Thumbs – July 2003

Carvedilol or Metoprolol European Trial (COMET)

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

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Enrollment

COMET enrolled 3029 patients with class II to IV heart failure.

• 1511 patients assigned carvedilol (target

dose 25 mg twice daily)• 1518 patients assigned metoprolol

(target dose 50 mg twice daily)

Primary endpoint: All-cause mortality andcomposite of all-cause mortality and all- cause hospitalization

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Trial history

Recruitment started December 1996, ended January 1999

Trial was focused on which beta-blocker was better -- a challenge to the uniformity of a class effect

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Primary results

Endpoint

Carvedilol (n=1511)

(%)

Metoprolol (n=1518)

(%) p

All-cause mortality

33.9% 39.5% 0.0017

All-cause mortality or all-cause hospitalization

73.9% 76.4% 0.1222

Poole-Wilson PA et al. Lancet 2003;362:7-13

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Short-acting metoprolol

Concerns raised over the dose and formulation of metoprolol used

• Short-acting metoprolol was used instead of the long-acting metoprolol which is the current standard

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Class effect

“My feeling about the study overall is that it is important because it does challenge the class effect.”

Califf

• All beta-blockers do not reduce mortality the same

• Metoprolol not the same as formulation used in MERIT-HF

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HR reductions and beta blockade

HR rate decreased more with carvedilol initially but no differences reported over time

HR reductions in the first few months:• 13.3 beats per min with carvedilol • 11.7 beats per min with metoprolol • After 16 months, no differences in HR

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Which comparison?

“At the end of the day we’re left with the question, ‘Is this comparing different levels of beta blockade or is it comparing two different beta blockers with different biological properties that produce different outcomes?’”

Califf

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Perplexing

“I’m fairly perplexed about COMET.”

Topol

• Carvedilol may have distinct biological properties

• Dosing of beta blocker remains an issue, as reflected in HR analysis

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Loaded trial?

“While there are some biologic basis where these two drugs from the beta blocker class could be differentiated, I’m not sure the trial wasn’t engineered, or loaded, to demonstrate carvedilol’s superiority.”

Topol

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Valid comparison?

There was not equally effective beta-blockade

Carvedilol appears more effective at the moment but we aren’t sure of the validity of the comparison

Topol

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Questions remain

The positioning of carvedilol as uniquely superior may not be appropriate

Perplexing questions remain because of the dosing choices and the short acting vs long acting forms of the drug

Topol

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Was it a fair match?

“At the moment, you’d have to conclude, based on the evidence, that carvedilol is the winner, but was it a fair match?”

Topol

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Background therapy

COMET (n=3029)

Diuretic 99%ACE inhibitor 91%Digitoxin 59%Warfarin 46%Aspirin 37%Spironolactone 11%ARB 7%

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Issue of dose

“All COMET is showing is that a higher-dose regimen is better than a lower one. Not very exciting.”

Dr Ake Hjalmarson, principal MERIT-HF investigator

“I am saying that it [carvedilol] is better than metoprolol tartrate 50 mg twice daily, and this must be due to actions other than beta-1 blockade.”

Dr Milton Packer

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Treatment options

What’s the right way to go about deciding about which treatment is best?

The comparative analysis once a product is on the market is often controlled by industry

Califf

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Neutral court

Hard to believe COMET investigators would proceed with a clinical trial skewed to favor carvedilol over metoprolol

Califf

Need for neutral court to arbitrate “fair and square” comparative analysis between active controls

Topol

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Consumer Reports

Consumer Reports exists for consumer products, and is trusted to provide independent evaluations of products

“In the arena that’s most directly related to our quality of life and longevity, we leave it up to companies which are making the products to do their own comparisons, to control the data and very often control the publication.”

Califf

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Not happy

“I don’t think [COMET] was rigged or engineered but I’m not happy with it.”

Califf

If trials were designed in an open system COMET may have been designed differently

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A case of cynical MDs?

“The sponsor is GlaxoSmithKline and [COMET] comes out in their favor. That’s at least a concern in the cynical world that we live in. Was there something about the trial that wasn’t completely level?”

Topol

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Bold trial

Getting a company to do an active control trial against another product, it’s very hard.

Califf

Usually you would expect that if you’re going to take on a drug in the class, you’re looking at non-inferiority designs.

Topol

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Issues in trial design

The label doses of the drugs were used, which is reasonable but leaves the question open as to whether the dosing is correct

The science has gotten far ahead of our ability to get the trials done in two ways

• Size of the study• Speed of making the comparisons

Modest differences become very important

Califf

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Conclusions from COMET

“The results are supportive that, until proven otherwise, carvedilol is the winner; is the drug of choice.”

Topol

• Carvedilol extends survival compared to metoprolol 50 mg twice daily

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Carvedilol at the CCF

“Our heart failure people are not thoroughly convinced…but it’s a very large group here and there is some inconsistency.”

Expense on a long-term basis is an important factor

“It isn’t a definitive knock-out of metoprolol XL here.”

Topol

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Carvedilol at Duke

Patients who want to know everything and can afford it are mostly picking carvedilol

“The majority of people [make a decision] based on some gestalt about what their pocket book can tolerate and what kind of insurance they have.”

“While the nod goes to carvedilol, a lot of people are getting prescribed metoprolol because of the combination of the uncertainty and the cost.”

Califf

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COMET vs GUSTO I

It is surprising Milton Packer made the comparison with GUSTO I (tPA vs SK)

Indisputable survival difference

Dose of streptokinase used was the one still used today while in COMET the dose issue is at the heart of the controversy

Topol

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Deficiencies in design

Payers are left with difficult, multimillion dollar decisions with a lack of decisive data

“It’s just not a good national strategy to leave this up to sales reps to convince the doctors of what to prescribe.”

Califf

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Changing infrastructure

NIH feels we need to re-invigorate research infrastructure to get these questions answered

“It seems the people at the end of the line of the research are having the least say in how the money is spent on research and I think that will change.”

Califf

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COMET trial review

Dr Eric Topol

1 thumb up

“I don’t think it measures up to the optimal clinical trial.”

Advances the field with some confusing results

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COMET trial review

Dr Rob Califf

1 thumb up

“It does clarify the questions but leaves us with an answer which is highly debatable.”

Thumbs – July 2003

Carvedilol or Metoprolol European Trial (COMET)

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