Milton Packer M.D.

Packer, M. (2019). “Heightened risk of intensive rate control in patients with atrial fibrillation who are obese or have type 2 diabetes: A critical review and re-evaluation.” J Cardiovasc Electrophysiol Oct 18. [Epub ahead of print].

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Atrial fibrillation (AF) is common in patients with obesity and diabetes; the arrhythmia (if long-standing) is typically managed by rate control and anticoagulation. However, the coexistence of these two metabolic disorders complicates therapeutic options for rate control. The likely pathogenesis of AF in these patients is an expansion of epicardial adipose tissue whose inflammation is transmitted to the left atrium causing electromechanical remodeling. However, this same process is also transmitted to the left ventricle (LV), impairing its distensibility and its ability to tolerate volume, leading to heart failure with preserved ejection fraction. Unfortunately, the latter diagnosis (although commonly present in patients with AF and a coexistent metabolic disorder) is often ignored. To achieve rate control, physicians prescribe intensive treatment with atrioventricular (AV) nodal-blocking drugs, often at doses that are titrated to blunt exercise as well as resting heart rate responses. However, strict rate control (target rate, <80/min) is associated with somewhat worse outcomes than lenient rate control (target rate, <110/min). Furthermore, any rate slowing that facilitates diastolic filling may aggravate filling pressures that are already disproportionately increased because the LV is stiff and overfilled as a result of cardiac inflammation. Rate slowing in AF with beta blockers may not achieve the benefit expected from the blockade of adrenergically mediated cardiotoxicity, and some AV nodal-blocking drugs (digoxin and dronedarone) can increase the risk of death in patients with AF. Finally, cardiac fibrosis in obesity and diabetes may affect the conduction system, which can predispose to serious bradyarrhythmias if patients are prescribed AV nodal-blocking drugs.

Packer, M. (2019). “Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction in Patients With Nonalcoholic Fatty Liver Disease.” Am J Med Oct 14. [Epub ahead of print].

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The most common causes of chronic liver disease in the developed world -nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) – are the hepatic manifestations of an insulin-resistant state that is linked to visceral adiposity and systemic inflammation. NAFLD and NASH lead to an expansion of epicardial adipose tissue and the release of proinflammatory adipocytokines that cause microcirculatory dysfunction and fibrosis of the adjoining myocardium, resulting in atrial fibrillation as well as heart failure with a preserved ejection fraction (HFpEF). Inflammatory changes in the left atrium lead to electroanatomical remodeling; thus, NAFLD and NASH markedly increase the risk of atrial fibrillation. Simultaneously, patients with NAFLD or NASH commonly show diastolic dysfunction or latent HFpEF. Interventions include (1) weight loss by caloric restriction, bariatric surgery or intensive exercise; and (2) drugs that ameliorate fat-mediated inflammation in both the liver and heart (e.g., statins, metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and pioglitazone). Patients with NAFLD or NASH commonly have an inflammation-related atrial and ventricular myopathy, which may contribute to symptoms and long-term outcomes.

Packer, M. (2019). “Are healthcare systems now ready to adopt sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in chronic heart failure? The culmination of a 20-year journey.” Eur Heart J 40(40): 3353-3355.

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As one of the two principal investigators of the PARADIGM-HF trial, I was dismayed when obstacles were placed in the path of physicians who sought to prescribe neprilysin inhibition to patients with chronic heart failure. As a matter of personal choice, I have had no financial relationship with the manufacturer of sacubitril/valsartan (Novartis) since the publication of the primary papers, and I have not been involved in any efforts to market or give sponsored presentations on behalf of the drug. However, at the same time, I have been an ardent supporter of the findings of the trial, which represented my second chance (after the disappointment of the OVERTURE trial) to finally demonstrate that neprilysin inhibitors can meaningfully potentiate the survival benefits of conventional antagonists of the renin–angiotensin system in patients with heart failure. If the PIONEER-HF trial allows all cardiologists to embrace that conclusion, I am very pleased. If the biomarker data published in this issue are motivating to practitioners to increase their appropriate prescribing of sacubitril/valsartan, I am delighted to hear that. If physicians, healthcare systems, and the manufacturer are prepared to work collaboratively to facilitate affordable unrestricted access to a life-saving treatment for heart failure, I doubt that patients will complain. (Excerpt from text of this editorial, p. 3355; no abstract available. Refers to “Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.” New England Journal of Medicine 381(17): 1609-1620.)

Butler, J., S. D. Anker and M. Packer (2019). “Redefining Heart Failure With a Reduced Ejection Fraction.” JAMA Sep 13. [Epub ahead of print].

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The current approach to classifying patients with heart failure based on the measurement of left ventricular ejection fraction (LVEF) lacks a strong clinical, pathophysiological, or evidentiary basis. In particular, the concept that there exists a unique group of patients with an LVEF of 40% to 50% that differs from those with an LVEF lower than 40% is based on an arbitrary historical distinction. Patients who have “heart failure with a mid-range ejection fraction” do not have a unique pattern of symptoms or pathophysiology; the range of values for those with a mid-range LVEF is so narrow that delineation of the subgroup is inconsistent with the accuracy and reproducibility of the methods routinely used to assess systolic function in clinical practice. Furthermore, consistent evidence across several classes of drugs now indicates that treatments that are effective in reducing the risk of major adverse clinical outcomes in patients with an LVEF of 40% or lower are also beneficial in those with an LVEF of 41% to 50%. The precise number of patients with heart failure and LVEF of 41% to 50% is not known. Yet it is important to emphasize that this proposal applies only to patients with LVEF of 41% to 50% who have established symptoms of chronic heart failure. Any role of neurohormonal antagonists in asymptomatic patients with such mild impairment of systolic function has not been evaluated or established. The current approach of distinguishing patients with heart failure and a reduced ejection fraction (HFrEF) from those with heart failure with a preserved ejection fraction (HFpEF) based on a threshold of 40% reflects the consequences of a nonphysiological distinction made by clinical trialists 30 years ago. Reliance on such a threshold may deprive patients who truly have impaired systolic function and a subnormal LVEF from treatments that are likely to reduce morbidity and mortality. It appears reasonable for physicians to consider patients with an abnormally low LVEF and established symptoms of heart failure to belong to the same group, ie, heart failure with a reduced LVEF, and to provide such patients the benefits of treatment known to be effective in HFrEF. Based on the findings of clinical trials and the need to reduce the adverse consequences of heart failure on public health, serious consideration should be given to increasing the LVEF threshold for the use of evidence-based treatments from its current value of 40% to a value of 50%. (Excerpt from text, p. E2; no abstract available.)

Selvaraj, S., B. Claggett, A. Pozzi, J. J. V. McMurray, P. S. Jhund, M. Packer, A. S. Desai, E. F. Lewis, M. Vaduganathan, M. P. Lefkowitz, J. L. Rouleau, V. C. Shi, M. R. Zile, K. Swedberg and S. D. Solomon (2019). “Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients with Heart Failure and Reduced Ejection Fraction:PARADIGM-HF.” Circulation Sep 12. [Epub ahead of print].

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Background: The contemporary prognostic value of the physical examination, beyond traditional risk factors including natriuretic peptides (NPs), risk scores, and symptoms, in heart failure with reduced ejection fraction (HFrEF) is unknown. We sought to determine the association between physical signs of congestion at baseline and during study follow up with quality of life (QoL) and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and S3) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up, and whether improvement in congestion is related to changes in clinical outcomes and QoL, assessed by Kansas City Cardiomyopathy Questionnaire clinical summary scores (KCCQ-OSS). Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2%. Patients with baseline congestion were older, more often female, had higher Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores and lower KCCQ-OSS (p<0.05). After adjusting for baseline NPs, time-updated MAGGIC score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (p<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (p=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than enalapril (p=0.011). Each 1-sign reduction was independently associated with a 5.1 (95%CI: 4.7-5.5) point improvement in KCCQ-OSS. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (p<0.001). Conclusions: In HFrEF, the physical exam continues to provide significant, independent prognostic value even beyond symptoms, NPs, and MAGGIC risk score. Sacubitril/valsartan improved congestion to a greater extent than enalapril. Reducing congestion in the outpatient setting is independently associated with improved QoL and reduced cardiovascular events, including mortality. Clinical Trial Registration: NCT01035255.