Milton Packer M.D.

Packer, M. (2018). “The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction.” Eur J Heart Fail Sep 17. [Epub ahead of print].

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Effect of epicardial adipose inflammation on coronary arteries: Classically, coronary atherosclerosis has been viewed as an inflammatory response to the transit of lipoproteins from the bloodstream across the endothelium and into the vessel wall. However, accelerated coronary atherosclerosis is also a prominent feature of many systemic inflammatory disorders, in a manner that is independent of circulating lipoproteins. How can systemic inflammation promote the development of obstructive coronary artery disease? Systemic inflammation leads to the accumulation and deranged biology of epicardial adipocytes. The resulting transmission of pro‐inflammatory cytokines and mesenchymal cells from the perivascular adipose tissue across the vascular adventitia can lead to plaque formation within the coronary vessels. In chronic inflammatory states, the accumulation of epicardial adipose tissue is closely associated with the presence, severity and progression of coronary artery disease, in a manner that is independent of circulating lipids or adiposity. Focal obstructive lesions reside in the coronary arterial segments that are immediately adjacent to areas of epicardial fat with the greatest thickness, and experimental resection of the epicardium ameliorates coronary atherosclerosis. These observations support the hypothesis that the accumulation of epicardial adipose tissue (and inflammation of perivascular fat) can act in a paracrine manner to adversely influence the structure and function of the coronary arteries. (Excerpt from text, p. 2; no abstract available.)

Bouabdallaoui, N., B. Claggett, M. R. Zile, J. J. V. McMurray, E. O’Meara, M. Packer, M. F. Prescott, K. Swedberg, S. D. Solomon and J. L. Rouleau (2018). “Growth differentiation factor-15 is not modified by sacubitril/valsartan and is an independent marker of risk in patients with heart failure and reduced ejection fraction: the PARADIGM-HF trial.” Eur J Heart Fail Sep 11. [Epub ahead of print].

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AIMS: Growth differentiation factor-15 (GDF-15) is associated with adverse prognosis in cardiovascular (CV) and non-CV diseases. We evaluated the association of GDF-15 with CV and non-CV outcomes in the PARADIGM-HF trial. METHODS AND RESULTS: In 1935 patients with heart failure and reduced ejection fraction (HFrEF) in PARADIGM-HF, median GDF-15 values were elevated and similar in sacubitril/valsartan and enalapril patients (1626 ng/L and 1690 ng/L, respectively). Diabetes, age, creatinine, high-sensitive troponin T, N-terminal pro-B-type natriuretic peptide, and New York Heart Association class III/IV were most strongly associated with elevated GDF-15 values (all P < 0.001) (adjusted R(2) = 0.3857). Baseline GDF-15 and changes in GDF-15 at both 1 month and 8 months (log-transformed) were associated with subsequent mortality and CV events. Each 20% increment in baseline GDF-15 value was associated with a higher risk of mortality [adjusted hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.08-1.18, P < 0.001], the combined endpoint of CV death or hospitalization for heart failure (adjusted HR 1.09, 95% CI 1.05-1.14, P < 0.001) and heart failure death (adjusted HR 1.16, 95% CI 1.05-1.28, P < 0.001). Changes in GDF-15 were not influenced by assigned therapy (all P-values >/= 0.1). CONCLUSION: In patients with ambulatory HFrEF, GDF-15 is not modified by sacubitril/valsartan and is strongly associated with mortality and CV outcomes, suggesting that GDF-15 is a marker of poor outcomes in these patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01035255.

Packer, M. (2018). “Risk of heart failure in diabetic patients receiving sulfonylureas: reply.” Eur J Heart Fail 20(9): 1372.

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I sincerely appreciate the comments of Vaccaro et al. regarding their experience in the TOSCA.IT trial. It seems clear that theTOSCA.IT investigators took specifc steps to enroll a population of patients with type 2diabetes, who were at low risk of developingheart 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 inpatients 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 10timesasmanyheart 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 w as not practical, the results ofTOSCA.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. met-formin and sodium–glucose co-transporter 2inhibitors) appear to reduce the risk of heartfailure. Preventing heart failure and other macrovascular complications of diabetes is acritical 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. Further-more, since risk reduction of macrovascular events is not clearly related to glycaemic control, the appropriate choice of an antidiabetic medication must be determined not only by its effects to lower glycated haemoglobin but by its independent actions to reduce the risk of cardiovascular death, myocardial infarction and heart failure. (Reply to Vaccaro’s comment on Packer, Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfony-lureas? Lessons from the TOSCA.IT trial. Eur J Heart Fail 2018;20: 49–51.)

Packer, M. (2018). “Questioning the obvious: does dyspnoea really matter in heart failure?” Eur Heart J 39(30): 2822-2824

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Many patients with heart failure continue to exercise despite the experience of dyspnoea, until they feel that their legs can no longer carry them. So do patients with chronic heart failure stop exercising with dyspnoea or because of dyspnoea? If we were able to suppress the sensation of dyspnoea, would patients with heart failure be able to exercise longer? Many investigators who have closely evaluated patients with chronic heart failure believe this is unlikely. Our inability to answer these simple questions highlights how little we know about the factors that influence the capacity of patients with heart failure to perform and enjoy activities of daily living. We have spent several decades prolonging the lives of patients with heart failure, but we have spent little time studying the symptoms that bring them to medical attention in the first place. Since heart failure has become not only the major cause of cardiac death but also the major cause of cardiac disability, this is a conundrum that we can no longer ignore. (Excerpt from text, p. 2224; no abstract available.)

Packer, M. (2018). “The CABANA Trial: an honourable view.” Eur Heart J 39(30): 2770.

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The CABANA trial randomized 2204 patients with atrial fibrillation to catheter ablation (n = 1108) or drug therapy to achieve rate or rhythm control (n = 1096). Both groups were anticoagulated, and most patients in the non-ablation group received membrane-active antiarrhythmic drugs. Only 10% had atrial fibrillation for >1 year; 15% had a history of heart failure. The original primary endpoint was all-cause mortality, which was amended to a combined endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. The original trial design anticipated that 25–30% of the patients assigned to drug therapy would receive ablation later in the trial. The investigators pre-specified that success of the trial would be determined by intention-to-treat analysis on the amended primary endpoint. This was an open-label trial; event adjudication was not blinded to the patients’ rhythm. Patients were followed for ≈5 years. According to the reported results, the ablation and non-ablation groups did not differ with respect to the risk of the original primary endpoint (P = 0.377) or the amended primary endpoint (P = 0.303). Ablation did not reduce the risk of any component of the primary endpoint. There was a nominally significant reduction in the combined risk of death or cardiovascular hospitalization, which was likely related to a decrease in admissions for atrial fibrillation in the ablation group. No particular benefit was seen in patients with heart failure. Unfortunately, the investigators showed ‘per-protocol’ and ‘as-treated’ analyses, which converted the randomized trial into an observational study . . . The CABANA trial is an important study that yielded a clear result, i.e. ablation does not prevent the serious consequences of atrial fibrillation. There is little justification to perform confounded observational analyses or rely on derivative subgroup effects. If this were a trial of a new pharmaceutical agent, these questionable analyses would be uniformly rejected as ‘wishful thinking’ and would not influence guidelines. Since ablation procedures are expensive, carry risks and are available to very few, evaluation of their efficacy should not be held to a lower standard of evidence. These thoughts on the CABANA trial are preliminary. We await publication of the full manuscript and a description of the analytical methods to fully understand how the investigators viewed their data. (Excerpt from text, p. 2770; no abstract available.)