Omapatrilat in heart failure study (OVERTURE) published: Would a twice-daily dose have made a difference?

July 31, 2002

Dallas, TX - The results of the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) study, in which the combined ACE-NEP inhibitor omapatrilat (VanlevTM - Bristol Myers Squibb) was not more effective than ACE inhibition alone in reducing a primary clinical event in heart failure patients, was published this week in Circulation[1]. The results were first presented at the American College of Cardiology meeting in March.

In the publication, the authors note that although the primary end point was not significantly different, there were promising differences in favor of omapatrilat in secondary and post-hoc analyses that relied on a broader definition of heart failure. They conclude that further studies could therefore be warranted and that studies of alternative dosing strategies giving more continuous and intense inhibition of both ACE and NEP would be of particular interest.

Twice-daily dosing would have been better?

In an interview with heartwire , Dr John McMurray (University of Glasgow, UK), a member of the OVERTURE steering committee, said he did not know of any further studies planned with omapatrilat. He believes that a better result may have occurred with a twice-daily dose of omapatrilat, rather than the once-daily dose used. "My feeling is that we should have dosed twice daily with omapatrilat and that, because we didn't, our omapatrilat-treated patients did not get the benefit of sustained 24-hour ACE inhibition in the same way as the enalapril patients did."

However, he added, "whether any company (and several have ACE-NEP inhibitors) is willing to gamble on the costly development program required to prove the hypothesis that ACE-NEP inhibitors are better is another question."

OVERTURE design and results

The OVERTURE study randomized 5770 patients with NYHA class 2 to 4 heart failure to enalapril (10 mg twice daily) or omapatrilat (40 mg once daily) for a mean of 14.5 months. The primary end pointthe combined risk of death or hospitalization for heart failure requiring intravenous treatmentwas not statistically different between the 2 groups, a result that fulfilled prespecified criteria for noninferiority but not for superiority of omapatrilat.

Primary end pointdeath or hospitalization for heart failure requiring IV treatment

Enalapril Omapatrilat HR 95% CI p value
n=973 n=914 0.94 0.86-1.03 0.187
HR: hazard ratio

Secondary endpoints showed a significant 9% lower risk of cardiovascular death or hospitalization and a nonsignificant 6% lower risk of death.

Secondary endpoints

Endpoint Enalapril Omapatrilat HR 95% CI p value
Death n=509 n=477 0.94 0.83-1.07 0.339
Death/hospitalization for CV reason n=1275 n=1178 0.91 0.84-0.99 0.024
CV death, MI, stroke, revascularization n=578 n=537 0.93 0.83-1.05 0.233
HR: hazard ratio

The authors, led by Dr Milton Packer (Columbia University, New York), also note that post-hoc analysis of the primary end point with the definition used in the SOLVD trial (death or any hospitalization for heart failure) showed a significant 11% lower risk with omapatrilat, a result they say would have "conclusively demonstrated its efficacy in the treatment of heart failure." They add that the difference between this post-hoc analysis and the prespecified analysis of the primary end point reflected the occurrence of hospitalizations for heart failure that were treated only with an intensification of oral drugs.

Post-hoc analysisdeath or any hospitalization for heart failure

Enalapril Omapatrilat HR 95% CI p value
n=1041 n=941 0.89 0.82-0.98 0.012
HR: hazard ratio

Even though these secondary and post hoc analyses suggest that omapatrilat may have been more effective than enalapril, the difference is still less than that which had been expected when the study was designed and than that observed in earlier experimental and smaller clinical studies, the researchers say. They suggest that this may be because of the failure of once-daily dosing with omapatrilat to maintain continuous ACE inhibition to the same degree as twice-daily dosing with enalapril.

In terms of safety, omapatrilat was well tolerated, the authors comment. Hypotension and dizziness were more common, but worsening renal function was less frequent in the omapatrilat group. "This pattern of response is similar to that reported in previous experimental and clinical studies, which showed that NEP inhibition can exert favorable effects on renal function and can counteract the risk of worsening renal function that predictably follows the use of ACE inhibitors," they report.

Angioedema not a major problem in heart failure?

Angioedema, which has prevented the approval of omapatrilat for hypertension, is not so much of a concern in heart failure, the OVERTURE investigators say. Although angioedema was reported more commonly with omapatrilat (0.8%) than enalapril (0.5%), the absolute frequency, incremental risk, and severity in the present trial were less than that reported in the OCTAVE trial in hypertension, possibly because patients with heart failure are resistant to the ability of bradykinin to produce cutaneous exudation, they comment.

Has omapatrilat got a future?

When asked if omapatrilat had a future in either hypertension or heart failure, McMurray commented to heartwire that he still believes ACE-NEP inhibitors represent a real therapeutic advance. "There is enough of a suggestion from OVERTURE and OCTAVE to suppose that careful dose and patient selection could lead to the demonstration of improved outcomes with these agents over existing ones."

"Obviously the recent FDA advisory panel decision was a major blow," he commented, adding that the high proportion of blacks in the US population was probably a key factor regarding the risk of angioedema.

"There is clearly great concern in the US about the risk of angioedemaI perceive it to be much less in Europe. Whites had a very small risk of angioedema, and even then most cases were mild. As far as I can see the risk of serious angioedema in a nonblack patient is less than that of rhabdomyolysis with a statin."

He added, however, that the concern about angioedema does mean that convincing efficacy is required to balance the risk/benefit equation. "In many peoples' eyes a few extra mm-Hg reduction in blood pressure may not be convincing enough."

Bristol Myers Squibb said that a decision on whether to conduct further studies with omapatrilat had not yet been made. The company was considering comments made at the recent FDA advisory committee meeting on the hypertension indication that further studies in a high-risk population may be warranted. Omapatrilat has not been filed for approval for hypertension anywhere else or for heart failure in the US or elsewhere, a spokesperson said.

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