Heartbeat – ESC 2004 ESC 2004 ESC 2004: Learning as a journey Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Staff cardiologist Brigham and Women’s Hospital Boston, MA James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, TX Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY

Heartbeat – ESC 2004 ESC 2004 PROVE-IT TIMI-22 Pravastatin or atorvastatin evaluation and infection therapy A to Z Aggrastat to Zocor RIO-EUROPE Rimonabant in Obesity - Europe Topics

Heartbeat – ESC 2004 ESC 2004 Pravastatin or Atorvastatin Evaluation and Infection Therapy PROVE-IT TIMI-22

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: Background Previous studies have shown that patients with high titers of Chlamydia pneumoniae at greater risk of MI PROVE-IT TIMI-22 and ACES presented at ESC 2004

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: Design Long-term study of antibiotic therapy against Chlamydia pneumoniae on the occurrence of cardiovascular events in patients with coronary heart disease 4162 patients with ACS (<10 days) Pravastatin (40 mg daily) vs atorvastatin (80 mg daily) Patients were randomized a second time to receive treatment with either gatifloxacin 400 mg/day for a full course of 10 days per month followed by 20 days without treatment or placebo Repeated each month for two years

Heartbeat – ESC 2004 ESC 2004 PROVE IT-TIMI 22: CVD events by treatment group Cannon C. ESC Congress 2004; August 28-September 1, 2004; Munich, Germany End point GatifloxacinPlaceboHazard risk reduction (95% CI) P CV events (%) (16, -8)0.41 Primary endpoint a composite of all-cause mortality, MI, unstable angina requiring hospitalization, revascularization, and stroke

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: Great hope “I think it’s a solid ‘no’ that this doesn’t work.” Cannon

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: No benefit “We’ve been at this antibiotic question a couple of times.” Can these results be extended to patients who have less atherosclerotic burden? For patients with established coronary disease, three “resounding studies” suggest no benefit Ferguson

Heartbeat – ESC 2004 ESC 2004 ACES: Design Study compared treatment with azithromycin 600 mg once a week for a year with placebo in 4012 patients with established coronary disease Patients were then followed for four years for the occurrence of primary end point events, any one of CHD death, nonfatal MI, coronary revascularization, or hospitalization for unstable angina RESULTS Primary end point was almost identical between the groups: 22.4% with placebo and 22.3% with azithromycin)

Heartbeat – ESC 2004 ESC 2004 Antibiotics in CHD “We’ve come to learn that things like hs- CRP can be produced by non-infectious causes.” Inflammatory markers do not necessarily reflect an infectious etiology Still possible that C pneumoniae and other organisms having an earlier etiologic role Weber

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: 30 days Difficult to translate into a primary prevention trial Two other leading infectious organisms are viruses Antiviral therapies still limited Cannon

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: Final thoughts “From the standpoint of using it in people with established coronary disease, I think we have the answer.” - Ferguson “It may be that we’ve identified that the process was over at the stage when patients were 60 years old with established disease and the infectious activity had been decades before.” - Cannon

Heartbeat – ESC 2004 ESC 2004 Aggrastat to Zocor A to Z

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: Design Intensive and moderate lipid lowering with statin therapy after acute coronary syndrome (ACS) (N Engl J Med 2004; 350: published March 8th) 4162 patients with ACS (<10 days) Pravastatin (40 mg daily) vs atorvastatin (80 mg daily) Primary end point: a composite of all-cause mortality, MI, unstable angina requiring hospitalization, revascularization, and stroke Two-year follow-up

Heartbeat – ESC 2004 ESC 2004 End pointPravastatin 40 mg (n=1973) Atorvastatin 80 mg (n=2003) P Primary composite end point PROVE-IT: Results N Engl J Med 2004; % reduction in risk favoring atorvastatin

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: 30 days Curves begin to diverge at 30 days Curves similar in terms of the overall time course Greater reductions in LDL and CRP levels with atorvastatin 80 mg

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: Understanding CRP Evolving understanding of lipid-lowering treatment LDL cholesterol as a major target to prevent major cardiovascular events and death Increasing focus on reducing CRP as a component of intensive statin therapy Cannon

Heartbeat – ESC 2004 ESC 2004 A to Z: Design Z phase of the A to Z trial evaluating aggressive versus conservative statin therapy in 4497 ACS patients TREATMENT Early intensive treatment: Simvastatin 40 mg for one month followed by simvastatin 80 mg for the remainder of the trial Conservative treatment: Placebo for four months followed by simvastatin 20 mg for the remainder of the trial Primary end point a composite of all-cause mortality, MI, unstable angina requiring hospitalization, revascularization, and stroke

Heartbeat – ESC 2004 ESC 2004 A to Z: Changes in LDL cholesterol GroupBaseline LDL cholesterol (mg/dL) 4 months (mg/dL) 24 months (mg/dL) Placebo/ simvastatin 20 mg Simvastatin 40 mg/ simvastatin 80 mg De Lemos J et al. JAMA 2004

Heartbeat – ESC 2004 ESC 2004 A to Z: Primary composite end point De Lemos J et al. JAMA 2004 End pointPlacebo/ simvastatin 20 mg (%) Simvastatin 40 mg/ simvastatin 80 mg (%) P Primary composite end point of cardiovascular death, MI, readmission for ACS, or stroke

Heartbeat – ESC 2004 ESC 2004 A to Z: Results “Now come the surprises.” Why do the curves not separate early, when one group was treated with placebo and the other simvastatin 40 mg? Curves begin to separate between months 4 and 24 – What is going on here?

Heartbeat – ESC 2004 ESC 2004 A to Z: What’s going on here? Easier to deal with what happens later in the study Not enough difference in LDL levels to reflect significant differences between the two treatment strategies at 24 months Effects of different statins beyond lipid lowering Weber

Heartbeat – ESC 2004 ESC 2004 A to Z: What’s going on here? “I have no problem with A to Z overall, but that first four months is troubling.” Is there something unique about atorvastatin that could explain the discrepancy between PROVE-IT and A to Z? Weber

Heartbeat – ESC 2004 ESC 2004 A to Z: Different patients “Is it the drug? Is it the population? Or is it the study design?” DIFFERENCES Patients in PROVE-IT recruited within 10 days, with many ‘out’ from acute episode versus those in A to Z who were in the midst of ACS A to Z underpowered Ferguson

Heartbeat – ESC 2004 ESC 2004 A to Z: No support for early use A to Z does not support early administration of statins in ACS patients “I’m a little bit mystified as to how some people have taken this as an endorsement of early administration of statins. It doesn’t support it. PROVE-IT TIMI-22 does, but A to Z goes in exactly the opposite direction.” Ferguson

Heartbeat – ESC 2004 ESC 2004 A to Z: Two hypotheses WHY THE DISCREPANCY WITH PROVE-IT? Final between-group reduction in CRP was 16.7%, whereas as in PROVE-IT, the difference between treated groups was 38% Different patient population Different dose Fuster

Heartbeat – ESC 2004 ESC 2004 PROVE-IT: Role of CRP CRP does provide a hint as to why no benefit observed at four months But, CRP issue clouded as A to Z patients stabilized with aggressive medical therapy, possibly resulting in more patients entering the trial with an ongoing thrombotic process PROVE-IT patients more stable Cannon

Heartbeat – ESC 2004 ESC 2004 A to Z: Safety profile Side effectPlacebo/ simvastatin 20 mg (%) Simvastatin 40 mg simvastatin 80 mg (%) Discontinued study for AST or ALT >3X upper limit of normal Discontinued study drug for muscle-related adverse event Myopathy (creatine kinase >3X upper limit of normal) (n=9; all on simvastatin 80 mg) Rhabdomyolysis (CK> units/L) --3 of 9 myopathy cases De Lemos J et al. JAMA 2004

Heartbeat – ESC 2004 ESC 2004 A to Z: Safety profile “It is a useful reminder to all of us that we do have to keep safety on the radar screen. We can’t put this in the drinking water.” Careful in using simvastatin 80 mg, whereas 40 mg dose looks fine - Cannon

Heartbeat – ESC 2004 ESC 2004 A to Z: Case study In a patient with unstable angina, are you concerned about lipid levels during the acute phase? Are you using a statin during the acute phase? If yes, what statin will you use, and what dose? Fuster

Heartbeat – ESC 2004 ESC 2004 A to Z: Three questions I care about the lipid levels, but I’m not going to treat elevated lipid levels in the acute phase Data still soft on benefit during the acute phase of treatment Once stable, I would start with high-dose atorvastatin Ferguson

Heartbeat – ESC 2004 ESC 2004 A to Z: Three questions “We’ve learned that there doesn’t seem to be any benefit from super-early treatment of high lipid levels.” Once stable, then start statin therapy Based on evidence, I would start with high-dose atorvastatin Weber

Heartbeat – ESC 2004 ESC 2004 A to Z: Three questions Start statin, on admission, across the board In ACS patients, start statin therapy aggressively and early Aim to lower LDL levels to 60 or 70 mg/dL as shown in PROVE-IT Atorvastatin 80 mg, but more cautious with simvastatin 80 mg Cannon

Heartbeat – ESC 2004 ESC 2004 A to Z: Switching statins In a patient with unstable angina who is currently taking simvastatin 40 mg, would you switch to atorvastatin? Fuster

Heartbeat – ESC 2004 ESC 2004 A to Z: Switching statins “On the one hand you say this guy’s already been on simvastatin and its let him down.” Not good enough for this patient Absolute event rate in A to Z still quite low Weber

Heartbeat – ESC 2004 ESC 2004 A to Z: Switching statins I would not reflexively switch from product X to product Y Depends on the LDL number and if patient is at goal Ferguson

Heartbeat – ESC 2004 ESC 2004 Rimonabant in Obesity – Europe RIO-Europe

Heartbeat – ESC 2004 ESC 2004 RIO-Europe: Rational Obesity a world wide epidemic The so-called “pleasure center” may generate appetite and tobacco addiction A new drug, rimonabant, blocks the CB1 receptor The question is, can taking this drug decrease appetite and help stop smoking at the same time?

Heartbeat – ESC 2004 ESC 2004 RIO-Europe: Design and Results 1500 overweight patients Randomized to rimonabant 20 mg, rimonabant 5 mg, or placebo One year follow-up Patients in the 20 mg dose lost 6.6 kg, those on the 5 mg dose lost 3.4 kg, and those on placebo lost 1.8 kg In patients on the 20 mg dose: HDL increased by 27%, triglycerides decreased by 10%, and proportion of patients with metabolic syndrome decreased by 50%

Heartbeat – ESC 2004 ESC 2004 RIO-Europe: Results “It seems to me that we are dealing with something quite striking.” Fuster

Heartbeat – ESC 2004 ESC 2004 RIO-Europe “ I am excited about this, I think that this is absolutely fascinating…[but] you gotta worry a little bit about a drug that’s a pleasure-center blocker.” Significant clinical applications No quick fix, no magic pill Ferguson

Heartbeat – ESC 2004 ESC 2004 RIO-Europe HDL and triglycerides linked to insulin sensitivity In early phase of weight loss: a sharp improvement in insulin sensitivity HDL: One of the most difficult things to manipulate – anything that can increase HDL is exciting “I am a bit concerned... What happens when you stop this drug?” - Weber

Heartbeat – ESC 2004 ESC 2004 RIO-Europe Smoking cessation aid is desperately needed Reduction in CRP also promising “It’s a fascinating, multifactorial agent.” - Cannon

Heartbeat – ESC 2004 ESC 2004 RIO-Europe Mood changes mild and transient So far, 3000 people in different trials Trials include: RIO-Europe, RIO Lipids, RIO North America, RIO-Diabetes, STRATUS-US (tobacco cessation) Fuster

Heartbeat – ESC 2004 ESC 2004 Final thoughts PROVE-IT: Antibiotic study “negative” but extremely definitive - We can go to the bank with that information A to Z: “A bit troubling” – is there really a difference between the statins? RIO-EUROPE: Rimonabant “very promising” Weber

Heartbeat – ESC 2004 ESC 2004 Final thoughts PROVE-IT: Antibiotics didn’t work - we need to focus on real things like diet, exercise, weight reduction, controlling lipids, antiplatelet therapy, and ACE inhibitors A to Z: Early effects may be linked to anti- inflammatory effects of statins RIO-EUROPE: going beyond LDL to control all other CV risk factors is the wave of the future Cannon

Heartbeat – ESC 2004 ESC 2004 Final thoughts “Each one of these trials is a doorway.” The antibiotic trial basically closed the door A to Z trial opened a door and showed us a lot more doors Rimonabant a whole new doorway Ferguson

Heartbeat – ESC 2004 ESC 2004 Final thoughts “I’m most excited about A to Z... I’m most excited when I’m wrong. The situation is a little more complicated than we thought.” Ferguson