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Original Contribution |

Glucose-Insulin-Potassium Therapy in Patients With ST-Segment Elevation Myocardial Infarction FREE

Rafael Díaz, MD; Abhinav Goyal, MD, MHS; Shamir R. Mehta, MD, MSc; Rizwan Afzal, MSc; Denis Xavier, MD; Prem Pais, MD, MSc; Susan Chrolavicius, RN, BA; Jun Zhu, MD; Khawar Kazmi, MD; Lisheng Liu, MD; Andrzej Budaj, MD, PhD; Mohammad Zubaid, MD; Alvaro Avezum, MD, PhD; Mikhail Ruda, MD; Salim Yusuf, MBBS, DPhil
[+] Author Affiliations

Author Affiliations: Etudios Cardiologica Latin America, Rosario, Argentina (Dr Díaz); Department of Epidemiology, Emory Rollins School of Public Health and Emory School of Medicine, Atlanta, Georgia (Dr Goyal); Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada (Drs Goyal, Mehta, Xavier, and Yusuf, Mr Afzal, and Ms Chrolavicius); Department of Medicine, McMaster University, Hamilton, Ontario, Canada (Drs Mehta and Yusuf, Mr Afzal, and Ms Chrolavicius); St John's Medical College National Academy of Health Sciences, Bangalore, India (Drs Xavier and Pais); Cardiovascular Institute and Fu Wai Hospital, Chinese Hypertension League Institute, Beijing, China (Drs Zhu and Liu); Aga Khan University, Karachi, Pakistan (Dr Kazmi); Postgraduate Medical School, Department of Cardiology, Grochowski Hospital, Warsaw, Poland (Dr Budaj); Mubarak Al-Kabeer Hospital, Safat, Kuwait (Dr Zubaid); Dante Pazzanese Cardiology Institute, São Paulo, Brazil (Dr Avezum); and Cardiology Research Center, Moscow, Russia (Dr Ruda).

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JAMA. 2007;298(20):2399-2405. doi:10.1001/jama.298.20.2399.
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Context The clinical benefit of glucose-insulin-potassium (GIK) infusion in patients with ST-segment elevation myocardial infarction (STEMI) is unclear. While some smaller trials suggest benefit, in the CREATE-ECLA trial, GIK infusion had no effect on 30-day mortality in 20 201 patients.

Objectives To determine the association between GIK infusion therapy and 30-day and 6-month outcomes in patients with STEMI.

Design, Setting, and Participants Primary analysis of the OASIS-6 GIK randomized controlled trial of 2748 patients with acute STEMI; prespecified analyses of the combined trial data from the OASIS-6 GIK and CREATE-ECLA GIK trial populations of 22 943 patients with acute STEMI; subgroup analysis on the timing of initiation of GIK infusion therapy and outcomes; and post hoc analyses exploring whether GIK infusion may cause early harm by increasing glucose and potassium levels and net fluid gain.

Intervention High-dose GIK solution consisting of 25% glucose, 50 U/L of regular insulin, and 80 mEq/L of potassium infused at 1.5 mL/kg per hour for 24 hours.

Main Outcome Measures Mortality rates at 30 days and 6 months in the OASIS-6 GIK trial and rates of death, heart failure, and the composite of death or heart failure at 3 and 30 days in the combined OASIS-6 GIK and CREATE-ECLA GIK trial populations.

Results At 6 months, 148 (10.8%) GIK infusion patients and 143 (10.4%) control patients died in the OASIS-6 trial (hazard ratio [HR], 1.04; 95% CI, 0.83-1.31; P = .72); 153 (11.1%) GIK patients and 185 (13.5%) control patients had heart failure (HR, 0.83; 95% CI, 0.67-1.02; P = .08); and 240 (17.5%) GIK patients and 264 (19.2%) control patients had a composite of death or heart failure (HR, 0.91; 95% CI, 0.76-1.08; P = .27). In the prespecified analyses of the combined trial data, there were 712 deaths (6.2%) in the GIK group and 632 deaths (5.5%) in the control group at 3 days (HR, 1.13; 95% CI, 1.02-1.26; P = .03). This difference disappeared by 30 days, with 1108 deaths (9.7%) in the GIK group and 1068 (9.3%) in the control group (HR, 1.04; 95% CI, 0.96-1.13; P = .33). GIK therapy increased levels of glucose, potassium, and net fluid gain postinfusion, all 3 of which predicted death after adjusting for multiple confounders. Adjusting for glucose, potassium, and net fluid gain eliminated the apparent increase in mortality at 3 days observed with GIK infusion, suggesting a direct association with these factors. Administration of GIK infusion within 4 hours of symptom onset yielded no benefit compared with later initiation.

Conclusions Infusion of GIK provided no benefit and may cause early harm following STEMI. Avoidance of infusion-related hyperglycemia, hyperkalemia, and net fluid gain may be advisable in future studies of metabolic modulation in patients with STEMI.

Trial Registration clinicaltrials.gov Identifier: NCT00064428

Figures in this Article

Small experimental and clinical studies have supported the use of glucose-insulinpotassium (GIK) infusion in the treatment of acute ST-segment elevation myocardial infarction (STEMI).14 However, the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation— Estudios Clinicos Latino America (CREATE-ECLA)5 of 20 201 patients with acute STEMI demonstrated a neutral effect of GIK infusion on 30-day mortality. A separate study, the Organization for the Assessment of Strategies for Ischemic Syndromes-6 (OASIS-6) trial, evaluated the effect of GIK infusion vs no infusion on 6-month clinical outcomes in 2748 patients with acute STEMI. The principal results of the GIK component of the OASIS-6 trial through 6 months are presented herein. The results from the combined analysis of the OASIS-6 and CREATE-ECLA GIK trials showing the association between GIK therapy and 30-day outcomes in a total of 22 943 patients with STEMI also are presented herein. We also examined whether GIK infusion may cause harm in the early postinfusion period and whether this early harm could be explained by infusion-related hyperglycemia, hyperkalemia, or net fluid gain.

OASIS-6 GIK Trial

The OASIS-6 randomized controlled trial compared fondaparinux with placebo in 12 000 patients with STEMI.6 Of the original patients in OASIS-6, 8000 were to be randomized to open-labeled GIK infusion or no infusion in a 2 × 2 partial factorial design.6 The steering committee terminated the GIK component of the trial after only 2748 patients had been randomized to GIK infusion or control, following the announcement of the neutral effect of GIK therapy in the CREATE-ECLA study in November 2004.5 However, results of the GIK component of OASIS-6 were not analyzed until completion of the fondaparinux arm of the trial. Local ethics committee approvals were obtained separately for each of the OASIS-6 and CREATE-ECLA trials, and participants provided informed consent in both trials.

In the GIK component of the OASIS-6 trial, each center prepared high-dose GIK solution consisting of 25% glucose, 50 U/L of regular insulin, and 80 mEq/L of potassium. Randomization and initiation of GIK infusion occurred as soon as possible after hospital presentation, and GIK was infused at a rate of 1.5 mL/kg per hour for 24 hours. Serum glucose and potassium levels were serially assessed at randomization, 6 hours, and 24 hours. Fluid input and urine output were monitored during the 24-hour infusion period. The primary outcome of the GIK component of the OASIS-6 trial was all-cause mortality at 30 days. Secondary outcomes included heart failure, the composite of death and congestive heart failure, MI, stroke, cardiogenic shock, and cardiac arrest at 30 days, as well as the 6-month rates of all clinical events.

CREATE-ECLA GIK Trial

The CREATE-ECLA randomized controlled trial had a 2 × 2 partial factorial design evaluating the effects of open-label 24-hour GIK infusion compared with no infusion in 20 201 patients with acute STEMI, 15 570 of whom also were randomized to a 7-day blinded comparison of reviparin with placebo.5,7,8 High-dose GIK infusion identical to that used in OASIS-6 was initiated immediately following randomization and continued for 24 hours. Serum glucose, potassium, and fluid balance were all measured as in OASIS-6. The primary end point (30-day mortality) and the secondary end points were the same as in OASIS-6, except that follow-up beyond 30 days was not performed in CREATE-ECLA.

Prespecified Outcomes of the Combined GIK Trial Analyses

The plan to combine the individual patient data of the OASIS-6 and CREATE-ECLA GIK trials was made prior to the unblinding of either trial. There were 3 prespecified 30-day outcomes in the combined analysis: death, new-onset heart failure (diagnosed by clinical criteria and corroboration by chest x-ray), and the composite of death or heart failure at 30 days. New-onset heart failure was included because prior studies suggested that GIK infusion could enhance the recovery of myocardial pump function following STEMI.9,10

Prespecified analyses also were performed to test the hypothesis that GIK infusion might have an early beneficial effect on clinical outcomes (≤3 days after randomization), with little benefit after this period (days 4-30). This hypothesized temporal difference in GIK infusion's effects was based on studies that showed that GIK infusion favorably affected myocardial pump function,9,10 free fatty acid levels,11 and arrhythmogenicity12 for 2 to 3 days after GIK infusion, with no additional improvement thereafter. In the analysis of events from 4 to 30 days, patients who had already experienced the event in question (death, heart failure, or the composite of death or heart failure) within the first 3 days were excluded. Data on time to heart failure were not collected in 3798 patients in CREATE-ECLA, and therefore they were excluded from the analyses of heart failure and the composite of death or heart failure from 0 to 3 days and 4 to 30 days.

Relationship of Postrandomization Glucose Levels, Potassium Levels, and Fluid Balance With Clinical Outcomes

On observing in prespecified analyses an unexpected early hazard in the GIK infusion group in the first 3 days, post hoc analyses were performed to explore the mechanisms by which GIK therapy might cause this early harm. In the CREATE-ECLA trial, serum glucose and potassium levels were higher at 6 and 24 hours after randomization in the GIK infusion group compared with the control (usual care) group, and the net fluid balance was almost 600 mL greater at 24 hours in the GIK infusion group.5 Therefore, to determine the effect of postrandomization glucose levels on clinical outcomes, the average of the 6- and 24-hour glucose levels for each patient was calculated, and then patients were classified into 1 of 3 categories: patients with an average postrandomization glucose level of less than 126 mg/dL (to convert to mmol/L, multiply by 0.0555); a level of 126 mg/dL or higher but less than 144 mg/dL; and a level of 144 mg/dL or higher. Similarly, patients were stratified by average postrandomization potassium level (ie, the average of 6- and 24-hour potassium levels) of less than 4.0 mEq/L (a level often considered to be hypokalemia in the setting of acute MI; to convert to mmol/L, multiply by 1.0); a level of 4 mEq/L or higher but less than 5 mEq/L (normokalemia); and a level of 5 mEq/L or higher. Finally, patients also were stratified by fluid balance in the first 24 hours: negative fluid balance for patients whose urine output was higher than 110% of the total fluid input; positive fluid balance when urine output was less than 90% of the total fluid input; and neutral fluid balance when the urine output was within 10% of the fluid input. Three-day rates of death, heart failure, and the composite of death or heart failure were compared among strata of postrandomization glucose, potassium, and fluid balance.

Analysis of Time to Initiation of GIK Infusion

Because there is continued interest in whether early administration of GIK therapy may prove beneficial in patients with acute STEMI,13 a subgroup analysis comparing the effect of GIK infusion vs control on clinical event rates (death, heart failure, and the composite of death or heart failure) also was performed in patients stratified by time from STEMI symptom onset to randomization (<2, 2-<4, 4-<8, and ≥8 hours).

Statistical Methods

Analyses of the overall 30-day and 6-month outcomes in the OASIS-6 GIK trial and 30-day outcomes in the combined trial population were performed using the intention-to-treat approach. Time to clinical events between the GIK infusion and control groups were compared using the log-rank statistic. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 2-sided 95% confidence intervals (CIs) for clinical events from 0 to 30 days, and then again separately for 0 to 3 days and 4 to 30 days. For the analyses of outcomes by strata of postrandomization glucose, potassium, and fluid balance, the Wald χ2 test for trend and Cox proportional hazards models were used to compare the proportion of events among the different strata.

All models for death and the composite of death or heart failure were adjusted for potential confounders including age, sex, history of diabetes, GIK infusion allocation, infarction location (eg, anterior vs other walls), reperfusion therapy (yes or no), and time from symptom onset to randomization. Models evaluating the effect of each covariate (glucose, potassium, and fluid balance) on outcomes also were adjusted for the other 2 covariates. The subgroup analysis comparing the effect of GIK infusion with control by strata of time to randomization did not require statistical adjustment because time to randomization was a prerandomization factor. P≤.05 was used to define statistical significance, and all tests were 2-sided. SAS version 9.1 (SAS Institute Inc, Cary, North Carolina) and SPSS version 14.0 (SPSS Inc, Chicago, Illinois) software were used for all statistical analyses.

OASIS-6 Trial

In the OASIS-6 trial, 2748 patients were randomized to GIK therapy (Figure 1). Baseline characteristics were well balanced between the groups (Table 1). There were no differences between the GIK infusion and control groups in the 30-day outcomes of death (P = .36), heart failure (P = .31), or the composite of death or heart failure (P = .41) (Table 2). There also were no differences in any secondary 30-day end points or in 6-month clinical event rates (Table 2).

Figure 1. Flow Diagram for the Glucose-Insulin-Potassium (GIK) Component of the OASIS-6 Trial
Graphic Jump Location

OASIS-6 indicates Organization for the Assessment of Strategies for Ischemic Syndromes-6.

Table Graphic Jump LocationTable 2. Clinical Outcomes in the OASIS-6 GIK Trial at 30 Days and at 6 Months
Combined Analysis of the OASIS-6 and CREATE-ECLA Trials

Overall, 22 949 patients were randomized in the OASIS-6 and the CREATE-ECLA GIK trials. Six patients (3 from each of the GIK and control groups) were lost to follow-up at 7 days in the CREATE-ECLA trial, and therefore 22 943 patients were included in the combined analysis. Compared with patients in CREATE-ECLA, patients in OASIS-6 were older, had a higher prevalence of previously diagnosed hypertension and congestive heart failure, and had a slightly lower prevalence of previously diagnosed type 2 diabetes mellitus (Table 1). Although rates of appropriate use of medical therapy were high in both trials, clopidogrel or ticlopidine, β-blockers, and glycoprotein IIb/IIIa inhibitors were used and primary percutaneous coronary intervention was performed more often in OASIS-6 than in CREATE-ECLA.

In the combined OASIS-6 and CREATE-ECLA GIK trial results (Table 3 and Figure 2), there were no differences between the GIK infusion and control groups in the 30-day rate of death (P = .33), heart failure (P = .82), or the composite of death or heart failure (P>.99). In the analyses from days 0 to 3 (Figure 2), the risks of death and the composite of death or heart failure were higher in the GIK group compared with the control group, with 712 deaths (6.2%) in the GIK group and 632 deaths (5.5%) in the control group (HR, 1.13; 95% CI, 1.02-1.26; P = .03); and 1509 death or heart failure events in the GIK group (15.8%) and 1388 events in the control group (14.5%) (HR, 1.09; 95% CI, 1.02-1.18; P = .02). There was a consistent but nonstatistically significant increase in heart failure in the GIK group (1233 events or 12.9%) compared with the control group (1153 events or 12.0%) at 3 days (HR, 1.08; 95% CI, 0.99-1.17; P = .07).

Figure 2. Early (Days 0-3) and Late (Days 4-30) Outcomes Associated With Treatment Allocation in the Combined Populations in the OASIS-6 and CREATE-ECLA GIK Trials
Graphic Jump Location

The analyses for heart failure and for the composite of death or heart failure exclude 3798 patients from the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation–Estudios Clinicos Latino America (CREATE-ECLA) in whom data on time to heart failure were not collected. The size of the data markers indicates the relative differences in the number of patients in the denominators for each of the 9 analyses. Error bars indicate 95% confidence intervals (CIs). GIK indicates infusion of glucose-insulin-potassium; OASIS-6, Organization for the Assessment of Strategies for Ischemic Syndromes-6.

aThe number of events from 0 to 3 days and 4 to 30 days do not total the number of events from 0 to 30 days because data on time to heart failure were not available in some patients.

Table Graphic Jump LocationTable 3. 30-Day Outcomes in the Combined OASIS-6 and CREATE-ECLA GIK Trials

From days 4 to 30 (Figure 2), GIK infusion was associated with a statistically significantly lower occurrence of heart failure (2.4% vs 3.1%; HR, 0.78 [95% CI, 0.65-0.94]; P = .10) and the composite outcome of death or heart failure (4.1% vs 5.0%; HR, 0.81 [95% CI, 0.70-0.93]; P = .004), as well as a nonstatistically significantly lower rate of death (3.7% vs 4.0%; HR, 0.91 [95% CI, 0.80-1.05]; P = .20).

The mean (SD) serum glucose level was 162 (85) mg/dL at randomization in both groups. Mean (SD) glucose levels were higher in the GIK infusion group compared with the control group at both 6 hours (186 [103] vs 148 [70] mg/dL) and at 24 hours (153 [79] vs 135 [63] mg/dL), respectively. The mean (SD) baseline serum potassium concentration was 4.0 (0.6) mEq/L in both groups. Potassium concentrations were higher in the GIK infusion group compared with control group at both 6 hours (4.2 [0.6] vs 4.1 [0.6] mEq/L) and 24 hours (4.4 [0.7] vs 4.0 [0.6] mEq/L), respectively. In the GIK infusion group, the median total fluid input was 3000 mL, median urine output was 1850 mL, and the median net fluid gain was 950 mL. In the control group, the median fluid input was 1700 mL, median output was 1300 mL, and the median net fluid gain was 400 mL.

After adjusting for confounders (including GIK infusion allocation), glucose, potassium, and fluid balance all independently predicted death at 3 days, and glucose and potassium predicted the combined outcome of death or heart failure at 3 days (Table 4). Even though GIK therapy caused a greater 3-day death rate than control (HR, 1.13 [95% CI, 1.02-1.26]; P = .03), GIK infusion allocation was no longer a predictor of 3-day death after adjusting separately for glucose (adjusted P = .86), potassium (adjusted P = .15), and fluid balance (adjusted P = .47).

Table Graphic Jump LocationTable 4. Rates of Death and Composite of Death or Heart Failure at 3 Days

In subgroup analyses for 30-day mortality (the primary outcome of the individual CREATE-ECLA and OASIS-6 GIK trials), GIK therapy provided no benefit in any stratum of time from symptom onset to randomization (Table 5), including in the 9388 patients randomized within 4 hours (HR, 1.08; 95% CI, 0.94-1.24). In analyses of 8 other end points (death at 3 days and 180 days; heart failure at 3, 30, and 180 days; and the combination of death or heart failure at 3, 30, and 180 days), a similar lack of effect of GIK therapy was observed for all time-to-randomization subgroups (data available from authors on request).

Table Graphic Jump LocationTable 5. Effect of Glucose-Insulin-Potassium (GIK) vs Control on Death at 30 Days From Symptom Onset to Randomizationa

Despite its early termination, the OASIS-6 GIK trial still represents the second-largest GIK trial in patients with acute STEMI published to date, and suggests that GIK therapy has no net clinical effect through 6 months. The combined OASIS-6 and CREATE-ECLA trial analysis of almost 23 000 patients with STEMI (the largest global experience with GIK therapy) demonstrates that GIK infusion has no effect on any important clinical end point through 30 days following STEMI.

However, contrary to our prespecified hypothesis, we observed a higher rate of death and the composite of death or heart failure at 3 days in patients allocated to GIK therapy compared with control. Between 4 and 30 days, there were lower rates of death and the composite of death or heart failure in the GIK infusion group than in the control group, and the overall effect of GIK therapy on 30-day outcomes was neutral. It is possible that despite its early harmful effects, GIK therapy may have delayed benefits that neutralize its early hazard, but a more likely explanation for the observed “late benefit” is postrandomization (survivor) bias.

Patients receiving GIK therapy had higher levels of postrandomization glucose, potassium, and fluid balance than in the control group. Even though GIK infusion had a harmful effect at 3 days, GIK infusion allocation was no longer prognostic of 3-day events after adjusting separately for glucose, potassium, and fluid balance. Moreover, in models adjusted for GIK infusion allocation and other confounders, increasing levels of each of the 3 covariates remained significant predictors of worse outcomes. Therefore, the early harmful effects of GIK therapy largely may be explained by its propensity to increase glucose, potassium, and net fluid gain.

In the combined analysis of almost 23 000 patients, GIK infusion had no effect compared with control on clinical outcomes. Even in subgroup analyses among patients who were randomized within 2 hours (>2800 patients) or within 4 hours (>9300 patients) of symptom onset, there was no reduction in mortality with GIK therapy. Although this subgroup analysis of more than 9300 patients may be underpowered, it is likely that either there is no benefit from early administration of GIK infusion, or there is at best a small effect of no greater than a 6% relative risk reduction (considering the 95% CI of 0.94-1.24 in the stratum randomized within 4 hours).

There are limitations. The OASIS-6 GIK trial was terminated early and therefore lacked power to detect actual differences in 6-month outcomes after GIK infusion. The analyses by strata of postrandomization glucose, potassium, and fluid balance were not prespecified; therefore, these post hoc analyses that suggest an increased mortality related to elevated glucose, potassium, and net fluid gain do not imply that lowering these factors will reduce mortality.

In conclusion, the combined OASIS-6 and CREATE-ECLA trials have demonstrated that GIK infusion does not produce a favorable clinical effect in patients with STEMI. Moreover, GIK therapy appears to initially increase the rate of death postinfarction, and this may be due to its propensity to increase glucose and potassium levels and net fluid gain. Early administration of GIK therapy (within 4 hours) after symptom onset does not appear to have benefit compared with later initiation of GIK therapy. Avoidance of infusion-related hyperglycemia, hyperkalemia, and net fluid gain may be advisable in future studies of metabolic modulation in patients with STEMI.

Corresponding Author: Abhinav Goyal, MD, MHS, Emory Rollins School of Public Health, 1518 Clifton Rd NE, Room 456, Atlanta, GA 30322 (agoyal4@sph.emory.edu).

Author Contributions: Drs Díaz, Goyal, and Yusuf had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Díaz and Goyal contributed equally and are joint first authors.

Study concept and design: Díaz, Goyal, Mehta, Xavier, Pais, Zhu, Liu, Budaj, Yusuf.

Acquisition of data: Díaz, Mehta, Xavier, Pais, Chrolavicius, Zhu, Kazmi, Liu, Budaj, Zubaid, Avezum, Ruda.

Analysis and interpretation of data: Díaz, Goyal, Mehta, Afzal, Yusuf.

Drafting of the manuscript: Díaz, Goyal, Afzal, Yusuf.

Critical revision of the manuscript for important intellectual content: Mehta, Xavier, Pais, Chrolavicius, Zhu, Kazmi, Liu, Budaj, Zubaid, Avezum, Ruda, Yusuf.

Statistical analysis: Goyal, Afzal.

Obtained funding: Díaz, Mehta, Yusuf.

Administrative, technical, or material support: Mehta, Xavier, Pais, Chrolavicius, Zhu, Kazmi, Liu, Budaj, Zubaid, Avezum, Ruda.

Study supervision: Díaz, Mehta, Xavier, Pais, Chrolavicius, Zhu, Kazmi, Liu, Budaj, Zubaid, Avezum, Ruda, Yusuf.

Financial Disclosures: Dr Mehta reported serving as a consultant for and on the speaker's bureau of Sanofi-Aventis and GlaxoSmithKline. Dr Budaj reported serving on the advisory board for and receiving honoraria for lectures from Sanofi-Aventis and GlaxoSmithKline. Dr Yusuf reported receiving honoraria for lectures, serving as a consultant for, and receiving research grants from Sanofi-Aventis and GlaxoSmithKline. No other authors reported financial disclosures.

Funding/Support: The OASIS-6 trial was jointly funded by Sanofi-Aventis, Organon, and GlaxoSmithKline.

Role of the Sponsor: The sponsors of the OASIS-6 trial had no role in the statistical analysis or data interpretation of the study, or in the preparation, review, or approval of the manuscript. Both trials were conducted independently by their respective steering committees and the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario. No direct compensation was received by these individuals.

Operations Committee of the OASIS-6 GIK Trial: S. Yusuf (principal investigator and chairman), S. R. Mehta (project director), J. P. Bassand, A. Budaj, S. Chrolavicius (project manager), K. A. A. Fox (co-chairman), C. B. Granger, C. Joyner, R. J. G. Peters, L. Wallentin.

Steering Committee of the OASIS-6 GIK Trial: A. Avezum, W. Boden, E. Cardona-Muñoz, L. Ceremuzynski, J. Col, P. J. Commerford, R. Diaz, D. Faxon, M. Flather, G. Fodor, M-G. Franzosi, C. Granger, D. Halon, D. Hunt, N. Karatzas, M. Keltai, M. Kenda, J-H. Kim, F. Lanas, C. P. Lau, B. Lewis, L. Lisheng, J. Morais, T. Moccetti, E. Paolasso, A. Parkhomenko, B. Petrauskiene, L. Piegas, T. Pipilis, D. Robaayah, M. Ruda, Z. Rumboldt, H-J. Rupprecht, E. Sitkei, P. G. Steg, E. Swahn, P. Theroux, V. Valentin, J. Varigos, J. Weitz, H. White, P. Widimsky, D. Xavier, J. Zhu, and members of the Operations Committee.

Adjudication Committee of the OASIS-6 GIK Trial: C. Joyner (committee chair), S. Ameriso, E. Anev, A. Avezum, E. C. Bonilla, E. Cardona-Muñoz, Y. K. Chan, W-H. Chen, E. A. Cohen, P. J. Commerford, Y. Cottin, A. Czepiel, H. De Raedt, R. Diaz, J. Eikelboom, G. Fodor, E. Gardinale, P. Gregor, M. Heras, D. Hunt, O. Irkin, S. S. Iyengar, P. Kalvach, N. Karatzas, M. Keltai, A. Komarov, C. P. Lau, E. Lundstrom, I. Lusic, Y. Lutay, A. P. Maggioni, A. Massaro, B. M. Mayosi, J. Morais, J. Narendra, E. Paolasso, A. Parkhomenko, A. Peeters, M. Penicka, A. Perakis, B. Petrauskiene, L. Piegas, S. Polic, S. Radhakrishnan, J. Renkin, Z. Rumboldt, E. Sitkei, I. Staikov, P. G. Steg, B. Stockins, K. Thygesen, V. Valentin, W. Wasek, P. Widimsky, Y. Yotov, J. Zaborski, J. Zhu.

Project Office: B. Meeks, J. Willcox, C. Horsman (coordinators), R. Afzal, J. Pogue (statisticians), N. Barr, S. Boccalon, B. Cracknell, K. Chrysler, A. Djuric, C. Easton, T. Gracie, T. Hoskin, B. Jedrzejowski, J. Johnson, M. Lawrence, R. Napoleoni, M. Smiley, C. Stevens.

Medical Help Line: S. Connolly, C. Demers, P. J. Devereaux, J. Healey, E. Lonn, P. Magloire, R. McKelvie, C. Morillo, M. Natarajan, M. Rokoss, K. Teo, N. Valettas, J. Velianou.

Data and Safety Monitoring Board: P. Sleight (chairman), J. L. Anderson, D. E. Johnstone, J. Hirsh, D. deMets, D. R. Holmes Jr.

Investigators Enrolling at Least 5 Patients in the OASIS-6 GIK Trial:Argentina (179 enrolled): A. Ahuad Guerrero, J. P. Albisu, J. J. Bluguermann, A. Caccavo, L. Cartasegna, R. Castellanos, C. Cuneo, E. G. Hasbani, M. Hominal, R. Kevorkian, H. L. Luciardi, E. M. Marzetti, R. Nordaby, A. Orlandini, M. Osvaldo, H. Ramos. Australia (49 enrolled): F. Nelson, J. Waites, R. Ziffer. Belgium (79 enrolled): J. Col, C. Convens, P. Coussement, D. El Allaf, R. Popeye, M. Vrolix. Brazil (286 enrolled): J. A. Abrantes, D. Campos de Albuquerque, A. C. C. Carvalho, M. Coutinho, R. D’Aurea Mora Jr, L. R. de Ataide Castro, O. Dutra, M. Esteves Hernandez, E. R. Fernandez Manenti, G. V. Greque, C. Gun, J. F. Kerr Saraiva, C. Polanczyk, A. Rabelo Jr, R. F. Ramos, P. R. F. Rossi, M. Silveira Teixeira. Bulgaria (89 enrolled): B. Chompalova, V. Hergeldjieva, A. Penev, I. Perchev, A. L. Popov, D. Raev G. Todorov, M. Tzekova. Canada (17 enrolled): S. Brons, J. Webb. Chile (35 enrolled): P. Castro, C. Conejeros, F. Lanas. Croatia (46 enrolled): M. Bergovec, M. Padovan, S. Polić. Czech Republic (199 enrolled): M. Branny, P. Červinka, A. Herman, F. Holm, P. Jansky, P. Jelínek, R. Jirmar, P. Kala, R. Stipal, M. Zelizko. Estonia (33 enrolled): Y. Soopõld. France (29 enrolled): B. Charbonnier, P. Legalery. Germany (29 enrolled): T. M. Muenzel. India (181 enrolled): C. Asokan Nambiar, A. Bharani, N. Chidambaran, V. Dayasagar Rao, J. Joseph, P. G. Kerbar, P. Kumar, S. Kumar Trivedi, A. Mathur, P. P. Mohanan, J. Narenda, R. B. Panwar, K. H. Parikh, K. Pradeep Kumar, P. Rajendra Kumar, P. Ramesh Babu, S. Sanghvi, S. Thanikachalam, R. K. Tongia. Italy (31 enrolled): M. Lettino, G. Marenzi. Latvia (12 enrolled): A. Erglis, J. Verbovenko. Lithuania (16 enrolled): B. Petrauskiene, R. Zaliunas. Mexico (44 enrolled): E. Cardona-Munoz, R. Gonzalez-Garcia, H. Hernandez-Garcia, E. Uruchurtu-Chavarin. Netherlands (90 enrolled): A. E. R. Arnold, J. P. R. Herrman, H. Suryapranata, M. W. J. van Hessen. New Zealand (54 enrolled): G. P. Devlin, H. Hart, M. Williams. Poland (230 enrolled): P. Achremczyk, P. Buszman, M. Dalkowski, H. Halaczkiewicz, A. Kleinrok, W. Krasowski, Z. Miastkowski, F. Monies, W. Pluta, T. Siminiak, R. Szelemej, M. Szpajer, M. Trusz-Gluza, A. Wester, J. Wodniecki. Romania (35 enrolled): P. Ionescu, C. Olariu. Russia (491 enrolled): G. Aroutiounov, O. Azarin, Y. Belousov, I. N. Bokarev, S. Bondarev, M. V. Boyarkin, R. Charchoglian, P. Y. Dovgalevsky, L. Egorova, B. M. Goloshchekin, A. Gruzdev, V. T. Ivashkin, Y. B. Karpov, O. A. Khrusalev, V. A. Lusov, V. A. Markov, V. Mkrtchian, V. Moiseev, Y. U. Nikitin, A. Panov, S. Schalaev, Y. S. Titkov, E. Vasilieva, A. Vishnevsky, V. Zadionchenko, D. Zateyshchikov, E. Zemtsovky. Slovakia (13 enrolled): P. Poliacik. Slovenia (19 enrolled): Z. Pehnec, G. Voga. South Africa (61 enrolled): H. du Toit Theron, J. M. Engelbrecht, G. Meintjies, M. Ntsekhe, M. Pretorius. Spain (186 enrolled): J. L. Carpintero Avellaneda, R. Coma Samartin, A. del Castillo, M. Fiol Sala, M. Heras, V. López García-Aranda, C. Macaya, R. Porcar, A. Rodriguez Llorian. Sweden (36 enrolled): M. Lycksell, J. Oldgren, A. Stjerna, E. Swahn. Switzerland (17 enrolled): T. Moccetti, M. Pieper. Ukraine (94 enrolled): O. I. Karpenko, Y. M. Kolchin, L. Kononenko, O. Kova, I. Kovalsky, A. V. Lehkonogov, Y. V. Malinovky, V. Netiazhenko, A. Parkhomenko, V. Tseluyko, N. T. Vatutin. United Kingdom (29 enrolled): P. J. Keeling. United States (6 enrolled): E. Rivera.

Previous Presentation: The primary results of the CREATE-ECLA GIK trial and the fondaparinux factorial of the OASIS-6 trial have been previously published in JAMA.5,6 However, all data in this manuscript are original and have not been previously published.

Additional Contributions: We are grateful to the patients for agreeing to participate in the trials, and to Judy Lindeman, BA (Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario), for secretarial assistance. Ms Lindeman did not receive any additional compensation for her work on the manuscript.

Maroko PR, Libby P, Sobel BE.  et al.  Effect of glucose-insulin-potassium infusion on myocardial infarction following experimental coronary artery occlusion.  Circulation. 1972;45(6):1160-1175
PubMed   |  Link to Article
Opie LH, Bruyneel K, Owen P. Effects of glucose, insulin and potassium infusion on tissue metabolic changes within first hour of myocardial infarction in the baboon.  Circulation. 1975;52(1):49-57
PubMed   |  Link to Article
Dalby AJ, Bricknell OL, Opie LH. Effect of glucose-insulin-potassium infusions on epicardial ECG changes and on myocardial metabolic changes after coronary artery ligation in dogs.  Cardiovasc Res. 1981;15(10):588-598
PubMed   |  Link to Article
Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials.  Circulation. 1997;96(4):1152-1156
PubMed   |  Link to Article
Mehta SR, Yusuf S, Díaz R.  et al. CREATE-ECLA Trial Group Investigators.  Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial.  JAMA. 2005;293(4):437-446
PubMed   |  Link to Article
Yusuf S, Mehta SR, Chrolavicius S.  et al. OASIS-6 Trial Group.  Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial.  JAMA. 2006;295(13):1519-1530
PubMed   |  Link to Article
Yusuf S, Mehta SR, Xie C.  et al. CREATE Trial Group Investigators.  Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation.  JAMA. 2005;293(4):427-435
PubMed   |  Link to Article
Yusuf S, Mehta SR, Diaz R.  et al.  Challenges in the conduct of large simple trials of important generic questions in resource-poor settings: the CREATE and ECLA trial program evaluating GIK (glucose, insulin and potassium) and low-molecular-weight heparin in acute myocardial infarction.  Am Heart J. 2004;148(6):1068-1078
PubMed   |  Link to Article
Rackley CE, Russell RO Jr, Rogers WJ, Mantle JA, McDaniel HG, Papapietro SE. Clinical experience with glucose-insulin-potassium therapy in acute myocardial infarction.  Am Heart J. 1981;102(6 pt 1):1038-1049
PubMed   |  Link to Article
Whitlow PL, Rogers WJ, Smith LR.  et al.  Enhancement of left ventricular function by glucose-insulin-potassium infusion in acute myocardial infarction.  Am J Cardiol. 1982;49(4):811-820
PubMed   |  Link to Article
Rogers WJ, Stanley AW Jr, Breinig JB.  et al.  Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion.  Am Heart J. 1976;92(4):441-454
PubMed   |  Link to Article
Rogers WJ, Segall PH, McDaniel HG.  et al.  Prospective randomized trial of glucose-insulin-potassium in acute myocardial infarction: effects on myocardial hemodynamics, substrates and rhythm.  Am J Cardiol. 1979;43(4):801-809
PubMed   |  Link to Article
IMMEDIATE Trial.  Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care Trial. http://www.clinicaltrials.gov/ct/show/NCT00091507?order=6. Accessed September 28, 2007

Figures

Figure 1. Flow Diagram for the Glucose-Insulin-Potassium (GIK) Component of the OASIS-6 Trial
Graphic Jump Location

OASIS-6 indicates Organization for the Assessment of Strategies for Ischemic Syndromes-6.

Figure 2. Early (Days 0-3) and Late (Days 4-30) Outcomes Associated With Treatment Allocation in the Combined Populations in the OASIS-6 and CREATE-ECLA GIK Trials
Graphic Jump Location

The analyses for heart failure and for the composite of death or heart failure exclude 3798 patients from the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation–Estudios Clinicos Latino America (CREATE-ECLA) in whom data on time to heart failure were not collected. The size of the data markers indicates the relative differences in the number of patients in the denominators for each of the 9 analyses. Error bars indicate 95% confidence intervals (CIs). GIK indicates infusion of glucose-insulin-potassium; OASIS-6, Organization for the Assessment of Strategies for Ischemic Syndromes-6.

aThe number of events from 0 to 3 days and 4 to 30 days do not total the number of events from 0 to 30 days because data on time to heart failure were not available in some patients.

Tables

Table Graphic Jump LocationTable 2. Clinical Outcomes in the OASIS-6 GIK Trial at 30 Days and at 6 Months
Table Graphic Jump LocationTable 3. 30-Day Outcomes in the Combined OASIS-6 and CREATE-ECLA GIK Trials
Table Graphic Jump LocationTable 4. Rates of Death and Composite of Death or Heart Failure at 3 Days
Table Graphic Jump LocationTable 5. Effect of Glucose-Insulin-Potassium (GIK) vs Control on Death at 30 Days From Symptom Onset to Randomizationa

References

Maroko PR, Libby P, Sobel BE.  et al.  Effect of glucose-insulin-potassium infusion on myocardial infarction following experimental coronary artery occlusion.  Circulation. 1972;45(6):1160-1175
PubMed   |  Link to Article
Opie LH, Bruyneel K, Owen P. Effects of glucose, insulin and potassium infusion on tissue metabolic changes within first hour of myocardial infarction in the baboon.  Circulation. 1975;52(1):49-57
PubMed   |  Link to Article
Dalby AJ, Bricknell OL, Opie LH. Effect of glucose-insulin-potassium infusions on epicardial ECG changes and on myocardial metabolic changes after coronary artery ligation in dogs.  Cardiovasc Res. 1981;15(10):588-598
PubMed   |  Link to Article
Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials.  Circulation. 1997;96(4):1152-1156
PubMed   |  Link to Article
Mehta SR, Yusuf S, Díaz R.  et al. CREATE-ECLA Trial Group Investigators.  Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial.  JAMA. 2005;293(4):437-446
PubMed   |  Link to Article
Yusuf S, Mehta SR, Chrolavicius S.  et al. OASIS-6 Trial Group.  Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial.  JAMA. 2006;295(13):1519-1530
PubMed   |  Link to Article
Yusuf S, Mehta SR, Xie C.  et al. CREATE Trial Group Investigators.  Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation.  JAMA. 2005;293(4):427-435
PubMed   |  Link to Article
Yusuf S, Mehta SR, Diaz R.  et al.  Challenges in the conduct of large simple trials of important generic questions in resource-poor settings: the CREATE and ECLA trial program evaluating GIK (glucose, insulin and potassium) and low-molecular-weight heparin in acute myocardial infarction.  Am Heart J. 2004;148(6):1068-1078
PubMed   |  Link to Article
Rackley CE, Russell RO Jr, Rogers WJ, Mantle JA, McDaniel HG, Papapietro SE. Clinical experience with glucose-insulin-potassium therapy in acute myocardial infarction.  Am Heart J. 1981;102(6 pt 1):1038-1049
PubMed   |  Link to Article
Whitlow PL, Rogers WJ, Smith LR.  et al.  Enhancement of left ventricular function by glucose-insulin-potassium infusion in acute myocardial infarction.  Am J Cardiol. 1982;49(4):811-820
PubMed   |  Link to Article
Rogers WJ, Stanley AW Jr, Breinig JB.  et al.  Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion.  Am Heart J. 1976;92(4):441-454
PubMed   |  Link to Article
Rogers WJ, Segall PH, McDaniel HG.  et al.  Prospective randomized trial of glucose-insulin-potassium in acute myocardial infarction: effects on myocardial hemodynamics, substrates and rhythm.  Am J Cardiol. 1979;43(4):801-809
PubMed   |  Link to Article
IMMEDIATE Trial.  Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care Trial. http://www.clinicaltrials.gov/ct/show/NCT00091507?order=6. Accessed September 28, 2007

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