Thumbs – July 2003 Carvedilol or Metoprolol European Trial (COMET) Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, 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

Thumbs – July 2003 Enrollment COMET enrolled 3029 patients with class II to IV heart failure 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

Thumbs – July 2003 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

Thumbs – July 2003 Primary results Endpoint Carvedilol (n=1511) (%) Metoprolol (n=1518) (%)p All-cause mortality 33.9%39.5% All-cause mortality or all-cause hospitalization 73.9%76.4% Poole-Wilson PA et al. Lancet 2003;362:7-13

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 Background therapy COMET (n=3029) Diuretic99% ACE inhibitor91% Digitoxin59% Warfarin46% Aspirin37% Spironolactone11% ARB7%

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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

Thumbs – July 2003 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 MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, 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