Milton Packer M.D.

Chandra, A., E. F. Lewis, B. L. Claggett, A. S. Desai, M. Packer, M. R. Zile, K. Swedberg, J. L. Rouleau, V. C. Shi, M. P. Lefkowitz, T. Katova, J. J. V. McMurray and S. D. Solomon (2018). “Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial.” JAMA Cardiol. Apr 4. [Epub ahead of print].

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Importance: Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Objective: To examine the effects of sacubitril/valsartan on physical and social activities. Design, Setting, and Participants: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017. Interventions: Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily. Main Outcomes and Measures: Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied. Results: At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P = .002); both persisted through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60], P < .001; and 2.36 [95% CI, 1.01-3.71], P = .001, respectively). Conclusions and Relevance: In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01035255.

Packer, M. (2018). “Worsening Heart Failure During the Use of DPP-4 Inhibitors: Pathophysiological Mechanisms, Clinical Risks, and Potential Influence of Concomitant Antidiabetic Medications.” JACC Heart Fail. Mar 1. [Epub ahead of print].

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Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis. These potentially deleterious actions of DPP-4 inhibitors might not become clinically apparent if these drugs were to promote sodium excretion. However, the natriuretic effect of DPP-4 inhibitors is modest, because they act on the distal (rather than proximal) renal tubules. Accordingly, both clinical trials and observational studies have reported an increase in the risk of heart failure in patients with type 2 diabetes who were receiving DPP-4 inhibitors. This risk may be muted in trials with a high prevalence of metformin use or with low and declining background use of insulin and thiazolidinediones. Still, the most vulnerable patients (i.e., those with established heart failure) were not well represented in these studies. The only trial that specifically evaluated patients with pre-existing left ventricular dysfunction observed important drug-related adverse structural and clinical effects. In conclusion, an increased risk of worsening heart failure appears to be a class effect of DPP-4 inhibitors, even in patients without a history of heart failure. Additional clinical trials are urgently needed to elucidate the benefits and risks of DPP-4 inhibitors in patients with established left ventricular dysfunction.

Packer, M. (2018). “Increased Mortality in Patients With Heart Failure Who Are Taking Commonly Prescribed Antidiabetic Medications and Achieve Recommended Levels of Glycemic Control.” Diabetes Obes Metab. Feb 22. [Epub ahead of print].

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Current guidelines for diabetes recommend that physicians attain a glycated hemoglobin (HbA1c) less than or equal to 7.0%, but this target may not be applicable to those with heart failure. Fourteen studies of patients with chronic heart failure that examined the relationship between the level of glycated hemoglobin and the risk of death specified whether the HbA1c was influenced by treatment with antidiabetic medications. In patients with heart failure not receiving glucose-lowering drugs, mortality was not increased if the HbA1c was less than 7.0%. In contrast, in patients who were treated with insulin, sulfonylureas and thiazolidinediones, an inverse or U-shaped relationship between HbA1c and the risk of death was generally observed, and mortality was lowest in patients with both heart failure and diabetes if the level of HbA1c was greater than 7.0%. These studies suggest that patients with both heart failure and diabetes are at increased risk of death if they are prescribed certain glucose-lowering drugs to achieve levels of HbA1c less than 7.0%.

Packer, M. (2018). “Do Dipeptidyl Peptidase-4 Inhibitors Cause Heart Failure Events by Promoting Adrenergically-Mediated Cardiotoxicity? Clues from Laboratory Models and Clinical Trials.” Circ Res. Feb 7. [Epub ahead of print].

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Rationale: Dipeptidyl peptidase-4 (DPP-4) inhibitors have increased the risk of heart failure events in both randomized clinical trials and observational studies, but the mechanisms that underlie their deleterious effect remain to be elucidated. Previous work has implicated a role of these drugs to promote cardiac fibrosis. Objective: This paper postulates that DPP-4 inhibitors increase the risk of heart failure events by activating the sympathetic nervous system to stimulate cardiomyocyte cell death, and it crystallizes the findings from both experimental studies and clinical trials that support the hypothesis. Methods and Results: Inhibition of DPP-4 not only potentiates the actions of glucagon-like peptide-1 (which can increase myocardial cyclic AMP), but it also potentiates the actions of stromal cell-derived factor-1 (SDF-1), neuropeptide Y and substance P to activate the sympathetic nervous system and stimulate beta-adrenergic receptors to cause cardiomyocyte apoptosis, presumably through a Ca++/calmodulin-dependent protein kinase II pathway. An action of SDF-1 to interfere with cyclic AMP and protein kinase A signaling may account for the absence of a clinically overt positive chronotropic effect. This conceptual framework is supported by the apparent ability of beta-blocking drugs to attenuate the increased risk of DPP-4 inhibitors in a large-scale clinical trial. Conclusions: Sympathetic activation may explain the increased risk of heart failure produced by DPP-4 inhibitors. The proposed mechanism has major implications for clinical care, since in the treatment of patients with type 2 diabetes, DPP-4 inhibitors are widely prescribed, but beta-blockers are underutilized because of fears that they might mask hypoglycemia.

Packer, M. (2018). “Do Most Obese People with Exercise Intolerance and a Normal Ejection Fraction Have Treatable Heart Failure?” Am J Med. Feb 22. [Epub ahead of print].

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Heart failure is a syndrome of exercise intolerance that results from an abnormal elevation in left ventricular filling pressure. However, the diagnosis can be difficult to make in clinical practice, particularly in obesity. Despite reduced exercise capacity, obese people may not report exertional dyspnea to their physicians, possibly because they have a preconception that their body mass should limit effort tolerance or because they elect to restrict their activities to minimize the possibility of experiencing unpleasant symptoms. Therefore, unless a motivated practitioner asks about and confirms the presence of exercise impairment, such individuals may not undergo an echocardiographic evaluation. If performed, in many obese people, this test would demonstrate an abnormality in early diastolic mitral annular velocity, which is indicative of increased left ventricular filling pressures, and often, the additional finding of mild left atrial enlargement. However, if the left ventricular ejection fraction is normal, these abnormalities are likely to be ignored or regarded as evidence of “diastolic dysfunction” that is attributed to associated hypertension. Moreover, many physicians find it difficult to examine a morbidly obese patient for the presence of distended jugular venous pressures or fluid retention. Given the pandemic of obesity in the United States, it is appropriate to ask: Are physicians systematically ignoring the diagnosis of heart failure in obese people? Can the limitations imposed by this disorder be effectively treated? (Excerpt from text, p.2, advance text; no abstract available.)