Milton Packer M.D.

Packer, M. and J. J. McMurray (2016). “Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure.” Lancet: 2016 Dec [Epub ahead of print].

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The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.

Zile, M. R., B. L. Claggett, M. F. Prescott, J. J. McMurray, M. Packer, J. L. Rouleau, K. Swedberg, A. S. Desai, J. Gong, V. C. Shi and S. D. Solomon (2016). “Prognostic implications of changes in n-terminal pro-b-type natriuretic peptide in patients with heart failure.” J Am Coll Cardiol 68(22): 2425-2436.

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BACKGROUND: Natriuretic peptides (NP) have prognostic value in heart failure (HF), although the clinical importance of changes in NP from baseline is unclear. OBJECTIVES: The authors assessed whether a reduction in N-terminal pro-B-type NP (NT-proBNP) was associated with a decrease in HF hospitalization and cardiovascular mortality (primary endpoint) in patients with HF and reduced ejection fraction, whether treatment with sacubitril/valsartan reduced NT-proBNP below specific partition values more than enalapril, and whether the relationship between changes in NT-proBNP and changes in the primary endpoint were dependent on assigned treatment. METHODS: In PARADIGM-HF (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 Trial), baseline NT-proBNP was measured in 2,080 patients; 1,292 had baseline values >1,000 pg/ml and were reassessed at 1 and 8 months. We related change in NT-proBNP to outcomes. RESULTS: One month after randomization, 24% of the baseline NT-proBNP levels 1,000 pg/ml had fallen to /=1,000 pg/ml. Risk of the primary endpoint was 59% lower in patients with a fall in NT-proBNP to /=1,000 pg/ml than in those without such a fall. In sacubitril/valsartan-treated patients, median NT-proBNP was significantly lower 1 month after randomization than in enalapril-treated patients, and it fell to =1,000 pg/ml in 31% versus 17% of patients treated with sacubitril/valsartan and enalapril, respectively. There was no significant interaction between treatment and the relationship between change in NT-proBNP and the subsequent risk of the primary endpoint. CONCLUSIONS: Patients who attained a significant reduction in NT-proBNP had a lower subsequent rate of cardiovascular death or HF hospitalization independent of the treatment group. Treatment with sacubitril/valsartan was nearly twice as likely as enalapril to reduce NT-proBNP to values /=1,000 pg/ml. (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 Trial)

Nadruz, W., Jr., B. L. Claggett, J. J. McMurray, M. Packer, M. R. Zile, J. L. Rouleau, A. S. Desai, K. Swedberg, M. Lefkowitz, V. C. Shi, M. F. Prescott and S. D. Solomon (2016). “Impact of body mass index on the accuracy of n-terminal pro-brain natriuretic peptide and brain natriuretic peptide for predicting outcomes in patients with chronic heart failure and reduced ejection fraction: Insights from the paradigm-hf study (prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure trial).” Circulation 134(22): 1785-1787.

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The design and primary results of the PARADIGM-HF trial have been previously described.5 The patients randomized in the trial (n=8399) were required to have a plasma BNP ≥150 pg/mL or an NT-proBNP ≥600 pg/mL or, if they were hospitalized for HF within the previous 12 months, a BNP ≥100 pg/mL or an NT-proBNP ≥400 pg/ mL. The present study included patients with available BMI data and who had BNP and NT-proBNP locally measured at the time of screening (n=8217). It considered the primary outcome of the PARADIGM-HF trial, the composite of death from cardiovascular causes or a first hospitalization for HF, as the study outcome. The patients were categorized into 4 groups according to BMI: <25.0 (nonoverweight/obese; n=2536); 25.0 to 29.9 (overweight; n=3116); 30.0 to 34.9 (obese; n=1694); and ≥35.0 kg/m2 (moderately/severely obese; n=871). BNP and NT-proBNP were divided into quartiles within the whole studied population. The trial was approved by the ethics committee at each participating institution, and all the patients provided written informed consent.

Packer, M. (2016). “Development and evolution of a hierarchical clinical composite end point for the evaluation of drugs and devices for acute and chronic heart failure: A 20-year perspective.” Circulation 134(21): 1664-1678.

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Traditional approaches to the assessment of new treatments for heart failure have generally evaluated individual components of the syndrome at fixed points in time or have relied on surrogate physiological measures that are poorly correlated with the clinical status of patients. Conventional time-to-event trials that focus on morbidity and mortality represent an important methodological advance, but they generally assign undue weight to clinical events of less importance and are insensitive to difference in functional capacity among individuals who do not experience a clinical event during follow-up. Twenty years ago, a hierarchical clinical composite was developed to address these limitations; it aims to assess the clinical course of patients as a physician would in practice by combining a symptomatic assessment of the patient at each visit with an evaluation of the clinical stability of the patient between visits. The composite does not generate a numeric score by summing arbitrarily assigned weights to certain symptoms or events; instead, the composite ranks relevant measures and outcomes according to clinical priority. In doing so, the clinical composite minimizes the biases created by noncompleting patients in the assessment of symptoms or exercise tolerance while expanding the range of patients who contribute to the treatment difference in a typical morbidity and mortality trial. When applied appropriately, the hierarchical clinical composite end point has reliably distinguished effective from ineffective treatments. The composite may have particular advantages in the evaluation of new devices and transcatheter interventions in chronic heart failure and of new drugs for acute heart failure. Recent modifications enhance its discriminant characteristics and its ability to accurately assess the efficacy of novel interventions for heart failure.

Packer, M., W. M. Armstrong, J. M. Rothstein and M. Emmett (2016). “Sacubitril-valsartan in heart failure: Why are more physicians not prescribing it?” Ann Intern Med 165(10): 735-736.

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What if you were a patient with heart failure with reduced ejection fraction and your physician did not prescribe sacubitril–valsartan, a new drug that could prolong your life? Clinical trial data supported the drug’s effectiveness, the U.S. Food and Drug Administration (FDA) expedited its approval, and U.S. guidelines recommended its use. Yet, you were stable while using several heart failure drugs, and the physician who saw you every 3 to 6 months never mentioned a newer medication, despite clinical trial data demonstrating mortality benefits of the drug in patients like you. You died suddenly one morning. Did your physician do anything wrong?