American Heart Association Scientific Sessions: Glucose-Insulin Infusion in Patients with Acute Myocardial Infarction
Speaker: Shamir R. Mehta, MD, MSc, Associate Professor of Medicine, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
High-dose glucose insulin-potassium (GIK) infusion, a promising low-cost intervention developed in Mexico in the 1950s, maintains its reputed beneficial effects in patients with ST-seg-ment elevation myocardial infarction (STEMI). It was found to improve myocardial energetics, decrease free fatty acids, and reduce the incidence of serious ventricular arrhythmias, with no impact on mortality, cardiac arrest, or cardiogenic shock.
In an exploratory subgroup of patients receiving primary percutaneous cardiovascular intervention (PCI) or thrombolytic therapy with recombinant tissue-plasminogen activator (rt-PA) (Activase®, Genentech), mortality was significantly reduced, but this was not part of the specified analyses.
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A total of 20,201 patients with STEMI, presenting within 12 hours, were enrolled into the CREATE-ECLA (Clinical Trial of Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation-Estudos Cardiologicos Latinoamerica) study from 518 centers in 21 regions, including North America, South America, Europe, the Middle East, India, China, and Pakistan. Patients were randomly selected to receive a GIK infusion plus the usual care or the usual care alone for 24 hours.
A subset of 15,500 patients in China and India (the CREATE trial) were also randomly assigned to receive a simple regimen of the low-molecular-weight heparin reviparin as an anticoagulant. The primary endpoints in the CREATE-ECLA trial were 30-day all-cause mortality. Secondary endpoints included nonfatal MI, cardiogenic shock, and a second MI at either the seventh day or up to the 30th day. The primary endpoints in the CREATE trial were death, a second heart attack or stroke at seven days, and refractory ischemia at seven days.
Mortality from any cause occurred in 10% of GIK patients and in 9.7% of controls. The rates of cardiac arrest were 1.4% in the GIK group and 1.5% in the controls; for cardiogenic shock, the rates were 6.6% and 6.3%, respectively; and for re-infarction, the rates were 2.3% and 2.4%, respectively. There was, however, a significant reduction in the rate of recurrent ischemia at seven days: 4.6% for the GIK patients and 6.5% for the controls.
The subgroup analyses were consistent with the overall result on mortality, including diabetic patients, patients with congestive heart failure, and patients receiving primary PCI or rt-PA.
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Tilarginine for Acute Myocardial Infarction Complicated by Cardiogenic Shock
Speaker: Vladimir Dzavik, MD, Director of Interventional Cardiology, University Health Network-Toronto Hospital, Toronto, Ontario
Tilarginine (L-N-monomethyl arginine) (ArgiNOx Pharmaceuticals, Inc.), a novel nonselective nitric oxide synthase (NOS) inhibitor capable of blocking the substantial increase in overall nitric oxide (NO) production during inflammatory events, was found to be safe and well tolerated in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock. Although there was no significant difference in mortality between actively treated patients overall and those taking placebo, there was a reduction in the mortality rate of approximately 25% in the highest-dose treatment groups of patients compared with those taking placebo.
The SHOCK-2 (SHould we inhibit nitric Oxide synthase in Cardiogenic ShocK) study, a phase 2, dose-ranging clinical trial, was designed to assess the efficacy and safety of four different doses of tilarginine to determine the optimal dosage for use in a pivotal phase 3 trial. A total of 79 patients (mean age, 68 ± 10 years) with persistent cardiogenic shock caused by left ventricular failure complicating AMI, were enrolled in the study.
The patients were randomly selected to receive a bolus of tilarginine, followed by a five-hour infusion of the NOS inhibitor in four dosage groups, with 13 to 15 patients assigned to each dose: at doses of 0.15 mg/kg bolus and 0.15 mg/kg per hour; 0.5 mg/kg bolus and 0.5 mg/kg per hour; 1.0 mg/kg bolus and 1.0 mg/kg per hour; and 1.5 mg/kg bolus and 1.5 mg/kg per hour; or placebo. The primary endpoint was a change in mean arterial pressure at two hours. Secondary endpoints included mortality at 30 days and six months and a change in urine output and creatinine.
Tilarginine proved to be safe and well tolerated in these patients. All of the patients were very sick, many were very old, and a high proportion of them had diabetes. The drug’s safety profile was similar to that seen in the placebo group.
Although there was no significant difference in mortality between the overall active-treatment groups and the placebo subjects, this was not surprising. In a small study of this type, with only 79 patients in five study arms, the randomization was unbalanced. There were fewer very sick patients in the placebo arm, compared with those receiving active treatment; cardio-genic shock resolved in 90% of the patients taking placebo. Because of the imbalance, the mortality rate in the placebo group was lower than expected, resulting in no significant difference between the overall active-treatment patients and the placebo patients. However, mortality was significantly reduced in the highest-dose treatment groups of patients compared with the placebo group.
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There is a need for an adequately powered randomized study, and the findings of the SHOCK-2 study support the expanded clinical testing of tilarginine as a drug with the potential to treat the often fatal condition of AMI complicated by cardiogenic shock. A phase 3 clinical trial, therefore, is being planned.