EMPEROR-Preserved: Empagliflozin in HFpEF
Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
Anker SD, Butler J, Filippatos G, et al.; EMPEROR-Preserved Trial Investigators.
N Engl J Med. 2021 Oct 14;385(16):1451-1461. [Full text]
Summary by Chase Sherman
Guideline directed medical treatments (GDMT) of heart failure with reduced ejection fraction (HFrEF) have been shown to reduce cardiovascular death and hospitalizations. To date there have been few treatments shown to decrease mortality, or even modify the disease course of heart failure with preserved ejection fraction (HFpEF). While loop diuretics are frequently relied upon to symptomatically treat HFpEF, therapies such as beta blockers, ACE inhibitors, ARBs have not been consistently shown to alter the disease course (summary of HFpEF trials). Recently, Mineralocorticoid receptor antagonists as well as Neprilysin inhibitors have been suggested to have modest benefit at decreasing hospitalizations in HFpEF patients, but on further subgroup analysis, most of the benefits observed were in patients with “mid-range” ejection fraction (HFmrEF, LVEF = 40-49%), which phenotypically may resemble HFrEF rather than HFpEF. Thus, a treatment that truly alters clinical outcomes in HFpEF continues to elude us.
Recent trials such as DAPA-HF (Dapagliflozin) have suggested that SGLT2i may reduce cardiovascular mortality and hospitalizations in patients with HFrEF independent of DM status. This finding was recently expounded upon by the EMPEROR-Reduced trial, where Empagliflozin in patients with HFrEF showed decrease HF hospitalizations. A parallel trial, called the EMPEROR-Preserved trial, was the first to assess if SGLT2i (Empagiflozin) could have such a benefit in HFpEF. Recently published in the NEJM; this study found that Empagliflozin use in patients with HFpEF significantly reduced the primary composite outcome of cardiovascular death and hospitalization compared to placebo, highlighting a potential emerging role of these medications in altering clinical outcomes in HFpEF.
Patient population and Design
This multicenter, randomized, double-blind, parallel-group, placebo-controlled, event-driven trial study enrolled 5988 patients with left ventricular ejection fraction (LVEF) >40% (82% NYHA Class II). Patients were randomized in a 1:1 fashion to either empagliflozin 10 mg daily (n = 2,997) or matching placebo (n = 2,991). The trial was stratified by geographic region, diabetes status, estimated glomerular filtration rate (eGFR), and LVEF<50% and ≥50%. All the patients were receiving appropriate treatments for HF. Other salient population characteristics were that 49% of patients had type 2 Diabetes Mellitus (DM), 45% were female, 51% had Atrial fibrillation (Afib), a major prognostic factor in HFpEF outcomes, and 50% had eGFR <60mL/min/1.73 m2.
Inclusion criteria were as follows: Age >18 years, NYHA Class II, III, or IV, preserved LVEF >40%, HF hospitalization within the prior 12 months, NT-pro-BNP >300 pg/mL without Afib or >900 pg/mL with Afib, structural heart disease within 6 months, and stable doses of diuretics if prescribed. Of note, patients were excluded based on having ACS, stroke or TIA within the past 90 days, being listed or having received OHT, having acute decompensated HF, SBP >180mm Hg or symptomatic hypotension <100mm Hg, liver or kidney disease with eGFR <20, and current or prior SGLT1/2 inhibitor use. The study duration was 26.2 months median follow up.
Outcomes
The primary outcome was a composite of cardiovascular death or hospitalization for heart failure, analyzed as time to first outcome. The secondary outcomes were analyzed in hierarchal testing procedure and consisted of total number of hospitalizations for heart failure, eGFR mean slope change per year, change in Kansas City Clinical Questionnaire at 52 weeks, total number of hospitalizations for any cause, composite renal outcomes (%), onset of new DM in patients with pre-DM, and death from any cause.
Results
The primary composite outcome event of cardiovascular death or hospitalization from heart failure occurred in 415 patients (13.8%) in the empagliflozin group and 511 patients (17.1%) in the placebo group (6.9 vs. 8.7 events /100 patient-yrs; HR, 0.79; 95% CI, 0.69 to 0.90; P<0.001). During the 26-month median duration of follow-up, the number needed to treat to prevent one primary outcome event was 31 (95% CI 20-69). Of note, hospitalization for heart failure occurred less frequently in the empagliflozin group, with 259 patients (8.6%) compared to 352 patients (11.8%) in the placebo group (HR, 0.71; 95% CI, 0.60 to 0.83). Death from cardiovascular causes occurred with similar frequency, 219 patients (7.3%) in the empagliflozin group and 244 patients (8.2%) in the placebo group (HR, 0.91; 95% CI, 0.76 to 1.09). The effect of empagliflozin on the primary outcome was consistent independent of DM status.
In subgroup analysis of the primary outcome, the HFmrEF (LVEF = 40-49%) subgroup received the bulk of the benefit (HR, 0.71; 95% CI, 0.57 to 0.88). In the LVEF ≥50-59% (HR, 0.80; 95% CI, 0.64 to 0.99) and LVEF ≥60% HR, 0.87; 95% CI, 0.69 to 1.10) groups the benefits were minimal, if at all.
For the secondary outcomes, the total number of hospitalizations for HF was lower with empagliflozin than with placebo (HR, 0.73; 95% CI, 0.61 to 0.88; P<0.001). The rate of decline in the eGFR was slower in the empagliflozin group than in the placebo group (–1.25 vs. –2.62 ml per minute per 1.73 m2 / year; P<0.001). A total of 422 patients (14.1%) in the empagliflozin group and 427 patients (14.3%) in the placebo group died from any cause (hazard ratio, 1.00; 95% CI, 0.87 to 1.15). Of note, composite renal outcome occurred in 108 (3.6%) vs 112 (3.7%) of empagliflozin and placebo groups, respectively (95% CI 0.73-1.24), and new onset DM: 120 (12.0%) vs 137 (14.0%) (95% CI 0.65-1.07) was not significantly different between groups either.
For safety/adverse effects, serious adverse events occurred in 1436 patients (47.9%) in the empagliflozin group and in 1543 patients (51.6%) in the placebo group. Adverse events leading to discontinuation of treatment occurred in 571 patients (19.1%) in the empagliflozin group and in 551 patients (18.4%) in the placebo group. Otherwise empagliflozin was tolerated, with the trial medication stopped (for reasons other than death) in 696 (23.2%) of patients receiving empagliflozin and 699 (23.4%) of patients receiving placebo.
Uncomplicated genitourinary (GU, 67 [ 2.2%] vs 22 [0.7 % ]) and urinary tract infections (UTI 297 [9.9%] vs 243 [8.1%]) as well as hypotension (311 [10.4%] vs 257 [8.6%]) were more common with empagliflozin than placebo, respectively (no p-value reported).
Discussion
The authors concluded that based on the results of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) that empagliflozin led to a 21% reduction in the composite outcome of cardiovascular death or hospitalization from heart failure. They admit that this composite was primarily driven by the significant 29% reduction in hospitalization for heart failure in the treatment group. Further, this study further reinforces the benefits of SGLT2i in HF patient exist independent of DM status.
As noted, the pathophysiology of HFpEF differs from HFrEF, and there have so far been few medications showing promise at changing clinical outcomes in this HF phenotype. The recent studies on MRA (TOPCAT) and neprilysin (PARAGON-HF) inhibitors have suggested a possible emerging role; however, on further sub-group analyses, these benefits largely extend to HFmrEF patients and less apparent for the truly “preserved” LVEFs ≥50%. The authors of EMPEROR-Preserved enlisted more patients with higher LVEFs (median LVEF was 54%). Upon sub-group analysis, HFmrEF patients had the most benefit. While the hazard ratio significance remained less than 1 for LVEF ≥50-59%, it did not for LVEF ≥60%.
The results of the EMPEROR-Preserved trial need to be compared with the other recent SGLT2i trials in HFrEF and HFpEF (DAPA-HF, EMPEROR-Reduced). The EMPEROR empagliflozin parallel trials (EMPEROR-Reduced and EMPEROR-Preserved) both showed significantly reduced hospitalization for HF; however, no significant decrease in cardiovascular death alone was observed regardless of LVEF. Meanwhile, the DAPA-HF trial showed that dapagliflozin significantly reduced both HF hospitalizations AND cardiovascular death in patients with HFrEF. Another trial with Dapagliflozin (DELIVER) is ongoing which considers dapagliflozin in HFpEF. If results from DELIVER parallel DAPA-HF one may have to consider the effect drug specific, rather than class/ SGLT2i specific and therefore dapagliflozin the preferred SGLT2i for HF.
Finally, rates of hypotension, GUIs and UTIs were higher with empagliflozin than placebo. While the latter two findings are known complications of this class, hypotension in HFpEF patients may be a limitation. Often HFpEF patients are on loop diuretics and/or spironolactone, which had a signal of reduced HF hospitalization in TOPCAT. Combining all these may lead to adverse outcomes or not be well tolerated. It is currently unclear if an SGLT2i should be prioritized over these other agents, and though this trial suggest it may, guidelines have not yet been updated.
Overall, the EMPEROR-Preserved trial shows that empagliflozin lowers hospitalization rates by 29% in HFpEF patients, independent of DM status. This may very well signal a change in clinical practice and represent a new medical therapy to change the clinical outcomes of HFpEF patients, a disease process with a lack of therapeutic options currently.
| F: Follow up | Median 26.2 months (interquartile range, 18.1 to 33.1) for primary outcome. |
| R: Randomization | Yes |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | Boehringer Ingelheim and Eli Lilly |
