Milton Packer M.D.

Anker, S.D., Butler, J., Filippatos, G., Khan, M.S., Marx, N., Lam, C.S.P., Schnaidt, S., Ofstad, A.P., Brueckmann, M., Jamal, W., Bocchi, E.A., Ponikowski, P., Perrone, S.V., Januzzi, J.L., Verma, S., Böhm, M., Ferreira, J.P., Pocock, S.J., Zannad, F. and Packer, M. (2021). “Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial.” Circulation 143(4): 337-349.

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BACKGROUND: Sodium-glucose cotransporter 2 inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. METHODS: Patients with Class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. RESULTS: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (hemoglobin A1c [HbA1c] 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio, 0.72 [95% CI, 0.60-0.87] and 0.78 [95% CI, 0.64-0.97], respectively, P-interaction=0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these end points, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. CONCLUSIONS: In EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c.

Anker, S.D., Butler, J., Filippatos, G., Khan, M.S., Ferreira, J.P., Bocchi, E., Böhm, M., Rocca, H.P.B., Choi, D.J., Chopra, V., Chuquiure, E., Giannetti, N., Gomez-Mesa, J.E., Janssens, S., Januzzi, J.L., Gonzalez-Juanatey, J.R., Merkely, B., Nicholls, S.J., Perrone, S.V., Piña, I.L., Ponikowski, P., Senni, M., Seronde, M.F., Sim, D., Spinar, J., Squire, I., Taddei, S., Tsutsui, H., Verma, S., Vinereanu, D., Zhang, J., Jamal, W., Schnaidt, S., Schnee, J.M., Brueckmann, M., Pocock, S.J., Zannad, F. and Packer, M. (2020). “Baseline Characteristics of Patients with Heart Failure with Preserved Ejection Fraction in the EMPEROR-Preserved Trial.” Eur J Heart Fail Nov 20. [Epub ahead of print.].

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BACKGROUND: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares it with patients enrolled in prior HFpEF trials. METHODS: EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients (left ventricular ejection fraction [LVEF] >40%) with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of HF hospitalization. RESULTS: Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72±9 years, 45% were women. Almost all patients had New York Heart Association (NYHA) Class II or III symptoms (99.6%), and 23% had prior HF hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54±9%) was slightly lower while the median NT-proBNP (974 [499-1731] pg/mL) was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin converting enzyme inhibitors/angiotensin receptor blockers/ARNi’s (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists. CONCLUSION: When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of co-morbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021.

Anker, S.D., Butler, J., Filippatos, G., Khan, M.S., Marx, N., Lam, C.S.P., Schnaidt, S., Ofstad, A.P., Brueckmann, M., Jamal, W., Bocchi, E., Ponikowski, P., Perrone, S.V., Januzzi, J.L., Verma, S., Böhm, M., Ferreira, J.P., Pocock, S.J., Zannad, F. and Packer, M. (2020). “Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status – Results from the EMPEROR-Reduced Trial.” Circulation Nov 29. [Epub ahead of print.].

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Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in patients with heart failure with reduced ejection fraction, but additional information is needed about whether glycemic status influences the magnitude of their benefits on heart failure and renal events. Methods: Patients with class II-IV heart failure and a left ventricular ejection fraction ≤40% were randomized to receive empagliflozin (10 mg daily) or placebo in addition to recommended therapy. We prespecified a comparison of the effect of empagliflozin in patients with and without diabetes. Results: Of the 3730 patients enrolled, 1856 (50%) had diabetes, 1268 (34%) had prediabetes (HbA1c 5.7-6.4%), and 606 (16%) had normoglycemia (HbA1c <5.7%). The risks of the primary outcome (cardiovascular death or hospitalization for heart failure), total hospitalizations for heart failure, and adverse renal outcomes were higher in patients with diabetes, but were similar between patients with prediabetes and normoglycemia. Empagliflozin reduced the risk of the primary outcome in patients with and without diabetes (hazard ratio 0.72 [95% CI 0.60-0.87] and 0.78 [95% CI 0.64-0.97], respectively, interaction P =0.57). Patients with and without diabetes also did not differ with respect to the effect of empagliflozin on total hospitalizations for heart failure, on the decline in estimated glomerular filtration rate over time, and on the risk of serious adverse renal outcomes. Among these endpoints, the effects of the drug did not differ in patients with prediabetes or normoglycemia. When analyzed as a continuous variable, baseline HbA1c did not significantly modify the benefits of empagliflozin on the primary outcome (P-interaction=0.40). Empagliflozin did not lower HbA1c in patients with prediabetes or normoglycemia and was not associated with increased risk of hypoglycemia. Conclusions: In the EMPEROR-Reduced trial, empagliflozin significantly improved cardiovascular and renal outcomes in patients with heart failure and a reduced ejection fraction, independent of baseline diabetes status and across the continuum of HbA1c.

Packer, M., Butler, J., Filippatos, G., Zannad, F., Ferreira, J.P., Zeller, C., Brueckmann, M., Jamal, W., Pocock, S. and Anker, S.D. (2020). “Design of a Prospective Patient-Level Pooled Analysis of Two Parallel Trials of Empagliflozin in Patients With Established Heart Failure.” Eur J Heart Fail Nov 30. [Epub ahead of print.].

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The EMPEROR-Reduced trial demonstrated that empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with a reduced ejection fraction, and the EMPEROR-Preserved trial is currently evaluating the effect of the drug on the same endpoint in patients with an ejection fraction > 40%. However, neither the trial was designed to have adequate statistical power to evaluate the effects of empagliflozin and dapagliflozin on major adverse renal outcomes or on mortality. Herein we describe the design of a prospective individual patient-level pooled analysis of two large-scale trials with empagliflozin (EMPEROR-Reduced and EMPEROR-Preserved) in patients with heart failure across the spectrum of ejection fraction. The trials were carried out in parallel using the same administrative structure and committees, randomization procedure, schedule of study visits and adjudication criteria and similar groups of investigators and case report forms. The two component trials specified the same primary and key secondary endpoints and used an identical hierarchical testing procedure, which included a pooled analysis of the two trials as a key component of the hierarchy. Consequently, the pooled analysis has been prospectively assigned a false positive error rate, which is conditional on one or both trials first achieving success on their primary and one or both key secondary endpoints. The pooled analysis has its own statistical plan with its own endpoints, and this plan was finalized before either trial had begun recruitment of patients into either study. The primary endpoint of the pooled analysis is a composite of serious adverse renal outcomes, defined by chronic dialysis, renal transplantation and a profound or sustained decrease in glomerular filtration rate. All-cause and cardiovascular mortality are specified as secondary endpoints. The planned pooled analysis has an unusually high degree of statistical rigor that will allow it to address important questions that cannot be fully addressed by the individual trials.

Yeoh, S.E., Dewan, P., Desai, A.S., Solomon, S.D., Rouleau, J.L., Lefkowitz, M., Rizkala, A., Swedberg, K., Zile, M.R., Jhund, P.S., Packer, M. and McMurray, J.J.V. (2020). “Relationship between duration of heart failure, patient characteristics, outcomes, and effect of therapy in PARADIGM-HF.” ESC Heart Fail Oct 19. [Epub ahead of print].

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AIMS: Little is known about patient characteristics, outcomes, and the effect of treatment in relation to duration of heart failure (HF). We have investigated these questions in PARADIGM-HF. The aim of the study was to compare patient characteristics, outcomes, and the effect of sacubitril/valsartan, compared with enalapril, in relation to time from HF diagnosis in PARADIGM-HF. METHODS AND RESULTS: HF duration was categorized as 0-1, >1-2, >2-5, and >5 years. Outcomes were adjusted for prognostic variables, including N-terminal pro-brain natriuretic peptide (NT-proBNP). The primary endpoint was the composite of HF hospitalization or cardiovascular death. The number of patients in each group was as follows: 0-1 year, 2523 (30%); >1-2 years, 1178 (14%); >2-5 years, 2054 (24.5%); and >5 years, 2644 (31.5%). Patients with longer-duration HF were older, more often male, and had worse New York Heart Association class and quality of life, more co-morbidity, and higher troponin-T but similar NT-proBNP levels. The primary outcome rate (per 100 person-years) increased with HF duration: 0-1 year, 8.4 [95% confidence interval (CI) 7.6-9.2]; >1-2 years, 11.2 (10.0-12.7); >2-5 years, 13.4 (12.4-14.6); and >5 years, 14.2 (13.2-15.2); P < 0.001. The hazard ratio was 1.26 (95% CI 1.07-1.48), 1.52 (1.33-1.74), and 1.53 (1.33-1.75), respectively, for >1-2, >2-5, and >5 years, compared with 0-1 year. The benefit of sacubitril/valsartan was consistent across HF duration for all outcomes, with the primary endpoint hazard ratio 0.80 (95% CI 0.67-0.97) for 0-1 year and 0.73 (0.63-0.84) in the >5 year group. For the primary outcome, the number needed to treat for >5 years was 18, compared with 29 for 0-1 year. CONCLUSIONS: Patients with longer-duration HF had more co-morbidity, worse quality of life, and higher rates of HF hospitalization and death. The benefit of a neprilysin inhibitor was consistent, irrespective of HF duration. Switching to sacubitril/valsartan had substantial benefits, even in patients with long-standing HF.