Research Spotlight

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?

Vallabhajosyula, S., T. M. Haddad, P. R. Sundaragiri, A. A. Ahmed, M. S. Nawaz, H. A. Rayes, H. C. Devineni, A. Kanmanthareddy, D. A. McCann, C. S. Wichman, A. M. Modrykamien and L. E. Morrow (2016). “Role of b-type natriuretic peptide in predicting in-hospital outcomes in acute exacerbation of chronic obstructive pulmonary disease with preserved left ventricular function: A 5-year retrospective analysis.” J Intensive Care Med: 2016 Dec [Epub ahead of print].

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BACKGROUND: The role of B-type natriuretic peptide (BNP) is less understood in the risk stratification of patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), especially in patients with normal left ventricular ejection fraction (LVEF). METHODS: This retrospective study from 2008 to 2012 evaluated all adult patients with AECOPD having BNP levels and available echocardiographic data demonstrating LVEF >/=40%. The patients were divided into groups 1, 2, and 3 with BNP /=501 pg/mL, respectively. A subgroup analysis was performed for patients without renal dysfunction. Outcomes included need for and duration of noninvasive ventilation (NIV) and mechanical ventilation (MV), NIV failure, reintubation at 48 hours, intensive care unit (ICU) and total length of stay (LOS), and in-hospital mortality. Two-tailed P < .05 was considered statistically significant. RESULTS: Of the total 1145 patients, 550 (48.0%) met our inclusion criteria (age 65.1 +/- 12.2 years; 271 [49.3%] males). Groups 1, 2, and 3 had 214, 216, and 120 patients each, respectively, with higher comorbidities and worse biventricular function in higher categories. Higher BNP values were associated with higher MV use, NIV failure, MV duration, and ICU and total LOS. On multivariate analysis, BNP was an independent predictor of higher NIV and MV use, NIV failure, NIV and MV duration, and total LOS in groups 2 and 3 compared to group 1. B-type natriuretic peptide continued to demonstrate positive correlation with NIV and MV duration and ICU and total LOS independent of renal function in a subgroup analysis. CONCLUSION: Elevated admission BNP in patients with AECOPD and normal LVEF is associated with worse in-hospital outcomes and can be used to risk-stratify these patients.

Schiffmann, R., M. Fuller, L. A. Clarke and J. M. Aerts (2016). “Is it fabry disease?” Genet Med 18(12): 1181-1185.

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Fabry disease is caused by mutations in the GLA gene that lower alpha-galactosidase A activity to less than 25-30% of the mean normal level. Several GLA variants have been identified that are associated with relatively elevated residual alpha-galactosidase A. The challenge is to determine which GLA variants can cause clinical manifestations related to Fabry disease. Here, we review the various types of GLA variants and recommend that pathogenicity be considered only when associated with elevated globotriaosylceramide in disease-relevant organs and tissues as analyzed by mass spectrometry. This criterion is necessary to ensure that very costly and specific therapy is provided only when appropriate.

Armstrong, A. W., M. P. Siegel, J. Bagel, E. E. Boh, M. Buell, K. D. Cooper, K. Callis Duffin, L. F. Eichenfield, A. Garg, J. M. Gelfand, A. B. Gottlieb, J. Y. Koo, N. J. Korman, G. G. Krueger, M. G. Lebwohl, C. L. Leonardi, A. M. Mandelin, M. A. Menter, J. F. Merola, D. M. Pariser, R. B. Prussick, C. Ryan, K. N. Shah, J. M. Weinberg, M. O. Williams, J. J. Wu, P. S. Yamauchi and A. S. Van Voorhees (2016). “From the medical board of the national psoriasis foundation: Treatment targets for plaque psoriasis.” J Am Acad Dermatol: 2016 Nov [Epub ahead of print].

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BACKGROUND: An urgent need exists in the United States to establish treatment goals in psoriasis. OBJECTIVE: We aim to establish defined treatment targets toward which clinicians and patients with psoriasis can strive to inform treatment decisions, reduce disease burden, and improve outcomes in practice. METHODS: The National Psoriasis Foundation conducted a consensus-building study among psoriasis experts using the Delphi method. The process consisted of: (1) literature review, (2) pre-Delphi question selection and input from general dermatologists and patients, and (3) 4 Delphi rounds. RESULTS: A total of 25 psoriasis experts participated in the Delphi process. The most preferred instrument was body surface area (BSA). The most preferred time for evaluating patient response after starting new therapies was at 3 months. The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or less from baseline. The target response at 3 months postinitiation was BSA 1% or less. During the maintenance period, evaluation every 6 months was most preferred. The target response at every 6 months maintenance evaluation is BSA 1% or less. LIMITATIONS: Although BSA is feasible in practice, it does not encompass health-related quality of life, costs, and risks of side effects. CONCLUSION: With defined treatment targets, clinicians and patients can regularly evaluate treatment responses and perform benefit-risk assessments of therapeutic options individualized to the patient.