Milton Packer M.D.

Shen, L., P. S. Jhund, M. C. Petrie, B. L. Claggett, S. Barlera, J. G. F. Cleland, H. J. Dargie, C. B. Granger, J. Kjekshus, L. Kober, R. Latini, A. P. Maggioni, M. Packer, B. Pitt, S. D. Solomon, K. Swedberg, L. Tavazzi, J. Wikstrand, F. Zannad, M. R. Zile and J. J. V. McMurray (2017). “Declining risk of sudden death in heart failure.” N Engl J Med 377(1): 41-51.

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BACKGROUND: The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail. METHODS: We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization. RESULTS: Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis. CONCLUSIONS: Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death.

Lewis, E. F., B. L. Claggett, J. J. V. McMurray, M. Packer, M. P. Lefkowitz, J. L. Rouleau, J. Liu, V. C. Shi, M. R. Zile, A. S. Desai, S. D. Solomon and K. Swedberg (2017). “Health-related quality of life outcomes in paradigm-hf.” Circ Heart Fail 10(8): 1-16.

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BACKGROUND: Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. METHODS AND RESULTS: Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (>/=5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. CONCLUSIONS: Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure.

Packer, M. (2017). “Who should deliver medical therapy for patients with chronic heart failure? An immediate call for action to implement a community-based collaborative solution.” Circ Heart Fail 10(8): 1-4.

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When we communicate with our colleagues in primary care medicine, why do we convey only a broad philosophical directive rather than a detailed list of specific actionable recommendations? The management of chronic heart failure is not simple. Optimal treatment requires the skillful orchestration of as many as 7 different classes of drugs, together with the appropriate application of different types of devices.2 Heart failure is generally more disabling and lethal than cancer,3 and its comprehensive management is frequently far more challenging. When chemotherapy is given to patients with cancer, its administration is tightly controlled by medical oncologists, who prescribe antineoplastic drugs aggressively and under close supervision, generally at doses and durations that closely resemble those used in randomized clinical trials. Serious adverse effects are expected, but patient compliance and provider enthusiasm is enhanced by societally reinforced fears about the need for aggressive therapy to prevent the silent spread of malignantcells. In contrast, although heart failure with a reduced ejection fraction also progresses silently and requires complex multidrug regimens over long periods of time, specialists are generally not involved, and intensive pharmacological strategies and doses are rarely achieved in clinical practice.4 Continued pursuit of optimal regimens often ceases at the first hint of patient intolerance or reluctance. As in the management of cancer, the treatment of patients with heart failure requires knowledge, experience, and perseverance, which necessitates a multidisciplinary team of healthcare providers that can deal effectively with each patient’s individual circumstances. Those who care for patients with cancer are richly rewarded for creating these conditions; those who care for patients with heart failure are not.5

Packer, M. (2017). “Why has a run-in period been a design element in most landmark clinical trials? Analysis of the critical role of run-in periods in drug development.” J Card Fail: 2017 Jul [Epub ahead of print].

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Prior exposure to one of the randomized treatments has been a routine design element of large-scale trials in patients at high cardiovascular risk. A run-in feature has allowed our trials to be more realistic; it has strengthened their ability to estimate the true treatment effect, and it has never undermined the validity of a trial’s findings. Those who suggest that run-in periods distort the results of large-scale trials should become more familiar with our history of drug development and our standards of clinical practice. Physicians use run-in periods every day in real life, and trialists have used run-in periods for decades to reliably establish the role of new cardiovascular drugs. Those who reflexively criticize the trials because of their inclusion of a run-in period need to carefully re-examine how medicine is practiced and how it advances.

Kotecha, D., M. D. Flather, D. G. Altman, J. Holmes, G. Rosano, J. Wikstrand, M. Packer, A. J. S. Coats, L. Manzano, M. Bohm, D. J. van Veldhuisen, B. Andersson, H. Wedel, T. G. von Lueder, A. S. Rigby, A. Hjalmarson, J. Kjekshus and J. G. F. Cleland (2017). “Heart rate and rhythm and the benefit of beta-blockers in patients with heart failure.” J Am Coll Cardiol 69(24): 2885-2896.

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BACKGROUND: The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF). OBJECTIVES: This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo. METHODS: The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization. RESULTS: A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p < 0.0001) but not in AF (n = 3,034; HR: 1.03 per 10 beats/min; 95% CI: 0.97 to 1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 beats/min in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomized to beta-blockers (HR: 0.73 vs. placebo; 95% CI: 0.67 to 0.79; p < 0.001), regardless of baseline heart rate (interaction p = 0.35). Beta-blockers had no effect on mortality in patients with AF (HR: 0.96, 95% CI: 0.81 to 1.12; p = 0.58) at any heart rate (interaction p = 0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR: 1.16 per 10 beats/min increase, 95% CI: 1.11 to 1.22; p < 0.0001). CONCLUSIONS: Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm.