Transcript document

AHA 2003: VALIANT and
SPORTIF V under debate
Eric J Topol MD
Provost and Chief Academic Officer
Chairman, Department of Cardiovascular Medicine
The Cleveland Clinic Foundation
Cleveland, OH
Robert M Califf MD
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Director, Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
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Topics
VALIANT
Valsartan in acute myocardial
infarction
SPORTIF V
Ximelagatran in atrial fibrillation
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Valsartan in Acute
Myocardial Infarction
VALIANT
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VALIANT
Background
Valsartan, captopril, or both in myocardial
infarction complicated by heart failure, LV
dysfunction, or both
N Engl J Med 2003; 349: 1893–1906
• ACE inhibitors reduce the risk of death by
25% in post-MI patients with LV
dysfunction
• Standard of care, but poorly adhered to
• ARBs cause fewer side effects
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VALIANT
Design
Objective: to test an ARB against standard
therapy and combination therapy
• 14 703 patients with recent MI
• Valsartan (160 mg twice/day) vs
captopril (50 mg three times/day) or
combination (valsartan 80 mg twice/day
+ captopril 50 mg three times/day)
• Primary end point: all-cause mortality
• Two-year follow-up
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VALIANT
Results
End points (%)
35
Valsartan
Captopril
Combination
31.1
31.9
31.1
30
25
20
19.9
19.5
19.3
15
10
5
0
All-cause mortality
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Secondary composite
end point
N Engl J Med 2003; 349: 1893–1906
VALIANT
Equal performance
"Amazingly enough, the three
treatment arms were identical in
terms of mortality."
Superiority test:
"There wasn't a winner among the
three treatments."
Inferiority test:
Valsartan is as good as captopril
for the clinical outcomes
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Califf
VALIANT
Adverse events
Valsartan
Captopril
34.8*
Adverse events
(%)
35
30
Combination
29.4
*difference from
captopril significant
at p<0.05
28.4
25
20
15
10
5.8*
7.7
9.0*
5
0
Resulting in dose
reduction
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Resulting in drug
discontinuation
N Engl J Med 2003; 349: 1893–1906
VALIANT
Concern
Arm of interest with captopril plus
valsartan showed no benefit
whatsoever
"The fact that valsartan came out
the same as captopril seems like a
major bust."
The headline of this trial: "New lifesaving alternative"
Concern about exuberant
interpretations of the results
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Topol
VALIANT
Importance
ALLHAT
Great that more people are treated
with a diuretic, especially in the US
JAMA 2002; 288: 2998-3007
VALIANT
The news here: for the first time an
ARB has been shown to be as good
as an ACE inhibitor
• Important for patients who
don't tolerate ACE inhibitors
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Califf
VALIANT
ARBs
CHARM
Candesartan highly effective for
patients intolerant of ACE inhibitors
Lancet 2003; 362: 759–66
People who developed a cough were
often being told to stick with ACE
inhibitors, because doctors didn't
know the performance of ARBs in
terms of mortality
Califf
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VALIANT
Presenting the results
The benefit of a much more
expensive substitute alternative was
maybe not the most appropriate
way to position the results
Topol
"You're responding more to the
newspaper headlines than to the
scientific presentation."
• The presentation didn't
recommend either drug
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Califf
VALIANT
Captopril
• Small percentage of the US population
gets generic captopril
• VALIANT showed that captopril is
great
Message from upcoming publications:
"Captopril is king of the hill"
Califf
I didn't find this major conclusion in
the primary publication
Topol
N Engl J Med 2003; 349: 1893–1906
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VALIANT
Potency of ARBs
In my interpretation the results are
a bust, except that valsartan is a
nice substitute for people not
tolerating ACE inhibitors
With respect to CHARM:
Lancet 2003; 362: 759–66
Is there a difference in potency
between candesartan and
valsartan?
Topol
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VALIANT
CHARM and Val-HeFT
Difference in potency is unknown, because
candesartan wasn't compared with an ACE
inhibitor
Val-HeFT
Reduction in hospitalization with valsartan,
but no mortality benefit
NEJM 2001; 345: 1667-75
CHARM/Val-HeFT vs VALIANT:
• ACE inhibitor not optimized
• Lower dose of the ACE inhibitor
at baseline
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Califf
VALIANT
Clinical indication
ACE given in the initial post-MI
setting is effective
• Over time: ACE escape mechanism
• Chronic situation: ARB added to
ACE inhibitor shows benefit
• No benefit if ACE inhibitor and
ARB therapy are started
together
• Total HF hospitalizations
significantly lower in the
combination arm
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Califf
VALIANT
Candesartan vs valsartan
"If one wants to claim that
candesartan is better than valsartan
I'd say that's based on vaporware
for the most part."
Superiority of valsartan over
candesartan has not been proven
either
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Califf
VALIANT
Platinum standard
Captopril: now the platinum standard
• Inexpensive
• Highly effective
• "Exceptionally well tolerated"
"I hope that that message comes
out from the VALIANT investigators
at some point."
Topol
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VALIANT
Thumbs
"I would give this trial itself the two
thumbs up, but I would take one away
for the dissemination phase."
• One thumb up
Topol
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SPORTIF V
Important message
We were amazed to see:
Only 52% of patients with
documented systolic dysfunction or
heart failure, who did not participate
in the trial, were sent home on an
ACE inhibitor
Main public health message:
"Almost everyone can get on one
or the other drug."
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Califf
VALIANT
Drug problem
In reference to
Your Doctor's Drug Problem
New York Times, Nov 18, 2003
"If two drugs came out the same,
and one is pennies and the other
one is dollars per day, I think we
need to show that the doctor
doesn't have
a drug problem."
Topol
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VALIANT
Cost
Would you advocate that people stop
prescribing nongeneric ACE inhibitors
also?
Califf
"Yeah, why not? We've got to tell it
like it is. Our job is not just efficacy
but also trying to help keep the cost
down."
Topol
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Stroke Prevention Using an
Oral Thrombin Inhibitor in
Atrial Fibrillation
SPORTIF V
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SPORTIF V
Design
Ximelagatran: direct thrombin inhibitor;
powerful anticoagulant
• 3922 patients with nonvalvular atrial
fibrillation
• Fixed dose ximelagatran, 36 mg
twice/day, compared with dose-adjusted
warfarin, target INR 2.0-3.0
• End point: prevention of strokes and
systemic embolic events
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SPORTIF V
Results
Warfarin
4
3.1
Events (%)
3
2.4
3
2
2
Ximelagatran
1.6
1.2
1
0.6
0.6
1
0
Stroke/SEE*
*SEE=systemic
embolic event
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Major
bleeding
Intracerebral
hemorrhage
AHA 2003
SPORTIF V
SPORTIF III: Primary events
Ximelagatran
2.5
Events (%)
2.0
p=NS
2.3
Warfarin
p=0.018
2.2
1.6
1.3
1.5
1.0
0.5
0.0
Intention-to-treat
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On-treatment
Lancet 2003; 362:1691-8
SPORTIF V
Noninferiority
VALIANT
Around 1000 events in each arm
SPORTIF V
37 + 51 events
"It's a little bothersome to put them
in the same category."
Califf
"I agree with you. This trial does not
demonstrate noninferiority."
Topol
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SPORTIF V
Spinning the results
Troublesome that the experimental
drug is going in the wrong direction
"The gap there is something I would
not be entirely comfortable with."
• Trial was misinterpreted
• Spin problem
• Trial did not ascertain favorable
results with ximelagatran from
earlier trials
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Topol
SPORTIF V
Story on heartwire
TheHeart.org ran a positive story on
the trial:
SPORTIF V: Ximelagatran
noninferior to warfarin for stroke
prevention in AF
Heartwire > News; Nov 11, 2003
Represents what was declared
"I don't agree with that."
Topol
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SPORTIF V
The real world
Ximelagatran
• Will be very expensive when on
the market
• Substitute for those who cannot
take warfarin
Question:
Can you go without measuring an
INR, especially since the burden of
disease is increasingly concentrated
in older people with renal
dysfunction?
Califf
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SPORTIF V
Liver enzymes
Ximelagatran
Warfarin
Patients (%)
6.0
5.0
4.0
6
3.0
2.0
1.0
0.0
0.8
Serum transaminase enzymes higher than
three times the upper limit of normal
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AHA 2003
SPORTIF V
FDA approval
Will ximelagatran be approved?
Not SPORTIF V but previous efficacy
trials will "carry the day."
"Overall, though, I think that this is
disappointing."
• Trials not presented accurately
• SPORTIF V data do not
suggest noninferiority
Topol
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SPORTIF V
Margin
The trial did not have a prespecified
margin
One issue about inferiority:
"If you have a drug that's a lot
easier to use and therefore could be
used in a lot more people,
would you give up a little bit of the
benefit for that increase
in tolerance?"
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Califf
SPORTIF V
The future of ximelagatran
The margin is somewhat arbitrary
It remains to be seen how this liverfunction-test abnormality is going to
play out in the real world
"Overall, though, I don't question
that ximelagatran is an advance."
• Perhaps even the current drug
of choice in the right population
if it gets approved
Topol
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SPORTIF V
Thumbs
Califf: "I would give this trial one
thumb up, not two, because of the
presentation and the fact that it's a
noninferiority trial with very few
events."
• One thumb up
Topol: "I agree with the one-thumbup assessment."
• One thumb up
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The Statin Wars
Lancet editorial on rosuvastatin
The Statin Wars: Why AstraZeneca
must retreat
Lancet 2003; 362: 1341
Response by AstraZeneca CEO
McKillop:
• Vastly more patients in trials with
rosuvastatin compared with trials
with other statins on the market
• Committed to large outcome trials
before drug entered the market
"A spirited defense."
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Califf
The Statin Wars
The Lancet attack
Horton's attack somewhat appropriate
• More data needed before a new drug is
launched in a widescale population
• Editor's concerns about massive
campaign before outcome trials
understandable
No editorial against Pfizer, despite similar
problems with atorvastatin
"It was a little surprising that there was
a lashing at this juncture."
Topol
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The Statin Wars
Changing the system
The editorial
"A little bit late in sequence and maybe
not directed at the primary offender."
Topol
Systemic reform of drug and device
development necessary
"The science has outstruck the
logistics."
"If we had to wait for outcomes before
things got on the market, there wouldn't
be any investment in industry."
Califf
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