Transcript Dosage of enalapril for congestive heart failure in USA

Clinical Trial Commentary
PPP and Complement Inhibition
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
PPP
Where we are now
Aspirin has been shown to be quite effective
in secondary prevention, but there has been
significant controversy about primary
prevention
Physicians’ Health Study – stopped early,
substantial reduction in non-fatal MI but an
excess of hemorrhagic strokes (nonsignificant trend)
British study – did not show dramatic
difference in primary prevention
PPP
Primary Prevention Project
Innovative approach: recruiting from daily
practice
Open 22 factorial design in 4495 people with
one or more major cardiovascular risk factor
(hypertension, hypercholesterolemia,
diabetes, obesity, family history of premature
myocardial infarction, or old age) but no prior
events or symptomatic angina
The PPP trial evaluated low-dose aspirin
(100 mg/day) and vitamin E (300 mg/day)
in a randomized, non-blinded study
PPP
Results
Aspirin
(n=2226)
No aspirin
(n=2269)
Relative risk
(95% CI)
Total
cardiovascular
events
6.3%
8.2%
0.77
(0.62–0.95)
Total mortality
2.8%
3.4%
0.81
(0.58-1.13)
Cardiovascular
mortality
0.8%
1.4%
0.56
(0.31–0.99)
All stroke
0.7%
1.1%
0.67
(0.36–1.27)
Roncaglioni et al. Lancet 2001; 357:89-95
PPP
Design
“The ability to inexpensively randomize a
large number of patients and get a result
that’s this dramatic not only is an important
finding for clinical practice, but also, I think,
points the way to a system that we might use
to more rapidly evaluate the effectiveness of
simple interventions in primary care
practice.”
Dr Robert Califf
Professor of Cardiology
Associate Vice Chancellor for
Clinical Research at Duke University
PPP
Issues with the trial
Primary endpoint not significant
CV death, non-fatal MI, non-fatal stroke
Relative risk = 0.71 (0.48–1.04)
Trial stopped early
enrolled 4495 instead of the projected
7500 patients owing to the results of
other trials that may not be germane
PPP
Choice of endpoint
Does total mortality trump a primary
endpoint?
Should you pull out cardiovascular mortality?
Do partial studies weaken the implications of
secondary endpoints?
PPP
Available dose
100-mg dose isn’t available in the US
Effectiveness of 80-mg dose seems to have
been corroborated by several studies
Hypertension may be a contraindication for
aspirin use (Hypertension Optimal
Treatment trial)
PPP
Optimal dose
The optimal dose remains unresolved
Currently anywhere from 80 mg to 325 mg
has been validated in one way or another
Correct dose of aspirin could be more
effective for developing countries than the
latest drug
A simple dose-comparison study is being
proposed
PPP
Conclusions
Califf
PPP and HOT push him to recommend aspirin
as primary prevention
Topol
Aspirin shows implications in many diseases
other than cardiology
This is convincing, but would be more
convincing if the trial had gone to completion
Complement inhibition
Pexelizumab study
Pexelizumab (Alexion/Procter & Gamble):
An anti-inflammatory C5 inhibitor monoclonal
antibody fragment
914 patients scheduled for CABG surgery, or
CABG plus valve replacement enrolled,
randomized to:
• placebo
• pexelizumab in a 2.0 mg/kg bolus
• pexelizumab in a 2.0 mg/kg bolus followed
by a 24-hour infusion of pexelizumab at
0.05 mg/kg/h
Complement inhibition
Results
30-day safety and efficacy follow-up
Results only available from a press release
CABG-only group (n=796)
Pexelizumab
Placebo
Death
0.4%
1.9%
Non-Q-wave MI
(CK-MB >100 ng/mL)
2.7%
8.0%
Death or MI
(non-Q-wave or Q-wave)
7.8%
13.2%
Press release, Jan 26, 2001: Alexion Pharmaceuticals, Inc.
Complement inhibition
Perioperative MI
An area that has not been sufficiently studied
C5 inhibition may reduce perioperative MI
The mechanism is still unclear
Will it be verified?
What were the changing definitions of MI?
Complement inhibition
Preventing necrosis
“I think it is important for cardiologists to be aware
that there’s tremendous activity right now on the
issue of preventing necrosis in the setting of bypass
surgery, [because] the complexity of the operation
and the morbidity is still quite high. This is despite
clear improvements in the technology and the skill
of the surgeons and the operating teams. But
they’re just operating on very high-risk patients as
we all know. So there’s a real niche for this type of
therapy if it really works.”
Dr Robert Califf
Professor of Cardiology
Associate Vice Chancellor for
Clinical Research at Duke University
Complement inhibition
Defining myocardial necrosis
Cardioplegia makes EKGs very unreliable
because the majority of patients have some
elevation of markers of necrosis
Where do you define the threshold?
How much necrosis do you need to prevent?
CARDINAL trials: direct angioplasty and
thrombolysis, should add to the picture
There are multiple methods of inhibiting
complement that are under investigation
Complement inhibition
Future of CABG
Bypass has been neglected for development
of therapeutics and adjunctive medications
The dangers of periprocedural MI during
CABG need to be examined, it isn’t revered
enough
We may see a resurgence of CABG as
technology allows for less severe patients to
be operated on
Complement inhibition
Cognitive decline
Percentage of patients who suffered a decline
of 20% or more in cognitive function from
pre-CABG baseline
Time frame
Patients suffering decline
Discharge
53%
6 weeks
36%
6 months
24%
5 years
42%
Newman M, et. al. N Engl J Med 2001; 344(6):395-402
Complement inhibition
Cognitive decline questions
Is this all related to bypass surgery, or is it
associated with severe athereosclerosis?
How much is due to the bypass machine?
Does off-pump surgery prevent cognitive
decline?
Does complement inhibition help?
What genetic markers may indicate risk?