Heart failure treatment: What’s new in HFpEF, HFmrEF and HFrEF?

Prof. Andrew Coats
Monash University
Melbourne, Australia
11 Jul 2022
Heart failure treatment: What’s new in HFpEF, HFmrEF and HFrEF?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (eg, empagliflozin) are now recommended by 2022 guidelines of the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) as one of the drug classes to be used in treatment of heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF). For patients with heart failure with reduced ejection fraction (HFrEF), the 2022 AHA/ACC/HFSA guidelines recommend SGLT2 inhibitors as one of the four pillars of step 1 medications. At the 26th Hong Kong Medical Forum, Professor Andrew Coats of the Monash University, Melbourne, Australia, reviewed evidence supporting these recommendations and highlighted the importance of protecting renal function in HF management.

2022 AHA/ACC/HFSA guidelines
Latest 2022 AHA/ACC/HFSA guidelines for management of heart failure (HF) recommend SGLT2 inhibitors as class 2a therapies in patients with HFpEF (left ventricular ejection fraction [LVEF] ≥50 percent) or HFmrEF (LVEF, 41–49 percent), indicating that these agents can be beneficial in decreasing hospitalization for HF (HHF) and cardiovascular (CV) mortality. Notably, the class of recommendation for SGLT2 inhibitors in HFpEF and HFmrEF is higher than that for renin-angiotensin-aldosterone system (RAAS) inhibitors (ie, angiotens inconverting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and angiotensin receptor-neprilysin inhibitor [ARNI]), mineralocorticoid receptor antagonists (MRAs), and beta-blockers. (Figure1) [J Am Coll Cardiol 2022;79:1757-1780]

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For patients with HFrEF (LVEF 40 percent), the 2022 AHA/ACC/HFSA guidelines recommend SGLT2 inhibitors (class 1), RAAS inhibitors (class 1; ARNI preferred in New York Heart Association [NYHA] class IIIII HF; ACEIs or ARBs in NYHA class IIIV HF), beta-blockers (class 1) and MRAs (class 1) as four classes of foundational step 1 medications, along with as-needed diuretics (class 1).

The 2022 AHA/ACC/HFSA guidelines are similar to those of the European Society of Cardiology [last updated in 2021], which recommend SGLT2 inhibitors, ARNI or ACEIs, beta-blockers and MRAs as four foundational drug classes to be started as quickly as possible and uptitrated to the maximum tolerated dose in HFrEF patients, said Coats. [Eur Heart J 2021;42:3599-3726]

Empagliflozin: Efficacy in HF across the LVEF spectrum
The 2022 AHA/ACC/HFSA guideline recommendations for use of SGLT2 inhibitors in HFpEF and HFmrEF are based on results of the EMPEROR-Preserved trial of empagliflozin in patients with HF with LVEF >40 percent, while recommendations for HFrEF are partly based on results of the EMPEROR-Reduced trial of empagliflozin in patients with LVEF ≤40 percent. Both trials included patients with or without type 2 diabetes. [N Engl J Med 2021;385:1451-1461; N Engl J Med 2020;383:1413-1424]

Why does HFpEF matter?
The proportion of HF patients with HFpEF had increased significantly over time, from 41 percent in 1985–1994 to 56 percent in 2005–2014 (p<0.001). [JACC Cardiovasc Imaging 2018;11:1-11] “With relentless progression in the proportion of hospitalized HF patients with LVEF >50 percent, HFpEF was projected to become the dominant form of HF, accounting for about 50 percent of HHFs in 2020,” said Coats. [Curr Heart Fail Rep 2013;10:401-410]

Also, HFpEF patients have similar mortality risk and experience similar or worse limitations with daily activities as patients with HFrEF, he continued. Before the EMPEROR-Preserved trial, no clinically proven therapies were available to reduce HF outcomes, and treatment options were limited to control of symptoms and comorbidities. [J Am Coll Cardiol 2014;63:1123-1133]

Reduction in CV death or HHF
“EMPEROR-Preserved is the first and only drug trial that demonstrates a reduction in CV death or HHF in patients with HFpEF. The 21 percent relative risk reduction [RRR] in this primary composite outcome [hazard ratio (HR), 0.79; 95 percent confidence interval (CI), 0.69–0.90; p<0.001] represents major benefit of empagliflozin, with a number needed to treat [NNT] of only 31. Furthermore, the benefit was early and sustained, with separation of curves between empagliflozin and placebo seen within the first few months of the trial,” Coats highlighted. “The RRR for total HHFs was 27 percent [HR, 0.73; 95 percent CI, 0.61–0.88; p<0.001].” [N Engl J Med 2021;385:1451-1461]

In an EMPEROR-Preserved subgroup analysis of patients with LVEF 50 percent, empagliflozin demonstrated a 17 percent RRR in the primary composite outcome of CV death or HHF vs placebo (HR, 0.83; 95 percent CI, 0.710.98; p=0.024). (Figure 2) [Anker SD, et al, AHA 2021]

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In patients with HFrEF, results of the EMPEROR-Reduced trial demonstrated a 25 percent RRR in CV death or HHF (HR, 0.75; 95 percent CI, 0.650.86; p<0.001) and a 30 percent RRR in total HHFs (HR, 0.70; 95 percent CI, 0.580.85; p<0.001) with empagliflozin vs placebo. [N Engl J Med 2020;383:1413-1424]

“A recent pooled analysis of these two trials showed that empagliflozin’s effect on CV death or HHF was consistent across the spectrum of LVEF [ie, <25–<65 percent], with no significant interaction [pinteraction=0.30] observed,” said Coats. (Figure 3) [Eur Heart J 2022;43:416-426]

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How about the kidneys?
“In patients with HF, worsening renal function and hypotension are main reasons for deviation from guideline-directed medical therapies,” said Coats. [J Am Heart Assoc 2018;7:e008789] “This highlights the need for medications that don’t decrease renal function or blood pressure reserve in HF patients, such as SGLT2 inhibitors.”

In the EMPEROR-Reduced trial, the annual rate of decline in estimated glomerular filtration rate (eGFR) was significantly lower in the empagliflozin vs placebo group (mean, -0.55 mL/min/1.73 m2 vs -2.28 mL/min/1.73 m2; p<0.001). The risk of the composite renal outcome (chronic dialysis or renal transplantation or a profound, sustained reduction in eGFR) was also lower with empagliflozin vs placebo (HR, 0.50; 95 percent CI, 0.32–0.77). [N Engl J Med 2020;383:1413-1424]

“In HF, reduction in renal blood flow is compensated by hyperfiltration, resulting in an increase in glomerular filtration pressure, which is harmful for the kidneys,” Coats explained. “The initial drop in eGFR seen in the first week of empagliflozin treatment is due to its protective effect of reducing glomerular filtration pressure, and is not a sign of kidney damage. Subsequently, eGFR in the empagliflozin group remained stable.”

In EMPEROR-Preserved, the annual rate of decline in eGFR was also significantly lower with empagliflozin vs placebo (mean, -1.25 mL/min/1.73 m2 vs -2.62 mL/min/1.73 m2; p<0.001). [N Engl J Med 2021;385:1451-1461]

Safety and tolerability
“In both trials, empagliflozin was well tolerated. Rates of adverse events [AEs] were similar between the empagliflozin and placebo groups,” said Coats.

AEs more commonly reported with empagliflozin vs placebo were uncomplicated genital and urinary tract infections (2.2 percent vs 0.7 percent and 9.9 percent vs 8.1 percent, respectively) and symptomatic hypotension (6.6 percent vs 5.2 percent) in EMPEROR-Preserved, as well as uncomplicated genital tract infections (1.7 percent vs 0.6 percent) in EMPEROR-Reduced. However, rates of complicated genital (0.3 percent vs 0.3 percent in both trials) and urinary tract infections (1.9 percent vs 1.5 percent in EMPEROR-Preserved; 1.0 percent vs 0.8 percent in EMPEROR-Reduced) showed little or no difference between empagliflozin and placebo in both trials. [N Engl J Med 2021;385:1451-1461; N Engl J Med 2020;383:1413-1424]

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