OVERTURE: Omapatrilat no better than enalapril in heart failure

March 20, 2002

Atlanta, GA - The joint ACE/NEP inhibitor omapatrilat (Vanlev® - Bristol Myers Squibb), was not superior to the ACE inhibitor enalapril in the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) heart failure (HF) trial, but the two drugs were shown to be equivalent. The trial, the biggest ever study of a new drug in HF, was a last-minute addition to the late-breakers presented at the American College of Cardiology 51st Annual Scientific Session today, as the results only became available a few days ago.

Dr Milton Packer

The results are disappointing, given that the dual mechanism of action of omapatrilat and promising results in earlier smaller studies had led to great expectations that it would outperform ACE inhibitors in HF. Nevertheless, chief investigator of the trial, Dr Milton Packer (Columbia University) noted that OVERTURE had shown omapatrilat to be an effective HF drug. "If it had been compared with placebo it would have shown a clear benefit."

But the drug probably needs to show a benefit over ACE inhibitors in order to have a place in treatment, given that ACE inhibitors are becoming available generically and as a new drug, omapatrilat is bound to be considerably more expensive. However, Packer seemed hopeful that some explanation could be found for the results and that maybe a benefit could be demonstrated in certain populations in further analyses: "The future direction of this drug in heart failure will be entirely determined after new analyses of the data in the next few weeks/months."

The news isn't all bad . . .

The main focus at this point is on the hypotensive effect of the drug, which could have negated the benefits of omapatrilat in the patients with the lowest blood pressures (BPs). "Many heart failure trials exclude patients with low systolic blood pressure. This one didn't. If we had done, the results could have been different," Packer speculated. "We will be looking at the data closely over the next few weeks to see if this is the case," he added.

Omapatrilat is the first of a new class of agents in development for both hypertension and HF. It has a novel dual vasodilatory action, inhibiting both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP). It is thus an ACE inhibitor with additional actions. NEP is an enzyme that breaks down several natriuretic peptides, such as ANP, BNP, and CNP. These peptides possess natriuretic, vasodilatory, and growth inhibiting properties. Inhibition of both ACE and NEP seems to give synergistic vasodilatory effects, which was hoped to translate into benefits in both hypertension and HF.

The OVERTURE trial included 5770 patients with severe HF (Class II, III or IV symptoms, LVEF less than 30% and a hospitalization for HF within the last 12 months). They were all receiving optimal therapies for HF - 50% were on beta-blockers, 40% on spironolactone and 60% on digoxin. They were then randomized to enalapril (10 mg bid) or omapatrilat 40 mg once daily.

The primary endpoint was all-cause mortality/CHF hospitalizations, which showed a 6% reduction with omapatrilat, but this did not reach statistical significance. The upper confidence limit of the hazard ratio (1.03) was however below that which had been predefined as the upper limit of equivalence (1.09), therefore "we can confidently say that omapatrilat is equivalent to enalapril and is an effective heart failure drug," Packer commented.

Primary and major secondary endpoints

Endpoint Enalapril (n=2884) Omapatrilat (n=2886) Hazard ratio (97.5% CI) p value
Death/CHF hospitalizations* 973 914 0.94
(0.86-1.03)
0.187
All-cause mortality 509 477 0.94
(0.83-1.07)
0.339
CV death/CV hospitalization 1275 1178 0.91
(0.84-0.99)
0.024
Death/MI/stroke/revascularization 578 537 0.93
(0.83-1.05)
0.233
*primary endpoint

All predefined subgroups showed similar results, with trends towards benefit with omapatrilat in all groups, but none of these reached significance.

Adverse effects showed a lower rate of HF and impaired renal function with omapatrilat, but a higher rate of hypotension and dizziness. Angioedema, which has been an issue with omapatrilat in the treatment of hypertension, was slightly increased in the omapatrilat group in this study, but Packer said this was not meaningful. "Angioedema is not a relevant adverse effect in heart failure," he commented to heartwire . "Angioedema is caused by blood vessels becoming leaky, and but the vessels of heart failure patients have lost this ability. There is thus no issue with angioedema in this population," he explained.

Adverse events

Event Enalapril (%) Omapatrilat (%)
CHF 25.6 22.6
Hypotension 11.5 19.5
Dizziness 13.9 19.4
Impaired renal function 3.6 2.3
Angioedema 0.5 0.8

Packer noted that several possible explanations had been suggested by the steering committee for the lack of a significant benefit of omapatrilat in this trial. These included the following:

  • A suboptimal dose of drug.

  • A ceiling of benefit for neurohomonal modulation.

  • Resistance to natriuretic peptides in advanced HF.

  • Excessive hypotension cancelling out the benefits.

Focus on hypotension

The reseachers are currently focusing on the last possibility. The only nonplanned analysis that has been conducted as yet is the relationship between efficacy of the drug and systolic BP at entry, with omapatrilat actually looking better than enalapril in patients with higher BPs, but having no benefit in patients with low systolic BPs, Packer noted: "The benefits of omapatrilat were largest in patients with systolic blood pressures above 140 mm Hg, and benefit progressively reduced as blood pressures reduced, down to patients with systolic pressures lower than 110mm Hg at entry who showed no benefit with omapatrilat over enalapril."

"Omapatrilat is a powerful hypotensive agent and it is posible that a detrimental hypotensive effect in the patients with the lowest bood pressure at entry could have cancelled out its benefit", Packer told heartwire . "We are not far off significance of the primary endpoint, and if we exclude patients with the lowest sytolic blood presure at baseline, the data could look meaningfully better."

As the results have only just become available, this analysis has not yet been done, but it will become one of the first focuses of interest in the next few weeks. "This is the largest ever clinical trial with a new drug in heart failure, and we have only just scratched the surface of the data. The were many other brand new ideas discussed at the steering committee meeting just last night, and many further analyses will be conducted to help identify future plans for the drug" Packer concluded.

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