Milton Packer M.D.

Packer, M. (2021). “Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure.” Circ Heart Fail 14(6): e008537.

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The rate of decline in eGFR is commonly assessed by the measurement of eGFR slope, but this calculation is fraught with methodological difficulties. Estimation of slope relies in statistical models that make assumptions about linearity and are typically skewed by values measured late in the course of follow-up. [No abstract; excerpt from article].

Selvaraj, S., Claggett, B.L., Packer, M., Zannad, F., Anand, I.S., Pieske, B., Zhao, Z., Shi, V.C., Lefkowitz, M.P., McMurray, J.J.V. and Solomon, S.D. (2021). “Effects of Sacubitril/Valsartan on Serum Lipids in Heart Failure with Preserved Ejection Fraction.” J Am Heart Assoc May 16;e022069. [Epub ahead of print]. e022069.

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Background Dyslipidemia is common in heart failure with preserved ejection fraction (HFpEF). Sacubitril/valsartan improves insulin sensitivity and augments natriuretic peptide (NP) signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4,744 participants from PARAGON-HF with available screening lipids. During follow-up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16-week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate (cGMP)/creatinine [a biomarker of NP activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides -5.0% (-6.6%, -3.5%), increased high-density lipoprotein cholesterol (HDL-c) +2.6% (+1.7%, +3.4%), and increased low-density lipoprotein cholesterol (LDL-c) +1.7% (+0.4%, +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (p-interaction<0.001), and at 16-weeks by -13.0% (-18.1%, -7.6%), or -29.9 (-44.3, -15.5) mg/dL, in this group. Adjusting for the change in urinary cGMP/creatinine significantly attenuated treatment effects on triglycerides and HDL-c, but not LDL-c, while adjusting for other biomarkers did not significantly alter the treatment effects. Conclusions Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was substantially stronger in those with elevated baseline triglycerides. Modest increases in HDL-c and LDL-c cholesterol were also observed with therapy. The underlying mechanism(s) of changes in HDL-c and triglycerides are related to sacubitril/valsartan's effects on NP activity.

Packer, M., Januzzi, J.L., Jr., Ferreira, J.P., Anker, S.D., Butler, J., Filippatos, G., Pocock, S.J., Brueckmann, M., Jamal, W., Cotton, D., Iwata, T. and Zannad, F. (2021). “Concentration-Dependent Clinical and Prognostic Importance of High-Sensitivity Cardiac Troponin T in Heart Failure and a Reduced Ejection Fraction and the Influence of Empagliflozin: the EMPEROR-Reduced Trial.” Eur J Heart Fail May 30. [Epub ahead of print].

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BACKGROUND: Circulating troponin is an important measure of risk in patients with heart failure, but it has not been used to determine if disease severity influences the responses to drug treatments in randomized controlled trials. METHODS: In the EMPEROR-Reduced trial, patients with class II-IV heart failure and a reduced ejection fraction were randomly assigned to placebo or empagliflozin 10 mg daily and followed for the occurrence of serious heart failure and renal events. High-sensitivity cardiac troponin T (hs-cTnT) was measured in 3636 patients (> 97%) at baseline, and patients were divided into four groups based on the degree of troponin elevation. RESULTS: With increasing concentrations of hs-cTnT, patients were progressively more likely to have diabetes and atrial fibrillation, to have New York Heart Association class III-IV symptoms and been hospitalized for heart failure within the prior year, and to have elevated levels of natriuretic peptides and worse renal function (P-trend <0.0001 for all comparisons), but importantly, the troponin groups did not differ with respect to ejection fraction. A linear relationship was observed between the logarithm of hs-cTnT and the combined risk of cardiovascular death or hospitalization for heart failure (P = 0.0015). When treated with placebo, patients with the highest levels of hs-cTnT had risks of cardiovascular death and hospitalization for heart failure that were 3-5 fold greater than those with values in the normal range. Patients with higher levels of hs-cTnT were also more likely to experience worsening of renal function and serious adverse renal events and show the least improvement in health status (as measured by the Kansas City Cardiomyopathy questionnaire). When compared with placebo, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, regardless of the baseline level of hs-cTnT, whether the effects of treatment were analyzed as hazard ratios or absolute risk reductions (Graphical Abstract).. CONCLUSIONS: Elevations in hs-cTnT reflect the clinical severity, stability and prognosis of patients with heart failure and a reduced ejection fraction, with biomarkers, comorbidities, clinical course and risks that are proportional to the magnitude of hs-cTnT elevation. Empagliflozin exerted favorable effects on heart failure and renal outcomes, regardless of the baseline concentration of hs-cTnT.

Ferreira, J.P., Konstam, M.A., McMurray, J.J.V., Butler, J., Girerd, N., Rossignol, P., Sharma, A., Voors, A.A., Lam, C.S.P., Packer, M. and Zannad, F. (2021). “Dosing of losartan in men vs. women with HFrEF: the HEAAL trial.” Eur J Heart Fail May 29. [Epub ahead of print].

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BACKGROUND: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit. METHODS: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and Machine Learning algorithms. RESULTS: The mean age was 66 years and 30% of the patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses: HR (95%CI) comparing high- vs- low-dose losartan for the composite outcome of all-cause death or all-cause hospitalisation was 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women, interaction P=0.018. Female sex clustered along with older age, ischemic HF, NYHA III/IV, and eGFR<60 ml/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe HF symptoms. CONCLUSIONS: Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g., kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders.

Tromp, J., Claggett, B.L., Liu, J., Jackson, A.M., Jhund, P.S., Køber, L., Widimský, J., Boytsov, S.A., Chopra, V.K., Anand, I.S., Ge, J., Chen, C.H., Maggioni, A.P., Martinez, F., Packer, M., Pfeffer, M.A., Pieske, B., Redfield, M.M., Rouleau, J.L., Van Veldhuisen, D.J., Zannad, F., Zile, M.R., Rizkala, A.R., Inubushi-Molessa, A., Lefkowitz, M.P., Shi, V.C., McMurray, J.J.V., Solomon, S.D. and Lam, C.S.P. (2021). “Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.” Circ Heart Fail 14(4): e007901.

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BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. METHODS: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. RESULTS: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P>0.05). CONCLUSIONS: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.