Milton Packer M.D.

Ferreira, J.P., Zannad, F., Pocock, S.J., Anker, S.D., Butler, J., Filippatos, G., Brueckmann, M., Jamal, W., Steubl, D., Schueler, E. and Packer, M. (2021). “Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced.” J Am Coll Cardiol 77(11): 1397-1407.

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BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction. OBJECTIVES: This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction). METHODS: Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization. RESULTS: The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group. CONCLUSIONS: In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Butler, J., Anker, S.D., Filippatos, G., Khan, M.S., Ferreira, J.P., Pocock, S.J., Giannetti, N., Januzzi, J.L., Piña, I.L., Lam, C.S.P., Ponikowski, P., Sattar, N., Verma, S., Brueckmann, M., Jamal, W., Vedin, O., Peil, B., Zeller, C., Zannad, F. and Packer, M. (2021). “Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial.” Eur Heart J 42(13): 1203-1212.

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AIMS: In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction. METHODS AND RESULTS: Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains. CONCLUSION: Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.

McMurray, J.J.V. and Packer, M. (2021). “How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction?: A Redefinition of Evidence-Based Medicine.” Circulation 143(9): 875-877.

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Large-scale trials have demonstrated the efficacy of sacubitril/valsartan, β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as disease-modifying agents that (when combined) represent foundational therapy for heart failure and a reduced ejection fraction (HFrEF). The conventional approach to achieving treatment with all 4 drug classes is to prescribe them in the precise sequence in which they were tested in clinical trials over the past 40 years. Physicians are asked to start with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, to be followed by a β-blocker, then an MRA, then a neprilysin inhibitor, and, finally, a SGLT2i. Prescribers are advised to titrate the dose of each drug class to the target dose used in large-scale trials before initiating the next recommended drug class. This approach recapitulates the sequence by which these agents were developed for the treatment of heart failure.[No abstract; excerpt from article].

Shahzeb Khan, M., Kristensen, S.L., Vaduganathan, M., Kober, L., Abraham, W.T., Desai, A.S., Solomon, S.D., Swedberg, K., Dickstein, K., Zile, M.R., Packer, M., McMurray, J.J. and Butler, J. (2021). “Natriuretic Peptide Plasma Concentrations and Risk of Cardiovascular Versus Non-Cardiovascular Events in Heart Failure with Reduced Ejection Fraction Insights from the PARADIGM-HF and ATMOSPHERE Trials.” Am Heart J Feb 20;S0002-8703(21)00054-5. [Epub ahead of print].

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BACKGROUND: N-terminal pro-B-type natriuretic peptide (NTproBNP) plasma concentrations are independent prognostic markers in patients with heart failure with reduced ejection fraction (HFrEF). Whether a differential risk association between NTproBNP plasma concentrations and risk of cardiovascular (CV) versus non-CV adverse events exists is not well known. OBJECTIVE: To assess if there is a differential proportional risk of CV versus non CV adverse events by NTproBNP plasma concentrations. METHODS: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV versus non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/ml) at baseline using Cox regression adjusting for traditional risk factors. RESULTS: 14,737 patients with mean age of 62±8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/ml group to 142.3 in the ≥3000 pg/ml group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to presence of AF at baseline and prior HF hospitalization within last 12 months. CONCLUSION: The absolute CV event rates per patient years of follow up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

Rohde, L.E., Vaduganathan, M., Claggett, B.L., Polanczyk, C.A., Dorbala, P., Packer, M., Desai, A.S., Zile, M., Rouleau, J., Swedberg, K., Lefkowitz, M., Shi, V., McMurray, J.J.V. and Solomon, S.D. (2021). “Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.” Eur J Heart Fail Feb 9. [Epub ahead of print].

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AIMS: Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment. METHODS AND RESULTS: We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (P(interaction)  < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05). CONCLUSIONS: Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.