The medication tilarginine, a drug that was believed could be beneficial for patients who develop cardiogenic shock (low blood pressure due to impaired cardiac function) after a heart attack, did not reduce the risk of death up to six months after a heart attack, according to a JAMA study published online March 26. The study is being released early to coincide with its presentation at the American College of Cardiology's annual conference.
Cardiogenic shock is the leading cause of death among hospitalized patients with acute myocardial infarction (MI; heart attack), with rates of death in excess of 50 percent. Early revascularization improves survival; however, early death rates remain high, particularly among patients with continued shock after revascularization, according to background information in the article. "Systemic inflammation, including expression of inducible nitric oxide synthase (NOS [enzyme that promotes nitric oxide]) and generation of excess nitric oxide, is believed to contribute to the pathogenesis and inappropriate vasodilatation [widening of blood vessels] of persistent cardiogenic shock. Preliminary, single-center studies suggested a beneficial effect of NOS inhibition on hemodynamics, renal [kidney] function, and survival in patients with cardiogenic shock."
Judith S. Hochman, M.D., of the New York University School of Medicine, New York, and the TRIUMPH (Tilarginine Acetate Injection in a Randomized lnternational Study in Unstable MI Patients With Cardiogenic Shock) trial investigators tested the effect of NOS inhibition with the drug tilarginine on risk of death on heart attack patients with cardiogenic shock. The study included 398 patients at 130 centers in eight countries. Participants were enrolled between January 2005 and August 2006 when the study was terminated early. Patients received either 1-mg/kg tilarginine intravenously followed by 1.0 mg/kg per hour of intravenous infusion for 5 hours, or matching placebo. Six-month follow-up was completed in February 2007.
The researchers found that there was no difference in the 30-day death rates between patients who received tilarginine and those who received placebo (48 percent vs. 42 percent mortality). At 6 months, 58 percent of patients assigned to tilarginine and 59 percent of patients assigned to placebo had died. Tilarginine had no effect on the 30-day rates of recurrent myocardial reinfarction or heart failure classification. For these shock patients with very low blood pressure, there was a greater early rise in blood pressure in those treated with tilarginine, but resolution and duration of shock were similar.
"Tilarginine, at the dose and duration studied, had no effect on mortality in patients with MI complicated by refractory cardiogenic shock. The increase in blood pressure in response to NOS inhibition suggests that excess nitric oxide may play a role in the pathophysiology of cardiogenic shock. Additional innovations in therapy and improved health care delivery systems are needed to establish earlier reperfusion to prevent shock following MI and to reduce the high short-term mortality rate of patients who develop cardiogenic shock," the authors conclude.
JAMA. 2007;297:(doi:10.1001/jama.297.15.joc70035). Available pre-embargo to the media at www.jamamedia.org.)
This study was sponsored by ArgiNOx Pharmaceuticals Inc. The ArgiNOx study team included David Hathaway, M.D., Steve Bell, Grendel Burrell and Kenneth Drazan, M.D. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.