant risk reduction for electromechanical dissociation (RR 0.25; CI 0.07–0.84; P"0.02). Patients receiving GIK had a significantly lower risk of mortal and major morbid events, including non-fatal severe heart failure (Killip class '2), and ventricular fibrillation (11.9 vs 20.1%; RR 0.59; CI 0.37–0.94; P"0.03). The risk reduction was borderline significant in the subset of reperfused patients. In post hoc analyses of patients in whom the infusion was completed, there was a large risk reduction in overall mortality (RR 0.44; CI 0.21–0.90) and mortality in reperfused patients (RR 0.21; CI 0.08–0.58).
MAIN RESULTS The mean infused volumes were 2422 and 1795 mL over 24 hours in the high- and low-dose groups, respectively. GIK infusion was completed in 88.8% of patients
CONCLUSION Infusion of glucose, insulin and potassium was feasible and effective in preventing in-hospital mortal and major morbid events in patients with acute MI.
Commentary
suggests that GIK can plausibly reduce in-hospital acute MI mortality by a fifth to a quarter, a treatment benefit comparable to some of the widely used therapies, such as thrombolytics.1 The finding that reperfused patients appear to derive a greater mortality benefit is important since this suggests that concomitant use of thrombolytic and GIK are compatible and may be synergistic. These mechanistic and clinical trial data suggest that a large, well-designed clinical trial to evaluate GIK in acute MI is timely. The mechanisms of benefit are convincing, the trial data are highly suggestive and such a trial appears feasible in the modern era. The potential synergy with thrombolysis will be an attraction for the clinician. Much needs to be thought and worked out. For example, details such as the GIK regimen, duration of infusion and time after onset of the acute MI may profoundly affect the trial outcome. If shown to be safe and efficacious, GIK treatment in acute MI, a cheap and commonly available therapy, will benefit many patients worldwide.
DESIGN Multi-center, randomized, controlled pilot study. SETTING 29 hospitals in six Latin American countries. PATIENTS 407 patients (mean age 59 years, 74% men) with suspected AMI presenting within 24 hours of onset of symptoms. Patients with severe renal impairment or hyperkalemia were excluded. INTERVENTION Patients were randomized to one of the three treatment arms: high-dose GIK (25% glucose, 50 IU/L insulin and 80 mmol/L KCl at an infusion rate of 1.5 mL/kg per hour over 24 hours); low-dose GIK (10% glucose, 20 IU/L insulin and 40 mmol/L KCl at an infusion rate of 1.0 mL/kg per hour over 24 hours); or usual care. Physicians were free to use any additional therapies considered necessary.
This feasibility pilot clinical trial by DmH az et al. showed that a trial of glucosedinsulindpotassium (GIK) infusion in acute MI is feasible and that the treatment has potential benefits in reducing mortality and major morbidity in acute MI. While it is not clear why it took the 29 participating hospitals 14 months to recruit 407 patients (only 1 patient per hospital per month), the treatment appeared safe. The mechanisms of benefit from GIK are known. The high sympathetic activity during acute MI increases free fatty acid levels which in turn increase myocardial oxygen demand and depress myocardial mechanical activity and contraction. In this situation, exogenous glucose is a more efficient fuel than free fatty acid or glycogen and is thought to be more likely to prevent ischemic myocardial injury. The individual components of GIK are also thought to be cardioprotective during this acute phase. Insulin lowers the plasma concentration of free fatty acid by inhibiting lipolysis. Other mechanisms include prevention of ischemic contracture, protection of ischemic coronary vasculature, restoration of intracellular potassium and facilitating spontaneous thrombolysis.1 This concept of modulating energy metabolism in the myocardial tissue at risk of undergoing necrosis has been widely studied but has yet to be applied in human subjects. The treatment has been evaluated by small trials in the 1960s and 1970s with inconclusive results. An overview of these trials
^ 1999 Harcourt Brace & Co. Ltd
Koon K. Teo, MD, PhD University of Alberta, Edmonton, Alberta, Canada
Literature cited 1. Fath-Ordoubadi F, Beatt KJ. Circulation 1997; 96: 1152d1156
Evidence-based Cardiovascular Medicine (1999) 3, 37
37