EMPEROR ‐Reduced: confirming sodium–glucose co‐transporter 2 inhibitors as an essential treatment for patients with heart failure with reduced ejection fraction
2020; Elsevier BV; Volume: 22; Issue: 11 Linguagem: Inglês
10.1002/ejhf.2006
ISSN1879-0844
Autores Tópico(s)Pancreatic function and diabetes
ResumoEuropean Journal of Heart FailureVolume 22, Issue 11 p. 1987-1990 ViewpointFree Access EMPEROR-Reduced: confirming sodium–glucose co-transporter 2 inhibitors as an essential treatment for patients with heart failure with reduced ejection fraction John J.V. McMurray, Corresponding Author John J.V. McMurray [email protected] BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK Corresponding author. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK. Tel: +44 141 330 3479, Email: [email protected]Search for more papers by this author John J.V. McMurray, Corresponding Author John J.V. McMurray [email protected] BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK Corresponding author. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK. Tel: +44 141 330 3479, Email: [email protected]Search for more papers by this author First published: 18 September 2020 https://doi.org/10.1002/ejhf.2006Citations: 2AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Unusually, I am starting this article with a conclusion: there are more similarities than differences between the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction trial (EMPEROR-Reduced) and the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure trial (DAPA-HF).1, 2 Moreover, the consistency between the two trials strongly supports the use of sodium–glucose co-transporter 2 (SGLT2) inhibitors to treat patients with heart failure and reduced ejection fraction (HFrEF), irrespective of type 2 diabetes status.3 Nevertheless, it is of interest to compare, and contrast, the two trials, while recognising that cross-trial comparisons are difficult and wholly qualitative. The major points of note are the size of the trials, their inclusion and exclusion criteria, the differences in baseline characteristics, study drug discontinuation, event rates and numbers for the key mortality and hospitalization outcomes and the effect of study drug on these various outcomes.4-7 Overall EMPEROR-Reduced (n = 3730) was smaller than DAPA-HF (n = 4744).1-7 As both trials were event-driven, with a similar target number of primary events (841 vs. 844), it might have taken much longer accrue the target number of events in EMPEROR-Reduced than in DAPA-HF. However, the inclusion criteria in EMPEROR-Reduced ensured the enrolled patients were at higher risk of the primary endpoint than those in DAPA-HF. Specifically, the EMPEROR-Reduced investigators devised a matrix of inclusion criteria based on left ventricular ejection fraction (LVEF), heart rhythm and N-terminal pro B-type natriuretic peptide (NT-proBNP) level that ensured patients either had a low LVEF or high NT-proBNP in comparison to DAPA-HF1-7 (Table 1). The lower limit of estimated glomerular filtration rate (eGFR) was also less in EMPEROR-Reduced than DAPA-HF (30 vs. 20 mL/min/1.73 m2). Table 1. Inclusion criteria for DAPA-HF and EMPEROR-Reduced based upon left ventricular ejection fraction, N-terminal pro B-type natriuretic peptide level and heart rhythm NT-proBNP (pg/mL) No AF/Fl AF/Fl DAPA-HF LVEF (%) ≤40 ≥600 ≥900 ≤40 and hospitalized for HF within 12 months ≥400 ≥900 EMPEROR-Reduced LVEF (%) ≤30 ≥600 ≥1200 31–35 ≥1000 ≥2000 36–40 ≥2500 ≥5000 ≤40 and hospitalized for HF within 12 months ≥600 ≥1200 AF/Fl, atrial fibrillation/flutter; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide. These different approaches led to expected differences in the baseline characteristics of patients enrolled in the two trials (Table 2), with a higher median NT-proBNP, and lower mean LVEF and eGFR in EMPEROR-Reduced. Another very important difference was the considerably higher rate of use of sacubitril/valsartan in EMPEROR-Reduced compared with DAPA-HF (19% vs. 11%).1-7 Table 2. Key baseline characteristics of patients in DAPA-HF and EMPEROR-Reduced DAPA-HF (n = 4744) EMPEROR-Reduced (n = 3730) Age, years 66 67 Female, % 23 24 NYHA class III/IV, % 32 25 LVEF, % 31 27 Prior HF hospitalization (or equivalent), % 47 31a Median NT-proBNP, pg/mL 1437 ∼1900 Atrial fibrillation, % 40 37 Diabetes (history), % 42 50 eGFR, mL/min/1.73 m2 66 62 Beta-blocker, % 96 95 MRA, % 71 71 ARNI, % 11 19 Values are means or proportions (%) unless otherwise stated. ARNI, angiotensin receptor–neprilysin inhibitor; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association. a Within the previous 12 months. The two trials had slightly different primary endpoints, with a composite of time-to-first occurrence of heart failure hospitalization or cardiovascular death in EMPEROR-Reduced, compared with a three-component composite in DAPA-HF that also included episodes of worsening heart failure treated with intravenous therapy in a non-ward setting; in fact, the latter added few first events in DAPA-HF, with 877 patients experiencing either a first heart failure hospitalization or cardiovascular death compared with 888 experiencing the three-component composite. Moreover, the EMPEROR-Reduced primary endpoint was the key secondary endpoint in DAPA-HF. Both trials also assessed: (i) total events, i.e. examined not just first events but also repeat events (although this was done for both cardiovascular death and heart failure hospitalizations in DAPA-HF and only for heart failure hospitalizations in EMPEROR-Reduced), (ii) clinical status using the Kansas City Cardiomyopathy Questionnaire (although used different sub-scores in the main analysis), (iii) renal function (although each trial used a slightly different event composite), and (iv) changes in blood pressure, haematocrit, weight and NT-proBNP.1-7 The key hospitalization and death outcomes in each trial, along with the effect of treatment are summarised in Table 3. As can be seen, both trials showed an essentially identical effect of SGLT2 inhibition on the key composite of time-to-first occurrence of heart failure hospitalization or cardiovascular death, as well as on first and total (i.e. first and repeat) hospitalizations for heart failure. The only 'difference' appears to be in reduction in death, either from cardiovascular causes or from any cause. What might have caused this apparent discrepancy? A difference in the efficacy of the two study drugs seems unlikely as both have been shown to reduce mortality in other trials. The more likely explanation is that EMPEROR-Reduced had substantially less power to show a difference in mortality than DAPA-HF. Specifically, there were 111 fewer cardiovascular deaths in EMPEROR-Reduced than in DAPA-HF (389 vs. 500) (Table 3). At first glance, this might seem counterintuitive given that EMPEROR-Reduced recruited higher-risk patients than enrolled in DAPA-HF, with a rate of heart failure hospitalization or cardiovascular death of 24.7 per 100 person-years in the placebo group, compared to a corresponding rate of 15.3 per 100 person-years in DAPA-HF. However, closer inspection of Table 3 shows that the higher primary endpoint rate in EMPEROR-Reduced was driven by an elevated rate of heart failure hospitalization, but not rate of death, compared with DAPA-HF. Indeed, the higher rate of the primary endpoint in EMPEROR-Reduced resulted in a shorter follow-up than in DAPA-HF (16 vs. 18.2 months) and this, along with the smaller overall trial size, led to the accrual of a smaller number of deaths than in DAPA-HF.1-7 An additional factor that may have reduced the power to show an effect of empagliflozin on mortality was the higher study treatment discontinuation rate in EMPEROR-Reduced, compared with DAPA-HF (17.1% vs. 10.7%) — a treatment cannot reduce events if it is not taken by patients. It is very important to note here that the rate of discontinuation of SGLT2 inhibitor was not different from placebo in either trial, i.e. the higher rate of discontinuation of study treatment in EMPEROR-Reduced reflected differences in patient or investigator preference or behaviour, or some other aspect of trial conduct, and not in tolerability of the SGLT2 inhibitor. The difference between empagliflozin and placebo may also have been reduced by 'drop-in' use of non-randomized SGLT2 inhibitor treatment, although this is usually uncommon in trials and was not reported by the EMPEROR-Reduced investigators. Table 3. Key results of DAPA-HF and EMPEROR-Reduced EMPEROR-Reduced (n = 3730) DAPA-HF (n = 4744) Placebo n (rate)a Empagliflozin n (rate) HR/RR (95% CI) Placebo n (rate) Dapagliflozin n (rate) HR/RR (95% CI) Composite outcome CV death or HF hospitalization 462 (21.0) 361 (15.8) 0.75 (0.65–0.86) 495 (15.3) 382 (11.4) 0.75 (0.65–0.85) HF hospitalization First hospitalization 342 (15.5) 246 (10.7) 0.69 (0.59–0.81) 318 (9.8) 231 (6.9) 0.70 (0.59–0.83) Total hospitalizations 553 388 0.70 (0.58–0.85) 469 340 0.71 (0.61–0.82) Death CV death 202 (8.1) 187 (7.6) 0.92 (0.75–1.12) 273 (7.9) 227 (6.5) 0.82 (0.69–0.98) All-cause death 266 (10.7) 249 (10.1) 0.92 (0.77–1.10) 329 (9.5) 276 (7.9) 0.83 (0.71–0.97) CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; RR, rate ratio. a All rates are expressed per 100 person-years. Another, more speculative, possibility for the absence of a clear reduction in mortality in EMPEROR-Reduced is that a subgroup of patients in that trial were less responsive to SGLT2 inhibitor treatment. The differences between the inclusion criteria and baseline characteristics of patients in the two trials mean this is a potential explanation which will no doubt be explored in forthcoming analyses. Difference in LVEF seems unlikely to be relevant given the consistency of benefit across the LVEF spectrum in DAPA-HF.8 It is also of interest to ask why enriching the EMPEROR-Reduced population for risk by including patients with a higher NT-proBNP and lower LVEF did not lead to a higher rate of death (as opposed to hospitalization)? One possibility is the better background treatment in EMPEROR-Reduced (not only the higher rate of use of sacubitril/valsartan as mentioned above, but also device therapy) but maybe also the relatively short duration of follow-up.1, 2 It is hard to believe that patients with a higher rate of heart failure hospitalization will not also eventually show a higher mortality rate, as all prior evidence suggests is the case.9 In my view, EMPEROR-Reduced contributes three other very important findings. First, the benefit of SGLT2 inhibition in patients without type 2 diabetes was clearly confirmed — these drugs have been repurposed as a treatment for HFrEF and are no longer just a therapy for type 2 diabetes.10 Second, the larger subgroup of patients taking sacubitril/valsartan in EMPEROR-Reduced allowed a more robust analysis of the effect of adding a SGLT2 inhibitor to this therapy and confirmed beyond doubt that the benefit of SGLT2 inhibition is incremental to neprilysin inhibition (and other core therapies).11, 12 Third, in EMPEROR-Reduced, empagliflozin delayed or prevented the development of worsening renal function significantly. The rate of worsening renal function was higher in EMPEROR-Reduced than in DAPA-HF because patients in EMPEROR-Reduced had a lower baseline eGFR and because the composite renal outcome included a 40% or greater decline in eGFR, rather than the 50% or greater decrease used in DAPA-HF. Both trials showed similar reductions in the rate of decline in eGFR over time.1-7 The EMPEROR-Reduced findings also support the improvement in symptoms and quality of life demonstrated in DAPA-HF.13 In summary, we continued to be blessed in the field of heart failure with robust evidence from randomized trials allowing us to make evidence-based treatment decisions for our patients. EMPEROR-Reduced is a landmark trial adding to our evidence base.3 Not only are the benefits of SGLT2 inhibitors substantial, but they are cost-effective as well, and now must be considered an essential therapy for HFrEF.14, 15 Conflict of interest: J.J.V.McM. was Principal Investigator of DAPA-HF, funded by AstraZeneca, and his employer, Glasgow University, was paid by AstraZeneca for his participation in DAPA-HF. 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