Milton Packer M.D.

Ferreira, J. P., Packer, M., Butler, J. and Zannad, F. (2022). “Reconsidering the ejection fraction centric view of pharmacologic treatment for heart failure.” Eur J Heart Fail.

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In the 1980s randomized, controlled, and double-blind trials in HF started to be conducted.14 The first large randomized controlled trial (RCT) with a survival endpoint, the Veterans Administration Cooperative Study (V-HeFT-I),15 selected patients taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin, or the combination of hydralazine and isosorbide dinitrate based on evidence of cardiac dilatation (cardiothoracic ratio >0.55 on chest X-ray or a left ventricular internal diameter in diastole >2.7 cm/m2 on echocardiography) or a radionuclide ejection fraction <45% in association with reduced exercise tolerance. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial randomized patients to enalapril or placebo based on the presence of severe symptoms and a radiologically-determined heart size >600 ml/m2 in men and >550 ml/m2 in women, without the characterization of ejection fraction.

Peikert, A., Vaduganathan, M., Mc Causland, F., Claggett, B. L., Chatur, S., Packer, M., Pfeffer, M. A., Zannad, F., Lefkowitz, M. P., Pieske, B., Düngen, H. D., McMurray, J. J. V. and Solomon, S. D. (2022). “Effects of sacubitril/valsartan versus valsartan on renal function in patients with and without diabetes and heart failure with preserved ejection fraction: insights from PARAGON-HF.” Eur J Heart Fail.

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AIMS: Diabetes is associated with a faster rate of renal function decline in patients with heart failure (HF). Sacubitril/valsartan attenuates the deterioration of renal function to a greater extent in patients with diabetes and HF with reduced ejection fraction compared with renin-angiotensin system inhibitors alone. We assessed whether the same may be true in HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: In the PARAGON-HF trial in patients with HF and left ventricular ejection fraction of ≥45% (n = 4796), we characterized the effects of sacubitril/valsartan on changes in estimated glomerular filtration rate (eGFR) over a period of 192 weeks, and on the pre-specified renal composite outcome (eGFR reduction of ≥50%, end-stage renal disease, or death attributable to renal causes) in patients with (n = 2388) and without diabetes (n = 2408). The decline in eGFR was greater in patients with diabetes than in those without (-2.6 vs. -1.7 ml/min/1.73 m(2) per year, p < 0.001), regardless of treatment assignment. Sacubitril/valsartan attenuated decline in eGFR similarly in patients with (-2.2 vs. -2.9 ml/min/1.73 m(2) per year, p = 0.001) and without diabetes (-1.5 vs. -2.0 ml/min/1.73 m(2) per year, p = 0.006) (p(interaction) for difference in eGFR slopes = 0.40). Compared with valsartan, sacubitril/valsartan reduced the renal composite outcome similarly in patients without diabetes (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.19-0.91) and those with diabetes (HR 0.54, 95% CI 0.33-0.89; p(interaction) = 0.59), as well as across a range of baseline glycated haemoglobin (p(interaction) = 0.71). CONCLUSION: Sacubitril/valsartan, compared with valsartan, attenuates the decline of eGFR and reduces clinically relevant kidney events similarly among patients with HFpEF with and without diabetes.

Pabón, M. A., Cunningham, J. W., Claggett, B. L., Packer, M., Zile, M., Pfeffer, M. A., Lefkowitz, M., Shi, V., Rizkala, A., McMurray, J. J. V., Solomon, S. D. and Vaduganathan, M. (2022). “Natriuretic peptide-based inclusion criteria in heart failure with preserved ejection fraction clinical trials: insights from PARAGON-HF.” Eur J Heart Fail.

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AIM: Natriuretic peptides (NPs) are now routinely incorporated as key inclusion criteria in clinical trials of heart failure with preserved ejection fraction (HFpEF) as objective measures of risk. An early amendment in PARAGON-HF required all participants to have elevated NP concentrations, but some were enrolled pre-amendment, providing a unique opportunity to understand the influence of enrolment pathway in HFpEF clinical trials. METHODS AND RESULTS: Among 4796 participants in PARAGON-HF, 193 (4.0%) did not meet the final NP-based enrolment criteria (N-terminal pro-B-type natriuretic peptide >300 pg/ml for patients in sinus rhythm or >900 pg/ml for patients in atrial fibrillation/flutter). These patients had lower rates of the primary endpoint of total heart failure hospitalizations and cardiovascular death as compared with patients meeting final enrolment criteria (8.6 [6.7-11.2] events per 100 patient-years vs. 14.0 [13.4-14.7] events per 100 patient-years; p = 0.01). The rate ratio for the treatment effect comparing sacubitril/valsartan with valsartan was 0.85 (95% confidence interval 0.74-0.99; p = 0.04) in those who met final criteria. CONCLUSIONS: Natriuretic peptides are an important tool in HFpEF clinical trials to objectively affirm diagnoses and enrich clinical event rates.

Mc Causland, F.R., Lefkowitz, M.P., Claggett, B., Packer, M., Senni, M., Gori, M., Jhund, P.S., McGrath, M.M., Rouleau, J.L., Shi, V., Swedberg, K., Vaduganathan, M., Zannad, F., Pfeffer, M.A., Zile, M., McMurray, J.J.V. and Solomon, S.D. (2022). “Angiotensin-Neprilysin Inhibition and Renal Outcomes Across the Spectrum of Ejection Fraction in Heart Failure.” Eur J Heart Fail Jan 5. [Epub ahead of print].

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AIMS: Patients with heart failure are at higher risk of progression to end-stage renal disease (ESRD), regardless of ejection fraction (EF). We assessed the renal effects of angiotensin/neprilysin inhibition in a pooled anlaysis of 13 195 patients with heart failure with reduced and preserved EF. METHODS AND RESULTS: We combined data from PARADIGM-HF (LVEF ≤40%; n = 8399) and PARAGON-HF (LVEF ≥45%; n = 4796) in a prespecified pooled analysis. We assessed the effect of treatment (sacubitril/valsartan vs. enalapril or valsartan) on a composite of either ≥50% reduction in eGFR, ESRD, or death from renal causes, in addition to changes in eGFR slope. We assessed whether baseline renal function, diabetes or EF modified the effect of therapy on renal outcomes. At randomization, eGFR was 68 ± 20 mL/min/1.73m(2) in PARADIGM-HF and 63 ± 19 mL/min/1.73m(2) in PARAGON-HF. The composite renal outcome occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and 123 of 6601 patients (1.9%) in the valsartan or enalapril group (HR 0.56, 95%CI 0.42-0.75; P < 0.001). The mean eGFR change was -1.8 (95%CI -1.9 to -1.7) ml/min/1.73m(2) /year for the sacubitril/valsartan group, compared with -2.4 (95%CI -2.5 to -2.2) ml/min/1.73m(2) /year for the valsartan or enalapril group. The treatment effect on the composite renal endpoint was not modified by categories of baseline eGFR (P-interaction = 0.64), but was most pronounced in those with baseline EF between 30%-60% (P-interaction = 0.001). CONCLUSIONS: In patients with heart failure, sacubitril/valsartan reduced the risk of serious adverse renal outcomes, and slowed decline in eGFR, compared with valsartan or enalapril, independent of baseline renal function.

Khan, M.S., Bakris, G.L., Packer, M., Shahid, I., Anker, S.D., Fonarow, G.C., Wanner, C., Weir, M.R., Zannad, F. and Butler, J. (2021). “Kidney function assessment and endpoint ascertainment in clinical trials.” Eur Heart J Dec 30;ehab832. [Epub ahead of print].

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Heterogeneity in the reporting of kidney function, kidney outcomes, and definitions for kidney endpoints in clinical trials makes it challenging to compare results and gauge incremental benefit of interventions across trials. We conducted a systematic review of the ascertainment of baseline kidney variables, reporting of kidney endpoints, and definitions used to characterize these endpoints in type 2 diabetes mellitus (T2DM), kidney, and heart failure (HF) trials. Medline, Scopus, and ClinicalTrials.gov were searched from January 2014 through January 2021 for large (>1000 participants) T2DM, HF, and kidney disease trials and their secondary analyses. Trial publication and supplementary appendices were searched to abstract relevant data. Thirty-three trials (16 T2DM; 10 HF; 7 kidney diseases) were included. Thirteen trials did not include patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and for trials that did, representation of this cohort ranged from 0.1% to 15%. Reporting of baseline kidney function and albuminuria remained low, especially in HF trials. Variability was observed in the definition of chronic kidney disease, sustained decline in eGFR, end-stage kidney disease, kidney death, and kidney composite endpoint across trials. eGFR slope was reported in less than half trials, with differences observed in statistical models, definition of acute or chronic slope, and follow-up duration across trials. Significant heterogeneity in reporting of kidney function and kidney outcomes in large T2DM, kidney, and HF trials underscores the need for future stakeholders to draft a consensus solution. Detailed profiling of patients at baseline, accrual of more patients with advanced kidney disease, and standardization of definitions in trials may improve the ability to compare the results across trials.