(Circulation. 1998;97:2295-2296.)
© 1998 American Heart Association, Inc.
FDA Panel Report: January 1998
Udho Thadani, MD;
; Dan M. Roden, MD
From the University of Oklahoma Health Sciences Center, Tulsa (U.T.) and
Vanderbilt University Medical Center, Nashville, Tenn (D.M.R.).
Correspondence to Dan M. Roden, MD, Vanderbilt University Medical Center, 532 Medical Research Bldg, Nashville, TN 37232-3304.
The
Cardiovascular and Renal Advisory Panel of the FDA met
January 27-28, 1998, to discuss (1) evaluation and use of
intravenous inotropic agents in patients with heart
failure; (2) liver function test abnormalities with a new
AT1 receptor blocker, tasosartan; and (3) the use
of the platelet IIb/IIIa receptor blocker eptifibatide in syndromes
of acute cardiac ischemia.
Intravenous Inotropic Agents for Heart Failure
Intravenous drugs for the treatment of heart failure
historically have been approved after demonstration of acute
dose-dependent hemodynamic effects in patients with
heart failure. Recently, however, there appears to have been a marked
increase in the intermittent or continuous use of
intravenous inotropic agents for longer periods than
originally anticipated, often without monitoring of cardiac rhythm.
This practice has become prevalent despite recent trials with oral
inotropic agents that have shown adverse effects on mortality and
morbidity during long-term treatment and preclinical data
presented to the committee that raised the possibility that
intermittent exposure to intravenously administered
positive inotropic agents may accelerate myocardial cell death. The
committee therefore voted unanimously that short-term use of
intravenous inotropic agents for decompensated heart
failure should be approved if an improvement in symptoms, renal
function, and/or hemodynamics (including patients after
bypass surgery) can be shown. However, for prolonged intermittent or
continuous intravenous use, an improvement in survival and
symptoms should be demonstrated in a placebo-controlled trial. The
committee unanimously recommended that labeling of
intravenous positive inotropic agents be revised to reflect
the following: (1) that these drugs are indicated for patients who are
hospitalized with acutely decompensated heart failure, (2) that there
is no experience in controlled trials with continuous infusions for
periods >24 to 48 hours, (3) that there is no evidence that these
drugs are effective or safe in patients with heart failure if used
intermittently or continuously as a short-term or long-term management
strategy, (4) that long-term oral use of these drugs has been
associated with an increased risk of hospitalization and death, and (5)
that there is no evidence that long-term use of these drugs given
intravenously does not carry a similar risk.
Tasosartan and Abnormal Liver Function Tests
Tasosartan is an AT1 receptor blocker with a
slowly eliminated active metabolite. Its antihypertensive efficacy
seems to be similar to that of irbesartan, losartan, and
valsartan. In the tasosartan database, however, values of AST or ALT
twice the upper limit of normal were seen in 16 of 950 patients (1.7%
versus 1.2% in placebo) and 8 times the upper limit of normal in 4 of
950 (0.4% versus 0%). Some patients with abnormal values were
continued on therapy, and in some, values decreased or returned to
normal. Drug rechallenge reproduced abnormal values in 6 of 6 patients.
The committee heard evidence indicating that elevated transaminases may
not correlate well with actual liver damage, and clinically apparent
liver disease (defined as serum bilirubin value >2.5 mg% or prolonged
prothrombin time) was not seen in the tasosartan database. A review of
the New Drug Application databases for losartan and valsartan
suggested an incidence of abnormal transaminases of 0.4% to 2.1%,
comparable to incidence with the respective placebos. In these
databases, however, liver function was assessed monthly, whereas it was
assessed weekly with tasosartan. Moreover, the committee heard evidence
from the FDA that postmarketing surveillance has identified 13 possible
cases of serious liver disease (including 2 fatalities) in association
with marketed AT1 receptor blockers. The
committee unanimously agreed that the higher incidence of abnormal
transaminases with tasosartan could well be attributed to the increased
frequency of the determinations compared with other
AT1 receptor blockers. The drug was recommended
for approval with labeling that would specify the incidence of abnormal
liver function tests with this and similar agents.
Eptifibatide (Integrilin)
An application to market eptifibatide, an inhibitor of
the platelet IIb/IIIa receptor that prevents platelet
aggregation via a mechanism different from that of aspirin, had been
previously reviewed and not recommended by the committee. That decision
was reached in part because only a single trial (with borderline
statistical significance) was presented, whereas the usual
standard is 2 efficacy trials. Moreover, in that trial (IMPACT II),
only a low-dose regimen and not a high-dose regimen was shown to be
effective. The results of IMPACT II were again presented
briefly. The patients studied were those undergoing intervention for
unstable myocardial ischemic syndromes. The primary composite
end point of death, MI, or urgent revascularization
at 30 days was reached in 11.6% of patients receiving placebo, 9.1%
of patients receiving low-dose Integrilin (bolus 135 µg/kg and
infusion 0.5 µg · kg-1 ·
min-1) for 24 hours, and 10.1% of patients
receiving high-dose Integrilin (bolus 135 µg/kg and infusion 0.75
µg · kg-1 ·
min-1) for 24 hours. A significant difference
compared with placebo was seen only in the low-dose group
(P=0.035). The committee noted that the publication of the
IMPACT II results reported this P value at
0.063,1 indicating the sensitivity of the
conclusions to different assumptions regarding the
analysis.
At the recent meeting, a second large trial (PURSUIT) was
presented. PURSUIT was conducted in North America, Europe, and
Latin America and was designed to evaluate the efficacy of eptifibatide
in preventing death or reinfarction in patients hospitalized with
unstable angina or non–Q-wave MI. The doses were higher than those
used in IMPACT II, because the goal was to achieve 80% platelet
inhibition, and in vitro data suggested that this was not achieved with
either the low or the high doses in IMPACT II. In PURSUIT, patients
were randomized to 1 of 3 groups: placebo, low-dose (180 µg/kg bolus
and 1.3 µg · kg-1 ·
min-1 infusion), or high-dose (180 µg/kg bolus
and 2.0 µg · kg-1 ·
min-1 infusion) for up to 72 hours, or up to 96
hours if balloon intracoronary intervention (stent and/or
percutaneous transluminal coronary angioplasty)
was performed. At a prespecified review after 3218 patients were
recruited, the high-dose regimen appeared to be safe, so recruitment
into the low-dose arm was stopped. The primary end point was death or
reinfarction at 30 days. Of a total of 10 948 patients enrolled, 4739
were assigned to placebo and 4722 to high-dose eptifibatide. The groups
were balanced: 
50% had ST depression, 14% ST elevation, 46%
elevated creatine kinase MB levels, 59% to 60% coronary
angiography, 23% to 24% percutaneous interventions,
and 14% bypass surgery. The composite primary efficacy end point was
reached in 15% of patients in the placebo group and in 14.2% of
patients in the Integrilin group (P=0.042), but there was no
difference in the individual end-point components of death or
reinfarction. When investigators, rather than an end-point event
committee, assessed the 30-day end point, composite end-point rates
were lower in both groups: 10.0% for the placebo group versus 8.1%
for the Integrilin group. This difference was driven primarily by
enzyme determination of reinfarction. There was no difference in the
incidence of strokes (0.8% versus 0.7%), whereas the eptifibatide
group had a higher incidence of bleeding; for example, using the TIMI
scale, bleeding rates were 9.3% versus 10.8% for major bleeding and
7.6% versus 13.1% for minor bleeding. The incidence of
thrombocytopenia was similar in the two groups. A post hoc, but
prespecified, analysis of patients who underwent
percutaneous coronary interventions showed that
the primary end point was reached in 16.8% of patients in the placebo
group and in 11.5% of patients in the Integrilin group. Conversely,
there was no difference in patients who did not undergo such
interventions. These subgroup results were driven primarily by patients
recruited in North America.
The discussion about approvability of eptifibatide centered on the
risks versus benefits shown in the two trials, which were thought to
have studied different populations, at different dosages, and with
different end points. The committee voted that the outcome of PURSUIT
was not sufficiently compelling alone to recommend approval of
eptifibatide for unstable angina or non–Q-wave myocardial infarction
and that the results of IMPACT II did not influence this conclusion.
Conversely, the outcome in the subset of patients in PURSUIT who
underwent revascularization procedures, along with
the outcome of IMPACT II, was thought to be sufficiently compelling
that, in a split vote, the committee recommended approval of
eptifibatide as concomitant therapy in the treatment of
coronary intervention for patients with characteristics similar
to those of patients who entered the IMPACT II trial. The dose
recommended was the one found to be effective in IMPACT II, 135 µg/kg
bolus and 0.5 µg · kg-1 ·
min-1, for up to 24 hours.
References
-
The IMPACT II Investigators. Randomised
placebo-controlled trial of effect of eptifibatide on complications of
percutaneous coronary intervention: IMPACT II:
Integrilin to Minimise Platelet Aggregation and Coronary
Thrombosis-II. Lancet. 1997;349:1422–1428.[Medline]
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