Milton Packer M.D.

Packer, M. and D. W. Kitzman (2018). “Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2.” JACC Heart Fail 6(8): 633-639.

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Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired. The features of this syndrome appear to be related (in part) to the overproduction of adipocyte-derived cell-signaling molecules, including aldosterone and neprilysin. The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis. Inhibitors of aldosterone, neprilysin, and the sodium-glucose transporter-2 (SGLT2) can ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines. All 3 classes of drugs can reduce the quantity of visceral adipose tissue and ameliorate its abnormal biological properties. This mechanistic framework is supported by the results of large-scale randomized trials with mineralocorticoid receptor antagonists and SGLT2 inhibitors and is being further tested in an ongoing large-scale trial of neprilysin inhibition. The promise of using mineralocorticoid receptor antagonists, neprilysin inhibitors, and SGLT2 inhibitors (alone or in combination) in the management of obesity-related HFpEF suggests that physicians might finally have a phenotype of HFpEF that they can understand and treat.

Packer, M. (2018). “Obesity-Associated Heart Failure as a Theoretical Target for Treatment With Mineralocorticoid Receptor Antagonists.” JAMA Cardiol Jul 25. [Epub ahead of print].

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Importance: Despite their clinical benefits, mineralocorticoid receptor antagonists are greatly underprescribed by most practitioners who treat patients with chronic heart failure. A novel approach to encouraging the use of these drugs is to enhance awareness about the intimate link between aldosterone and obesity. Observations: There is a strong association between abdominal obesity and circulating levels of aldosterone, and markers of abdominal obesity identify patients most likely to benefit from mineralocorticoid receptor antagonism. In a trial of patients with heart failure and a reduced ejection fraction, patients with an increased waist circumference exhibited an approximately 50% reduction in the risk of a primary end point. The magnitude of benefit was more than twice as great in patients with abdominal obesity than in those with a normal waist circumference, and patients with abdominal obesity tolerated treatment better than nonobese patients. Similarly, in a trial of patients with heart failure and a preserved ejection fraction, those who were most likely to have abdominal obesity (identified by their level of natriuretic peptides) were most likely to demonstrate a benefit of treatment with spironolactone, exhibiting an approximately 80% reduction in the risk of a primary end point (based on a small number of events). Conclusions and Relevance: Although these analyses are post hoc, their concordance and strong biological foundation suggests that abdominal obesity may identify patients who respond most favorably to mineralocorticoid receptor antagonism. Given the easy availability of its measurement, targeting patients with an increased waist circumference could enhance the adoption of these important drugs for the treatment of chronic heart failure in clinical practice.

Packer, M., B. Claggett, M. P. Lefkowitz, J. J. V. McMurray, J. L. Rouleau, S. D. Solomon and M. R. Zile (2018). “Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial.” Lancet Diabetes Endocrinol 6(7): 547-554.

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BACKGROUND: Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of neprilysin inhibition on the course of renal function in patients with type 2 diabetes. METHODS: In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. FINDINGS: eGFR decreased by 1.1 mL/min per 1.73 m(2) per year (95% CI 1.0-1.2) in patients without diabetes, but by 2.0 mL/min per 1.73 m(2) per year (1.9-2.1) in those with diabetes (p<0.0001). Compared with patients treated with enalapril, those treated with sacubitril/valsartan had a slower rate of decline in eGFR (-1.3 vs -1.8 mL/min per 1.73 m(2) per year; p<0.0001), and the magnitude of the benefit was larger in patients with versus those without diabetes (difference 0.6 mL/min per 1.73 m(2) per year [95% CI 0.4-0.8] in patients with vs 0.3 mL/min per 1.73 m(2) per year [0.2-0.5] in those without diabetes; pinteraction=0.038). The greater effect of neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA1c. The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0.41). INTERPRETATION: In patients in whom the renin-angiotensin system is already maximally blocked, the addition of neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. FUNDING: Novartis.

Vaduganathan, M., B. Claggett, M. Packer, J. J. V. McMurray, J. L. Rouleau, M. R. Zile, K. Swedberg and S. D. Solomon (2018). “Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure.” JACC Heart Fail 6(7): 564-569.

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OBJECTIVES: This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF). BACKGROUND: The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies. METHODS: The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control- or placebo-corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios). RESULTS: Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro-B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone system (r = 0.97; p = 0.0002). CONCLUSIONS: When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials.

Packer, M. (2018). “Risk of heart failure in diabetic patients receiving sulfonylureas: reply.” Eur J Heart Fail 2018 Jun 11. [Epub ahead of print].

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Editors: I sincerely appreciate the comments of Vaccaro et al. regarding their experience in the TOSCA.IT trial. It seems clear that the TOSCA.IT investigators took specific steps to enroll a population of patients with type 2 diabetes, who were at low risk of developing heart failure during follow‐up. As a result, very few heart failure events were recorded in the trial, and consequently, the trial did not have adequate statistical power to determine if the risks of heart failure were truly similar in patients taking sulfonylureas and pioglitazone. In order to validly conclude that the two classes of drugs were associated with similar risks of heart failure, the TOSCA.IT trial would have had to record 10 times as many heart failure events. Given the low risk of the population that was studied, achievement of this target number of events would have required the enrolment of substantially more patients and a far longer period of follow‐up. Since this was not practical, the results of TOSCA.IT cannot provide reliable information concerning comparative risks of heart failure related to the use of sulfonylureas and pioglitazone. Even if additional data were to show that the increased risks of heart failure with sulfonylureas and pioglitazone were similar, it is important to worry about whether any increase in risk is acceptable, especially since certain antidiabetic medications (i.e. metformin and sodium–glucose co‐transporter 2 inhibitors) appear to reduce the risk of heart failure.1 Preventing heart failure and other macrovascular complications of diabetes is a critical goal of treatment. For most middle‐aged to elderly patients with type 2 diabetes, the heightened risk of macrovascular events is much greater and occurs much earlier than the risk of microvascular events. Furthermore, since risk reduction of macrovascular events is not clearly related to glycemic control, the appropriate choice of an antidiabetic medication must be determined not only by its effects to lower glycated hemoglobin but by its independent actions to reduce the risk of cardiovascular death, myocardial infarction and heart failure. (Full text of this letter; no abstract available.)