Milton Packer M.D.

Malik, A., R. Masson, S. Singh, W. C. Wu, M. Packer, B. Pitt, F. Waagstein, C. J. Morgan, R. M. Allman, G. C. Fonarow and A. Ahmed (2019). “Digoxin Discontinuation and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction.” J Am Coll Cardiol 74(5): 617-627.

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BACKGROUND: The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES: The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS: Of the 11,900 hospitalized patients with HFrEF (EF less-than-or-equal-to 45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS: Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS: Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.

Lam, P. H., M. Packer, G. C. Fonarow, C. Faselis, R. M. Allman, C. J. Morgan, S. Singh, B. Pitt and A. Ahmed (2019). “Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.” Am J Med Aug 8. [Epub ahead of print].

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BACKGROUND: In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by post-randomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril. METHODS: 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (HFrEF; ejection fraction less-than-or-equal-to 35%) were randomized to receive starting doses (5-10mg/day) of placebo (n=1284) or enalapril (n=1285). At day 14, both study drugs were blindly up-titrated to the target dose (20mg/day). Overall, 89% (2284/2569) of the patients returned for dose up-titration, which was achieved in 56% (1444/2248), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated. RESULTS: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06) 0.82, respectively. Corresponding HRs (95% CIs) at 30days were (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68). The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose. CONCLUSION: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.

Packer, M. (2019). “Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events.” Circulation 140(6): 443-445.

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Two sodium-glucose cotransporter 2 (SGLT2) inhibitors (ie, empagliflozin and canagliflozin) are currently approved by the Food and Drug Administration to reduce cardiovascular death or major adverse thromboembolic events in patients with type 2 diabetes mellitus. Yet, the current labeling for this class of drugs is misleading. The Food and Drug Administration indication reflects certain design features of the major cardiovascular outcome safety trials with these drugs, but it does not accurately describe the most important efficacy findings of these studies. In none of the 3 major cardiovascular trials did SGLT2 inhibitors reduce the risk of myocardial infarction and stroke.1 Instead, the primary benefit of SGLT2 inhibitors was a 25% to 35% decrease in the risk of heart failure hospitalizations, which was seen consistently across the trials. The additional benefit of empagliflozin to decrease the risk of cardiovascular death is primarily driven by an effect on pump failure deaths and sudden deaths: the 2 most common modes of death in patients with heart failure. How can inhibition of glucose transport in the proximal renal tubule lead to such a striking decrease in the risk of heart failure events? The effect of these drugs to block glucose reabsorption is accompanied by a lowering of hemoglobin A1c, body weight, and blood pressure. However, the magnitude of these effects is modest, and these changes are not well correlated with the observed decrease in the risk of heart failure deaths or hospitalizations. Furthermore, most drugs that lower blood glucose, body weight, and blood pressure do not have beneficial effects on, and they often adversely influence, the course of heart failure. Inhibition of SGLT2 in the proximal renal tubule causes a meaningful natriuresis, and the resulting decrease in plasma volume could conceivably lead to a decrease in cardiac dimensions and pressures, resulting in favorable effects on ventricular remodeling. However, it is difficult to ascribe the benefits of these drugs primarily to an increase in urinary sodium excretion, because the reduction in heart failure events was seen in patients already receiving diuretics. Intensification of diuretic therapy has not led to a dramatic decrease in cardiovascular mortality or sudden death in patients with heart failure. Similarly, the increase in hemoglobin (that is typically seen with SGLT2 inhibitors) does not lead to clinical benefits in patients with heart failure. (Excerpt from text, p. 443; no abstract available.)

Packer, M. (2019). “Nonarrhythmic Sudden Cardiac Death in Chronic Heart Failure-A Preventable Event?” JAMA Cardiol Jul 17. [Epub ahead of print].

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Sudden cardiac death is the mode of demise in 30% to 50% of patients with chronic heart failure with reduced ejection fraction. Traditionally, physicians have assumed that the abrupt collapse of the circulation is invariably caused by sustained ventricular tachycardia or fibrillation. These arrhythmias may occur without an identifiable trigger or be precipitated by a circadian catecholamine surge, electrolyte imbalances, or the use of drugs with proarrhythmic effects. Regardless of the cause, sustained ventricular tachyarrhythmias are highly responsive to treatment with an implantable cardioverter-defibrillator (ICD). Implantable cardioverter-defibrillators are recommended for patients with heart failure who demonstrate persistent systolic dysfunction after treatment with neurohormonal antagonists and in whom nonsudden deaths are not an important competing short-term risk for demise.

Packer, M. (2019). “Risks of Intensive Treatment of Long-Standing Atrial Fibrillation in Patients With Chronic Heart Failure With a Reduced or Preserved Ejection Fraction.” Circ Cardiovasc Qual Outcomes 12(8): e005747.

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Properly designed and executed randomized controlled trials are needed to understand the appropriate strategy for rate or rhythm control for AF in patients with chronic heart failure. Such trials should focus on both patients with HFpEF and HFrEF (particularly those with an ejection fraction <30%); both phenotypes are common among patients with AF in the community. Participants would be randomized to pharmacological rate control (target rate <110/min) or to catheter ablation; because patients would have long-standing AF, they would not need cardiotoxic drugs to achieve rhythm control. Although it would be relevant to assess the effect of ablation on symptoms, quality-of-life, or exercise tolerance, these measures are readily influenced by knowledge of the treatment received. Unfortunately, sham procedures would not address the issue of blinding because patients and physicians could readily unblind the identity of their treatment by examining the pulse. However, if the trials are powered to detect a reduction in the primary end point of death, no blinding is needed. Mortality is a persuasive end point, and if the benefit of ablation on mortality is as large as is currently claimed, future trials in high-risk patients will not need to be large or follow patients for long periods of time. The proposed trial could also compare the effects of different rate targets (ventricular rate <80/min versus 90–110/min) in patients randomized to rate control and could determine if the treatment strategies yield different effects in patients with HFrEF or HFpEF . . . Until appropriate trials of rate or rhythm control are performed, physicians have little evidence to guide to the management of AF in patients with chronic heart failure. Aside from the risk of thromboembolic events, we are uncertain about the pathophysiological and clinical importance of the arrhythmia, especially in those with a long-standing arrhythmia. When intensively applied, all current therapeutic strategies—pharmacological or ablative rhythm control or drug-induced rate control—carry an important potential for harm. (Excerpts from text, p. 3-4; no abstract available.)