Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Chronic therapy of...
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Transcript of Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Chronic therapy of...
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
Chronic therapy of cardiovascular disease
Eric J Topol MDProvost and Chief Academic OfficerChairman, Department of Cardiovascular MedicineThe Cleveland Clinic FoundationCleveland, Ohio
Robert M Califf MDProfessor of MedicineAssociate Vice Chancellor for Clinical ResearchDirector, Duke Clinical Research InstituteDuke University Medical CenterDurham, North Carolina
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE and OVERTURE/OCTAVE
LIFE
•Losartan Intervention For Endpoint Reduction in Hypertension
OVERTURE•Omapatrilat Versus Enalapril
Randomized Trial of Utility in Reducing Events
OCTAVE•Omapatrilat Cardiovascular Treatment
Assessment Versus Enalapril
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Inclusion criteria
Atenolol vs Losartan
• 9193 patients
• Age 55-80 years
• Previously treated or untreated hypertension
• Systolic BP 160-200 mm Hg or diastolic BP 95-115 mm Hg
• ECG LVH
• Primary composite endpoint of cardiovascular morbidity and mortality, defined as stroke, MI, or cardiovascular death
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Direct coronary intervention for MI
ACC 2002
LIFE: Event rate
0%
2%
4%
6%
8%
10%
12%
14%
Composite MI Stroke Death
Losartan Atenololp=0.021
p=0.491 p=0.001 p=0.206
11% 13%
4%
4%
5% 7%
4%5%
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Direct coronary intervention for MI
LIFE: Implications
Beta-blockade had been on such a high pedestal and now this puts the sartans in a whole other light
"I'm a little bit stunned about the results, not knowing exactly
how to change practice."
Topol
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Direct coronary intervention for MI
LIFE: Expectations
Investigators expected the primary beneficial effect to be on the heart as a result of the animal data
"The trial was done extremely well and measured the right things, but the result was unexpected. The benefit was in the direction the investigators had postulated but […] not for the outcome reason they had thought."
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Head-to-head clinical trials
As we get head-to-head trials, interpreting them will be very complicated.
"The Evidence-Based Medicine Mafia […] has been extremely high on beta-blockers […], and I haven't lost any enthusiasm for beta-blockers from this trial but I've gained a lot of respect for ARBs and their potential to produce benefit."
Califf
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Direct coronary intervention for MI
LIFE: Blood pressure follow-up (4.8 years)
0 6 12 18 24 30 36 42 48 54Study Month
40
60
80
100
120
140
160
180
Systolic
Diastolic
mm
Hg
AtenololLosartan
Atenolol 145.4 mm Hg
Losartan 144.1 mm Hg
Atenolol 80.9 mm Hg
Losartan 81.3 mm Hg
B Dahlof et al. Lancet 2002;359:995-1003
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Blood pressure
The real role of blood pressure can be difficult to determine
We don't have any information about the pulse wave, which is potentially important
"Nor do we have quite yet the full sense of the distribution of blood pressure effects in the population or across time."
Califf
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Direct coronary intervention for MI
LIFE: How generalizable?This trial had an overwhelmingly white patient population. Can we generalize to the more heterogeneous population you would find in general practice?
Topol
"I wouldn't abandon the fundamental principles that you treat blood pressure with a low-dose thiozide diuretic and in someone who has a risk of MI [ …] you err toward beta-blocker and an ACE inhibitor."
Califf
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Direct coronary intervention for MI
LIFE: Not cheap
These are exciting new drugs with real potential but they are not cheap
"For people who can take an ACE inhibitor and who don't cough and feel fine and can get them at a lower price, I'm all for
that."
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Stroke belt
Source: CDC
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Applying the data
There could be a genetic component to the stroke belt, making the LIFE data difficult to generalize
"I've been using ARBs a fair amount, this will make me feel even better about using them more often but to make a radical change in the fundamental approach to blood pressure based on one trial, I think would be a mistake."
Califf
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Direct coronary intervention for MI
LIFE: New onset diabetes
6
Pro
po
rtio
n o
f p
atie
nts
wit
h f
irst
eve
nt
(%)
18 24 30 36 42 48 54
Losartan
Atenolol
Dahlof et al. Lancet 2002;359:995-1003
60 660
Intention-to-Treat
12
Adjusted Risk Reduction 25%, p=0.001
Study Month
8
7
6
5
4
3
2
1
0
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Lifestyle changes
Walking 4 times a week for 30 minutes a day would be more effective than losartan
"But the changes in lifestyle are hard to come by.
Unfortunately, our society relies too much on some pill and potion rather than the discipline of exercise and diet."
Topol
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Direct coronary intervention for MI
LIFE: Start with ARBs for hypertension?
Maybe we could start with ACE inhibitors or ARBs in a newly diagnosed hypertensive patient•Patients successfully on beta-blockers
shouldn't be switched•These patients are hypertensives with
serious left-ventricular hypertrophy and have already tried diuretic therapy and failed
•This may all be rendered moot by advances in genomics, proteonomics, and tailored therapy
Topol
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Multiple drugs
The average person with real systolic hypertension will require 2.6 drugs at maximal FDA levels to get their pressure below 140
•The ARB option is well-tolerated, making it very attractive
•ALLHAT does not include ARBs, but should give us the first real evidence about what drug you should start with
Califf
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Direct coronary intervention for MI
LIFE: The pocketbook
We have to balance what we need to do and the pocketbook
Economic factors get in the way of proper treatment
"It's difficult to take someone who feels fine and has not had a stroke and convince them that they should take not one, and not two, but three drugs that cost 2 or 3 bucks a day apiece."
Califf
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Direct coronary intervention for MI
Diabetes Prevention Program Research Group. N Engl J Med 2002;346(6):393-403
LIFE: DPP
0.0
2.0
4.0
6.0
8.0
10.0
12.0
Cases per 1000 person years
I ncidence of type 2 diabetes
Lifestyle modification Metformin Placebo
4.8
7.8
11.0
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Direct coronary intervention for MI
Source: CDC
LIFE: Obesity
0%
5%
10%
15%
20%
Year
US population with BMI > 30
1991 1995 1998 1999 2000
12.0%
17.9%18.9%
15.3%
19.8%
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Direct coronary intervention for MI
LIFE: NAVIGATOR
Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research
Nateglinide (60mg before main meals) vs valsartan (160mg daily) vs placebo•> 60 000 patients screened for
impaired glucose tolerance (IGT)•7500 subjects to be enrolled•600-800 centers in 40 countries•Age > 50 with at least 1 CV risk factor
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Direct coronary intervention for MI
LIFE: Outpatient cardiology
Outpatient cardiology is really a metabolic clinic; we're seeing the classic lifestyle problems
It is hoped we can integrate the diabetologists' understanding of glucose management
"We're going to see much attention to focused metabolic clinics run by major cardiovascular centers."
Califf
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Direct coronary intervention for MI
LIFE: Marinating the blood vessels
Jay Cohn advocates we abandon measuring blood pressure; we should focus on getting patients on effective doses of drugs
"The concept of marinating blood vessels with the right doses of drugs as opposed to trying to hit these targets, which have never really been proven to be correct, might be the way to go."
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
LIFE: Diabetes prevention
Diabetes prevention has been seen in 3 rigorous trials; there is a theme
"I think it's more than just marinating the blood vessels. There must be an anti- inflammatory effect that's afforded by working on this neurohumoral axis of ACE and ARBs and I think it's fascinating."
Topol
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Direct coronary intervention for MI
Topol: 2 thumbs up for LIFE
"Very provocative trial. I love to see trials where you get a surprise finding, shake the bushes. It's good for the field."
"I hope this one does get the interest it deserves in the cardiovascular community."
Topol
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Direct coronary intervention for MI
OVERTURE and OCTAVE
"[OVERTURE and OCTAVE were] supposed to be the big trials to validate omapatrilat as a cornerstone of heart failure and hypertension therapy. And I guess that didn't exactly turn out to be the case."
Topol
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Direct coronary intervention for MI
OVERTURE: Background
Omapatrilat vs enalapril for heart failure •An ACE-NEP inhibitor (works through
angiotension converting enzyme and the neutral endopeptidase)
•More effective than straight ACE inhibitor in lowering systolic blood pressure
•Two phase 2 trials both trended to mortality reduction
Califf
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Direct coronary intervention for MI
Packer et al. ACC 51st Annual Scientific Session.
OVERTURE: Event rate
0
200
400
600
800
1000
1200
1400
Even
ts
Composite CVdeath/ hospital
All-causemortality
Death/ CHFhospitalization*
Omapatrilat Enalapril
HR=0.93p=0.233
HR=0.91p=0.024
HR=0.94p=0.339
HR=0.93p=0.187
*primary endpoint
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Direct coronary intervention for MI
OVERTURE: Negative perception
Most portrayals seem overly negative
"If your expectation was that omapatrilat was going to have to be way better than ACE inhibitor then it's definitely a negative. If your expectation was that we could make a modest incremental
improvement, it may not have knocked omapatrilat out of the box, at least in the field of heart failure."
Califf
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Direct coronary intervention for MI
OVERTURE: Event rate
0
250
500
750
1000
1250
CVdeath/ hospital
HR=0.91p=0.024 In a head-to-head trial,
how do you know either is better than placebo?
If you use the ACE inhibitor mortality trial end point, you get a nominally significant result
Califf
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Direct coronary intervention for MI
OVERTURE: Adverse events
Event enalapril omapatrilat
CHF 25.6% 22.6%
Hypotension 11.5% 19.5%
Dizziness 13.9% 19.4%
Impaired renal function 3.6% 2.3%
Angioedema 0.5% 0.8%
Packer et al. ACC 51st Annual Scientific Session.
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Direct coronary intervention for MI
OVERTURE: Shades of benefit
ACE inhibitors are generic now, making for an inexpensive reference standard
"You have some shades of benefit but it’s going to be an expensive alternative and the benefit is not assured. […] And angioedema is not exactly a nuisance, it's life-threatening."
Topol
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Direct coronary intervention for MI
OVERTURE: Interpreting the data
"I think fundamentally, the most important point about the pragmatic interpretation of the data is that to replace an ACE inhibitor, you've got to really beat it. And this trial did not
beat it."
Califf
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Direct coronary intervention for MI
OVERTURE: The future
"For those more interested in research and its future implications, does this mean the death of the ACE/NEP combination? I don't think so. Yet."
Califf
"Unfortunately, though, for the expectations of the drug, which were far greater than validating it as an alternative, it was demonstrating its superiority, and it was far from that."
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OVERTURE: Before and after
"Going into the ACC I would have thought most people would say, ARBs, that's
a yawner. You know, they're nice to have around, but so what? ACE/NEP, that's
where the action is."
"Now after the ACC we say, Jeez, ARBs, they're phenomenal, and the
ACE/NEP – well, you know, you've got a drug that's maybe a little better but has the same side effects or worse."
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OVERTURE: Benefit of sartans
"This whole class has been kind of clouded by lack of data
showing precise benefits."
"You're right, I think that was one of the major themes that came out of this meeting [is that] there were some big benefits that I guess were not fully expected."
Topol
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: Risk of angioedema
Event enalapril omapatrilat
All patients 0.68% 2.17%
Blacks 1.62% 5.54%
Nonblacks 0.55% 1.78%
Smokers 0.81% 3.93%
Nonsmokers 0.66% 1.79%
The OCTAVE Study Group. ACC 51st Annual Scientific Session.
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Direct coronary intervention for MI
OCTAVE: Pharmacogenetics
"This could be a great drug for managing blood pressure if you could just screen out the people who were gonna be getting angioedema. And that could be easily done by a SNP analysis."
"This could be one of the earliest applications of pharmaco- genetics."
Topol
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: At-risk patients
We need a way to identify the population at high-risk for angioedema
"Those who look on the rosy side say, 'Well, there's not been a death yet due to angioedema in the omaptrilat
experience.' But the setting of a clinical trial is very different from the setting
in a community health clinic where people with hypertension are being treated and sent out there."
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: Good blood pressure response
No one has seen the full data from OCTAVE
•Blood pressure response was better with omapatrilat
• If blood pressure effects are important in hypertension, this could be of benefit for those with the worst levels of systolic hypertension
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: How important is BP
"I'm uncertain how much of it is really a pressure effect."
A meta-analysis by Curt Furberg implies that 50% of the benefit of any hypertensive drug is based purely on the blood pressure lowering
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: Benefits of low BP
I can't argue there is no benefit to lowering blood pressure per se
"I can bleed you into a trash can and lower your blood pressure and it doesn't mean its good for you."
"You've got to consider the full effects of a drug you're going to give people."
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: Screening
Omapatrilat is a potent drug, but it has a relatively infrequent serious side effect we could screen out
"Perhaps some day we'll see broad application but in a pharmacogenetic way. It only takes a few dollars to run a polymorphism and it could mean a very effective therapy in those patients who are not at risk."
Topol
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: Applying polymorphisms
"How are you going to get doctors to run a polymorphism test
when they can't even give the drug in the first place?"
Califf
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: Genetics in cancer
Cancer specialists are ahead of cardiovascular specialists in using pharmacogenetics•Talking about specific genetic linkages
used to design therapies •Omapatrilat is an attractive case
because we know the pathway and it is easy to find SNPs in particular genes
•By next year, it should be a "no-brainer"
Topol
Thumbs up/Thumbs down – June 2002
Direct coronary intervention for MI
OCTAVE: The big issue
Getting the drugs to the people who benefit the most is the big issue
"Oftentimes I'm afraid that people just assume that operationalizing a concept is automatic. We've got a lot of work to do."
Califf