Wrong patients with the wrong presentation
Perhaps just as big a flaw of the acute heart failure trials has been their target patient population, patients with rest dyspnea at the time of admission. “Why do we think that dyspnea is a clinically relevant symptom for acute heart failure?” Dr. Packer asked.
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Dr. John G.F. Cleland
It’s not because it’s the most prevalent, according to new findings reported at the meeting by John G.F. Cleland, MD, professor of cardiology at Imperial College, London.
Dr. Cleland and his associates analyzed data on 116,752 hospitalizations for acute heart failure in England and Wales during April 2007–March 2013, a database that included more than 90% of hospitals for these regions. “We found that a large proportion of admitted patients did not have breathlessness at rest as their primary reason for seeking hospitalization. For about half the patients, moderate or severe peripheral edema was the main problem,” he reported. Roughly a third of patients had rest dyspnea as their main symptom.
An unadjusted analysis also showed a stronger link between peripheral edema and the rate of mortality during a median follow-up of about a year following hospitalization, compared with rest dyspnea. Compared with the lowest-risk subgroup, the patients with severe peripheral edema (18% of the population) had more than twice the mortality. In contrast, the patients with the most severe rest dyspnea and no evidence at all of peripheral edema, just 6% of the population, had a 50% higher mortality rate than the lowest-risk patients.
”It’s peripheral edema rather than breathlessness that is the important determinant of length of stay and prognosis. The disastrous neutral trials for acute heart failure have all targeted the breathless subset of patients. Maybe a reason for the failures has been that they’ve been treating a problem that does not exist. The trials have looked at the wrong patients,” Dr. Cleland said.
‘We’ve told the wrong story to industry” about the importance of rest dyspnea to acute heart failure patients. “When we say acute heart failure, we mean an ambulance and oxygen and the emergency department and rapid IV treatment. That’s breathlessness. Patients with peripheral edema usually get driven in and walk from the car to a wheelchair and they wait 4 hours to be seen. I think that, following the TRUE-AHF and RELAX-AHF-2 results, we’ll see a radical change.”
But just because the focus should be on peripheral edema rather than dyspnea, that doesn’t mean better drugs aren’t needed, Dr. Cleland added.
“We need better treatments to deal with congestion. Once a patient is congested, we are not very good at getting rid of it. We depend on diuretics, which we don’t use properly. Ultimately I’d like to see agents as adjuncts to diuretics, to produce better kidney function.” But treatments for breathlessness are decent as they now exist: furosemide plus oxygen. When a simple, cheap drug works 80% of the time, it is really hard to improve on that.” The real unmet needs for treating acute decompensated heart failure are patients with rest dyspnea who don’t respond to conventional treatment, and especially patients with gross peripheral edema plus low blood pressure and renal dysfunction for whom no good treatments have been developed, Dr. Cleland said.
Another flaw in the patient selection criteria for the acute heart failure studies has been the focus on patients with elevated blood pressures, the logical target for vasodilator drugs that lower blood pressure, noted Dr. Felker. “But these are the patients at lowest risk. We’ve had a mismatch between the patients with the biggest need and the patients we actually study, which relates to the types of drugs we’ve developed.”
Acute heart failure remains a target
Despite all the talk of refocusing attention on chronic heart failure and peripheral edema, at least one expert remained steadfast in talking up the importance of new acute interventions.
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Dr. Milton Packer (left) and Dr. Alexandre Mebazaa
“Acute heart failure is mostly excess cardiovascular congestion” coupled with congestion in organs like the kidneys and liver, insisted Alexandre Mebazaa, MD. “Drugs that improve dyspnea don’t necessarily improve kidney and liver dysfunction,” which are important targets for decongestion treatment, he said. “The treatments we’ve tested have not been effective in decongesting organs,” but he still held out hope for new agents with vasodilating properties.
Part of the problem in believing that existing treatments can adequately manage heart failure and prevent acute decompensations is that about 75% of acute heart failure episodes either occur as the first presentation of heart failure, or occur in patients with heart failure with preserved ejection fraction (HFpEF), a type of heart failure that, until recently, had no chronic drug regimens with widely acknowledged efficacy for HFpEF. (The 2017 U.S. heart failure management guidelines update listed aldosterone receptor antagonists as a class IIb recommendation for treating HFpEF, the first time guidelines have sanctioned a drug class for treating HFpEF [Circulation. 2017 Apr 28. doi: 10.1161/CIR.0000000000000509].)
“For patients with heart failure with reduced ejection fraction, you can give optimal treatments and [decompensations] are prevented,” noted Dr. Mebazaa, a professor of anesthesiology and resuscitation at Lariboisière Hospital in Paris. “But for the huge number of HFpEF patients we have nothing. Acute heart failure will remain prevalent, and we still don’t have the right drugs to use on these patients.”
The TRUE-AHF trial was sponsored by Cardiorentis. RELAX-AHF-2 was sponsored by Novartis. Dr. Ruschitzka has been a speaker on behalf of Novartis, and has been a speaker for or consultant to several companies and was a coinvestigator for TRUE-AHF and received fees from Cardiorentis for his participation. Dr. Packer is a consultant to and stockholder in Cardiorentis and has been a consultant to several other companies. Dr. Felker has been a consultant to Novartis and several other companies and was a coinvestigator on RELAX-AHF-2. Dr. Butler has been a consultant to several companies. Dr. Cleland has received research support from Novartis, and he has been a consultant to and received research support from several other companies. Dr. Mebazaa has received honoraria from Novartis and Cardiorentis as well as from several other companies and was a coinvestigator on TRUE-AHF.
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