AHA 2004: A-HeFT, PEACE, and RIO-NA Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Associate Professor of Medicine 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

African-American Heart Failure Trial A-HeFT African-American Heart Failure Trial A-HeFT

A-HeFT 1000 black patients, NYHA class 3 or 4 Isosorbide dinitrate (ISDN) plus hydralazine, or placebo, plus standard therapy Primary end point: death, hospitalization, change in quality of life (QoL)

A-HeFT Study terminated because primary end point reached early ISDN/hydralazine group: 6.2% event rate, compared with 10.2% in placebo group ISDN/hydralazine group: 43% reduction in the rate of death, 53% in first hospitalization, plus "significant" improvement in QoL

A-HeFT results End point ISDN- hydralazine (n=518) Placebo (n=532) p Primary end point composite score -0.1 -0.5 0.01 All-cause mortality (%) 6.2 10.2 0.02 First HF hospitalization (%) 16.4 24.4 0.001 Change in QoL score at 6 months -5.5 -2.7

A-HeFT "I was delighted with the results of this study because we have been hearing of late that when it came to HF, African Americans were not seeing the same kinds of benefits that white patients were seeing with the use of ACE inhibitors. . . . Now we have a very clear direction in which to go." Weber

A-HeFT "I hadn't really kept this on my radar screen, and I'm very excited to see another major advance even on top of all the other standard therapies." Cannon

"This trial absolutely blew me away." A-HeFT "This trial absolutely blew me away." Benefits on top of optimum therapy: 70% of patients on ACE inhibitors 16% to 17% on ARBs High usage of beta blockers 40% on spironolactone Ferguson

A-HeFT Can we extrapolate to all patients with heart failure? Whites? Asians? ACE inhibitors were first proven against ISDN/hydralazine Must find out whether there is additivity or patient-/population-specific needs Weber

A-HeFT Fuster Seven or eight drugs with proven benefit: "Do you think we are going to combine all of these in the future with a single pill for this particular group of patients? It seems to me that it's going to be impossible to take all of these drugs at the same time." Fuster

A-HeFT Ferguson "It would have to be a really, really big pill!" "I don't think a fixed-dose combination is necessarily going to be helpful. . . . One size does not fit all." Nitric-oxide mechanism revisited Despite all of the therapies, these are still class 3 patients Ferguson

A-HeFT "This is the first time we have [an indication that with] the combination of the two different mechanisms of vasodilation and/or invoking NO as a pathway, there is added benefit." "Could this, if tested in a white population, be just as good?" Cannon

A-HeFT "Now everyone is going to be wondering if we can extrapolate from this to the broader population of people with HF, and I don't think there's much alternative other than to go out and test it." -Weber "We've really begun to come drilling into the science and have had the opportunity to reexamine things that worked in the past and now begin to understand a little bit more about how they're working." -Ferguson "Should we be thinking about starting this in our black patients with HF now? I would guess we probably should." -Cannon

Prevention of Events with Angiotensin Converting Enzyme Inhibition PEACE

PEACE: Design Patients with stable CAD with normal or slightly reduced LV function >8000 patients randomized to trandolapril 4 mg/day or placebo Aggressive lipid management, high proportion of previous revascularization 4.8 year follow-up

PEACE: Results "Our first outlook is disappointment." Fuster Death, MI, or revascularization: 21.9% over five years in trandolopril group to 22.5% in the placebo group "Our first outlook is disappointment." Fuster

PEACE results End point Trandolapril Placebo P Composite primary end point* 21.9 22.5 0.43 CV death 3.5 3.7 0.67 Nonfatal MI 5.3 1.00 CAGB 6.5 7.1 0.24 PCI 12.4 12.0 0.65 *Cardiovascular death, nonfatal MI, and coronary revascularization

PEACE In patients who are treated very well, there may be very little added benefit of an ACE inhibitor Would higher-risk subgroups have some hint of benefit? For clinical practice—should you or shouldn't you start an ACE inhibitor? Cannon

PEACE In PEACE, we are using a drug that we think is a great winner against placebo, and we find no effect Do the other therapies we use for CAD— statins and/or revascularization—do the job? Fuster

PEACE In HF, you have multimechanism, multifaceted derangement of the system In atherosclerosis, you don't have multifaceted derangement, you have multifaceted triggers Results not a huge surprise, since effects will be related to underlying risk and event rates A lower event-rate population, relatively low numbers of events, a disease that progresses over time with multiple causes on a background of multiple therapies Ferguson

PEACE Weber HOPE was a riskier population, but not dramatically so High use of statins in PEACE likely played a role Statins and ACE inhibitors may share some common pathways affecting the vasculature Were the good results in HOPE explained by BP effects? Is ramipril a different drug than trandolopril ? Weber

PEACE Perindopril, captopril, enalapril, and ramipril have all shown benefit We don't want to add medicines if they are redundant, ie, low-risk patients on clopidogrel not needing GP IIb/IIIa inhibitors "This concept of redundancy of medications in terms of preventing events is certainly being seen in a few different areas." Cannon

PEACE Issues around risk stratification compounded if you have multiple therapies It's easy to identify very low- and very high-risk patients How much risk do you need to accumulate before you need to add another therapy? Ferguson

PEACE PEACE looked at coronary disease patients without cardiac failure ACE inhibitors, perhaps with an additional vasodilator, remain "rock solid" in HF In people with no LV dysfunction, an ACE inhibitor may not be beneficial in lowest-risk patients Cannon

PEACE "I think this was very useful in defining how far ACE-inhibitor therapy goes and in identifying the limits up to which it is broadly beneficial. Rather than regarding this as a spectacularly negative trial, I think we regard it as an incremental piece of information that really helps us as we begin to sort out all the different kinds of therapies." Ferguson

PEACE Can clinical characteristics or BNP predict a subgroup of patients in whom there might be benefit of an ACE inhibitor or in whom it is not needed? Cannon

Rimonabant in Obesity– North America RIO-NA

RIO-NA: Rationale and design Rimonabant targets the endocannaboid system: the "center of pleasure" RIO-NA a two-year, phase 3, double-blind, placebo- controlled trial 3000 patients randomized to 5 mg daily, 20 mg daily, or placebo in 72 centers: US, Canada Patients in rimonabant arms rerandomized to drug or placebo after one year to test maintainability of drug effects Primary end points: change in weight at one year; maintenance of weight loss at two years

RIO-NA: Results At one year, patients taking 20-mg rimonabant had significant reductions in waist circumference, body weight, triglycerides Insulin sensitivity improved and HDL levels rose Second part of the study "disappointing"; at one year, if you discontinue dose, the weight comes back Changes in lipid parameters and insulin resistance were out of proportion to weight loss

RIO-NA results Change in Placebo 5-mg rimonabant 20-mg rimonabant Weight (kg) -2.8 -4.4 -8.7 Waist circumference (cm) HDL (mg/dL) -3.9 +7.2 -4.7 +9.3 -8.2 +16.1 Triglycerides (mg/dL) +4.1 -0.6 -11.5 Metabolic syndrome (%) -2.5 -6.3 -13.7

RIO-NA "Maybe the drug is one of these miracle drugs that does other things than just weight reduction?" Fuster

RIO-NA Hard not to be excited, but we have to be careful Some reports of CNS side effects Concerns over blocking the "pleasure receptor" and over weight gain after drug cessation "As far as I'm concerned, this is a big positive. I was quite astonished at how good the changes were in the measures of insulin sensitivity and the lipids." Weber

RIO-NA "The good news is, it really works; the bad news is, you have to keep taking it. It's not a Band-Aid, it's not a quick fix." "Some of us are more attached to our pleasure centers than others, but this has the potential to be a tremendously impactful drug." Ferguson

RIO-NA A very exciting window into a whole new system that regulates a lot of the CV risk factors "It's very exciting to see a whole new way to go after all these other risk factors." Cannon

RIO-NA Questions still to answer: How much food are people eating? Long-term safety, efficacy? Fuster

RIO NA Only caveat: Once the drug is approved, we're going to have to be vigilant with postmarketing surveillance For now, rimonabant may be the only forceful method we have for treating metabolic syndrome Weber

RIO-NA Every third person in New Orleans looked like a "walking metabolic syndrome" Nice to have something to tackle obesity Smoking cessation, HDL effects also promising Looking forward to large outcome studies with cardiac end points and the safety data Cannon

A-HeFT, PEACE, RIO-NA: Final thoughts Which one of the these trials was most exciting, and what did you learn?

Final thoughts Ferguson "The heart meetings are about science and friends." A-HeFT is like rediscovering an old friend and discovering new things about that friend PEACE is about learning the limitations of an old friend Rimonabant is like making a whole new friend Ferguson

Final thoughts "The most exciting aspect to me right now is A-HeFT . . . discovering some really new and interesting things that have the potential to substantially advance the science and our understanding in areas that we had just not appreciated at all." Ferguson

Final thoughts New pathways and new mechanisms—even for old medicines—are making steps forward Uncovering the endocannabinoid system—other new drugs being developed to block this system Cannon

Final thoughts A-HeFT: "We're going to be very enthusiastic about using this nitric oxide–based treatment. To me, it's wonderful when you can come home and say, I know what I'm going to do tomorrow that's different from what I was doing yesterday." PEACE trial: "Troubling"; CAMELOT study trial also raises questions about ACE inhibitors in stable CAD RIO-NA: So many potential patients can benefit Weber