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Safety and Efficacy of a Novel Calcium Sensitizer, Levosimendan, in Patients With Left Ventricular Failure due to an Acute Myocardial Infarction - RUSSLAN
Description:
This was a randomized, double-blind, placebo-controlled trial of levosimendan, an intravenous calcium sensitizer, in patients with left ventricular failure after acute myocardial infarction (AMI).
Hypothesis:
A six-hour infusion of levosimendan would be well-tolerated and improve symptoms of heart failure in patients with recent AMI.
Study Design
Study Design:
Patients Enrolled: 504
NYHA Class: IV
Mean Follow Up: 180 days
Mean Patient Age: 67 ± 11 years
Female: 48
Patient Populations:
AMI within five days, evidence of left ventricular failure on chest X-ray, and clinical need for inotropic therapy despite conventional therapy
Exclusions:
Right ventricular infarction, systolic blood pressure <90 mm Hg, sustained or frequent nonsustained ventricular tachycardia, atrial fibrillation with rapid ventricular response, immediate need for cardiac pacing or revascularization, myocardial rupture or tamponade, use of beta-adrenergic agonists within 30 minutes, septic shock or acute respiratory distress syndrome, history of moderate or severe renal failure or hepatic failure, or agonal status
Primary Endpoints:
Hypotension or coronary ischemia
Secondary Endpoints:
Combined risk of death and worsening heart failure during the first six and 24 hours, change in dyspnea and fatigue, and death
Drug/Procedures Used:
Subjects were randomized to placebo or one of four doses of levosimendan: 6 μg/kg loading dose + 0.1 μg/kg/min infusion; 12 μg/kg loading dose + 0.2 μg/kg/min infusion; 24 μg/kg loading dose + 0.2 μg/kg/min infusion; or 24 μg/kg loading dose + 0.4 μg/kg/min infusion. The loading dose was infused over 10 minutes and the continuous infusion was continued for six hours.
Invasive hemodynamic monitoring was not performed. Patients with persistent hypotension or refractory heart failure during infusion were permitted to receive intravenous dopamine. Subsequent follow-up was performed at 24 hours, 14 days, and 180 days. Invasive hemodynamic monitoring was not mandated and was not performed in most patients (number not reported).
Concomitant Medications:
Dopamine (10%), other intravenous inotropes (7%), thrombolytics (17%), diuretics (74%), ACE inhibitors (47%), beta-blockers (39%), calcium channel blockers (13%), aspirin (88%), and heparin (85%)
Principal Findings:
The proportion of patients with hypotension or cardiac ischemia was not significantly different between placebo and levosimendan groups (10.8% with placebo vs. 13.4% with levosimendan, p=0.456). Infusion of the highest dose of levosimendan was associated with an increased incidence of hypotension or cardiac ischemia (19% with the 24 μg/kg loading dose + 0.4 μg/kg/min infusion vs. 10.8% with placebo, p=0.05).
A lower incidence of death or worsening heart failure at 24 hours was associated with levosimendan infusion versus placebo (4% vs. 8.8%, p=0.04). At 14 and 180 days, a lower mortality was also associated with levosimendan infusion versus placebo (11.7% vs. 19.6%, p=0.03 and 22.6% vs. 31.4%, p=0.05, respectively). A similar rate of adverse events was recorded in patients receiving levosimendan and placebo (23.4% vs. 17.6%, p=0.233). There was a dose-dependent decrease in systolic and diastolic blood pressure and increase in heart rate associated with levosimendan.
Interpretation:
Among patients with left ventricular failure after AMI, administration of levosimendan was associated with similar rates of hypotension, cardiac ischemia, and adverse events compared with placebo. A decreased incidence of death at 180 days, which was a secondary endpoint, was associated with levosimendan infusion versus placebo.
References:
Moiseyev VS, Poder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction: a randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 2002;23:1422-32.
Keywords: Myocardial Ischemia, Myocardial Infarction, Follow-Up Studies, Hypotension, Coronary Disease, Blood Pressure, Dopamine, Heart Rate, Calcium, Pyridazines, Pharmaceutical Preparations, Heart Failure, Hydrazones
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