Transcript Dosage of enalapril for congestive heart failure in USA

Clinical Trial Commentary
OPTIME CHF and PRAISE II:
Recent heart failure trials
Dr Eric Topol
Chairman and Professor, Department of Cardiology
Director of the Joseph J Jacobs Center for Thrombosis and
Vascular Biology at the Cleveland Clinic
Dr Robert Califf
Professor of Cardiology
Associate Vice Chancellor for
Clinical Research at Duke University
OPTIME CHF
Study objective
OPTIME CHF: Outcomes of a Prospective Trial of
Intravenous Milrinone for Exacerbations of Chronic
Heart Failure
The OPTIME CHF trial was designed to evaluate
whether intravenous treatment with milrinone (a
bipyridine inotropic/vasodilator that improves
hemodynamics in the short term), in addition to best
medical therapy, in patients admitted with an
exacerbation of CHF but not requiring pressor or
inotrope support, would reduce the number of days of
hospitalization for cardiovascular events in the
intermediate (60-day) term.
Mihai Gheorghiade MD (Northwestern University, Chicago, Illinois, USA)
OPTIME CHF
Study design
OPTIME CHF was a prospective, randomized, doubleblind placebo-controlled trial with a 60-day follow-up.
951 patients from 78 US centers were randomized
within 48 hours of admission to intravenous milrinone
0.5 g/kg/min without a bolus dose (n=477) or placebo
(n=472) for 48 hours.
Primary endpoint: rehospitalization for cardiovascular
events within 60 days of treatment
Secondary endpoints: subjective improvement; length of
initial hospitalization; treatment failures within the first
48 hours; proportion of patients reaching, and time to
reach, the target dose of the ACE inhibitor; and
mortality and adverse events
OPTIME CHF
Study results
There was no significant difference in the primary
endpoint (days of hospitalization for cardiovascular
events within 60 days)
IV
milrinone
Controls
Number of patients
Median hospital stay (days)
Mean hospital stay (days)
Days until discharge
477
6
12.3 ± 14
5.7 ± 13
472
7
12.5 ± 14
5.9 ± 13
Total mortality rates (in hospital and at 60 days) were
not significantly different between the 2 groups.
A subgroup analysis by cause of heart failure revealed a
small trend favoring milrinone in the non-ischemic heart
failure group, and the opposite in the ischemic heart
disease group.
OPTIME CHF
Secondary endpoints
Milrinone
Placebo
p value
7.9%
6.6%
0.536
12.6%
2.1%
<0.001
Treatment-related new
atrial fibrillation
4.6%
1.5%
0.004
Sustained hypotension
10.7%
3.2%
<0.001
1.5%
0.4%
0.178
Reduction in treatment
failures or progression
of CHF
Number of
complications
Myocardial infarcts
OPTIME CHF
Study conclusions
OPTIME CHF is the largest randomized trial of
hospitalized patients with CHF conducted to date.
Patients who are admitted for exacerbation of chronic
CHF but are not believed to require inotropic support do
not derive any additional benefit from milrinone therapy.
The potential benefit that milrinone may have in nonischemic heart failure needs further investigation.
Caution should be exercised before making an early
jump to aggressive therapy (ie, inotropes) in patients
admitted with CHF but preserved blood pressures.
Aggressive diuresis should be tried before initiating
intravenous inotropic support.
Outcome-based trials
FDA requirements
It has always been assumed that improving the
hemodynamics in acute heart failure is good for the
patient in the long term.
Because of this assumption, the FDA does not require
clinical outcome trials in this area; this made it
difficult to conduct the OPTIME CHF trial.
Several types of agents are now being studied
 neutral endopeptidase (NEP) inhibitors
 and brain natriuretic peptide (BNP)
ANP was turned down by the FDA recently in a study
that looked at hemodynamics; an outcome-based
clinical trial with ANP is currently being conducted.
PRAISE 1
Advanced heart failure patients
PRAISE (Prospective Randomized Amlodipine Survival
Evaluation): a randomized, placebo-controlled trial with
more than 1100 cardiomyopathy patients, randomized
to amlodipine (a calcium channel blocker), or placebo.
The primary endpoint of the study (all-cause mortality
or cardiovascular morbidity) was not significantly
different between the 2 groups.
Unexpected results
Amlodipine was beneficial for patients with non-ischemic
cardiomyopathy — a 31% risk reduction (95% CI 2%–
51%; p=0.04) in the primary endpoint.
All-cause mortality (a secondary endpoint) was reduced
by 46% (95% CI 21%–63%; p<0.001), a benefit not
seen in the ischemic heart disease patients receiving
amlodipine.
PRAISE 1
Trial results
The study results were considered by many to be highly
credible because the reduction in mortality was seen in
a prospectively defined subgroup and the p value was
very small (<0.001), in addition to the fact that
mortality is an unbiased and incontrovertible endpoint.
Critics argued that although prospectively defined, the
subgroup was small (only 119 patients) and all-cause
mortality was a secondary endpoint.
Moreover, no plausible mechanisms could explain the
risk reduction in patients with non-ischemic
cardiomyopathy; risk reduction had been expected in
the ischemic heart disease population.
PRAISE 2
Non-ischemic heart failure patients
PRAISE 2 was designed as a follow-up trial to evaluate
prospectively the benefit of amlodipine seen in PRAISE 1.
It was powered at 90% to detect a 25% difference in
mortality between the treatment arms.
Patients were randomized to double-blind therapy with
amlodipine or placebo; amlodipine was started at 5 mg a
day and then increased to 10 mg a day after 2 weeks.
PRAISE 2 was designed to recruit 1800 patients and
follow them for 36 months; enrollment in the trial was to
continue until 263 deaths occurred in the placebo arm.
In reality, the trial recruited 1652 patients and it took 48
months to record the required number of deaths in the
placebo arm; recruitment was halted in January 2000.
Packer M, et al
(Columbia University College of Physicians & Surgeons, New York, NY)
PRAISE 2
Study results
PRAISE 2
Amlodipine Placebo
PRAISE 1 and 2
Amlodipine
Placebo
Patients
826
826
1408
1397
Deaths
262*
278
479†
466
31.7%
33.6%
34.0%
33.4%
Mortality
*Odds ratio = 1.09 (p=0.28)
†Odds ratio = 0.98
No differences were seen in different subgroups of the
study population (age, sex, NYHA class, ejection
fraction).
PRAISE 2
Conclusions
The results of PRAISE 2 do not confirm the survival
benefit of amlodipine seen in non-ischemic
cardiomyopathy in the PRAISE 1 trial.
The favorable survival benefit of amlodipine seen in
PRAISE 1 was likely due to chance, despite the fact
that mortality is an unequivocal endpoint; the benefit
was seen in a prespecified subgroup and the p value
for the subgroup was very small.
The combined results of PRAISE 1 and PRAISE 2
indicate that long-term treatment with amlodipine is
neither beneficial nor harmful in patients with severe
chronic heart failure.
The results of PRAISE 2 emphasize the need for
replication, even when the results define a mortality
benefit and are associated with low p values.
ELITE I
Evaluation of Losartan in the Elderly
ACE inhibitor-naive patients (aged 65 years or more) with
NYHA class II–IV heart failure and ejection fractions  40%
were randomly assigned to losartan titrated to 50 mg daily
or captopril titrated to 50 mg 3 times daily, for 48 weeks.
Losartan Captopril
(n=352) (n=370)
Increase in serum creatinine
Discontinuation of therapy
because of side effects
Death and/or hospital
admission for heart failure
All-cause mortality
p
value
10.5%
10.5%
12.2%
20.8%
0.002
9.4%
13.2%
0.075
4.8%
8.7%
0.035
Treatment with losartan was associated with an
unexpected lower mortality than treatment with captopril.
Pitt B, et al. Lancet 1997;349(9054):747-752
ELITE II
Confirmatory study of ELITE I
Losartan Captopril
(n=1578) (n=1574) p value
All-cause mortality
11.7%
10.4%
0.16
Sudden death or
resuscitated arrests
9.0%
7.3%
0.16
Discontinuation of
therapy because of side
effects
9.7%
14.7%
<0.001
There were no significant differences in the primary
endpoint of all-cause mortality or the secondary endpoint
of sudden death or resuscitated arrests between the 2
treatment groups (hazard ratios 1.13 [95% CI 0.95–1.35],
p=0.16 and 1.25 [95% CI 0.98–1.60], p=0.16 ).
Pitt B, Lancet 2000;355(9215):1582-1587
Clinical trial results
Understanding pathophysiology
Large trials with many events are optimal, but
biologic plausibility and a foundation are also
desirable.
In the PRAISE trials, there was no good
explanation of why patients with non-ischemic
heart failure would specifically benefit.
All too often, explanations that fit the data are
used, rather than pathophysiological confirmations
of the results.
Omapatrilat
New drug approval application
A new drug approval (NDA) application was submitted to the
FDA with data on patients who had taken omapatrilat.
Omapatrilat had been given fast-track status and was
scheduled for review by an FDA advisory committee at the
beginning of May 2000; approval was expected a few
months later.
Among the 7000 patients, there were 44 cases of
angioedema, 4 of which were classed as severe (requiring
intubation).
The incidence of angioedema is no higher than that seen
with ACE inhibitors; angioedema occurs with ACE inhibitors
in about 0.3%–0.5% of white patients and about 3 times
more frequently in black patients.
Because omapatrilat has an ACE inhibitor component, the
presence of this side effect is not surprising.
Omapatrilat
NDA application withdrawn
Having been criticized in the past for not being
concerned about rare side effects; the FDA now wants
to see safety data from more patients.
As with ACE inhibitors, angioedema with omapatrilat
normally occurred with the first dose of the drug, and
seems to be dose related; it is more likely to occur at
a starting dose of 20 mg than at 10 mg.
The incidence of angioedema should be kept to a
minimum if patients are started on the lowest dose,
and gradually titrated up.
Another 2000 patients have already been enrolled in
the 2 major clinical trials underway in hypertension
and heart failure.
TTP and clopidogrel
11 patients developed TTP
6 women and 5 men, aged 35 to 70 years (median=55)
6 patients received clopidogrel for coronary artery
disease, 3 of whom received clopidogrel after placement
of a coronary artery stent
10 patients used clopidogrel for fewer than 14 days,
1 patient used clopidogrel for 330 days
Concomitant medications
5 patients were taking atorvastatin or simvastatin, 2 of
whom began taking the cholesterol-lowering drug 3
weeks before TTP onset
3 patients were on long-term atenolol therapy
1 kidney-pancreas transplantation patient was on longterm cyclosporine therapy
www.nejm.org/content/bennett/1.asp
Bennett CL, Connors JM, Carwile JM, et al. N Engl J Med 2000 (June 15)
TTP and clopidogrel
False alarm?
The 11 cases were scrutinized by TTP experts, who
determined that at least 5 of them were not TTP.
The incidence of clopidogrel-induced TTP is no higher than
the incidence of TTP the general population.
The incidence of clopidogrel-induced TTP is much lower
than that seen with ticlopidine, which has been reported to
be from 1 in 6001 patients to 1 in 50002 patients.
Because the chemical structure between clopidogrel and
ticlopidine is similar, an association with TTP was not
surprising.
Rare side effects, which have also been seen recently with
Rezulin (troglitazone) and Posicor (mibefradil
dihydrochloride), can limit the availability of agents that
could be useful to specific patients.
1. Bennett CL, et al. Arch Intern Med 1999 Nov 22;159(21):2524-2528
2. Steinhubl SR, et al. JAMA 1999 Mar 3;281(9):806-810