E f f e c t s o f S t r e s s a n d B e h a v i o r a l

I n t e r v e n t i o n s i n H y p e r t e n s i o n
Thomas G. Pickering, MD, DPhil, Section Editor

The Rise and Fall of Omapatrilat

Thomas G. Pickering, MD, DPhil

appears to be weak. Furthermore, when omapatrilat

T his column does not usually deal with antihy-
pertensive drug issues, but I happened to be a
participant in the recent review by the Food and
is added to a thiazide, there is an additional antihy-
pertensive effect.4 One factor that may give
Drug Administration (FDA) Cardiorenal Advisory vasopeptidase the edge over ACE inhibitors as anti-
Committee of the application for omapatrilat as an hypertensives may be their greater potentiation of
antihypertensive agent by Bristol-Myers Squibb bradykinin,5 but as we shall see below, this may also
(BMS), and it makes an interesting story. This was be their Achilles heel. These encouraging results in
its second FDA review, and when it was first the treatment of hypertension were bolstered by
reviewed in March, 2000 it was hailed as the first of equally exciting initial results in heart failure. The
an entirely new class of antihypertensive agents, the Inhibition of Metallo Protease by BMS-186716 in a
vasopeptidase inhibitors. These agents are essential- Randomized Exercise and Symptoms Study in
ly “super ACE inhibitors,” and have a dual action, Subjects With Heart Failure (IMPRESS) trial6 ran-
combining inhibition of both the angiotensin-con- domized patients with congestive heart failure to
verting enzyme (ACE) and neutral endopeptidase. either omapatrilat (289 patients) or lisinopril (284).
The latter enzyme is responsible for the breakdown At the end of 7 months there were significantly
of the three natriuretic peptides—atrial natriuretic fewer end points (hospitalizations for heart failure
peptide, brain-derived natriuretic peptide, and C- or mortality) in the omapatrilat group. In 2000,
type natriuretic peptide—and bradykinin. The natri- confident that they had a blockbuster antihyperten-
uretic peptides have actions that might be consid- sive in the wings, BMS took out one page nonpro-
ered beneficial for hypertensive patients—vasodila- motional advertisements in the national press titled
tion, natriuresis, and inhibition of the sympathetic “an open letter to healthcare providers nationwide,”
nervous system and the renin-angiotensin-aldos- which pointed out that hypertension control in the
terone system. Neutral endopeptidase inhibition United States was abysmal, and exhorting health
was tested as a possible means of lowering blood care providers to make a commitment to improve
pressure, but on its own was found to be ineffec- the situation. It was signed by 35 hypertension
tive.1 However, numerous studies of omapatrilat experts (including Dr. Marvin Moser and myself
(not all of which appear to have been published as and many members of the editorial board of this
full papers) have shown that it is a highly potent journal). No drugs were mentioned.
antihypertensive agent, and when compared with As a result of these findings, two large and more
some of the leading antihypertensives such as losar- definitive outcome studies were planned. The first
tan, amlodipine,2 lisinopril,3 and enalapril, it beat was OVERTURE (Omapatrilat Versus Enalapril
them all. Somewhat surprisingly, this extra potency Randomized Trial of Utility in Reducing Events),
cannot be attributed to a diuretic effect, which which enrolled 5770 heart failure patients random-
ized to enalapril or omapatrilat. The results, which
were announced at the American College of
From the Integrative and Behavioral Cardiovascular Health Cardiology in 2002,7 were disappointing, since there
Program, Zena and Michael Wiener Cardiovascular was no effect on the major end points, which includ-
Institute, Mt. Sinai School of Medicine, New York, NY
Address for correspondence: ed death and hospitalization for heart failure. The
Thomas G. Pickering, MD, DPhil, Mt. Sinai School of second was OPERA (Omapatrilat in Persons With
Medicine, 50 East 98th Street, New York, NY 10029 Enhanced Risk of Atherosclerotic Events).8 This was

VOL. IV NO. V SEPTEMBER/OCTOBER 2002 THE JOURNAL OF CLINICAL HYPERTENSION 371

 an interesting design, since it proposed to study peo- First, the time course was quite different, with many
ple with borderline isolated systolic hypertension of the omapatrilat cases occurring soon after the first
(systolic pressures between 140–159 mm Hg), who dose; thus, there were 91 cases reported on the first
were randomized to be treated either with omapatri- day of exposure to the study drugs, of which 88 were
lat or placebo. Such individuals are known to be at in the omapatrilat group. Second, the cases of
increased risk, but it is not known if treating them angioedema seen with omapatrilat were more likely to
will lower it. The plan was to study 12,600 subjects, be severe; the relative risk of all cases of angioedema
who would be followed for 5 years. The OPERA was 3.1 times higher in the omapatrilat group, but the
study has now been dropped. risk for angioedema requiring hospitalization was 9.5
The FDA reviewed the original application for times higher. It was also possible to identify risk fac-
omapatrilat in March of 2000. The safety database tors predisposing to angioedema, foremost among
consisted of 9372 patients who had been treated which were black race (2.96 times higher for omapa-
with omapatrilat. No deaths were reported, but the trilat) and smoking (2.58 times higher). The higher
most serious adverse event was angioedema, which risk in blacks was compounded by the fact that
occurred in 0.5% of patients, and was life threaten- angioedema from ACE inhibitors is also more com-
ing in four (requiring emergency intubation or mon in blacks than whites, so the absolute risk of
cricothyrotomy/tracheostomy). At the FDA meeting angioedema from omapatrilat in OCTAVE was
it appeared that the occurrence of severe angioede- 5.54% in blacks, or more than 1 in 20 patients.
ma was higher than with any ACE inhibitors, and The issue confronting the committee was thus a
BMS was instructed to find a way around this prob- classic question of balancing risks versus benefits. The
lem, or the approval of omapatrilat would be at sponsors of the application, BMS, recognized the
risk. In these studies, many of the patients had been increased risk, and proposed that the approval should
started on the 20 mg dose, and it appeared that be limited to patients at high risk for cardiovascular
starting with the 10 mg dose might be associated events, such as a previous history of cardiovascular
with a lower incidence of angioedema. disease, target organ damage, or diabetes, and hyper-
OCTAVE9 (Omapatrilat Cardiovascular Treatment tension that is difficult to control. The central argu-
Assessment Versus Enalapril) was primarily designed ment of BMS was that an additional reduction of 3/2
to see if starting with a smaller dose of omapatrilat mm Hg in these patients would lower the risk of
would result in a lower incidence of angioedema. The events by 20–30 per 10,000 patient-years, and that
study design involved recruiting 25,000 patients with would more than outweigh the 1.6 per 10,000 risk of
previously treated or untreated hypertension who serious angioedema. It sounds like a convincing argu-
were randomized to be treated with either enalapril ment, so why did the Committee not approve the
(starting at 5 mg and increasing to 40 mg daily) or drug? Central to the discussion was the validity of the
omapatrilat (10–80 mg). Patients with a history of assumption that the addition of omapatrilat would
angioedema, anaphylaxis, or multiple drug allergies automatically lead to improved blood pressure con-
were excluded. For the first 8 weeks only the study trol. Looking at the trends in blood pressure control
drugs could be used, but at 8 and 16 weeks addition- over the last 20 years does not actually lend any sup-
al medications could be added to try to get the patients port to this idea. We have witnessed the introduction
to the goal blood pressure of 140/90 mm Hg. of two completely new classes of antihypertensive
Throughout the 24-week study the blood pressure drugs, the ACE inhibitors and the angiotensin recep-
readings were lower (by about 3/2 mm Hg) in the tor blockers, and the annual expenditure on antihy-
omapatrilat group. The primary hypothesis was that pertensive drugs has increased dramatically, but there
by starting with the smaller dose of omapatrilat the is not a shred of evidence that there has been any
incidence of angioedema would be no greater than meaningful improvement in the rate of blood pressure
twice the amount seen with enalapril, putting omapa- control, which remains at 27%–29%.10 In contrast to
trilat in the ballpark of the ACE inhibitors. However, this dismal state of affairs, two recent studies, the
the data failed to confirm this hypothesis, and showed Antihypertensive and Lipid-Lowering Treatment to
a risk that was 3.2 times higher than that for enalapril. Prevent Heart Attack Trial (ALLHAT)11 and the
An independent committee that adjudicated the Controlled Onset Verapamil Investigation of
reported angioedema events concluded that there were Cardiovascular End Points (CONVINCE),12 both
274 events in the omapatrilat group, and 86 in the treating hypertensive patients who were at somewhat
enalapril group. increased risk, have reported that simply following a
Apart from the larger numbers, there were two predetermined protocol, and using conventional and
other important differences between the two groups. readily available drugs, could increase the control rate

372 THE JOURNAL OF CLINICAL HYPERTENSION VOL. IV NO. V SEPTEMBER/OCTOBER 2002

to more than 65%. In addition, there was some con- tion in this class has just been suspended. Hopefully
cern that the design of OCTAVE, the results of which this event may spur more research on the causes and
were the basis of the 3/2 mm Hg superiority claim for prevention of angioedema. How many of us routinely
omapatrilat, did not really allow or encourage aggres- warn our patients about it when we start them on
sive addition of other antihypertensives to get the ACE inhibitors? Ironically, the first patient I saw after
patients to the goal blood pressure. In part, this was returning from the meeting, who happened to be
because there were only two visits at which additional black, was complaining of swelling of the face and lips;
drugs could be added. Thus, in the previously untreat- he was taking an ACE inhibitor.
ed group of patients, only 19% in the enalapril group
and 13% in the omapatrilat group were given any REFERENCES
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3 Campese VM, Lasseter KC, Ferrario CM, et al. Omapa-
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Omapatrilat in Persons with Enhanced Risk of Atherosclerotic
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