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Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock - TRIUMPH – Presented at ACC 2007
Description:
The goal of the trial was to evaluate treatment with the nitric oxide synthase (NOS) inhibitor tilarginine compared with placebo among patients with cardiogenic shock complicating acute myocardial infarction (MI).
Study Design
Study Design:
Patients Screened: 1,611
Patients Enrolled: 398
Mean Follow Up: 6 months
Mean Patient Age: Median age, 67 years
Female: 28
Patient Populations:
MI, confirmed by ischemic symptoms for at least 30 minutes with elevated cardiac markers and/or ST-segment elevation or left bundle branch block; patency (<70% stenosis) of the infarct artery; refractory cardiogenic shock of <24 hours' duration, systolic blood pressure <100 mm Hg despite vasopressor therapy continuing >1 hour after infarct artery patency; clinical or hemodynamic evidence of elevated LV filling pressures; and LVEF <40%.
Exclusions:
Resolving shock, suspected or documented infection, other causes of shock, shock due to acute mitral regurgitation or rupture of the ventricular septum or free wall, severe valvular heart disease, predominant right ventricular failure or severe right ventricular dysfunction of any cause, serum creatinine >3.0 mg/dl or end-stage renal disease requiring dialysis, adult respiratory distress syndrome, anoxic brain injury precluding survival, irreversible multisystem failure, recent thoracic or abdominal surgery, primary pulmonary hypertension, and need for emergency coronary artery bypass graft surgery within 24 hours
Primary Endpoints:
All-cause mortality at 30 days
Secondary Endpoints:
Shock resolution and duration, New York Heart Association functional class at 30 days, and mortality at 6 months
Drug/Procedures Used:
Patients were randomized in a double-blind manner to treatment with tilarginine (1 mg/kg bolus and 1 mg/kg/hour infusion for 5 hours; n = 206) or placebo (n = 190).
Principal Findings:
The trial was discontinued early following a futility analysis.
At study entry, median left ventricular ejection fraction (LVEF) was 27% in both groups. Median time from MI to shock was 4.6 hours and time from shock to open artery was 1.4 hours. Infarct artery was the left anterior descending in 58% of patients and the left main in 12%. Intra-aortic balloon pump was used in 90% of patients and 12% of patients had an LV assist device placed.
There was no difference in the primary endpoint of 30-day mortality between groups (48% for tilarginine vs. 42% for placebo, risk ratio [RR] 1.14, p = 0.24), nor was there a difference by 6 months (58% vs. 59%, p = 0.80). Heart failure at 30 days had occurred in 48% of the tilarginine group and 51% of the placebo group (p = 0.51) and recurrent MI in 4.0% and 3.9%, respectively (p = 0.95). There was also no difference in resolution of shock (66% vs. 61%, p = 0.31) or duration of shock (median 156 hours for tilarginine vs. 190 hours for placebo; p = 0.16). Change in systolic blood pressure at 2 hours was higher in the tilarginine group than the placebo group (increase of 12.0/5.0 mm Hg vs. 7.0/1.0 mm Hg).
Interpretation:
Among patients with cardiogenic shock complicating acute MI, treatment with the NOS inhibitor tilarginine was not associated with a difference in the primary endpoint of death at 30 days compared with placebo.
In the earlier SHOCK-2 trial, tilarginine was associated with improvements in hemodynamic measures, which prompted the undertaking of the present study to evaluate mortality. Despite seeing improvements in blood pressure in the present study, no improvement in mortality was observed. Cardiogenic shock complicating MI remains a challenging condition with limited treatment options.
References:
The TRIUMPH Investigators. Effect of Tilarginine Acetate in Patients With Acute Myocardial Infarction and Cardiogenic Shock: The TRIUMPH Randomized Controlled Trial. JAMA 2007;297; 1657-1666.
Presented by Dr. Judith S. Hochman at the American College of Cardiology Annual Scientific Session, New Orleans, LA, March 2007.
Keywords: Shock, Cardiogenic, Odds Ratio, Vasoconstrictor Agents, Nitric Oxide Synthase, Heart Failure, Bundle-Branch Block, Stroke Volume, Medical Futility, Blood Pressure, Constriction, Pathologic, Intra-Aortic Balloon Pumping
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