A new horizon for guideline-directed medical therapy in HFpEF
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Approximately 52% of patients with HF are categorized as those with a preserved ejection fraction. Hospitalizations in this patient population are continuing to increase.
Despite positive data demonstrating mortality benefit and prevention of hospitalizations for HF (HHF) with pharmacotherapy in HF with reduced EF, defined by a left ventricular EF of 40% or less, a paucity of therapeutic options proven to affect outcomes remains a clinical challenge in treatment of HFpEF, now defined as LVEF of at least 50%.
To make matters confusing, current clinical trials that enrolled patients with HFpEF when the definition was LVEF greater than 40% now include patients in both groups of HFpEF and what is now known as HF with mildly reduced EF (HFmrEF) of 41% to 49%. Whether these patient groups respond differently to pharmacotherapy treatment is an ongoing question requiring further investigation. The 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America guideline for HF further comments on this concern, reiterating the absence of prospective randomized controlled trials for patients specifically with HFmrEF. Previous ACC/AHA/HFSA guideline updates have provided recommendations for pharmacologic treatment options in the population of LVEF greater than 40%, although limited due to inability for large randomized controlled trials to demonstrate benefit. The 2022 guideline expands on these recommendations to further delineate treatment options for HFmrEF and HFpEF, including diuretics for symptom control, SGLT2 inhibitors, angiotensin receptor-neprilysin inhibitors (ARNI), angiotensin II receptor blockers (ARB) and mineralocorticoid receptor antagonists (MRA) for both classifications, in addition to ACE inhibitors and evidence-based beta blockers (in HFrEF) as options for HFmrEF. Although data limitations still exist across this classification spectrum, recent evidence incorporated into these recommendations has been promising to support the use of currently available guideline-directed medical therapy for the treatment of HFpEF/HFmrEF.
Empagliflozin: What we know
EMPEROR-Preserved, which analyzed 5,988 patients with an LVEF greater than 40%, included patients with an N-terminal pro-B-type natriuretic peptide level of more than 300 pg/mL (or > 900 pg/mL in presence of atrial fibrillation). Patients with HFmrEF represented 33.2% of the empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) group. The trial showed a combined risk reduction of CV death and HHF in patients taking empagliflozin vs. placebo, with HHF driving reduction of the composite endpoint.
These data mirror the benefit seen in EMPEROR-Reduced, of which a reduction in the same composite endpoint tested was also significantly reduced in patients with HFrEF. In both trials, this reduction was seen across patients with and without diabetes. Breaking down the LVEF at baseline, in EMPEROR-Preserved, a reduction of the composite endpoint was seen in LVEF less than 50% and up to 60%; however, effect was not statistically significant at LVEF of at least 60%. In EMPEROR-Reduced, a reduction in the composite endpoint was seen in LVEF of 30% or less regardless of baseline NT-proBNP levels; however, it was not statistically significant at LVEF greater than 30%. It is interesting to note that LVEF 30% to 40% was not individually analyzed, even though the inclusion criteria included those with a LVEF of 40% or less. No significant differences in adverse events were seen within either trial, with a numerically more frequent incidence of urinary tract infections seen in the empagliflozin group. Rates of urinary tract infections seen in the treatment arms were 9.9% in EMPEROR- Preserved and 4.9% in EMPEROR-Reduced.
Limitations observed in EMPEROR-Preserved and EMPEROR- Reduced included a small population of Black patients, representing only 4.4% and 6.6%, respectively, of the empagliflozin participants. Given the high burden of HF in this population, generalizability of empagliflozin use in Black patients remains limited, with further study needed to confirm the treatment benefit. Both trials showed improvement in reported Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary scores at 52 weeks compared with placebo in the empagliflozin group. While not statistically significant, KCCQ clinical summary scores showed potential overall improvement in patients’ quality of life and symptom control.
The combined data from the EMPEROR trial program led empagliflozin to gain FDA approval in February to reduce HHF and CV death, regardless of EF cutoff, in patients with HF. This approval is reflected in the 2022 AHA/ACC/HFSA guideline as a class 2a recommendation for both HFmrEF and HFpEF.
Beyond EMPEROR-Preserved, a recent meta-analysis including CV outcomes trials of other SGLT2 inhibitors that included patients with HFpEF, including the SOLOIST-WHF trial of the nonselective SGLT inhibitor sotagliflozin (approved in the European Union as Zynquista and developed by Lexicon), further echoes the treatment effects seen with empagliflozin. SGLT2 inhibitors in patients with HFpEF showed a statistically significant lower risk for the combined endpoint of HHF and CV death occurrence compared with placebo (HR = 0.79; 95% CI, 0.71-0.88; I2 = 0%). Similar to EMPEROR- Preserved, rates of HHF were lower in patients receiving SGLT2 inhibitors (HR = 0.71; 95% CI, 0.61-0.82; I2= 0%), whereas individual reduction in CV death did not meet statistical significance (HR = 1.01; 95% CI, 0.8-1.28; I2 = 23%). The EMPULSE trial also observed a consistent clinical benefit across the LVEF spectrum in a primary composite endpoint of time to death, frequency of HF events, time to first HF event, and change in quality of life score from baseline in hospitalized patients with acute HF receiving empagliflozin vs. placebo, although the subgroup of patients with LVEF greater than 40% only represented 29% and 35% of the 530 patients randomly assigned to the treatment and placebo groups, respectively.
Upcoming trials that will further add to understanding of SGLT2 inhibition in HFpEF include the DELIVER trial, which will evaluate the effect of dapagliflozin (Farxiga, AstraZeneca) compared with placebo regarding CV death and worsening HF events, as well as DETERMINE-Preserved, analyzing change in baseline KCCQ total symptom scores, KCCQ physical limitation score and 6-minute walk distance.
Examining the expanded role of ARNI
In 2019, the PARAGON-HF trial provided a first look into the effects of the ARNI sacubitril/valsartan (Entresto, Novartis) on CV outcomes in a large population of ambulatory patients with HFpEF. No statistically significant reduction was seen in the composite primary endpoint of HHF and CV death compared with valsartan in 4,822 patients with NYHA class II to IV HF with an LVEF of at least 45% (Table on page 7); however, several interactions among subgroups were notable. Primary endpoint benefit was identified in subgroups of women and LVEF at or below the median of 57%, providing further insight into the possible heterogeneity of treatment effect among patients with HFpEF, including patients now defined as HFmrEF. In comparison to EMPEROR-Preserved, baseline prevalence of diabetes was similar between these trials (43% in PARAGON-HF vs. 49% in EMPEROR-Preserved). However, in contrast to the maintained treatment effect on composite CV mortality and HHF seen in patients with or without diabetes in EMPEROR-Preserved as well as PARADIGM-HF, a nonsignificant numerical trend toward benefit was observed in these subgroups within PARAGON-HF. Subsequent analyses have highlighted the overall greater magnitude of benefit with empagliflozin compared with sacubitril/valsartan in the comparable HFpEF populations of these trials, including a maintained reduction of time to first HHF across LVEFs 42.5% to 62.5% that was not seen with sacubitril/valsartan. Given low utilization of sacubitril/valsartan within EMPEROR-Preserved (2.2% overall), further data are needed to evaluate combined treatment effects of these agents in HFpEF as well as ARNI use among phenotypes of HFpEF.
After the release of PARAGON-HF, the FDA expanded labeling for sacubitril/valsartan to include chronic HF across the LVEF spectrum, including the statement that benefit is most clearly evident in patients with LVEF below normal. ARNI is included within the 2022 AHA/ACC/HFSA guideline as a class 2b recommendation for HFmrEF and HFpEF, although with different level of evidence grade between classifications and noted particularly among patients with LVEF on the lower end of the EF spectrum. Additional data exploring treatment effects in acute HF and de novo initiation in hospitalized patients with preserved LVEF is anticipated to further define the role of ARNI across the spectrum of HF.
Currently available evidence in the setting of acute HF has been limited to studies including small subgroups of patients with preserved LVEF. The PARAGLIDE-HF trial, due to be completed later this year, will evaluate change in NT-proBNP, secondary outcomes of CV death and HF events, as well as safety and tolerability of sacubitril/valsartan in patients with HFpEF with acute decompensated HF recently stabilized during hospitalization and initiated in-hospital or within 30 days after discharge. Given the similar trial design to PIONEER-HF, results of PARAGLIDE-HF will provide a more comprehensive understanding of the role in-hospital ARNI therapy plays between different LVEF phenotypes.
Recent additions to the body of evidence on ARNI and SGLT2 inhibitors in HFpEF have been a breakthrough given the historical absence of effective therapies for this significantly prevalent classification of HF. Further data determining their pharmacologic place in therapy and the evolving significance of HFmrEF will serve to better identify specific patient populations that may benefit most, and hopefully expand the clinical approach to improving outcomes and preventing HHF.
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- For more information:
- Ryan Kinnavy, PharmD, BCPS, is a clinical pharmacy specialist in cardiology at NorthShore University HealthSystem in Evanston, Illinois.
- Jennifer Verna, PharmD, BCPS, is clinical pharmacist at NorthShore University HealthSystem.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.
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