Chronic therapy of cardiovascular disease

1
Chronic therapy of cardiovascular disease

• Eric J Topol MD Provost and Chief Academic
  Officer Chairman, Department of Cardiovascular
  Medicine The Cleveland Clinic Foundation Clevela
  nd, Ohio
• Robert M Califf MD Professor of
  Medicine Associate Vice Chancellor for Clinical
  Research Director, Duke Clinical Research
  Institute Duke University Medical
  Center Durham, North Carolina

2
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

3
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

4
LIFE Event rate
p0.021
13
11
p0.491
p0.001
p0.206
7
5
4
4
5
4
ACC 2002
5
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

6
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

7
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

8
LIFE Blood pressure follow-up (4.8 years)
Atenolol
Losartan
Atenolol 145.4 mm Hg
Systolic
Losartan 144.1 mm Hg
mm Hg
Losartan 81.3 mm Hg
Diastolic
Atenolol 80.9 mm Hg
Study Month
B Dahlof et al. Lancet 2002359995-1003
9
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

10
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

11
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

12
LIFE Stroke belt
Source CDC
13
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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LIFE New onset diabetes
8
Intention-to-Treat
7
Atenolol
6

Losartan
5
Proportion of patients with first event ()
4

3

2

Adjusted Risk Reduction 25, p0.001
1

0
6
18
24
30
36
42
48
54
60
66
0
12

Study Month
Dahlof et al. Lancet 2002359995-1003
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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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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

17
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

18
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

19
LIFE DPP
11.0
7.8
4.8
Diabetes Prevention Program Research Group. N
Engl J Med 2002346(6)393-403
20
LIFE Obesity
19.8
18.9
17.9
15.3
12.0
Source CDC
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LIFE NAVIGATOR

• Nateglinide And Valsartan in Impaired Glucose
  Tolerance Outcomes Research
• Nateglinide (60mg before main meals) vs valsartan
  (160mg daily) vs placebo
• gt 60 000 patients screened for impaired glucose
  tolerance (IGT)
• 7500 subjects to be enrolled
• 600-800 centers in 40 countries
• Age gt 50 with at least 1 CV risk factor

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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

23
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

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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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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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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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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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OVERTURE Event rate
HR0.91p0.024
HR0.93p0.187
HR0.93p0.233
HR0.94p0.339
primary endpoint
Packer et al. ACC 51st Annual Scientific Session.
29
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

30
OVERTURE Event rate
HR0.91p0.024
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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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.
32
OVERTURE Shades of benefit

• ACE inhibitors are generic now, making for an
  inexpensive reference standard
• "You have some shades of benefit but its 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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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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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

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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

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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

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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.
38
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

39
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

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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

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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

42
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

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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

44
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

45
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

46
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