Omapatrilat in high-risk hypertensives: does the benefit outweigh the risks?

Julia Rommelfanger

September 04, 2002

Berlin, Germany - In a subgroup analysis of the OCTAVE hypertension trial including just those patients with a history of atherosclerotic disease, the dual ACE/NEP inhibitor omapatrilat (Vanlev® - Bristol-Myers Squibb [BMS]) showed an improved risk benefit ratio, which justifies its approval for this group of patients, lead OCTAVE investigator Dr Michael Weber (SUNY Downstate College of Medicine, Brooklyn, NY), claims.

Dr Michael Weber

However, doctors are still concerned about a 1.18% incidence of angioedema with omapatrilat vs 0.60% with enalapril in this patient population.

Weber, who presented this new subgroup analysis here at the European Society of Cardiology Congress 2002, was enthusiastic about the beneficial outcome in this patient population.

Risk vs benefit

"In high-risk patients the benefit is substantially greater than the risk. Thus, in these patients this drug is a very effective treatment," he told heartwire after the presentation. He said that BMS was currently in discussions with the FDA about possible approval for omapatrilat in this high-risk population. The FDA's cardiorenal committee voted against approving the drug at a meeting earlier this year.

Not everyone, however, shares Weber's optimism concerning the new agent. Dr J Nussberger (Lausanne, Switzerland), who discussed the OCTAVE trial, pointed out that, "the benefit risk ratio must guide any therapeutic decision. No doubt the trial showed that omapatrilat decreases blood pressure more than enalapril, but it also showed that, overall, omapatrilat induced 3 times as many angioedemas as enalapril."

In high-risk patients the benefit is substantially greater than the risk. Thus, in these patients this drug is a very effective treatment.

The Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial, a 25000-patient hypertension trial, first presented at the ACC Meeting 2002 in Atlanta in March, showed significantly better reductions in systolic blood pressure (BP) but a 3-fold higher incidence of angioedema with omapatrilat vs enalapril, as reported by heartwire .

All patients were divided into 3 categories:

  • Those not been previously treated for hypertension, who were started on 1 of the study drugs (initial group).

  • Those already controlled on medication, who were switched to 1 of the study drugs (replacement group).

  • Those uncontrolled on current medication and had 1 of the study drugs added to their therapy (add-on group).

The new analysis included 2371 patients (9% of the OCTAVE study) who had a history of atherosclerotic disease, such as MI, angina pectoris, stroke, or transient ischemic attack.

Change in systolic BP at week 24 in atherosclerotic patients





Initial group (n=368) -24.8 -20.2 0.007
Replacement group (n=1122) -14.5 -11.8 0.007
Add-on group (n=793) -27.6 -25.7 0.117

The researchers found that in patients with atherosclerotic history, blood pressure was substantially more reduced with omapatrilat vs enalapril, said Weber. "Even in people getting 3 meds in addition to omapatrilat or enalapril there was still a huge difference." He also pointed to particularly strong BP-lowering benefits of 5 mm Hg to 8 mm Hg with omapatrilat over enalapril in diabetic patients.

Incidence of angioedema by week 24



No. of events

Incidence (%)

Difference (%)

Atherosclerotic disease Omapatrilat
No atherosclerotic disease Omapatrilat

Striking benefits

"Compared with a traditional ACE inhibitor close to 30 events are prevented for every 10.000 patients treated with omapatrilat every year," Weber commented to heartwire . "In terms of risk only at the most 6 patients would be expected to have severe angioedema and no deaths. In that sense the benefit is very clear and the risk is very low."

Striking risks

While Weber stressed the benefits of omapatrilat, Nussberger remained focused on the severity of the angioedema risk, showing a photo of a woman who suffered several facial swellings. She, Nussberger said, "would be a bagatelle case in Weber's statistics." He pointed out that the actual risk for angioedema would be greater than Weber's study shows. "Please note that the true incidence of angioedema per year is higher than reported in the OCTAVE trial. The patients were treated for 24 weeks only, they were selected for compatibility with ACE inhibitor treatment, and gastrointestinal and peripheral edemas were not accounted for," he commented. "If we use these drugs, we have to observe the benefit-risk ratio."

FDA approval?
Where the stakes are high and the probability of major events is high I think that omapatrilat is very well justified.

Weber, on the other hand, downplayed the increased risk in favor of the benefits. Referring to the 2-fold increase in angioedema with omapatrilat vs enalapril in the atherosclerotic population, he said: "When you double the likelihood of something occurring very infrequently you still have a drug that is very safe and relatively easy to use." He said that in high-risk patients, which make up about one fourth of all hypertensives, "where the stakes are high and the probability of major events is high, I think that omapatrilat is very well justified."

Weber is convinced that the FDA will approve omapatrilat for hypertension in this high-risk population, despite a 5:1 committee vote against approval. "It could have easily been 5:1 in favor," he said. "When I spoke to people at the committee afterwards they all seemed to think it's going to get approved. They just voted no because they wanted to see more data. I am pretty confident that they will approve omapatrilat in the future."

At its meeting on omapatrilat, the FDA's cardiorenal advisory committee said it generally accepted the likelihood that a population could be found in which control of hypertension could not be achieved with currently available regimens and for which, therefore, the addition of omapatrilat would provide clinical benefits that exceeded the risks associated with angioedema of the frequency and severity reported in OCTAVE. However, it was concerned that that population had not been defined with adequate precision for labeling and the efficacy and safety of omapatrilat had not been specifically assessed in this patient group. Whether Weber's analysis will be enough to persuade the FDA otherwise remains to be seen.

Subgroup analysis: a slippery slope

Commenting on Weber's new analysis to heartwire , Prof Paul Armstrong (University of Alberta), who sat on the FDA advisory committee that voted against approval of omapatrilat in July, warned of the hazards of subgroup analysis: "Subgroups are a slippery slope and even when a biologic rationale exists, they sometimes lead to conclusions that do not stand the test of time, eg, PRAISE 1 vs 2."

He said he could not speak for the FDA and the committee, but that "the thorough review of all data that are provided to the committee is often insightful in understanding and balancing the risks and benefits of novel therapies."

He noted that "when efficacy is measured with a biologic surrogate (ie, blood pressure) and safety assessed with meaningful clinical end points such as angioedema, special care is required to judge the appropriateness of introducing a new therapy."

He added, "That therapy may be warranted if conventional therapies have failed and the risk of poorly controlled hypertension presents a genuine threat of future vascular events to the patient. But in making that judgment one needs to be particularly mindful of the expected duration of treatment, who will be prescribing the therapy, how it will be monitored, and what precautions will be taken to ensure an appropriate risk/benefit ratio outside the controlled and somewhat artificial circumstances of a clinical trial."


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