Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial

Stephen A. Geraci, MD, FCCP
Chair, Cardiovascular Medicine and Surgery NetWork

Alexander JH, Reynolds HR, Stebbins AL, et al. Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA 2007; 297:1657-1666

This study tested the hypothesis that nitric oxide synthase inhibition using NG-monomethyl-L-arginine (L-NMMA) by bolus plus a 5 h moderate dose infusion would reduce 30-day all-cause mortality in patients with cardiogenic shock due to acute myocardial infarction in patients with an open infarct-related artery. Secondary endpoints included shock duration/resolution, 30-day NYHA class, and 6-month mortality. The study recruited patients from 130 centers across North America and Europe, using reasonable inclusion criteria (ECG, biomarker, BP, and vasopressor requirements, evidence of tissue hypoperfusion, evidence of elevated left ventricular end-diastolic pressure, and left ventricular ejection fraction <40%). Exclusion criteria covered other diseases likely to influence short- and intermediate-term survival, and the need for an emergency coronary artery bypass graft. A prespecified subgroup analysis, based on age, was included in the study design. The study was powered to identify a 25% relative risk reduction in the primary endpoint with 90% power and planned for two interim analyses, at 50% and 75% enrollment, for study termination due to efficacy or futility. Statistical analyses were sophisticated and appropriate for the data collected. Randomization was successful with good matching of treatment and placebo groups for all reported characteristics; baseline vasopressor use, in-hospital procedures (including intraaortic balloon pump support and primary percutaneous coronary intervention), and concomitant medications after randomization were similar in both groups.

The study was stopped after 50% patient enrollment (n = 398) when the prespecified futility analysis thresholds were met. There were no differences in primary or secondary endpoints between the two groups. Early (2 h) improvement of hypotension in the active treatment arm was not associated with any difference in outcome.

The study results, though negative, are an important step in developing comprehensive treatment strategies for acute cardiogenic shock. To date, only emergent reperfusion and establishment of normal blood flow through the infarct-related artery has been shown to reduce mortality, which remains above 50% even in this setting. Postreperfusion mortality is driven by a host of pretreatment variables, but even when optimized, systemic inflammation triggered during the shock period can continue and lead to early or intermediate-term mortality. Studies of a complement inhibitor were likewise negative. The complex physiologic response in cardiogenic shock may mimic the response in multiple trauma, sepsis, and other acute, severe systemic illnesses. It will likely require ongoing trials of other, or a combination of, mediator inhibitors. The focus on systemic, rather than isolated, cardiac aspects of this syndrome will be the next threshold in understanding the relevant pathophysiology and possible avenues of effective treatment.