Carvedilol or Metoprolol European Trial COMET

1
Carvedilol or Metoprolol European Trial (COMET)

• 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
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 and
• composite of all-cause mortality and all- cause
  hospitalization

3
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

4
Primary results
Poole-Wilson PA et al. Lancet 20033627-13
5
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

6
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

7
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

8
Which comparison?

• At the end of the day were 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

9
Perplexing

• Im fairly perplexed about COMET.
• Topol
• Carvedilol may have distinct biological
  properties
• Dosing of beta blocker remains an issue, as
  reflected in HR analysis

10
Loaded trial?

• While there are some biologic basis where these
  two drugs from the beta blocker class could be
  differentiated, Im not sure the trial wasnt
  engineered, or loaded, to demonstrate
  carvedilols superiority.
• Topol

11
Valid comparison?

• There was not equally effective beta-blockade
• Carvedilol appears more effective at the moment
  but we arent sure of the validity of the
  comparison
• Topol

12
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

13
Was it a fair match?

• At the moment, youd have to conclude, based on
  the evidence, that carvedilol is the winner, but
  was it a fair match?
• Topol

14
Background therapy
15
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

16
Treatment options

• Whats 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

17
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

18
Consumer Reports

• Consumer Reports exists for consumer products,
  and is trusted to provide independent evaluations
  of products
• In the arena thats 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

19
Not happy

• I dont think COMET was rigged or engineered
  but Im not happy with it.
• Califf
• If trials were designed in an open system COMET
  may have been designed differently

20
A case of cynical MDs?

• The sponsor is GlaxoSmithKline and COMET comes
  out in their favor. Thats at least a concern in
  the cynical world that we live in. Was there
  something about the trial that wasnt completely
  level?
• Topol

21
Bold trial

• Getting a company to do an active control trial
  against another product, its very hard.
• Califf
• Usually you would expect that if youre going to
  take on a drug in the class, youre looking at
  non-inferiority designs.
• Topol

22
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

23
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

24
Carvedilol at the CCF

• Our heart failure people are not thoroughly
  convincedbut its a very large group here and
  there is some inconsistency.
• Expense on a long-term basis is an important
  factor
• It isnt a definitive knock-out of metoprolol XL
  here.
• Topol

25
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

26
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

27
Deficiencies in design

• Payers are left with difficult, multimillion
  dollar decisions with a lack of decisive data
• Its just not a good national strategy to leave
  this up to sales reps to convince the doctors of
  what to prescribe.
• Califf

28
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

29
COMET trial review

• Dr Eric Topol
• 1 thumb up
• I dont think it measures up to the optimal
  clinical trial.
• Advances the field with some confusing results

30
COMET trial review

• Dr Rob Califf
• 1 thumb up
• It does clarify the questions but leaves us
  with an answer which is highly debatable.

31
Carvedilol or Metoprolol European Trial (COMET)

• 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