Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Chronic therapy of cardiovascular disease Eric J Topol MD Provost and Chief Academic

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



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



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



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%



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



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



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



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



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



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



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



LIFE: Stroke belt

Source: CDC



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



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



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



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



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



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



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



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%



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



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



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



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



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



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



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



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



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



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



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.



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



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



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



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



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



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.



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 pharmacogenetics."

Topol



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



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



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



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



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



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



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



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

Documents

Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Chronic therapy of cardiovascular disease Eric J Topol MD Provost and Chief Academic