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
James Ferguson MD
Associate Director, Cardiology
St Luke's Episcopal Hospital and Texas Heart Institute
Michael Weber MD
Professor of Medicine
SUNY Downstate College of Medicine
African-American Heart Failure Trial
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)
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
"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."
"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."
"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
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
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."
"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
"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?"
"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."
"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."
"Should we be thinking about starting this in our black patients with HF now? I would guess we probably should."
Prevention of Events with Angiotensin Converting Enzyme Inhibition
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
Death, MI, or revascularization:
21.9% over five years in trandolopril group
to 22.5% in the placebo group
"Our first outlook is disappointment."
*Cardiovascular death, nonfatal MI, and coronary revascularization
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?
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?
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
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 ?
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."
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?
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
"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."
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?
Rimonabant in Obesity– North America
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
At one year, patients taking 20-mg rimonabant had significant reductions in waist circumference, body weight, triglycerides
Insulin sensitivity improved and HDL levels rose