The phase II SOCRATES-PRESERVED trial also missed its primary endpoint but showed a clinically meaningful improvement in quality of life in patients with heart failure with preserved ejection fraction (HFpEF) (Eur Heart J. 2017 Mar 22. doi: 10.1093/eurheartj/ehw593). Discussions are ongoing as to whether the next step should be a confirmatory phase II study or a move straight to phase III.
The bad news
• NSAIDs linked to increased risk of heart failure. European investigators analyzed five population-based databases totaling more than 8.3 million individuals and determined that current use of any of more than two dozen NSAIDs was associated with significantly increased risk of hospital admission for heart failure. The risk appeared to be dose dependent and varied between individual agents, ranging from a 16% increased risk with naproxen to an 83% increase with ketorolac (Toradol) (BMJ. 2016 Sep 28. doi: 10.1136/bmj.4857).
• Therapeutic natriuretic peptides hit bottom. The negative results for the investigational agent ularitide in patients with acute decompensated heart failure in the large phase III TRUE-AHF trial presented at the 2016 meeting of the American Heart Association, following upon an earlier negative study of the related drug nesiritide (Natrecor) in more than 7,100 acute heart failure patients (N Engl J Med. 2011 Jul 7; 365:32-43), probably spells the end of the line for this strategy of boosting outcomes in acute heart failure, according to Dr. O’Connor.
Moreover, Novartis has announced that the phase III RELAX-AHF-2 trial of serelaxin in 6,600 patients with acute heart failure failed to meet its primary endpoints of reduced cardiovascular deaths or reduced worsening of heart failure. The trial will be formally presented later this year.
“Ularitide seemed to show an early improvement in heart failure events that was not sustained in-hospital, and there was absolutely no difference in mortality. The drug probably acts like a pharmacologic tourniquet, in my view. So I think this field of therapeutic natriuretic peptides is probably closed,” he said.
• ICDs don’t reduce mortality in patients with nonischemic heart failure. This was the conclusion reached in the DANISH trial, in which more than 1,100 patients with symptomatic systolic heart failure were randomized to an ICD or usual care (N Engl J Med. 2016 Sep 29;375[13]:1221-30).
“This study really shook up the field, raising the question, ‘Are we using defibrillators too frequently in this population?’ It has stimulated a lot of discussion, including within the guidelines committee,” according to Dr. O’Connor.
• Tolvaptan nixed for acute decompensated heart failure. The TACTICS-HF trial studied the use of tolvaptan (Samsca), an oral vasopressin-2 receptor antagonist, to reduce dyspnea in patients hospitalized with acute decompensated heart failure. Dr. O’Connor was a coinvestigator in the study, which showed that tolvaptan was no better than placebo at 8 and 24 hours (J Am Coll Cardiol. 2017 Mar 21;69[11]:1399-406).
“For now, the routine use of vasopressin antagonists in acute heart failure is not to be encouraged, although there may still be subsets where it’s worth trying – certainly in severe hyponatremia,” the cardiologist said.
• GUIDE-IT gets lost. This was a roughly 1,000-patient randomized trial of a treatment strategy aimed at improving clinical outcomes by aggressively titrating evidence-based heart failure therapies in order to suppress natriuretic peptide biomarkers. GUIDE-IT was stopped early by the data safety monitoring board due to a lack of discernible difference in outcomes, compared with usual care. Dr. O’Connor, a coinvestigator, termed the soon-to-be-published study “a disappointment.”
Sleep apnea studies show silver lining
Sleep apnea is common in patients with heart failure and is associated with worse clinical heart failure outcomes. But in the large, randomized SERVE-HF trial, investigators showed that treatment of central sleep apnea with adaptive servo-ventilation in patients with HFrEF unexpectedly increased mortality, compared with optimal medical therapy (N Engl J Med. 2015 Sep 17;373:1095-105). In a more recent secondary analysis, however, the SERVE-HF investigators found that the increased risk for cardiovascular death associated with adaptive servo-ventilation was actually restricted to patients with a very poor left ventricular ejection fraction of 30% or less, and there was a signal of possible benefit in patients in the top tier of LVEF, at 36%-45% (Lancet Respir Med. 2016 Nov; 4[11]:873-81).
This observation dovetails nicely with the findings of the CAT-HF trial presented by Dr. O’Connor at the 2016 World Congress on Heart Failure. In this phase II study, 215 patients with acute decompensated heart failure and either obstructive or central sleep apnea were randomized to optimal medical therapy alone or in combination with adaptive servo-ventilation. There was no overall difference in outcome between the two groups; however, in the subgroup of patients with HFpEF, the risk of the primary composite endpoint was reduced by 62% with adaptive servo-ventilation.
As a result of these intriguing findings from SERVE-HF and CAT-HF, a registry and/or randomized clinical trial of adaptive servo-ventilation in patients with HFpEF is now being considered under NIH sponsorship, according to Dr. O’Connor.
He reported having no financial conflicts.
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