Milton Packer M.D.

Packer, M. (2019). “The Parable of Schrodinger’s Cat and the Illusion of Statistical Significance in Clinical Trials.” Circulation 140(10): 799-800.

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The field of quantum physics offers important lessons for those involved in the interpretation of clinical trials. A key distinction between quantum physics and classical Newtonian physics is that the latter is deterministic; it describes the future state of a system with definitiveness, and it is useful for understanding the behavior of large objects (ie, those encountered on a human scale). However, at a subatomic level, the utility of Newtonian physics breaks down; it is superseded by quantum physics, in which the future state of a system is defined in a probabilistic rather than deterministic manner. The quantification of uncertainty allows quantum physics to resolve issues that classical physics cannot address. In many ways, the evolution of thinking about clinical evidence parallels the evolution of thinking in physics. When the effect size of a drug or device is large, descriptive studies generally suffice in establishing the efficacy of an intervention. If the mortality rate of pneumococcal pneumonia is uniformly 90% and declines to 10% with the advent of penicillin, there is no need for a randomized controlled trial. The response to imatinib in leukemia was so dramatic that the Food and Drug Administration approved the drug based on an open-label uncontrolled trial of <50 patients.1 If the clinical course of a serious event is highly predictable, a substantial benefit after an intervention represents compelling evidence for efficacy. However, just as classical physics loses its applicability when one shifts to very small effects, the usefulness of descriptive studies evaporates when physicians move from drugs with a 90% benefit to agents that reduce risk by only 10% to 20%. Cardiovascular drugs typically exert small treatment effects and are studied in a setting where outcomes cannot be predicted with precision. (Excerpt from text, p. 799.)

Packer, M. (2019). “Lessons Learned from the Dapa-Hf Trial Concerning the Mechanisms of Benefit of Sglt2 Inhibitors on Heart Failure Events in the Context of Other Large-Scale Trials Nearing Completion.” Cardiovasc Diabetol 18(1): 129.

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Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.

Packer, M. (2019). “Epicardial Adipose Tissue Inflammation Can Cause the Distinctive Pattern of Cardiovascular Disorders Seen in Psoriasis.” Am J Med Sep 11. [Epub ahead of print].

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Psoriasis is a systemic inflammatory disorder that can target adipose tissue; the resulting adipocyte dysfunction is manifest clinically as the metabolic syndrome, which is present in approximately 20-40% of patients. Epicardial adipose tissue inflammation is likely responsible for a distinctive pattern of cardiovascular disorders, consisting of(1): accelerated coronary atherosclerosis leading to myocardial infarction,(2) atrial myopathy leading to atrial fibrillation and thromboembolic stroke, and(3) ventricular myopathy leading to heart failure with a preserved ejection fraction. If cardiovascular inflammation drives these risks, then treatments that focus on blood pressure, lipids and glucose will not ameliorate the burden of cardiovascular disease in patients with psoriasis, especially in those who are young and have severe inflammation. Instead, interventions that alleviate systemic and adipose tissue inflammation may not only minimize the risks of atrial fibrillation and heart failure, but may also have favorable effects on the severity of psoriasis. Viewed from this perspective, the known link between psoriasis and cardiovascular disease is not related to the influence of the individual diagnostic components of the metabolic syndrome.

Packer, M. (2019). “Drugs That Ameliorate Epicardial Adipose Tissue Inflammation May Have Discordant Effects in Heart Failure With a Preserved Ejection Fraction as Compared With a Reduced Ejection Fraction.” J Card Fail Sep 18. [Epub ahead of print].

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Heart failure with a preserved ejection fraction (HFpEF) and heart failure with a reduced ejection fraction (HFrEF) have distinctive pathophysiologies, and thus, therapeutic approaches to the 2 disorders should differ. Neurohormonal activation drives the progression of HFrEF, and neurohormonal antagonists are highly effective in HFrEF, but not in HFpEF. Conversely, a broad range of chronic systemic inflammatory or metabolic disorders cause an expansion and inflammation of epicardial adipose tissue; the secretion of adipocytokines may lead to microvascular dysfunction and fibrosis of the underlying myocardium, which (if the left atrium is affected) may lead to atrial fibrillation (AF) and (if the left ventricle is affected) may lead to HFpEF. Anti-inflammatory drugs (such as statins and anticytokine agents) can ameliorate epicardial adipose tissue dysfunction. Statins appear to ameliorate the development of atrial myopathy (both experimentally and clinically), and in randomized controlled trials, they reduce the incidence of new-onset and recurrent AF and decrease the risk of heart failure with the features of HFpEF; yet, they have no benefits in HFrEF. Similarly, anticytokine agents appear to prevent heart failure in patients with or prone to HFpEF, but adversely affect HFrEF. Several antihyperglycemic agents also reduce epicardial fat mass and inflammation, but this benefit may be offset by additional actions to cause sodium retention and neurohormonal activation. Thiazolidinediones have favorable effects on experimental AF and HFpEF, but their antinatriuretic actions negate these benefits, and they worsen the clinical course of HFrEF. Glucagon-like peptide-1 receptor agonists also ameliorate AF and HFpEF in laboratory models, but their positive inotropic and chronotropic effects may be deleterious in HFrEF. By contrast, metformin and sodium-glucose cotransporter 2 inhibitors alleviate epicardial adipose tissue dysfunction and may reduce the risk of AF and HFpEF; yet, they may have additional actions to promote cardiomyocyte survival that are useful in HFrEF. The concordance of the benefits of anti-inflammatory and antihyperglycemic drugs on AF and HFpEF (but not on HFrEF) supports the paradigm that epicardial adipose tissue is a central pathogenetic mechanism and therapeutic target for both AF and HFpEF in patients with chronic systemic inflammatory or metabolic diseases.

Packer, M. (2019). “Disease-Treatment Interactions in the Management of Patients with Obesity and Diabetes Who Have Atrial Fibrillation: The Potential Mediating Influence of Epicardial Adipose Tissue.” Cardiovasc Diabetol 18(1): 121.

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Both obesity and type 2 diabetes are important risk factors for atrial fibrillation (AF), possibly because they both cause an expansion of epicardial adipose tissue, which is the source of proinflammatory adipocytokines that can lead to microvascular dysfunction and fibrosis of the underlying myocardium. If the derangement of epicardial fat adjoins the left atrium, the result is an atrial myopathy, which is clinically manifest as AF. In patients with AF, there is a close relationship between epicardial fat volume and the severity of electrophysiological abnormalities in the adjacent myocardial tissues, and epicardial fat mass predicts AF in the general population. The expansion of epicardial adipose tissue in obesity and type 2 diabetes may also affect the left ventricle, impairing its distensibility and leading to heart failure with a preserved ejection fraction (HFpEF). Patients with obesity or type 2 diabetes with AF often have HFpEF, but the diagnosis may be missed, if dyspnea is attributed to increased body mass or to the arrhythmia. The expected response to the treatment for obesity, diabetes or AF may be influenced by their effects on epicardial inflammation and the underlying atrial and ventricular myopathy. Bariatric surgery and metformin reduce epicardial fat mass and ameliorate AF, whereas insulin promotes adipogenesis and cardiac fibrosis, and its use is accompanied by an increased risk of AF. Rate control strategies for AF may impair exercise tolerance, because they allow for greater time for ventricular filling in patients who cannot tolerate volume loading because of cardiac fibrosis and HFpEF. At the same time, both obesity and diabetes decrease the expected success rate of rhythm control strategies for AF (e.g., electrical cardioversion or catheter ablation), because increased epicardial adipose tissue volumes and cardiac fibrosis are important determinants of AF recurrence following these procedures.