Transcript Dosage of enalapril for congestive heart failure in USA

Clinical Trial Commentary
TARGET and TACTICS
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
TARGET
Do Tirofiban And ReoPro Give
similar Efficacy Trial
This trial was the first of the glycoprotein (gp)
IIb/IIIa inhibitor comparative trials.
TARGET enrolled 4812 patients from 18
countries who were undergoing coronary
stenting.
Patients were randomized to tirofiban or
abciximab.
Tirofiban was given at the dose previously
tested in the RESTORE trial and abciximab was
given at the normal dose used in clinical
practice.
TARGET
Primary endpoint
The primary endpoint, 30-day outcomes of
death, MI, and urgent revascularization, was
powered to detect noninferiority of tirofiban.
Tirofiban
Abciximab
OR
p-value
7.55%
6.01%
1.26
0.037
OR odds ratio
TARGET
Individual outcomes
Effects of individual components on the
primary endpoint
Endpoint
Tirofiban
Abciximab
Death
0.5%
0.4%
MI
6.9%
5.4%
Urgent
revascularization
0.8%
0.7%
TARGET
Class effect
TARGET directly addresses the issue of class
effect.
Class effect seems to be called upon as a
reason to use a drug when it's to the
advantage of the manufacturer of that drug.
The absence of class effect is similarly given
as a reason to use a drug when that is to the
manufacturer’s advantage.
TARGET calls into question any presumptions
that one makes about whether 2 different
drugs attacking the same mechanism may be
different.
TARGET
Points of discussion
In TARGET, as in many interventional trials
done in the recent past, patients who were
randomized and then found not to be suitable
for intervention or treatment were not
counted in the primary endpoint. This
comprised a total of 496 patients.
The dosing of tirofiban may also not have
been adequate, although an aggressive
dosing regimen was used compared to the
currently recommended label dosing.
TARGET
Intention to treat?
Most of the 496 patients (9% total) who were
randomized but not treated were enrolled
before any knowledge of their coronary
anatomy had been obtained - they either had
a coronary anatomy requiring surgical
intervention or had no significant disease.
The trial protocol included only patients who
were randomized and received study drug.
The trial was designed using a rigorous
double-dummy, double-blind format.
TARGET
Dose of tirofiban?
The dose of tirofiban was the same dose used
in the RESTORE trial.
At this dose, it had previously been shown
that the platelet inhibition at 5 minutes into
the procedure and right before the end of the
infusion and several hours into the procedure
was approximately 95% to 5 μmol ADP as an
agonist.
The benefit seen in the abciximab group may
have been due to additional effects at the
level of integrin interactions.
TARGET
Subgroup analysis
Non-US patients (approximately 1000) had a
more pronounced benefit in the trial as a
subgroup.
Non-ACS (acute coronary syndrome) patients
receiving tirofiban showed a trend toward benefit.
Primary composite endpoint at 30-days
Treatment group
Tirofiban
Abciximab
ACS
9.3%
6.3%
Non-ACS
4.5%
5.6%
ACS acute coronary syndrome
TARGET
Clinical implications
From the results of TARGET, the use of
tirofiban in the cath lab should now be
restricted to the following:
1) patients in randomized trials with new
dosing regimens
or
2) in financially constrained healthcare
environments with insufficient funding to
pay for abciximab
TACTICS
Treat angina with Aggrastat and determine
the Cost of Therapy with Invasive or
Conservative Strategies
This study, also known as TIMI-18, looked at
an early invasive strategy incorporating
upstream gp IIb/IIIa inhibition with tirofiban
and catheterization for the treatment of
patients with unstable angina (UA) and nonST segment elevation MI (NSTEMI).
This is one of a series of trials trying to
establish a place and need for aggressive
intervention in clinical practice.
TACTICS
Design
2220 patients with UA or NSTEMI received
medical treatment with aspirin, heparin, beta
blockers as well as tirofiban (administered for
48 to 108 hours).
They were then randomized to
catheterization within 4 to 48 hours or to a
more conservative strategy where they were
referred for catheterization only for recurrent
rest pain or a positive functional test.
The trial's primary endpoint was the
combined incidence of death, MI or
rehospitalization for ACS at 6 months followup.
TACTICS
Primary endpoint
Cardiac events at 6 months
Outcome
Conservative
(n=1106) %
Invasive
(n=1114) %
Odds
ratio
p-value
Primary
endpoint
19.4
15.9
0.78
0.025
Death/MI
9.5
7.3
0.74
<0.05
Death
3.5
3.3
0.93
0.74
MI
6.9
4.8
0.67
0.029
13.7
11.0
0.78
0.054
Rehosp
ACS
TACTICS
Troponin subgroup
The researchers also tested blood levels of
troponin, which have been shown to predict a
high increased risk of adverse outcome in
acute coronary syndromes, upon arrival to
hospital.
Patients who had a positive troponin had an
absolute 10% reduction in the trial's primary
endpoint, from 24% down to 14%.
TACTICS
Points of discussion
This is the only contemporary trial that
reflects (and now validates) the US practice
of the invasive interventional approach.
The trial did not address the question of
whether or not you have to have the gp
IIb/IIIa inhibitor on board, since both arms
received tirofiban.
It did not address the controversy
surrounding the use of low-molecular weight
heparin.
TACTICS
Clinical implications
No benefit to the invasive approach was seen
in patients who had no ST changes, and
there was no benefit in patients who were
troponin negative.
Abciximab is still the only gp IIb/IIIa inhibitor
to date that has been shown to reduce
mortality.
Despite validation of the treatment of ACS
from these trials, there are still a large
number of events in the longer term followup of patients with ACS that need to be
studied.
The role of eptifibatide
There are no troponin or foundation strategy
data on eptifibatide.
Data from the PURSUIT trial, using
eptifibatide, are similar to the results from
TACTICS.
Direct comparative data and data from an
aggressive versus waiting approach using
eptifibatide are necessary.