Heartbeat – April 2004 ACC 2004 ACC 2004: Rimonabant, GAP, and CABG Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Bernard Gersh MD Professor of Medicine Mayo Clinic College of Medicine Rochester, MN Robert Harrington MD Professor of Medicine Duke University Medical Center Durham, NC Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY

Heartbeat – April 2004 ACC 2004 Rimonabant trials RIO-Lipids and STRATUS-US GAP Projects Guidelines Applied in Practice PRAGUE-4 Off-pump CABG study Topics

Heartbeat – April 2004 ACC 2004 Rimonabant trials RIO-Lipids STRATUS-US

Heartbeat – April 2004 ACC 2004 Rimonabant Cannaboid receptor 1 (CB1) antagonist Weight loss Smoking cessation Reduction in alcohol consumption

Heartbeat – April 2004 ACC 2004 Rimonabant in Obesity RIO-Lipids

Heartbeat – April 2004 ACC 2004 RIO-Lipids: Design Presented by Dr Jean-Pierre Després (Laval Hospital Research Centre, St Foy, QC) Sponsored by Sanofi-Synthélabo More than 1030 overweight or obese patients Randomized to placebo, 5-mg rimonabant, or 20-mg rimonabant for one year

Heartbeat – April 2004 ACC 2004 RIO-Lipids: Results End point20-mg rimonabant p (vs placebo) Weight-15 lb<0.001 Waist circumference -9.1 cm<0.001 HDL+23%<0.001 Triglycerides-15%<0.001 CRP-27%<0.001

Heartbeat – April 2004 ACC 2004 RIO-Lipids "As a person whose main interest is in preventive cardiology, this is very exciting. In fact, it has the potential to put me out of business altogether." Not a short term study—a 12-month observation Showed a meaningful weight difference at the end Weber

Heartbeat – April 2004 ACC 2004 "I think this is just extraordinary. It could not happen at a better time— that we should develop a drug that attacks smoking, obesity, and lipids all in one go." RIO-Lipids Gersh

Heartbeat – April 2004 ACC 2004 "I hope it holds up in clinical outcome studies—that we actually can take the surrogate markers of weight loss and metabolic improvement and demonstrate that administration of a drug like this can truly improve cardiovascular health." Harrington RIO-Lipids

Heartbeat – April 2004 ACC 2004 "Hopefully the public will not see this tool as an alternative to some of the basic preventive lifestyle measures that it has to take." RIO-Lipids Gersh

Heartbeat – April 2004 ACC 2004 Tendency to blame overweight individuals Likely a significant genetic aspect to obesity Only just beginning to understand Fuster RIO-Lipids

Heartbeat – April 2004 ACC 2004 Studies with Rimonabant and Tobacco Use STRATUS-US

Heartbeat – April 2004 ACC 2004 STRATUS-US: Design Presented by Dr Robert Anthenelli (University of Cincinnati, OH) Sponsored by Sanofi-Synthélabo Looked at more than 780 smokers Included smokers who had failed to quit on an average of four previous occasions Short-term study that included 10 weeks of treatment

Heartbeat – April 2004 ACC 2004 STRATUS-US: Prolonged smoking abstinence Group20-mg rimonabant (%) Placebo (%) p Intention-to-treat population Trial completers

Heartbeat – April 2004 ACC 2004 Smokers on rimonabant 20 mg were twice as likely to quit They lost about 0.5 lb, whereas those on placebo gained almost 2.5 lbs STRATUS-US: Results

Heartbeat – April 2004 ACC 2004 "They took a tough group of patients— these patients have failed to quit smoking on multiple other occasions... and they demonstrated a rather large difference between those patients who took the drug and those who took placebo. This is an important step." Harrington STRATUS-US

Heartbeat – April 2004 ACC 2004 "What will happen to the weight over a longer period of time? I think we just don't know." Gersh STRATUS-US

Heartbeat – April 2004 ACC 2004 Rimonabant seems to have few side effects These include: nausea and dizziness It would be interesting to evaluate the drug over a longer period of time STRATUS-US Fuster

Heartbeat – April 2004 ACC 2004 STRATUS-US: Finding Group20-mg rimonabant (%) Placebo (%) p Trial completers

Heartbeat – April 2004 ACC 2004 "It goes to show that even with placebo, a lot of people will stop smoking if they come back on a regular basis to see a doctor and they know that stopping smoking is the primary interest of the physician and the physician's office, and I think there's a lesson in that as well." Weber STRATUS-US

Heartbeat – April 2004 ACC 2004 Rimonabant Cannaboid receptor 1 (CB1) antagonist Weight loss Smoking cessation Reduction in alcohol consumption

Heartbeat – April 2004 ACC 2004 American College of Cardiology Guidelines Applied in Practice GAP

Heartbeat – April 2004 ACC 2004 GAP: Design Sponsored by the American College of Cardiology Implementation of standardized care based on clinical practice guidelines to reduce mortality in elderly MI patients 2857 patients in 33 hospitals in southeastern Michigan Compared patient care before and after implementation of GAP program In-hospital, 30-day, and one-year mortality end points

Heartbeat – April 2004 ACC 2004 End pointBaseline (%) Post-GAP (%) P In-hospital mortality day mortality One-year mortality GAP: Results ACC 2004

Heartbeat – April 2004 ACC 2004 GAP: Systematic approach Need for more systematic approach to treating patients Adherence to guidelines may translate into improved patient outcomes Fuster

Heartbeat – April 2004 ACC 2004 GAP: Important study Gersh "This is a very important initiative." Guidelines prominent but not always translated into real actions and results Cardiologists not effectively communicating the results of trials that underlie the guidelines' recommendations "The GAP project is a demonstration that a system works."

Heartbeat – April 2004 ACC 2004 GAP: The future Technology, such as Palm Pilots, may assist patients and doctors with outpatient requirements Link Palm Pilots to doctor's office for enhanced communication "What's exciting here is that we see that following guidelines saves lives." Weber

Heartbeat – April 2004 ACC 2004 GAP: Better outcomes "Guidelines produce better outcomes for patients." Guidelines not just a surrogate marker; there is now a direct link to clinical outcomes Imperative to follow the "simple things" (ie, aspirin, beta blockers, ACE inhibitors) "This should be big news that we get out there." Harrington

Heartbeat – April 2004 ACC 2004 GAP: Guidelines too dry Recent guidelines are an advance, but still very "dry" for physicians In GAP, a "summary" of guidelines more appetizing than the guidelines themselves Fuster

Heartbeat – April 2004 ACC 2004 GAP: Important study Gersh "Guidelines are, of necessity, somewhat dry." GAP project shows guidelines can translate across a wide range of hospitals

Heartbeat – April 2004 ACC 2004 GAP: Doing the simple things US News and World Report Differences between major clinics not the result of access to new technologies, but rather better adherence to the "simple things" Harrington

Heartbeat – April 2004 ACC 2004 GAP: Responsibilities Helps when doctors applying guidelines are ones who understand or are up-to- date with evidence Apply guidelines in realistic way Patients also need to know their responsibilities Weber

Heartbeat – April 2004 ACC 2004 GAP: Patient population GAP Elderly patients are a complex patient population (ie, adjustment of medications, application of invasive technologies) "No reason to believe [the results] shouldn't apply to the younger patient, although observing the difference might be a little more difficult." Harrington

Heartbeat – April 2004 ACC 2004 GAP: Differences in care ACC involvement and Dr Kim Eagle's enthusiasm may have helped the results Expanding the GAP project further may help to eliminate some of the socioeconomic differences observed in outcomes after MI "If all the hospitals treated everyone the same way, that would take one variable out." Gersh

Heartbeat – April 2004 ACC 2004 GAP: Infrastructure issues Issues with implementing the GAP project across the US More than just doctors at work Lack of manpower and time MORTALITY DATA "We may have to say to hospitals that having this sort of system in place is no longer an option if you want to get accredited." Weber

Heartbeat – April 2004 ACC 2004 PRAGUE-4

Heartbeat – April 2004 ACC 2004 PRAGUE-4: Patency rates OutcomeOn-pump group (%) Off-pump group (%) One-year patency saphenous vein grafts One-year patency LIMA grafts 91

Heartbeat – April 2004 ACC 2004 PRAGUE-4 "Certainly the low patency rate of the vein grafts got a lot of attention in the presentation. I'd caution us, though, to say: How much do we really know about patency rates of bypass patients?" Harrington

Heartbeat – April 2004 ACC 2004 PRAGUE-4 "I'm astounded by that very low patency rate." "It is a phenomenally low rate." Gersh

Heartbeat – April 2004 ACC 2004 PRAGUE-4: Design Presented by Dr Petr Widimsky (Cardiocenter Vinohrady, Prague, Czech Republic) 400 patients randomized to off-pump or on-pump CABG Single-center study with four surgeons Primary end point was death, MI, stroke, or hemodialysis within 30 days

Heartbeat – April 2004 ACC 2004 PRAGUE-4: Results Primary end point: death, MI, stroke, or hemodialysis On-pump group (%) Off-pump group (%) p Intention- to-treat

Heartbeat – April 2004 ACC 2004 PRAGUE-4: Results Outcome (n)On-pump group (%) Off-pump group (%) 30-day mortality4 2 Periprocedural MI3 2 Stroke2 0

Heartbeat – April 2004 ACC 2004 PRAGUE-4 Does the future lie in off-pump CABG? Fuster

Heartbeat – April 2004 ACC 2004 PRAGUE-4 "But there is this troubling trend, which has now appeared in several studies as lesser patency in the off-pump patients. And so before we wholeheartedly abandon on-pump surgeries, I do think... we need to be a bit cautious." Harrington

Heartbeat – April 2004 ACC 2004 PRAGUE-4 "I don't believe that we're anywhere near to seeing off-pump bypass surgery accepted as the standard technique." "Where I'd really like to see this technique put to the test is the patient with an elevated creatinine who may be 70 who has aortic atherosclerosis and who's high-risk." Gersh

Heartbeat – April 2004 ACC 2004 PRAGUE-4 "My feeling is that the results, in terms of a major end point—the mortality, the MI, and so forth, didn't show much difference between the two. But they were both so overwhelmed by the noise of the graft occlusion that I really don't know what to make of this study at all." Weber

Heartbeat – April 2004 ACC 2004 Rimonabant trials RIO-Lipids and STRATUS-US GAP Projects Guidelines Applied in Practice PRAGUE-4 Off-pump CABG study Topics

Heartbeat – April 2004 ACC 2004 Final thoughts "I think the single most important message for me comes from the GAP study. It has kind of pushed guidelines, much as I hate to admit it, over the top and I think all of us now have to work hard." Weber

Heartbeat – April 2004 ACC 2004 Final thoughts "I think the most important thing we've talked about tonight is the GAP project." Get systems in place that encourage evidence-based medicine Utilize what we already know Quickest way to move forward Harrington

Heartbeat – April 2004 ACC 2004 Final thoughts Rimonabant Could it be too good to be true? Will it stand the test of time? GAP project A step forward Translating guidelines into clinical practice PRAGUE-4 The jury is still out Gersh

Heartbeat – April 2004 ACC 2004 Preview Next session: Cell therapy for myocardial regeneration Fuster