Milton Packer M.D.

Packer, M. (2017). “Why is the use of digitalis withering? Another reason that we need medical heart failure specialists.” Eur J Heart Fail: 2017 Oct [Epub ahead of print].

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Contrary to popular opinion, William Withering did not discover digitalis nor was he the first to describe its use for heart failure. In 1785, the esteemed English botanist and physician wrote a pamphlet that summarized his experiences in 163 patients with dropsy. Yet, at the time, digitalis had been known to exert important pharmacological effects for 2000 years. In the first century, the Greek physician, Pedanius Dioscorides, noted the use of digitalis as a therapeutic agent; its application to heart failure was first recorded in print by Leonard Fuchs in 1542.1 Nevertheless, Withering was the first to systematically carry out clinical studies with the plant in a scientific manner, eliminating the superstition that had long surrounded it. Withering’s work was ground-breaking, not because of what he discovered, but how he approached its evaluation. It was the first use of the scientific method for the characterization of a pharmaceutical.

Packer, M. (2017). “Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure.” Circulation 136(16): 1548-1559.

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The mechanisms underlying the progression of diabetes mellitus and heart failure are closely intertwined, such that worsening of one condition is frequently accompanied by worsening of the other; the degree of clinical acceleration is marked when the 2 coexist. Activation of the sodium-hydrogen exchanger in the heart and vasculature (NHE1 isoform) and the kidneys (NHE3 isoform) may serve as a common mechanism that links both disorders and may underlie their interplay. Insulin insensitivity and adipokine abnormalities (the hallmarks of type 2 diabetes mellitus) are characteristic features of heart failure; conversely, neurohormonal systems activated in heart failure (norepinephrine, angiotensin II, aldosterone, and neprilysin) impair insulin sensitivity and contribute to microvascular disease in diabetes mellitus. Each of these neurohormonal derangements may act through increased activity of both NHE1 and NHE3. Drugs used to treat diabetes mellitus may favorably affect the pathophysiological mechanisms of heart failure by inhibiting either or both NHE isoforms, and drugs used to treat heart failure may have beneficial effects on glucose tolerance and the complications of diabetes mellitus by interfering with the actions of NHE1 and NHE3. The efficacy of NHE inhibitors on the risk of cardiovascular events may be enhanced when heart failure and glucose intolerance coexist and may be attenuated when drugs with NHE inhibitory actions are given concomitantly. Therefore, the sodium-hydrogen exchanger may play a central role in the interplay of diabetes mellitus and heart failure, contribute to the physiological and clinical progression of both diseases, and explain certain drug-drug and drug-disease interactions that have been reported in large-scale randomized clinical trials.

Packer, M. (2017). “Heart failure with a mid-range ejection fraction: A disorder that a psychiatrist would love.” JACC Heart Fail 5(11): 805-807.

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Over the past 5 decades, cardiologists have become obsessed with the ejection fraction. The term can be found in the abstracts of more than 52,000 papers; 10s of 1,000s of additional papers refer to it in their texts. The measurement yields important prognostic information in patients without heart failure, yet the field of heart failure has been particularly consumed by its assessment. We rarely find a paper about heart failure that does not mention it, guidelines mandate its evaluation in all patients, and it has been an entry criterion for every heart failure trial over the past 30 years. Its importance seems odd, however, because ejection fraction is not related to or associated with any specific clinical feature or pathophysiological abnormality of heart failure.

Packer, M. (2017). “The absence of an ideal observer: Why some clinical trials may not be what we think they are.” Circulation 136(12): 1085-1086.

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A large clinical trial typically involves a leadership committee, a sponsor, numerous geographically dispersed investigators, and a group responsible for operational functions. The leadership committee helps to define the trial hypotheses and the methods by which they are tested; however, its members personally make no observations and may not know exactly how observations are made. The sponsor invests substantial sums of money, without assurance that the hypothesis is valid and generally without direct involvement in the collection of data. The investigators are paid to recruit patients, but they may have little vested in the overall results of the trial. The operations group ensures that patients are recruited rapidly, knowing that it will be difficult to confirm whether patients were recruited appropriately or trial procedures were followed faithfully. Among these trial components, who is the ideal, fully informed and impartial observer? Could the parties (each acting in self-interest but within regulatory standards) collectively yield a flawed product? Here are a few hypothetical possibilities.

Packer, M., S. D. Anker, J. Butler, G. Filippatos and F. Zannad (2017). “Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: Proposal of a novel mechanism of action.” JAMA Cardiol: 2017 Aug [Epub ahead of print].

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Importance: Only 1 class of glucose-lowering agents-sodium-glucose cotransporter 2 (SGLT2) inhibitors-has been reported to decrease the risk of cardiovascular events primarily by reducing the risk of the development or progression of heart failure. In a landmark trial called Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes [EMPA-REG Outcomes], long-term treatment with empagliflozin prevented fatal and nonfatal heart failure events but did not reduce the risk of myocardial infarction or stroke in diabetic patients. Observations: The beneficial effect of SGLT2 inhibitors on heart failure cannot be explained by their actions on glycemic control or as osmotic diuretics. Instead, in the kidneys, SGLT2 functionally interacts with the sodium-hydrogen exchanger, which is responsible for the majority of sodium tubular reuptake following filtration. The activity of sodium-hydrogen exchanger is markedly increased in patients with heart failure and may be responsible for both resistance to diuretics and to endogenous natriuretic peptides. In addition, in the heart, empagliflozin appears to inhibit sodium-hydrogen exchange, which may in turn lead to a reduction in cardiac injury, hypertrophy, fibrosis, remodeling, and systolic dysfunction. Furthermore, the major pathophysiological derangements of heart failure and a preserved ejection fraction may be mitigated by the actions of SGLT2 inhibitors to reduce blood pressure, body weight, and fluid retention as well as to improve renal function. The benefits of spironolactone in patients with heart failure with either a reduced or a preserved ejection fraction may also be attributable to the actions of the drug to inhibit the sodium-hydrogen exchange mechanism. Conclusions and Relevance: The benefits of SGLT2 inhibitors in heart failure may be mediated by the inhibition of sodium-hydrogen exchange rather than the effect on glucose reabsorption. This hypothesis has important implications for the design and analysis of large-scale outcomes trials involving diabetic or nondiabetic patients with chronic heart failure.