An opportunity for ‘simpler and easier’ treatments
“This is an opportunity to disrupt the way we’ve been doing things and think about something that is simpler and easier,” said Dr. Yancy, who chaired some of the panels serially formed by the American Heart Association and American College of Cardiology to write guidelines for treating heart failure. “An approach that would be easier to implement without worrying about staggering the start of each drug class and an incessant focus on titrating individual elements and taking 6 months to get to a certain place.”
Results from EMPEROR-Preserved and the combined EMPEROR-Pooled analysis triggered these paradigm-shifting sentiments by showing clear evidence that treatment with empagliflozin exerts consistent benefit – and is consistently safe – for patients with heart failure across a spectrum of EFs, from less than 25% to 64%, though its performance in patients with HFpEF and EFs of 65% or greater in the EMPEROR-Preserved trial remains unclear.
The consequence is that clinicians should feel comfortable prescribing empagliflozin to most patients with heart failure without regard to EF, even patients with EF values in the mid-60% range.
The EMPEROR-Preserved results showed a clear signal of attenuated benefit among patients with an EF of 65% or greater “on a population basis,” stressed Dr. Packer. “But on an individual basis, ejection fraction is not that reproducible, so measuring ejection fraction will not help you determine whom to treat or not treat. “
“There is significant variability” measuring EF using the most common modality, echocardiography, noted Javed Butler, MD, an EMPEROR coinvestigator who also spoke at the meeting session. A person with a measured EF of 65% could actually have a value that may be as low as 58% or as high as about 72%, noted Dr. Butler, who is professor and chair of medicine at the University of Mississippi, Jackson. The upshot is that any patient diagnosed with heart failure should receive an SGLT2 inhibitor “irrespective of their ejection fraction,” Dr. Butler advised.
“Ejection fraction is very crude, and probably not sufficient to identify a phenotype,” for treatment, said Dr. Yancy. “The real takeaway may be that we need to revisit what we call HFrEF, and then let that be the new standard for treatment.”
“Is [an EF of] 60% the new 40%?” asked Dr. Packer, implying that the answer was yes.
Results from several trials suggest redefining HFrEF
The idea that patients without traditionally defined HFrEF – an EF of 40% or less – could also benefit from other classes of heart failure drugs has been gestating for a while, and then rose to a new level with the August 2021 report of results from EMPEROR-Preserved. Two years ago, in September 2019, Dr. Butler, Dr. Packer, and a third colleague advanced the notion of redefining HFrEF by raising the ejection fraction ceiling in a published commentary.
They cited the experience with the angiotensin receptor blocker candesartan in a post hoc analysis of data collected in the CHARM-Preserved trial, which showed a strong signal of benefit in the subgroup of patients with EFs of 41%-49%, but not in those with an EF of 50% or higher. This finding prompted Dr. Konstam to express doubts about relying on EF to define heart failure subgroups in trials and guide management in a commentary published more than 3 years ago.
Another crack in the traditional EF framework came from analysis of results from the TOPCAT trial that tested spironolactone as a treatment for patients with HFpEF, according to the 2019 opinion published by Dr. Butler and Dr. Packer. Once again a post hoc analysis, this time using data from TOPCAT, suggested a benefit from the mineralocorticoid receptor antagonist spironolactone in patients with heart failure and an EF of 45%-49% (45% was the minimum EF for enrollment into the study).
Recently, data from a third trial that tested sacubitril/valsartan in patients with HFpEF, PARAGON-HF, showed benefit among patients with EFs below the study median of 57%. This finding led the Food and Drug Administration in February 2021 to amend its initial approval for sacubitril/valsartan by removing a specific EF ceiling from the drug’s indication and instead saying that patient’s receiving the drug should have a “below normal” EF.
Writing in a recent commentary, Dr. Yancy called the FDA’s action on sacubitril/valsartan “reasonable,” and that the subgroup assessment of data from the PARAGON-HF trial creates a “new, reasonably evidence-based therapy for HFpEF.” He also predicted that guideline-writing panels will “likely align with a permissive statement of indication” for sacubitril/valsartan in patients with HFpEF, especially those with EFs of less than 57%.
The idea of using an SGLT2 inhibitor like empagliflozin on all heart failure patients, and also adding agents like sacubitril/valsartan and spironolactone in patients with HFpEF and EFs in the mid-50% range or lower may take some time to catch on, but it already has one influential advocate.
“If a patient has HFpEF with an EF of less than 55%, use quadruple-class therapy,” summed up Dr. Butler during the HFSA session, while also suggesting prescribing an SGLT2 inhibitor to essentially all patients with heart failure regardless of their EF.
The EMPEROR-Preserved and EMPEROR-Reduced trials and the EMPEROR-Pooled analysis were sponsored by Boehringer Ingelheim and Lilly, the companies that jointly market empagliflozin (Jardiance). Dr. Packer has had financial relationships with BI and Lilly and numerous other companies. Dr. Konstam has served on data monitoring committees for trials funded by Boehringer Ingelheim and by Amgen, Luitpold, and Pfizer, and has been a consultant to Arena, LivaNova, Merck, SC Pharma, and Takeda. Dr. Yancy had no disclosures. Dr. Butler has had financial relationships with Boehringer Ingelheim and numerous other companies.