Milton Packer M.D.

Chandra, A., M. Vaduganathan, E. F. Lewis, B. L. Claggett, A. R. Rizkala, W. Wang, M. P. Lefkowitz, V. C. Shi, I. S. Anand, J. Ge, C. S. P. Lam, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, M. M. Redfield, J. L. Rouleau, D. J. Van Veldhuisen, F. Zannad, M. R. Zile, J. J. V. McMurray and S. D. Solomon (2019). “Health-Related Quality of Life in Heart Failure with Preserved Ejection Fraction: The Paragon-Hf Trial.” JACC Heart Fail 7(10): 862-874.

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OBJECTIVES: This study sought to describe baseline health-related quality of life (HRQL) in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, the largest heart failure with preserved ejection fraction (HFpEF) trial to date. BACKGROUND: There are limited data characterizing HRQL in patients with HFpEF using validated metrics. METHODS: The PARAGON-HF trial randomized symptomatic patients with HFpEF (>/=45%) >/=50 years of age to either sacubitril/valsartan or valsartan. The study reports comprehensive baseline HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) administered at randomization after active run-in period. The study then compares baseline HRQL with patients with heart failure with reduced ejection fraction (HFrEF) (less-than-or-equal-to 40%) enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Forward multivariable stepwise regression modeling was performed separately in both trials to identify independent clinical correlates of KCCQ-Overall Summary (KCCQ-OS) score. PARADIGM-HF trial patients <50 years of age were excluded to enable comparison. RESULTS: In the PARAGON-HF trial, 4,735 of 4,822 patients (mean age 73 +/- 8 years; 48% men) completed baseline KCCQ at randomization. Mean KCCQ-OS score was 71. Women had worse mean KCCQ-OS score than men did. Patients in the PARAGON-HF trial reported lower KCCQ scores in nearly all domains when compared with the PARADIGM-HF trial (KCCQ-OS score 71 +/- 19 vs. 73 +/- 19; p < 0.001). The strongest independent clinical correlates of adverse HRQL in both the PARAGON-HF and PARADIGM-HF trials were New York Heart Association functional class, female gender, lower extremity edema, body mass index, angina, dyspnea, and paroxysmal nocturnal dyspnea. After accounting for these clinical correlates of adverse HRQL that were common to both HFpEF and HFrEF patients, KCCQ-OS score did not differ significantly. CONCLUSIONS: HRQL was largely worse in women and was similar in HFpEF and HFrEF after accounting for variation in demographics, functional status, and symptom burden. (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF [PARAGON-HF] NCT01920711; Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).

Anker, S. D., J. Butler, G. S. Filippatos, W. Jamal, A. Salsali, J. Schnee, K. Kimura, C. Zeller, J. George, M. Brueckmann, F. Zannad and M. Packer (2019). “Evaluation of the Effects of Sodium-Glucose Co-Transporter 2 Inhibition with Empagliflozin on Morbidity and Mortality in Patients with Chronic Heart Failure and a Preserved Ejection Fraction: Rationale for and Design of the Emperor-Preserved Trial.” Eur J Heart Fail Sep 16. [Epub ahead of print].

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BACKGROUND: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium-glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. STUDY DESIGN: The EMPEROR-Preserved Trial is enrolling approximately 5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. STUDY AIMS: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

Packer, M. (2019). “Neurohormonal Antagonists Are Preferred to an Implantable Cardioverter-Defibrillator in Preventing Sudden Death in Heart Failure.” JACC Heart Fail 7(10): 902-906.

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One-third to one-half of patients with chronic heart failure and a reduced ejection fraction die suddenly. The terminal event has generally been attributed to a sustained ventricular tachyarrhythmia, whose lethal consequences can be prevented by an implantable cardioverterdefibrillator (ICD). Current guidelines provide a Class I recommendation for ICD placement in patients with heart failure and systolic dysfunction who do not have serious comorbidities, even in patients who have not previously experienced sudden death. Yet the trials that have demonstrated the efficacy of ICDs were largely carried out over 10 to 15 years ago, and during this time, there has been a progressive decline in sudden cardiac death, independent of ICDs, most likely related to advances in heart failure therapeutics that have ameliorated the myocardial substrate that is required for sudden death. Can modern therapy with neurohormonal antagonists pre-empt the need for ICD placement in patients with heart failure? Do randomized controlled trials support their use as first-line agents? (Excerpt from text, p. 902; no abstract available.)

Packer, M. (2019). “Why Are Physicians So Confused about Acute Heart Failure?” New England Journal of Medicine 381(8): 776-777.

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For most of the past 3000 years, physicians believed that all patients with heart failure had acute heart failure. Heart failure was viewed as an episodic disorder — that is, patients were considered to have heart failure when they presented with fluid retention, and they no longer had heart failure after diuresis. The chronicity of heart failure was recognized only when invasive and noninvasive measurements showed severe ongoing structural and functional abnormalities between episodes. To develop approaches to preventing hospitalizations and minimizing the functional and prognostic consequences of heart failure, clinical investigators needed to focus on the underlying disease process. Extensive research beginning in the 1980s established that combination therapy with neurohormonal antagonists reverses ventricular remodeling, improves functional capacity, and reduces the risk of disease progression and death. However, use of these drugs in primary care has been distinctly suboptimal, possibly because physicians have been inclined to discount the importance of intensive treatment for a disease whose progression is typically clinically silent. Instead, practitioners have focused on the treatment of worsening episodes that require hospitalization . . . However, most patients who are hospitalized with worsening heart failure do not have a new, acute disorder. Instead, they present with decompensation of chronic underlying ventricular dysfunction as a consequence of gradual but progressive increases in cardiac filling pressures in the preceding weeks. Sometimes the deterioration is triggered by cardiac arrhythmia or pulmonary infection, but typically the deterioration is not sudden or immediately life-threatening. Are these episodes of worsening heart failure a medical emergency akin to acute pulmonary edema decades ago? Most patients recover within a few days after intensification of medical therapy. However, these events are often accompanied by the early release of troponin, indicating a small degree of myocardial injury that is possibly related to acute ventricular distention. Could emergency interventions to reduce volume overload salvage a few cardiomyocytes, which might (in turn) have benefits for long-term prognosis? We know that each hospitalization accelerates the rate of progression of heart failure. So, is decompensated heart failure similar to an acute coronary syndrome, for which it is critical to perform an emergency intervention to minimize irreversible cardiac injury? The hypothesis that exceptionally early short-term therapy during a hospitalization for heart failure might yield long-term benefits was supported by the findings of the Relaxin in Acute Heart Failure (RELAX-AHF) trial. In that trial, a 48-hour infusion of the vasodilator serelaxin decreased the release of troponin and resulted in a remarkable 37% lower risk of death during the subsequent 6 months than placebo. However, because the benefit with respect to mortality was based on a sparse number of deaths, it was greeted with great skepticism. Outsized mortality benefits that have been observed in underpowered phase 2 trials in patients with heart failure often have not been subsequently confirmed in definitive phase 3 trials . . . Hospitalization for worsening symptoms is an important event in chronic heart failure; it identifies patients with particularly rapid advancement of the underlying disorder. However, decompensation is not an acute illness or an indicator of subclinical myocardial injury that requires emergency intervention with a novel treatment; the acute elevation of troponin level may subside, but the troponin level remains elevated after hospital discharge. Although it is important to achieve clinical stabilization, it is more critical to ensure that patients are treated vigorously between hospitalizations to decrease the risk of readmission and death. A focus on intensive outpatient care (rather than an obsession with inpatient therapy) is needed to reduce the burden of heart failure. (Excerpts from text, p. 776-777; no abstract available.)

Solomon, S. D., J. J. V. McMurray, I. S. Anand, J. Ge, C. S. P. Lam, A. P. Maggioni, F. Martinez, M. Packer . . . and M. P. Lefkowitz (2019). “Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.” New England Journal of Medicine. Sep 1. [Epub ahead of print].

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BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).