Randal I. Goldberg, MD
NYU Langone Health

The American Heart Association’s (AHA) Scientific Sessions 2021, held virtually with live programming offered from November 13th through 15th, brought together experts from around the world to discuss the latest advancements in heart disease and heart failure (HF) research. Randal I. Goldberg, MD, discussed key takeaways from selected HF studies presented at the meeting. Dr Goldberg, from NYU Langone Health, is an assistant professor of Medicine at NYU Grossman School of Medicine and Heart Failure Director at Bellevue Hospital in New York.

Did the research presented at AHA 2021 report on any novel therapies for HF?

We have 4 good classes of therapies for HF with reduced ejection fraction (HFrEF): angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), and angiotensin receptor-neprilysin inhibitors (ARNis); beta-blockers; mineralocorticoid receptor antagonists (MRAs); and the “new kid on the block,” sodium-glucose cotransporter 2-(SGLT2) inhibitors. All of these agents significantly reduce morbidity and mortality in patients with HFrEF. In contrast, our armamentarium is barren when it comes to therapies for patients with heart failure with preserved ejection fraction (HFpEF). To address this issue, the EMPEROR-Preserved trial (ClinicalTrials.gov Identifier: NCT03057951) evaluated extending the use of the SGLT2 inhibitor empagliflozin to the HFpEF population, effectively adding a new therapeutic option for the treatment of a disease for which clinical trial results have been almost exclusively negative up to this point. Based on data presented at the meeting, SGLT2 inhibitors have now been proven to be effective across the heart failure spectrum with benefit maintained throughout subgroup analysis. 

What clinical goals currently take priority in HFrEF?

In HFrEF, efforts are now concentrated on improving patients’ access to available therapies and identifying all patients who may be eligible for treatment. A big part of this is understanding why there are deficiencies in care and then developing approaches to address these deficiencies. We can continue to emphasize discovery of newer and better medications, but if these newer options are not reaching patients, then patients are not deriving the benefit of these pivotal therapeutic advances. So, identifying and managing barriers to access is paramount.

The findings from a few phase 3 trials presented at AHF Scientific Sessions 2021 were especially important regarding care of patients with HFpEF, such as EMPEROR-Preserved, as you mentioned earlier. Can you comment on the impact of results from this trial in particular?

EMPEROR-Preserved was a phase 3, double-blind trial in patients with HFpEF, which is defined as a left ventricular ejection fraction (LVEF) of at least 50%. The patients were randomly assigned to receive either empagliflozin 10 mg daily or placebo and followed for a median of 26 months.1 The primary outcome was a composite endpoint of cardiovascular death or hospitalization due to HF. Patients with HFpEF who received empagliflozin had a significant clinical benefit, with a reduction in risk for the composite endpoint. 

It is important to emphasize cardiovascular death was not significantly reduced between the placebo and treatment groups. However, in a population of HF patients with very limited therapies available to them, the ability to prevent hospitalization is key. In addition, subgroup analyses showed quality-of-life benefits among the treated patients.

If empagliflozin is determined to be an economically viable therapeutic option for patients with HFpEF and no contraindications emerge from additional clinical studies, it should be included in the HFpEF treatment armamentarium and coupled with efforts to control cardiovascular risk factors such as high blood pressure, coronary artery disease, and diabetes.

Did any other studies serve to enhance understanding of the management of heart failure?

Yes. DREAM-HF-1 (ClinicalTrials.gov Identifier: NCT02032004) was a phase 3, multicenter, double-blind, sham-controlled trial in 537 patients with HFrEF, defined as an EF of 40% or lower with New York Heart Association Class II or III symptoms, who had either ischemic or nonischemic HF.2 The patients were randomly assigned to receive an endocardial allogeneic mesenchymal stem cell precursor injection or undergo a sham procedure. The primary outcome was recurrent nonfatal decompensated HF events. DREAM-HF-1 was the largest such trial to investigate the impact of stem cell therapy on clinical outcomes in patients with HF. The researchers selected a population with fairly advanced disease and ongoing symptoms despite the use of optimized guideline-directed medical therapy.

While no differences were observed between the 2 groups for the primary endpoint, there was a reduction in the composite of major adverse cardiovascular events among patients treated with endocardial allogeneic mesenchymal stem cell precursor injection. While this benefit is intriguing, I would consider these results to be only hypothesis-generating given the negative primary outcome.  The findings do not change our clinical practice at this time. The use of stem cells is still experimental and additional trials are needed in order for clinicians to determine whether they are a useful additional therapy in the setting of HFrEF.

A different investigation examined the impact of an HF clinic on guideline-directed medical therapy in patients with newly diagnosed HFrEF in the community.4 What did this study find?

This retrospective cohort study, comprising 1160 patients diagnosed with HFrEF from 2007 to 2017, assessed the prescribing patterns of ACEis/ARBs/ARNis, MRAs, beta-blockers, and HF-specific beta-blockers.4 In the first year after diagnosis, 92.1% of patients received a beta-blocker, and 86.5% received either an ACEi, ARB, or ARNi. Only 63.6% of patients received an HF-specific beta-blocker, and only 17.4% were treated with an MRA. The target doses were also 25% or lower for all 3 medication types.

The researchers then separately assessed patients who had received their treatment at an HF clinic, which was approximately 380 of the 1160 patients. In this subset, they found greater odds of receiving all medications; the odds ratio for receiving a beta-blocker, HF-specific beta-blocker, ACEi, ARB, or ARNi were all 3.85, and the odds ratio for receiving an MRA was 3.03. For patients seen in an HF clinic, there was an approximately 3-fold greater odds of receiving these medications that are really paramount for patients with HFrEF.

This study demonstrates the importance of the HF clinic. Heart failure physicians have an increased comfort level when it comes to prescribing certain medications for this vulnerable population, and I think that they can be an important clinical care adjunct to general cardiologists. Additionally, the fact that this occurred in Olmsted County, Minnesota, often in a quaternary academic center, further emphasizes the benefit of the HF clinic in the community setting where general practitioners may not be as adept at managing such sick patients and prescribing the medications needed.


While improving the cost of medications is important to increase patient access, it’s also essential to address provider-related barriers to prescribing medications so that we can elevate the care of all our patients.

Related to the focus on identifying which patients with HFrEF may benefit from HF therapies, an abstract was presented on the use of machine learning to evaluate patient characteristics associated with guideline-directed prescribing for HFrEF.3 Can you comment on this study?

The authors employed machine learning to try to uncover previously unrecognized barriers to prescribing guideline-directed medical therapies.  They used electronic health record data and separated medications into groups by drug class — ACEi/ARB/ ARNi, MRA, and beta-blockers — and they looked for barriers within each medication grouping. Among 3835 patients who met the inclusion criteria, 70% received an ACE/ARB, 8% received an ARNi, 75% received a beta-blocker, and 40% received an MRA, which is well below what we would hope for in this population. The researchers then constructed a heat map to visualize the most important barriers for each medication class.

The machine-learning approach confirmed a lot of known prescribing barriers such as renal function, systolic blood pressure, and heart rate. While the study did not necessarily find an actionable variable to address the limitations of prescribing, the idea of using machine learning is very interesting and could help us identify previously unforeseen variables that could be addressed. Understanding the barriers is the first step toward improving access to, and prescribing patterns for, various HF medications. 

A different investigation examined the impact of an HF clinic on guideline-directed medical therapy in patients with newly diagnosed HFrEF in the community.4 What did this study find?

This retrospective cohort study, comprising 1160 patients diagnosed with HFrEF from 2007 to 2017, assessed the prescribing patterns of ACEis/ARBs/ARNis, MRAs, beta-blockers, and HF-specific beta-blockers.4 In the first year after diagnosis, 92.1% of patients received a beta-blocker, and 86.5% received either an ACEi, ARB, or ARNi. Only 63.6% of patients received an HF-specific beta-blocker, and only 17.4% were treated with an MRA. The target doses were also 25% or lower for all 3 medication types.

The researchers then separately assessed patients who had received their treatment at an HF clinic, which was approximately 380 of the 1160 patients. In this subset, they found greater odds of receiving all medications; the odds ratio for receiving a beta-blocker, HF-specific beta-blocker, ACEi, ARB, or ARNi were all 3.85, and the odds ratio for receiving an MRA was 3.03. For patients seen in an HF clinic, there was an approximately 3-fold greater odds of receiving these medications that are really paramount for patients with HFrEF.

This study demonstrates the importance of the HF clinic. Heart failure physicians have an increased comfort level when it comes to prescribing certain medications for this vulnerable population, and I think that they can be an important clinical care adjunct to general cardiologists. Additionally, the fact that this occurred in Olmsted County, Minnesota, often in a quaternary academic center, further emphasizes the benefit of the HF clinic in the community setting where general practitioners may not be as adept at managing such sick patients and prescribing the medications needed.

Do you have any final thoughts on this year’s conference?

I think it’s great that, in the studies that we’ve discussed, importance was placed on prescribing these medications that have been so helpful. Investigations often lack a real-world ability to move what we do [in research] over into the clinic so we can reach as many patients as possible. While improving the cost of medications is important to increase patient access, it’s also essential to address provider-related barriers to prescribing medications so that we can elevate the care of all our patients.

Key Takeaways

  • At the AHA Scientific Sessions 2021, investigators reported on several important phase 3 clinical trials in HF and on studies focused on improving access to HF medications and identifying patients who may benefit from treatment.
  • Results of the EMPEROR-Preserved trial revealed a significant benefit from empagliflozin in HFpEF, a population for whom therapeutic options are limited.
  • In the DREAM-HF trial, injection of allogeneic mesenchymal precursor cells was not found to be beneficial in patients with HFrEF who had either ischemic or nonischemic HF.
  • Ongoing studies focused on improving patient selection and removing provider barriers to effective prescribing of HF medications have the potential to profoundly impact patient care.

This Q&A was edited for clarity and length.

References

  1. Anker SD. Empagliflozin in heart failure with a preserved ejection fraction – results from the EMPEROR-Preserved clinical trial. Presented at: American Heart Association Scientific Sessions 2021; November 13-15, 2021. Late Breaking Science abstract.
  2. Perin EC, Borow KM, Henry TD. Randomized trial of targeted transendocardial delivery of mesenchymal precursor cells in high-risk chronic heart failure patients with reduced ejection fraction. Presented at: American Heart Association Scientific Sessions 2021; November 13-15, 2021. Late Breaking Science abstract.
  3. Trinkley K, Suresh K, Kim R, et al. A machine learning evaluation of patient characteristics associated with guideline-directed prescribing for heart failure and reduced ejection fraction. Presented at: American Heart Association Scientific Sessions 2021; November 13-15, 2021. Abstract P1688.
  4. Dunlay SM, Killian J, Roger VL, et al. Guideline directed medical therapy in newly diagnosed heart failure with reduced ejection fraction in the community: Impact of heart failure clinic. Presented at: American Heart Association Scientific Sessions 2021; November 13-15, 2021. Abstract P1633.

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Reviewed December 2021