Milton Packer M.D.

Shen, L., Jhund, P.S., Anand, I.S., Bhatt, A.S., Desai, A.S., Maggioni, A.P., Martinez, F.A., Pfeffer, M.A., Rizkala, A.R., Rouleau, J.L., Swedberg, K., Vaduganathan, M., Vardeny, O., van Veldhuisen, D.J., Zannad, F., Zile, M.R., Packer, M., Solomon, S.D. and McMurray, J.J.V. (2021). “Incidence and Outcomes of Pneumonia in Patients With Heart Failure.” J Am Coll Cardiol 77(16): 1961-1973.

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BACKGROUND: The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). OBJECTIVES: This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials. METHODS: The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide). RESULTS: In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58). CONCLUSIONS: The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711).

Packer, M. and McMurray, J.J.V. (2021). “Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction.” Eur J Heart Fail Mar 11. [Epub ahead of print].

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Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. However, the conventional approach to the implementation is based on a historically-driven sequence that is not strongly evidence-based, typically requires ≥6 months, and frequently lead to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2-4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease-of-use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over uptitration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated 3-step approach, which consists of the simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by the initiation of sacubitril/valsartan, and 1-2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be reordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence-based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.

Packer, M. and McMurray, J.J.V. (2021). “Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction.” Eur J Heart Fail Mar 11. [Epub ahead of print].

Full text of this article.

Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. However, the conventional approach to the implementation is based on a historically-driven sequence that is not strongly evidence-based, typically requires ≥6 months, and frequently lead to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2-4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease-of-use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over uptitration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated 3-step approach, which consists of the simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by the initiation of sacubitril/valsartan, and 1-2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be reordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence-based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.

Packer, M., Anker, S.D., Butler, J., Filippatos, G., Ferreira, J.P., Pocock, S.J., Sattar, N., Brueckmann, M., Jamal, W., Cotton, D., Iwata, T. and Zannad, F. (2021). “Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.” J Am Coll Cardiol 77(11): 1381-1392.

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BACKGROUND: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention. OBJECTIVES: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload. METHODS: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment. RESULTS: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients. CONCLUSIONS: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Packer, M. (2021). “What causes exertional dyspnoea in patients with atrial fibrillation? Implications for catheter ablation in patients with heart failure.” Eur J Heart Fail Mar 26. [Epub ahead of print].

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Patients with atrial fibrillation (AF) often complain of exertional dyspnoea, and many physicians believe that the atrial tachyarrhythmia is the cause of the impairment in functional capacity. The assumption of a causal relationship has led electrophysiologists to propose that suppression of AF (either pharmacologically or by catheter ablation) can improve exercise tolerance and yield important clinical benefits, both with respect to quality of life and major outcomes. [No abstract; excerpt from article].