Omapatrilat- the story of Overture and Octave

Abstract

At the American College of Cardiology in March two major trials were presented. The publicity surrounding the two could not have been more different. The LIFE demonstrated clear superiority of losartan-based therapy over atenolol-based therapy for the treatment of hypertension. It was published the same week in the Lancet and received major press coverage all over the world.

The OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) study in contrast received a subdued reception, very little publicity and is yet to be published. 5770 NYHA class II–IV heart failure patients (LVEF≤30%, recent heart failure hospital admission) were randomised and uptitrated to either 10 mg BD of Enalapril or 40 mg once a day Omapatrilat. The primary end-point of all cause mortality or heart failure related hospitalisation did not differ significantly: 914/2884 for Enalapril and 914/2886 for Omapatrilat (hazard ratio 0.94, CI’s 0.86–1.03, P=0.187) [1]. Mortality was also similar: 509 for Enalapril and 477 for Omapatrilat (hazard ratio 0.94, CI’s 0.83–1.07, P=0.339). Omapatrilat was as good as Enalapril but not better. The worrying trend was however, that angioedema was more common with Omapatrilat; 24 (0.8%) versus 14 cases (0.5%).

The OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) study was also presented at this time. 25,267 hypertensives were randomised to Omapatrilat or enalapril and a difference of approximately 3 mmHg in favour of Omapatrilat was seen. Significantly more cases of angioedema were seen with Omapatrilat, 274 (2.17%) compared to 86 (0.68%) with enalapril. Overall death rates were similar, 0.18% for enalapril and 0.15% for Omapatrilat. All adverse events were similar, 51.0% for Omapatrilat and 50.4% for enalapril. The rates of angioedema were much higher in blacks, 5.54% for Ompatrilat and 1.62% for enalapril and for smokers, 3.93% for Omapatrilat and 0.81% for enalapril. We were left with a drug that was, for heart failure, not superior to an ACE inhibitor already off patent, and, as an anti-hypertensive, with an angioedema rate more than double that of an ACE inhibitor in a large head to head comparison. The medical community will be watching to make sure these data are published in full in the medical literature in a timely fashion, in the order of end-points specified in the protocol and with appropriate emphasis on the logical points of presentation.