Milton Packer M.D.

Lam, C.S.P., Ferreira, J.P., Pfarr, E., Sim, D., Tsutsui, H., Anker, S.D., Butler, J., Filippatos, G., Pocock, S.J., Sattar, N., Verma, S., Brueckmann, M., Schnee, J., Cotton, D., Zannad, F. and Packer, M. (2021). “Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.” Eur Heart J 42(43): 4442-4451.

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AIMS: The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial. METHODS AND RESULTS: Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%. CONCLUSIONS: There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events.

Butler, J., Filippatos, G., Siddiqi, T.J., Brueckmann, M., Böhm, M., Chopra, V., Ferreira, J.P., Januzzi, J.L., Kaul, S., Piña, I.L., Ponikowski, P., Shah, S.J., Senni, M., Vedin, O., Verma, S., Peil, B., Pocock, S.J., Zannad, F., Packer, M. and Anker, S.D. (2021). “Empagliflozin, Health Status, and Quality of Life in Patients with Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial.” Circulation Nov 15. [Epub ahead of print].

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Background: Patients with heart failure and preserved ejection fraction (HFpEF) have significant impairment in health-related quality of life (HRQoL). In EMPEROR-Preserved, we evaluated the efficacy of empagliflozin on HRQoL in patients with HFpEF and whether the clinical benefit observed with empagliflozin varies according to baseline health status. Methods: HRQoL was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 12, 32 and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles and the effect of empagliflozin on outcomes were examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score (TSS) and Overall Summary Score (OSS) were evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin. Results: The effect of empagliflozin on reducing the risk of time to cardiovascular death or HF hospitalization was consistent across baseline KCCQ-CSS tertiles (HR 0.83 [0.69-1.00], HR 0.70 [0.55-0.88] and HR 0.82 [0.62-1.08] for scores <62.5, 62.5-83.3 and ≥83.3, respectively; P trend=0.77). Similar results were seen for total HF hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24 and +1.50 at 12, 32 and 52 weeks, respectively P<0.01); similar results were seen for TSS and OSS. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (OR 1.23; 95%CI 1.10, 1.37), ≥10 points (1.15; 95%CI 1.03, 1.27), and ≥15 points (1.13; 95%CI 1.02, 1.26) and lower odds of deterioration ≥5 points in KCCQ-CSS (0.85; 95%CI 0.75, 0.97). A similar pattern was seen at 32 and 52 weeks, and results were consistent for TSS and OSS. Conclusions: In patients with HFpEF, empagliflozin reduced the risk for major HF outcomes across the range of baseline KCCQ scores. Empagliflozin improved HRQoL, an effect that appeared early and was sustained for at least one year.

Packer, M., F. Zannad and S. D. Anker (2021). “Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials.” Circulation 144(15): 1193-1195.

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Heart failure and a preserved ejection fraction (HFpEF) is characterized in many patients by the coexistence of a systemic metabolic or inflammatory disorder that causes coronary endothelial dysfunction, microvascular rarefaction, and cardiac fibrosis, leading to impaired left ventricular distensibility. Neurohormonal antagonists that are effective in patients with heart failure and a reduced ejection fraction have generally not been useful in patients with HFpEF. Until recently, large-scale trials of patients with HFpEF have reported no benefit or only a modest reduction in the risk of heart failure outcomes, with borderline levels of statistical significance. The trials have also noted meaningful subgroup interactions, which have further complicated interpretation of the results.[No abstract; excerpt from article].

Tromp, J., M. Packer and C. S. Lam (2021). “The diverging role of epicardial adipose tissue in heart failure with reduced and preserved ejection fraction: not all fat is created equal.” Eur J Heart Fail Oct 16. [Epub ahead of print].

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In this issue of the Journal, the study by Pugliese et al. significantly extends prior knowledge on the role of EAT in HF by studying the association of EAT with clinical biomarkers and outcomes in patients with HFrEF and HFpEF. The authors measured EAT thickness on echocardiography in a total of 393 patients with HF (48% HFpEF) and 44 controls. The HF diagnosis in participants was corroborated by objective signs and symptoms of HF, a reduced ejection fraction or increased natriuretic peptides. All participants underwent comprehensive exercise testing with measurement of peak oxygen consumption (VO2 max) and arterial–venous oxygen content difference (AVO2diff) and were followed up for 21 months. EAT thickness was significantly increased in patients with HFpEF relative to controls and decreased in patients with HFrEF. In HFrEF, EAT was inversely associated with the inflammatory biomarkers high-sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), N-terminal pro-B-type natriuretic peptide and troponin T. In HFpEF, thicker EAT was associated with higher concentrations of troponin T, hs-CRP, and IL-6. Notably, thinner EAT was associated with worse (lower) VO2 max and an increased risk for cardiovascular death or hospitalization for HF in HFrEF. In HFpEF, the converse was true: thicker EAT was associated with a decreased VO2 max and increased risk for cardiovascular death or hospitalization for HF.

Packer, M., J. Butler, F. Zannad, S. J. Pocock, G. Filippatos, J. P. Ferreira, M. Brueckmann, W. Jamal, C. Zeller, C. Wanner and S. D. Anker (2021). “Empagliflozin and Major Renal Outcomes in Heart Failure.” N Engl J Med 385(16): 1531-1533.

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Sodium–glucose cotransporter 2 inhibitors reduce the risk of serious adverse renal outcomes in type 2 diabetes, but the renal effects of these drugs in patients with heart failure remain uncertain. Although empagliflozin and dapagliflozin have been reported to slow the rate of decline in the estimated glomerular filtration rate (eGFR), changes in the eGFR slope may not predict the effects of these drugs on major renal outcomes. [No abstract, excerpt from article].