ACC: TRIUMPH Kills Tilarginine

NEW ORLEANS, March 27 -- Tilarginine offers no benefit to heart attack patients suffering cardiogenic shock, researchers reported here. The finding rang the death knell for the agent.

Despite promising early results that led the FDA to grant the drug orphan status in 2005, a phase III trial showed no improvement in 30-day all-cause mortality over placebo (48% versus 42% P=0.24), said Judith S. Hochman, M.D., of New York University.

Nor was there an advantage in resolution of cardiogenic shock or any other signal of benefit, she reported at the American College of Cardiology meeting. The study results were published simultaneously online in the Journal of the American Medical Association.

The drug inhibits nitric oxide synthase, which factors in the pathogenesis and vasodilation of persistent cardiogenic shock. It was previously studied for sepsis and likewise showed good phase II results but failed in phase III, Dr. Hochman said.

Now, the drug's developer, ArgiNOx Pharmaceuticals, has halted development of tilarginine, Dr. Hochman said. Representatives of the company could not be reached for comment.

The prospective, double-blind TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock) study randomized 398 patients in North America and Europe before early termination on the basis of a futility analysis.

The patients had refractory cardiogenic shock complicating confirmed acute myocardial infarction despite an open infarct artery (less than 70% stenosis). Those with resolving shock or suspected or documented infection or other causes of shock were excluded.

They received tilarginine as a 1.0 mg/kg intravenous bolus followed by 1.0 mg/kg per hour intravenous infusion for five hours or matching placebo.

The groups were similar in baseline characteristics (about 25% over age 75, predominantly white males), duration or use of intra-aortic balloon counterpulsation and mechanical ventilation before randomization, and concomitant medication use. Nearly all patients required percutaneous coronary intervention to open the infarct artery.

Resolution of shock was defined as vasopressor discontinuation, except low-dose dopamine, and at least one day off intra-aortic balloon pump support. The treatment protocol strongly recommended against decreasing vasopressor doses during tilarginine infusion.

Despite funding withdrawal when the study was ended, the researchers obtained six-month follow-up on nearly all treated patients. They reported (tilarginine versus placebo):

• No significant difference between groups in the primary endpoint of 30-day all-cause mortality (risk ratio 1.14, 95% confidence interval 0.92 to 1.41).
• No significant difference between groups in all-cause mortality adjusted for baseline differences in vasopressor use (odds ratio 1.27, 95% CI 0.84 to 1.94, P=0.26).
• Similar six-month all-cause mortality rates between groups (58% versus 59%, hazard ratio 1.04, 95% CI 0.79 to 1.36, P=0.80).
• Significantly greater increases in systolic blood pressure at two hours with tilarginine (12.0 versus 7.0 mm Hg, P=0.001).
• Similar timing of resolution of shock (P=0.16).

Mortality was also not impacted among any patient subgroups, though the systolic blood pressure effect appeared to be greater for patients age 75 or older than those younger than 75 (P=0.02).

While tilarginine yielded slightly more serious adverse events than placebo (144 versus 130), there were no significant safety differences.

"It's a very definitive negative trial," said Bernard J. Gersh, M.D., of the Mayo Clinic in Rochester, Minn., who was a panelist at the session in which the results were presented.

However, the strategy of blocking the effects of nitric oxide synthase via production or absorption may still be valid, Dr. Hochman said.