Milton Packer M.D.

Packer, M. (2018). “The Alchemist’s Nightmare: Might Mesenchymal Stem Cells That Are Recruited to Repair the Injured Heart Be Transformed Into Fibroblasts Rather Than Cardiomyocytes?” Circulation 137(19): 2068-2073.

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The injection of mesenchymal stem cells into the injured myocardium to induce cardiac regeneration has yielded disappointing results, conceivably because cells with cardioreparative potential must be supplied for long periods of time to produce a salutary effect. Accordingly, investigators have devised ways of directing such cells to the heart on an ongoing basis: by enhancing the action of endogenous peptides that function as cardiac homing signals (eg, stromal cell-derived factor-1). Stromal cell-derived factor-1 is released during acute cardiac injury and heart failure, but it has a short half-life because of degradation by dipeptidyl peptidase-4. Inhibition of dipeptidyl peptidase-4 potentiates the actions of stromal cell-derived factor-1 and, theoretically, could enhance cardiac recovery. However, in large-scale trials in patients with type 2 diabetes mellitus, dipeptidyl peptidase-4 inhibitors have not reduced the risk of atherosclerotic ischemic events, and they have unexpectedly increased the risk of heart failure, most probably heart failure with a preserved ejection fraction. Such an outcome might be explained if the channeling of mesenchymal stem cells to the heart by the actions of stromal cell-derived factor-1 (especially from nearby adipose tissue) were followed by the transformation of these cells into fibroblasts rather than cardiomyocytes. This concern has been supported by experimental studies; the resulting fibrosis would be expected to exacerbate the pathophysiological derangements that lead to heart failure with a preserved ejection fraction. Given the widespread use of dipeptidyl peptidase-4 inhibitors, the possibility that these drugs potentiate the cardiac homing of mesenchymal stem cells that cause myocardial fibrosis (rather than repair) warrants further study.

Packer, M. (2018). “Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure.” Diabet Med 35(6): 707-713.

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Three classes of anti-hyperglycaemic medications are distinguished by their urinary sodium excretion-enhancing and blood pressure-lowering actions: long-acting glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon-like peptide-1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium-glucose co-transporter-2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase-4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure. Similarly, the three classes of drugs differ in their early effects on renal function. Dipeptidyl peptidase-4 inhibitors produce a small decrease in renal function that persists for the duration of treatment, and they do not prevent serious adverse renal events. For glucagon-like peptide-1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes. In contrast, an initial decrease in glomerular filtration with sodium-glucose co-transporter-2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events. These differences may be related to different actions on the proximal tubular reabsorption of sodium, and thereby, on glomerular hyperfiltration. Anti-hyperglycaemic drugs that have natriuretic actions differ markedly in their ability to modulate macrovascular and microvascular risk. These contrasting profiles cannot be predicted by their effects on blood glucose or blood pressure.

Damman, K., M. Gori, B. Claggett, P. S. Jhund, M. Senni, M. P. Lefkowitz, M. F. Prescott, V. C. Shi, J. L. Rouleau, K. Swedberg, M. R. Zile, M. Packer, A. S. Desai, S. D. Solomon and J. J. V. McMurray (2018). “Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure.” JACC Heart Fail 6(6): 489-498.

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OBJECTIVES: The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction. BACKGROUND: Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin-angiotensin system. METHODS: In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR. RESULTS: At screening, the eGFR was 70 +/- 20 ml/min/1.73 m(2) and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range [IQR]: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m(2)/year; [95% confidence interval: -1.77 to -1.44 ml/min/1.73 m(2)/year] vs. -2.04 ml/min/1.73 m(2)/year [95% CI: -2.21 to -1.88 ml/min/1.73 m(2)/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38). CONCLUSIONS: Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.

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. Apr 13. [Epub ahead of print].

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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.

Packer, M. (2018). “Why is the use of digitalis withering? Another reason that we need medical heart failure specialists.” Eur J Heart Fail 20(5): 851-852.

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The evolution of the use of digoxin in heart failure provides additional evidence that the treatment of chronic heart failure may have become too complex for most practitioners who are tasked with the long‐term management of patients with this disease. Optimal treatment now requires the expert orchestration of as many as seven different classes of drugs, together with the appropriate application of different devices. Neither primary care physicians nor cardiologists generally have the time, experience, motivation or supporting infrastructure to tackle the complexities of this progressively disabling and lethal disorder. As a result, the typical patient with heart failure is prescribed low doses of a diuretic, an inhibitor of the renin–angiotensin system, and (if they are fortunate) a β‐blocker. Most patients do not receive target doses of these drugs nor are they offered therapy with a mineralocorticoid receptor antagonist, a neprilysin inhibitor or digoxin. When digitalis – a drug that has been used by generalists for more than 200 years – is now recommended for use only by specialists, it is time to ask who these specialists might be. Those who currently regard themselves as heart failure specialists often focus on devices and cardiac transplantation and are not incentivized for optimizing drug therapy. If patients with cancer have dedicated specialists (i.e. medical oncologists) who devote their energies to optimizing drug therapy, patients with chronic heart failure also need dedicated practitioners who will do the same. Perhaps we can call them ‘medical heart failure specialists’. But we should ask: will national health services pay for physicians to think? (Excerpt from text, p. 852; no abstract available.)