For death, hazard ratio (HR), 1.03 (95% confidence interval [CI], 0.95-1.13); P = .45. For death or nonfatal cardiac arrest, HR, 1.01 (95%
CI, 0.93-1.10); P = .73. GIK indicates glucose-insulin-potassium.
The solid black squares indicating hazard ratios are sized proportionally
to the number of patients in each group.
The CREATE-ECLA Trial Group Investigators* . Effect of Glucose-Insulin-Potassium Infusion on Mortality in Patients With Acute ST-Segment Elevation Myocardial InfarctionThe CREATE-ECLA Randomized Controlled Trial. JAMA. 2005;293(4):437-446. doi:10.1001/jama.293.4.437
*Authors/Writing Committee:Shamir R.MehtaMD, MSc, FRCPC, Department of Medicine, McMaster University, and Population Health Research
Institute, Hamilton Health Sciences, Hamilton, Ontario;
Department of Medicine, McMaster University, and Population Health Research
Institute, Hamilton Health Sciences;
Estudios Cardiologica Latin America, Rosario, Argentina;
Cardiovascular Institute and Fu Wai Hospital, Chinese Hypertension League Institute, Beijing, China;
St John’s Medical College National Academy of Health Sciences, Bangalore,
St John’s Medical College National Academy
of Health Sciences;
Estudios Cardiologica Latin America;
Department of Medicine, McMaster University, and Population Health Research
Institute, Hamilton Health Sciences;
Department of Medicine, McMaster University, and Population Health Research Institute, Hamilton Health
Aga Khan University, Karachi, Pakistan;
Estudios Cardiologica Latin America;
Department of Medicine, McMaster University, and Population Health Research Institute, Hamilton Health Sciences;
Cardiovascular Institute and Fu Wai Hospital, Chinese Hypertension League Institute.
Context Glucose-insulin-potassium (GIK) infusion is a widely applicable, low-cost
therapy that has been postulated to improve mortality in patients with acute
ST-segment elevation myocardial infarction (STEMI). Given the potential global
importance of GIK infusion, a large, adequately powered randomized trial is
required to determine the effect of GIK on mortality in patients with STEMI.
Objective To determine the effect of high-dose GIK infusion on mortality in patients
Design, Setting, and Participants Randomized controlled trial conducted in 470 centers worldwide among
20 201 patients with STEMI who presented within 12 hours of symptom onset.
The mean age of patients was 58.6 years, and evidence-based therapies were
Intervention Patients were randomly assigned to receive GIK intravenous infusion
for 24 hours plus usual care (n = 10 091) or to receive usual
care alone (controls; n = 10 110).
Main Outcome Measures Mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30
days after randomization.
Results At 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients
(10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95-1.13; P = .45). There were no significant differences
in the rates of cardiac arrest (1.5% [151/10 107] in control and 1.4%
[139/10 088] in GIK infusion; HR, 0.93; 95% CI, 0.74-1.17; P = .51), cardiogenic shock (6.3% [640/10 107] vs 6.6%
[667/10 088]; HR, 1.05; 95% CI, 0.94-1.17; P = .38),
or reinfarction (2.4% [246/10 107] vs 2.3% [236/10 088]; HR, 0.98;
95% CI, 0.82-1.17; P = .81). The rates
of heart failure at 7 days after randomization were also similar between the
groups (16.9% [1711/10 107] vs 17.1% [1721/10 088]; HR, 1.01; 95%
CI, 0.95-1.08; P = .72). The lack of benefit
of GIK infusion on mortality was consistent in prespecified subgroups, including
in those with and without diabetes, in those presenting with and without heart
failure, in those presenting early and later after symptom onset, and in those
receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous
Conclusion In this large, international randomized trial, high-dose GIK infusion
had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in
patients with acute STEMI.
The concept of metabolic modulation of acute myocardial infarction (AMI)
with glucose-insulin-potassium (GIK) infusion was originally proposed in the
1960s.1 This infusion is a simple, low-cost,
and widely practicable therapy. If effective, it has the potential to widely
affect mortality due to AMI in all regions of the world, including those of
both lower and higher income.
Glucose-insulin-potassium infusion may reduce mortality through several
different mechanisms.2 Exogenous insulin suppresses
circulating levels and myocardial uptake of free fatty acids, which are toxic
to the ischemic myocardium.3- 5 Provision
of high-dose glucose can improve the efficiency of myocardial energy production
during acute ischemia by becoming the preferred fuel for the heart.2,6 Because intracellular levels of potassium
are depleted during ischemia, provision of exogenous potassium increases levels
within the myocyte, thereby raising the threshold for ventricular arrhythmias.7,8
A meta-analysis of 16 trials of GIK infusion vs control involving almost
5000 patients indicated a reduction in mortality risk with GIK infusion therapy
of 18%, with wide confidence intervals (CIs) (hazard ratio [HR], 0.82; 95%
CI, 0.68-0.98; P = .03).9 The
benefit appeared to be larger in trials that tested a high-dose GIK infusion
regimen (HR, 0.70; 95% CI, 0.51-0.95; P = .02).9
Although these data are promising, given the variability and limitations
in the design of the various trials included and the wide CIs of the estimates
of benefit, a large and well-designed randomized trial is needed to reliably
assess the effects of high-dose GIK infusion on mortality in patients with
AMI. The CREATE-ECLA program was born from the common goal of several international
investigators interested in answering the question of whether this promising,
low-cost, and widely applicable therapy is beneficial in patients presenting
CREATE-ECLA was a randomized trial with a partial 2 × 2
factorial design evaluating the effects of a 24-hour infusion of high-dose
GIK and 7 days of treatment with the low-molecular-weight heparin reviparin
in patients with acute ST-segment elevation MI (STEMI). Details of the trial
design have been published previously.9 The
results of the comparison of reviparin with placebo are reported separately.10 All 470 centers worldwide obtained local ethics committee
approval; in addition, the Population Health Research Institute Project Office
obtained approval from the shared institutional review board of McMaster University
and Hamilton Health Sciences, Hamilton, Ontario.
Following written or witnessed oral informed consent, patients presenting
with AMI with ST-segment elevation or new left bundle-branch block within
12 hours of symptom onset were randomly assigned to receive, in addition to
usual care, either GIK infusion for 24 hours or usual care alone (control).
Individuals with contraindications for GIK infusion, including type 1 diabetics
and those with known renal impairment (creatinine >2 mg/dL [>176.8 μmol/L])
or known hyperkalemia at randomization were excluded. To meet the reviparin/placebo
eligibility criteria, patients in India and China were further excluded if
they had active bleeding or were at high risk of bleeding or had recent major
surgery or trauma within 2 weeks, systolic blood pressure of 180 mm Hg or
more, severe anemia, hemorrhagic stroke within 12 months, oral anticoagulant
therapy, heparin-induced thrombocytopenia, pregnancy, or other conditions
limiting life expectancy to less than 1 month. Patients with anticipated poor
compliance with randomized treatments and any factor that jeopardized 30-day
follow-up (eg, no fixed address, long distance to hospital) were excluded.
The study infusion was prepared locally and consisted of 25% glucose,
50 U/L of regular insulin, and 80 mEq/L of potassium to be infused at a rate
of 1.5 mL/kg per hour for 24 hours. The GIK infusion was initiated immediately
after randomization. For patients undergoing primary percutaneous coronary
intervention (PCI), it was recommended that the infusion be started before
the procedure and continued for 24 hours. For patients receiving thrombolytic
therapy, the infusion was started as soon as possible after randomization.
Serum glucose, potassium, and sodium levels were measured at baseline and
6 and 24 hours after randomization. Adjustments to GIK infusion rate for Killip
class and blood potassium level were made according to a standard nomogram
similar to that used in the ECLA pilot trial.11 The
fluid balance during the 24 hours of treatment was carefully monitored in
The Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial
Infarction Treatment Evaluation (CREATE) began enrollment in July 2001 as
a 2 × 2 factorial randomized trial of reviparin vs placebo
and GIK infusion vs control in China and India. A separate trial of GIK infusion
vs control (Estudios Cardiologicas Latin America Study Group [ECLA] 2 GIK
Full Scale Trial) using an identical GIK regimen in patients similar to that
in CREATE had begun enrolling patients in August 1998. Both studies were formally
merged into 1 trial, called the CREATE-ECLA International GIK Study, on November
14, 2002, with a single steering and operations committee and a single data
and safety monitoring board. The rationale for combining the 2 studies into
1 large trial was to optimize study power to reliably detect or exclude even
a moderate benefit of treatment. The study was extended to include Pakistan
in October 2003. The design of the overall CREATE-ECLA program therefore used
a partial 2 × 2 factorial design, with one randomization to
GIK infusion or control (all patients) and a second randomization to double-blind
therapy with reviparin or matching placebo (in India and China).
The Population Health Research Institute (PHRI), McMaster University
and Hamilton Health Sciences, coordinated the overall trial. Regional coordination
occurred through national coordinating offices. Data for ECLA were coordinated
at the ECLA coordinating center in Rosario, Argentina; for China at the Beijing
Hypertension League Institute, Beijing; for India at St John’s National
Academy of Health Sciences, Bangalore; and for Pakistan at Aga Khan University
Hospital, Karachi. An international steering committee, consisting of national
coordinators and members of the PHRI, oversaw the conduct of the study. An
independent data and safety monitoring board periodically reviewed safety
and efficacy data. An event adjudication committee performed adjudication
of reinfarction, stroke, life-threatening/major bleeding, and recurrent ischemia
with electrocardiographic changes in all regions except for ECLA countries.
The national coordinating offices in India, China, and Pakistan established
a streamlined monitoring program regionally, with each site having at least
1 monitoring visit to check key source data, informed consent, and protocol
adherence. The regional coordinating centers entered the data into an Internet-based
database that was connected online to the PHRI, McMaster University and Hamilton
Health Sciences. Extensive consistency and edit checks at the national coordinating
offices as well as at the PHRI ensured high data quality.
Patients returned to the hospital at 30 days or shortly thereafter for
a prearranged follow-up clinic appointment with study personnel. A list of
patients with overdue 30-day follow-up forms was regularly compiled and mailed
to centers using the Internet database. Patients, close family relatives,
neighbors, or the patients’ physicians were contacted by telephone or
mail in the event of a missed follow-up appointment, inability to attend clinic,
Randomization to GIK infusion or control was grouped in blocks, with
the block size kept confidential and the randomization list stratified by
center. All patients in ECLA countries, China, and Pakistan were randomized
by telephone to the national coordinating offices in Rosario, Argentina; Beijing,
China; or Karachi, Pakistan. In India, patients were initially randomized
using sealed opaque envelopes (n = 5127), but subsequent patients
(n = 2933) had central telephone randomization. Despite extensive
precautions, randomization errors occurred in 173 of 15 570 patients
(1.1%). These patients were included in their originally intended allocations
The primary outcome measure was mortality from any cause at 30 days
after randomization. Secondary outcome measures included the composite of
death or nonfatal cardiac arrest, death or cardiogenic shock, death or reinfarction,
and each of these individually. Definitions of primary outcome measures have
been reported previously.9
With a mortality rate of 10% in the control group at 30 days, the study
had 99% power to detect a 20% relative risk reduction with GIK infusion, and
95% power to detect a 15% relative risk reduction.
All analyses were performed using the intention-to-treat approach. Time
to death up to 30 days between the GIK infusion and control groups was compared
using the log-rank statistic. After confirming the proportional hazards assumption,
the point estimate of the relative risk and its associated 95% CI were derived
from the Cox proportional hazards model. The primary comparisons between GIK
infusion and control were adjusted for randomization to reviparin or placebo.
Statistical significance was claimed at a computed (2-sided) P≤.05.
Predefined subgroup analyses included time from symptom onset to treatment
(<4, 4 to <8, and ≥8 hours), baseline reperfusion therapy (thrombolysis
or primary PCI) vs no reperfusion therapy, heart failure at presentation vs
no heart failure at presentation, and diabetes vs no diabetes. Tests for interaction
between GIK infusion and reviparin were not significant (P = .99 for mortality and P = .85
for death, MI, or stroke). All statistical analyses were carried out with
SAS software, version 8.2 (SAS Institute Inc, Cary, NC).
Overall, 20 201 patients were randomized; 8060 from India, 7510
from China, 3804 from ECLA centers, and 827 from Pakistan. Follow-up was 99.97%
complete at 7 days and 99.85% complete at 30 days (Figure 1). Only 30 (0.15%) of 20 201 patients randomized were
lost to follow-up. Six of these 30 patients (3 infusion and 3 control) had
no in-hospital or follow-up data collected, yielding a total data set of 20 195
patients for analysis. The median time from symptom onset to randomization
was 4.7 hours, with 8361 (41.4%) of patients randomized within 4 hours, 7661
(37.9%) between 4 and 8 hours, and 4073 (20.2%) between 8 and 12 hours.
Of patients allocated to GIK infusion in China, India, and Pakistan,
8020 (97.9%) received therapy. Nonstudy GIK was used in 152 (1.9%) control
patients randomized (ECLA did not collect these data). Study infusion was
started within 1 hour of randomization in more than 90% of patients (8882/9835).
The full 24-hour infusion was completed in 84.2% (8280/9835), with 92.2% (9069/9835)
receiving at least 10 hours of therapy.
Reperfusion therapy was given in 16 711 patients (82.7%); 14 957
(74.1%) patients received thrombolytic therapy and 1831 (9.1%) received primary
PCI (77 patients received both). Among patients receiving reperfusion therapy,
the median time from symptom onset to reperfusion (thrombolysis or primary
PCI) was 3.9 hours in the GIK infusion group and 3.8 hours in the control
Baseline patient characteristics were similar in the 2 groups (Table 1). The mean age was 58.6 years, with 1589
(7.9%) older than 75 years. A total of 3582 patients (17.7%) had diabetes
and 7494 (37.1%) had a known history of hypertension. Mean systolic blood
pressure was 129.0 mm Hg and mean diastolic blood pressure was 81.5 mm Hg.
The majority of patients (n = 17 096; 84.7%) presented as Killip
class I and 3091 (15.4%) presented as Killip class II, III, or IV.
Medications in the hospital were similar between the groups (Table 2). A total of 19 644 (97.3%) were
treated with aspirin, 9811 (48.6%) received clopidogrel or ticlopidine, 14 137
(70%) received β-blockers, and 14 522 (72.4%) received angiotensin-converting
enzyme inhibitors. A total of 11 102 (67.7%) received lipid-lowering
therapy in CREATE (data not recorded in ECLA). In CREATE, 766 (53.3%) of 1438
with type 2 diabetes in the control group and 720 (53.3%) of 1436 with type
2 diabetes in the GIK infusion group received supplemental nonstudy insulin
(data not recorded in ECLA). Overall, in CREATE, any nonstudy insulin was
used in 1325 control patients (16.1%) and any supplemental nonstudy insulin
was used in 1479 GIK infusion patients (18.1%).
At 30 days, a total of 976 control patients (9.7%) and 1004 GIK infusion
patients (10.0%) died within 30 days of randomization (HR, 1.03; 95% CI, 0.95-1.13; P = .45) (Table 3 and Figure 2A). Cardiac arrest
occurred in 151 control patients (1.5%) and in 139 GIK infusion patients (1.4%)
(HR, 0.93; 95% CI, 0.74-1.17; P = .51).
Cardiogenic shock developed in 640 control patients (6.3%) and 667 GIK infusion
patients (6.6%) (HR, 1.05; 95% CI, 0.94-1.17; P = .38).
There were no significant differences in the number of patients with the composite
of death or nonfatal cardiac arrest (Table 3 and Figure 2B). Similarly, there were no significant
differences in the composites of death or cardiogenic shock and death or reinfarction.
There were no significant differences between the groups in any of these outcomes
at 7 days (Table 3).
After the first day, 1.9% of control patients had recurrent ischemia
(with or without electrocardiographic changes) compared with 1.5% in the GIK
infusion group (absolute risk reduction, 0.4%; HR, 0.80; 95% CI, 0.65-1.00; P = .047). At 7 days, the absolute risk reduction
in recurrent ischemia widened (660 [6.5%] in the control group vs 560 [5.6%]
in the GIK infusion group; absolute risk reduction, 0.9%; HR, 0.85; 95% CI,
0.76-0.95; P = .004) and was maintained
at 30 days (784 [7.8%] in the control group vs 703 [7.0%] in the GIK infusion
group; absolute risk reduction, 0.8%; HR, 0.90; 95% CI, 0.81-0.99; P = .04).
There were no significant differences between the groups in the occurrence
of ventricular fibrillation/tachycardia (21.4% [2166/10 107] in the control
group vs 21.0% [2122/10 088] in the GIK infusion group; HR, 0.98; 95%
CI, 0.92-1.04; P = .53), advanced second-
or third-degree heart block (19.8% [2002/10 107] vs 19.9% [2010/10 088];
HR, 1.01; 95% CI, 0.95-1.07; P = .71) or
in electromechanical dissociation (0.5% [46/10 107] vs 0.4% [44/10 088];
HR, 0.96; 95% CI, 0.64-1.46; P = .86).
There was no difference between the groups in outcomes related to fluid
volume overload. A new episode of heart failure at 7 days after randomization
occurred in 1711 patients (16.9%) in the control group and 1721 (17.1%) in
the GIK infusion group (HR, 1.01; 95% CI, 0.95-1.08; P = .72)
(Table 4). At 30 days, the rates of
heart failure were 17.4% (1761/10 107) and 17.4% (1758/10 088) in
each group (HR, 1.00; 95% CI, 0.94-1.07; P = .88).
Symptomatic hypoglycemia was uncommon in CREATE but was more frequent in the
GIK infusion group (0.1% [11/8206] in the control group and 0.4% [34/8191]
in the GIK infusion group) (Table 4).
Hyperkalemia (>5.5 mEq/L) was also more frequent in the GIK infusion group
than in the control group (4.3% [431/10 088] in the GIK infusion group
vs 1.6% [161/10 107] in the control group; HR, 2.76; 95% CI, 2.30-3.31)
(Table 4). Further analysis of the subgroup
with hyperkalemia indicated more deaths at 30 days in the control group (38/161;
23.6%) compared with the GIK infusion group (62/431; 14.4%), suggesting that
the hyperkalemia associated with GIK use was not deleterious. Significant
phlebitis (at the site of infusion) was more frequent in the GIK infusion
group (339/10 088; 3.4%) compared with the control group (17/10 107;
The neutral effect of GIK on mortality was not significantly heterogenous
in any of the prespecified subgroup analyses (Figure 3). Consistent results were observed in those defined by
baseline glucose levels, Killip class, and time from symptom onset to randomization
(<4, 4 to <8, and ≥8 hours). Among patients presenting very early,
there was also no evidence of benefit with GIK infusion: within 1 hour, 21
of 288 controls vs 27 of 275 GIK infusion patients (HR, 1.36; 95% CI, 0.77-2.40);
between 1 and 2 hours, 78 of 1022 vs 82 of 954, respectively (HR, 1.14; 95%
CI, 0.83-1.55); and between 2 and 4 hours, 251 of 2908 vs 257 of 2895, respectively
(HR, 1.03; 95% CI, 0.87-1.23). Similarly, there was consistency of the neutrality
of GIK infusion in those receiving and not receiving baseline reperfusion
therapy (Figure 3). Although the point
estimate for mortality was lower in those who received primary PCI (57/906
in the control group vs 44/925 in the infusion group; HR, 0.75; 95% CI, 0.51-1.11)
compared with those who did not (919/9201 vs 960/9163, respectively; HR, 1.05;
95% CI, 0.96-1.15; P = .26), there was
no significant interaction with the overall result in this group of patients
In patients in whom GIK infusion was started before initiation of reperfusion
therapy, mortality was 12.2% (175/1437), and in patients in whom GIK infusion
was started after initiation of reperfusion therapy, mortality was 8.2% (569/6900).
Mortality in control patients who received reperfusion therapy was 8.7% (729/8368).
We noted no heterogeneity of treatment effect by region.
Mean glucose levels were 162 mg/dL (9.0 mmol/L) in the GIK infusion
and control groups at baseline. At 6 hours after randomization, the mean glucose
level in the GIK infusion group increased to 187 mg/dL (10.4 mmol/L); in the
control group it decreased to 148 mg/dL (8.2 mmol/L). By 24 hours after randomization,
the mean glucose level was 155 mg/dL (8.6 mmol/L) in the GIK infusion group
and 135 mg/dL (7.5 mmol/L) in the control group. When baseline glucose levels
in the control group were divided into tertiles, higher baseline glucose levels
were associated with higher mortality at 30 days (6.6% in the lowest tertile,
8.5% in the middle tertile, and 14.0% in the highest tertile).
Mean serum potassium concentration was 4.0 mEq/L in both groups at baseline.
At 6 and 24 hours after randomization, potassium concentration was higher
in the GIK infusion group (4.2 mEq/L and 4.4 mEq/L, respectively) compared
with the control group (4.1 mEq/L and 4.0 mEq/L, respectively). Serum sodium
levels were similar in the 2 groups.
In the GIK infusion group, a mean of 2941 mL of fluid was administered
and the urine output was 1923 mL, for a net fluid gain of 1018 mL. In the
control group, a mean of 1843 mL of fluid was administered and the urine output
was 1397 mL, for a net fluid gain of 446 mL. Therefore, the net difference
in fluid gain between the GIK infusion and control groups was 572 mL.
The CREATE-ECLA trial demonstrated that high-dose GIK solution given
for 24 hours in patients presenting with acute STEMI has a neutral effect
on mortality, cardiac arrest, and cardiogenic shock. The goal of our study
was to reliably assess the effects of high-dose GIK in preventing mortality
and major cardiovascular events in patients with STEMI. Given that there were
more than 1900 deaths in the study, it was well powered to detect even a moderate
effect on mortality. The lack of benefit on the secondary outcomes and the
narrow 95% CIs excluded even a 5% relative risk benefit of the infusion. The
very high adherence to the protocol and the excellent 30-day follow-up (99.85%)
provide confidence in the validity of our findings and suggest that it is
very unlikely that the current regimen of high-dose GIK is of any material
benefit in reducing mortality in patients with STEMI.
The lack of benefit with high-dose GIK in this trial involving more
than 20 000 patients differs from the meta-analyses of the much smaller
trials of GIK in AMI.9,12 The
phenomenon in which favorable results in small trials (or phase 2 studies)
or their meta-analyses are not confirmed when a definitive trial is performed
has been observed before.13- 18 The
apparent discrepancy between meta-analysis of small trials and a definitive
large trial may relate to publication bias involving smaller trials, for which
neutral studies are less likely to be published compared with similar studies
with favorable results. Furthermore, the integrity of any meta-analysis is
dependent on the quality of the studies on which it is based. Many of the
smaller trials of GIK in AMI had methodological flaws, such as postrandomization
exclusion of patients, improper randomization methods, inadequate concealment
of randomization allocation, and incomplete follow-up, which may have affected
the internal validity of these studies.9
Another problem with interpretation of previous trials is that overemphasis
of subgroups in studies with a small sample size is potentially misleading.19 Of the 3 most recent trials, performed within the
last decade, none was associated with a significant result in the primary
outcome measure based on an analysis of all randomized patients. The ECLA
pilot trial found a favorable trend with GIK therapy on mortality, but a significant
benefit was observed only in the subgroup receiving reperfusion therapy.11 The Polish trial was the largest previous trial of
GIK in AMI and found no benefit of a low-dose GIK regimen on cardiovascular
death.20 The Dutch Glucose-Insulin-Potassium
Study (GIPS) found no significant benefit of GIK therapy in AMI patients undergoing
primary PCI21 but observed an apparent benefit
in the subgroup presenting as Killip class I. The first DIGAMI (Diabetes Mellitus
Insulin-Glucose Infusion in Acute Myocardial Infarction) trial found a nonsignificant
favorable trend toward early reduction in mortality in patients with diabetes
given glucose-insulin infusion during the initial hospitalization.22 Only with longer-term aggressive glucose lowering
was there a significant reduction in mortality at 1 year.
The results of the CREATE-ECLA trial raise some important questions.
First, we found that higher baseline glucose concentrations were associated
with higher mortality, a finding observed previously.23 Although
patients with higher baseline glucose levels may differ from those with normal
glucose levels, the higher glucose concentration itself has been shown in
other studies to be associated independently with a poorer prognosis.23,24 In our study, we observed an increase
in serum glucose concentration in the GIK infusion group compared with the
control group at 6 and 24 hours after treatment, raising the possibility that
the higher serum glucose level in the GIK infusion group may have blunted
the potential benefits of insulin. It may be worthy of further study to assess
whether lowering serum glucose concentration with a modified regimen is associated
with improved outcomes, especially in those with elevated glucose at baseline,
as in the first DIGAMI study.
Second, would greater use of GIK in conjunction with reperfusion regimens,
such as primary PCI or fibrin-specific thrombolytic agents that achieve higher
early patency of the infarction-related artery, be associated with greater
benefit with GIK? We found no evidence of heterogeneity in the lack of benefit
of GIK infusion in the group of patients receiving thrombolytic therapy, nor
in the more than 1800 patients receiving primary PCI. Similarly, there was
a consistent lack of benefit of GIK in patients presenting very early (<1,
1-2, or >2-4 hours) after symptom onset. In addition, mortality was not lower
in patients in whom GIK infusion was started before initiation of reperfusion
therapy compared with those in whom it was started after initiation of reperfusion
therapy. Thus, it seems unlikely from our data that initiation of GIK infusion
very early after symptom onset, prior rather than shortly after initiation
of reperfusion therapy, or in conjunction with strategies that provide greater
infarction-related artery patency would provide any material benefit.
Third, was the higher serum potassium concentration in the GIK infusion
group harmful? There was no excess of bradycardia- or tachycardia-related
deaths in the GIK infusion group. In fact, in the post hoc analysis of patients
with hyperkalemia (>5.5 mEq/L), mortality was lower in the GIK infusion group
compared with the control group. Prior studies25- 27 have
documented a clear relationship between ventricular arrhythmias and potassium
concentrations less than 5.0 mEq/L in the setting of AMI, making it unlikely
that the higher potassium concentration observed in the GIK infusion group
The reduction in recurrent ischemia with GIK infusion was unexpected,
especially since the apparent anti-ischemic benefit, although detectable at
24 hours, emerged largely after 24 hours, when the GIK infusion was stopped.
It is possible that this outcome was subject to investigator reporting bias,
especially since the trial was open label and this outcome was somewhat open
to investigator interpretation. An alternative mechanistic explanation may
have been that the GIK had an anti-ischemic effect by reducing free fatty
acid uptake by the myocardium while providing glucose and insulin to promote
glycolysis, thereby improving the efficiency of energy production and theoretically
reducing ischemia in the process.3,4
Overall, the GIK solution was well tolerated. Initially, there were
concerns that the higher fluid volume associated with GIK would cause heart
failure. However, despite a differential in net volume between the groups
of 572 mL, there was no excess in heart failure in the GIK infusion group,
regardless of baseline Killip class. It is possible that the higher concentrations
of glucose in the GIK solution had an osmotic diuretic effect, thus facilitating
a greater diuresis. The incidence of severe phlebitis was more frequent in
the GIK infusion group compared with the control group, a problem that was
overcome in the trial by using larger veins (such as the antecubital vein)
Our study was conducted mainly in low- and middle-income regions; therefore,
our experiences have implications for trial design and conduct in these settings.
First, the use of therapies of proven value (including reperfusion therapies,
aspirin, β-blockers, angiotensin-converting enzyme inhibitors, and statins)
was high, suggesting that these regions are fully capable of treating STEMI
patients equally well as in higher-income regions. Second, the data quality
and follow-up were excellent, allaying concerns that clinical trials conducted
in these settings are less reliable. Third, CREATE-ECLA is an example of a
trial that was conducted without the financial backing of any pharmaceutical
company. Therefore, it serves as an example that investigators are willing
to invest the time into reliably answering generic questions of high scientific
merit, independent of industry, as long as protocols are kept very simple.
Mechanisms to fund and facilitate such low-cost trials will allow evaluation
of other simple and inexpensive therapies. Fourth, trials of affordable therapies
that have the potential to make a large impact on the management of common
diseases need to be performed worldwide. This need is particularly great in
lower- and middle-income regions of the world, where the burden of cardiovascular
diseases is highest.
In conclusion, the CREATE-ECLA randomized trial has reliably established
that high-dose GIK infusion in patients with STEMI has no impact on mortality,
cardiac arrest, or cardiogenic shock and is unlikely to be of any material
value in patients with STEMI.
Corresponding Author: Shamir R. Mehta, MD,
MSc, FRCPC, McMaster University and Hamilton Health Sciences, 237 Barton St
E, Hamilton, Ontario, Canada L8L 2X2 (firstname.lastname@example.org).
Author Contributions: Dr Mehta had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Mehta, Yusuf, Díaz,
Pais, Xavier, Paolasso, Orlandini, Pogue, Liu.
Acquisition of data: Mehta, Zhu, Pais, Xavier,
Ahmed, Kazmi, Tai, Orlandini, Pogue, Liu.
Analysis and interpretation of data: Mehta,
Yusuf, Xavier, Ahmed, Xie, Pogue.
Drafting of the manuscript: Mehta, Yusuf, Xie,
Critical revision of the manuscript for important
intellectual content: Mehta, Yusuf, Díaz, Zhu, Pais, Xavier,
Paolasso, Ahmed, Xie, Kazmi, Tai, Orlandini, Pogue, Liu.
Statistical analysis: Xie, Pogue.
Obtained funding: Yusuf, Orlandini.
Administrative, technical, or material support:
Mehta, Yusuf, Díaz, Zhu, Pais, Xavier, Ahmed, Kazmi, Tai, Pogue, Liu.
Study supervision: Mehta, Yusuf, Pais, Xavier,
Paolasso, Ahmed, Kazmi, Tai, Orlandini, Liu.
Funding/Support: This study had no external
funding. Aventis Pharma donated human insulin in India. Aventis Pharma had
no role in the design and conduct of the study, in the collection, analysis,
and interpretation of the data, or in the preparation, review, or approval
of the manuscript.
CREATE-ECLA Trial Group:International Steering Committee: S. Yusuf (principal investigator
[PI] and chair), S. R. Mehta (co-PI and project director), R. Díaz
(joint PI-ECLA), E. Paolasso (joint PI-ECLA), P. Pais (PI-India), S. Reddy
(co-PI–India), L. Liu (PI-China), K. Kazmi (PI-Pakistan), R. J. Ahmed
(global study coordinator), L. Cronin (global study coordinator), D. Xavier
(coordinator-India), J. Zhu (coordinator-China), J. Tai (coordinator-Pakistan),
C. Xie (project statistician); Indian Steering Committee: R. Gupta, K. K. Haridas, T. M. Jaison, P. P. Joshi, P. G. Kerkar,
A. K. Maity, S. C. Manchanda, S. Naik, P. Pais, D. Prabhakaran, S. Reddy,
B. Singh, S. Thanikachalam, D. Xavier; Chinese Steering
Committee: X. J. Bai, T. Chen, J. J. Cui, T. X. Cui, S. Y. Fu, H. Ge,
Q. L. Li, S. M. Li, W. Li, Y. Q. Li, L. Liu, Y. H. Liu, Z. R. Lu, S. P. Ma,
D. Qiao, Y. C. Song, N. L. Sun, L. H. Wang, S. W. Wang, W. Wang, Y. Wang,
N. Wu, Y. S. Wu, C. B. Xu, S. C. Xu, Z. M. Xu, G. J. Yang, H. S. Yang, C.
Z. Zhang, S. T. Zhang, W. J. Zhang, J. C. Zhou, J. Zhu; ECLA GIK 2 Steering Committee: W. Almahmeed, A. Avezum, P. Castro,
R. Corbalán, R. Díaz, R. Pitarch Flors, B. M. Lombana, L. Marano,
D. Mcguire, A. Orlandini, E. Paolasso, J. E. Isea Perez, L. Soares Piegas,
F. Van De Werf, H. White, M. Zubaid; Pakistani Steering
Committee: A. M. Faruqi, K. Kazmi, I. Rasool, K. Soomro, J. Tai, H.
ul Banna; Population Health Research Institute: S.
Yusuf, S. R. Mehta, R. J. Ahmed, L. Cronin, S. Pavlov (database programmer),
C. Xie, J. Pogue, F. Zhao, I. Tsuluca, M. Molec, I. Holadyk-Gris, K. Ahmed; India National Coordinating Office (NCO), Institute of Population
Health and Clinical Research, St John’s National Academy of Health Sciences,
Bangalore: P. Pais, D. Xavier, D. Freeda, S. Lidwin; Indian Adjudication Committee: M. Chenniappan, B. Isaac, S. S. Iyengar,
T. M. Jaison, P. Joshi, S. P. Kalantri, S. K. Kaushik, P. G. Kerkar, U. K.
Mahorkar, J. Narendra, S. K. Paul, M. J. Santhosh, B. K. S. Sastry, B. Singh,
S. B. Siwach, K. Varghese; China NCO, Beijing Hypertensive
League Institute, Beijing: L. Liu, J. Zhu, H. Yang, Y. Yang, X. Zhang,
H. Tan, J. Tang, X. Li, L. Yan, Y. Zhang, J. Li; Chinese
Adjudication Committee: M. Y. Bai, Y. Q. Jiang, S. Y. Lang, X. Y. Shi,
Y. C. Song, Z. R. Tian, K. Wang, D. H. Yan, S. Y. Yu; ELCA,
Rosario, Santa Fé, Argentina: A. Pascual, H. Ozcoidi, C. Cuesta,
D. Wojdyla, G. M. Font, M. I. Genisans; Pakistan NCO, Cardiology
Section, Department of Medicine, Aga Khan University Hospital, Karachi:
K. Kazmi, J. Tai, I. Chandna, M. Rafiq, N. Dadani, S. S. Fatima, S. Rehman; Pakistani Adjudication Committee: S. Adil, K. Bhojomal,
A. Hameed, S. A. Khan; Data and Safety Monitoring Board: P. Sleight (chair), C. Baigent, J. Hirsh, W. Taylor, G. Tognoni; Abbott GmbH & Co KG (reviparin sponsor): P. Bacher,
N. Bender, U. Legler, U. Magin, U. Raschke. Investigators:
Argentina: Berazategui: M. San Mauro; Capital Federal: M. A. Brito, A. Alves De Lima, R. A. Ahuad Guerrero, R. Nordaby; Cordoba: R. J. Barcudi, J. Bono, R. E. Ledesma, H. R. Ramos; Coronel Suarez: A. Caccavo; Corrientes: S. M. Macin; Haedo: S. N. Ferreyra Cantante; La Plata: G. D. Caime, L. R. Cartasegna, O. A. Perrino; Mendoza: A. J. Gambarte, E. Marzetti; Merlo: M. Garrido;
Olavarria: R. J. Balado; Posadas: C. B. Martinez; Quilmes: A. A. Fernandez; Resistencia: E. Ferro Queirel; Rio Grande: J. O. Balbi; Rio IV: G. Amuchastegui; Rosario: G. Covelli, A. Gentile, C. E. Girino, J. López, R. Monti, A. D. Orlandini, O. Pellizon, J. L. Ramos, G. Zapata; Salta: C. A. Cuneo, J. A. Sanchez; San Luis: J. P. Albisu; Santa Fe: M. A. Berli, M. A. Hominal; Santa Teresita: R. A. Peleteiro Mariño; Tandil: V. Mezzina; Tucuman: E. M. Avila, P. Baselga, C. R. Castellanos, H. L. Luciardi, L. L. Lobo Marquez, J. Muntaner; Belgium: Leuven: F. Van De Werf;Brazil: Belo Horizonte: E. M. Good God, G. Reis; Blumenau: D. M. Mello Soares; Porto Alegre: L. C. Bodanese, E. Manenti, L. Prestes; Rio De Janeiro: J. G. De Castro Amino; Sao Paulo: R. Uchoa Azevedo, A. C. C. Carvalho, R. F. Ramos; Chile: Las Condes: M. Alcaino; Santiago: P. Castro Galvez, R. Corbalán Herreros; China: An Yang: H. Liu; Angang: R. Wang; Anshan: Z. C. Liu, X. Tian, G. Wang, Y. Zhang; Baoding: Z. Nan, J. Zhang; Bazhou: C. Zai; Beijing: W. Chen, M. Gao, D. Hu, S. Jia, D. X. Li, Q. Li, W. Li, S. L. Liu, Y. Sun, B. Wang, G. F. Xie, Z. Xu, X. Yang, M. Zhao, X. Zhao; Beipiao: Z. Fang; Benxi: S. Y. Liu; Cangzhou: Z. Ma; Changchun: Y. Jiang, S. M. Li; Changsha: Z. Zhen; Chendu: F. Huo; Chengde: H. G. Yang; Chengwu: H. Liu; Chifeng: Y. Miao; Chongqing: C. M. Yang; Dalian: X. Chi, Z. X. Liu, S. Zhou; Dandong: Y. Sun; Dashiqiao: F. S. Zhou; Fenyang: R. Guo; Gaoping: K. Jing; Guan: Z. Xu; Haicheng: S. Ren, J. Zhao; Hebei: H. Bai, H. Bai, C. Cheng, J. Cheng, X. Hao, H. Li, W. G. Li, S. Wang, W. Zhang; Heilongjiang: L. Li, Y. Sun; Helongjiang: S. Fu, J. Shao, X. Tan; Henan: S. Chen, J. Fu; Hengshui: Q. Zheng; Huai Ren: J. Ma; Inner Mongolia: H. Chen, H. Ma; Jiamusi: L. Gong; Jiaozhou: Z. Zhang; Jiaxiang: F. Li; Jilin: B. Yang; Jinan: L. S. Zhou; Jinlin: Z. Wang; Jinning: X. Sun; Jinzhou: G. Tao; Jiujiang: Q. Wang; Jun: J. Li; Lankao: X. Guo; Lian Yungang: X. Wang; Liao cheng: K. Zai; Liaoning: Q. Cui, S. Fan, H. Li, W. Liu, Q. Meng, G. Qi, Y. Qin, G. Wang, N. Wang, G. Xu, X. Yin, Q. Zhang, S. Zhang, Y. Zhang, Z. Zhang; Liao yang: R. Liu, F. Wang; Linfen: Y. Zhang; Lingbao: W. K. Li; Lingshou: H. Zhang; Linyi: X. Xu; Longkou: R. Ma; Luoyang: F. Guan, T. Yang; Mongolia: R. Zhqo; Nanjing: J. Huang; Nanle: A. Li; Neimeng: J. Zhou; Panjin: X. You; Qi: L. Hao; Qingdao: F. Zhangfang; Qinyuang: X. Ma; Ruyang: C. Shen; Sanhe: Q. Li; Shangdong: Z. Hou; Shanghai: N. F. Zho; Shangqiu: G. Huang; Shanxi: P. Guo, J. Lou, Q. P. Wang, Z. Wang; Shenyang: X. Jiang, Z. Li, D. Tian, S. Wang, Z. D. Wu, M. G. Yang; Shi Jiazhuang: Z. C. Li; Taian: S. G. Yang; Tangshan: Y. Tu; Taonan: C. He; Tianjin: Y. Cao, Y. Han; Wangdu: J. H. Yang; Wangrong: S. Dong; Wuxiang: D. F. Li; Xiang Cheng: Q. F. Zhang; Xianxian: Z. Fan; Xinjiang: D. Q. An; Xinxiang: J. Liu; Xiping: G. Yang; Xiuwu: X. C. Xu; Xuzhou: Y. Xia; Yantai: H. Xu; Yanzhou: T. Wang; Yichun: D. Li; Yingkou: J. Wei; Yongji: P. Yang; Yuci: C. Y. Liu; Zhengzhou: S. Shang; Zhumadian: Y. G. Zhang; Colombia: Bogota: E. Hernandez Leyva; Manizales: N. Cano Lopez; Dominican Republic: Santo Domingo: A. R. Gonzalez Medina; Greece: Athens: J. E. Kanakakis, J. N. Nanas, P. D. Papazoglou; India: Adoni: J. Srinivas, B. Srinivasulu; Ahmedabad: S. Dani, J. Prajapati; Alappuzha: G. Deepak, J. F. Shallam; Ambur: K. J. Nesaraj; Amritsar: A. Kumar, R. K. Sharma; Annamalainagar: S. Balasubramaniyan, N. Chidambaram, R. Umran
Chennai: D. Barkavi, A. Kalanidhi, T. Pradeep, J. Rajesh, M. Ramesh, S. Shanmugasundaram, S. Thanikachalam; Cochin: K. K. Haridas, P. Kumar; Doraha: G. Sidhu, R. Singh; Ernakulam: K. N. Pradeep; Ghaziabad: A. Kumar, A. Mittal;
Gulbarga: J. B. Bijapure, M. S. Rao; Guntur: N. G. Mohanarjun, M. B. Rao; Hyderabad: B. R. Babu, N. Dinesh, R. K. Jain, P. A. Jiwani, S. R. Naik, T. N. C. Padmanabhan, B. S. Raju, R. Rajaram, A. S. V. N. Rao, D. Rao, V. S. P. Rao, B. K. S. Sastry, S. Sinha; Indore: A. Bharani, G. Verma; Jaipur: R. Gupta, R. K. Tongia, S. Kalra, S. Sharma; Jodhpur: R. Mehrotra, S. Sanghvi, O. P. Soni; Kolkata: A. D. Biswas, A. K. Maity, S. K. Paul; Kottayam: J. Boben, G. Jacob, J. Joseph; Lucknow: A. Puri, V. K. Puri, H. Singh; Ludhiana: R. Calton, T. M. Jaison; Meerut: G. K. Aneja; Mumbai: P. G. Kerkar, P. Nyayadhish, P. J. Nathani, S. K. Rane; Nagpur: M. Fulwani, A. S. Jain, P. P. Joshi, A. Khan, U. K. Mahorkar, R. G. Salkar, A. Somani, R. Wadhwani, S. D. Zawar; Nanded: V. E. Shegokar, S. L. Tungikar; Nashik: V. Vijan; New Delhi: B. Singh, R. Trehan; Patiala: A. Garg, H. Singh, S. Verma; Pune: S. Borade, D. Duggal, J. Hiremath; Rohtak: Jagdish, V. K. Katyal, S. B. Siwach; Shimoga: H. R. Devendrappa, J. Narendra, Ratnakar; Thrissur: P. B. Latha, E. B. Manoj, P. P. Mohanan; Trichy: M. Chenniappan, P. Gandhimadhinathan, K. Jeremaiah, B. S. V. Raj, R. Udaysankar; Udaipur: J. K. Chhaparwal, S. K. Kaushik; Vellore: S. T. Chandy, S. N. Gupta, S. Raghavan; Vijayawada: P. Ramesh, V. S. Reddy, P. Srinivas; Vishakapatnam: K. D. Rao, B. R Malipeddi, G. S. R. Murthy; Wardha: R. Joshi, S. P. Kalantri, S. Patil; Italy: Busto Arsizio: S. Tredici; Erba: D. Agnelli; Milano: E. Assanelli, L. Marano; Monza: A. Bozzano, Scorrano (Le): L. Marsano; Torino: R. Crivello, A. Nejrotti; Kuwait: Safat: A. Abdulminem, H. Saad, M. Zubaid; Mexico: Mexico City: J. Martinez Sanchez; San Luis Potosi: J. Carrillo Calvillo; New Zealand: Auckland: H. White; Nelson: A. Hamer; Pakistan: Karachi: I. Chandna, A. M. Faruqi, M. Rafiq, I. Rasool, K. Soomro; Lahore: H. U. Banna; Panama: Bella Vista: B. M. Lombana; Spain: Manacor: J. Lopez Ferre, R. Pitarch Flors; United States: Alexandria: R. J. Freedman; Dallas: D. Mcguire; Myrtle Beach: N. Transk III; United Arab Emirates: Abu Dhabi: W. Almahmeed; Venezuela: Caracas: D. Almeida; Catia: P. J. C. Lujan; El Llanito: C. Mata, J. E. Isea Perez; La Guaira: C. Becerra, K. Gonzalez, F. Torres; Maturin: M. A. Alvarez; Valencia: E. Carrillo.