Baylor Research Institute

Fernandez, O., G. Giovannoni, R. J. Fox, R. Gold, J. T. Phillips, J. Potts, M. Okwuokenye and J. L. Marantz (2017). “Efficacy and safety of delayed-release dimethyl fumarate for relapsing-remitting multiple sclerosis in prior interferon users: An integrated analysis of define and confirm.” Clin Ther: 2017 Jul [Epub ahead of print].

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PURPOSE: In Phase III studies (DEFINE [Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS]/CONFIRM [Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis]), delayed-release dimethyl fumarate (DMF) demonstrated significant efficacy and a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS). Post hoc analyses of integrated data from DEFINE/CONFIRM were conducted to evaluate the effect of DMF in patients previously treated with interferon (IFN) beta. METHODS: Patients (age 18-55 years; Expanded Disability Status Scale score, 0-5.0) were randomized to receive DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only) for up to 2 years. Previous IFN users received at least 1 IFN treatment >3 months before randomization. Data for DMF 240 mg BID (approved dosing regimen) are reported. FINDINGS: In the integrated intention-to-treat population, 172 and 169 patients receiving DMF or placebo, respectively, had received >/=1 prior IFN. In this subgroup, significant reductions with DMF versus placebo were observed for the annualized relapse rate (rate ratio, 0.55 [95% CI, 0.40-0.77]), new/newly enlarging T2-hyperintense lesions (lesion mean ratio, 0.16 [95% CI, 0.09-0.29]), odds of having more gadolinium-enhancing lesions (odds ratio, 0.17 [95% CI, 0.07-0.44]), and new T1-hypointense lesions (lesion mean ratio, 0.25 [95% CI, 0.14-0.45]). Median Expanded Disability Status Scale scores remained stable during the study period. Adverse events associated with DMF included flushing and gastrointestinal events. IMPLICATIONS: In this post hoc analysis in patients with previous IFN treatment, DMF demonstrated significant efficacy over 2 years versus placebo and an adverse event profile consistent with the overall population of DEFINE/CONFIRM.

McCullough, P. A. (2017). “How trialists and pharmaceutical sponsors have failed us by thinking that acute heart failure is a 48-hour illness.” Am J Cardiol 120(3): 505-508.

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Trials of novel therapies for acute heart failure (HF) have followed a convention of short term, most commonly a 48-hour infusion of parenteral therapy compared with placebo or an active drug in a randomized, double-blind study design. Such trials include OPTIME-CHF, SURVIVE, VERITAS, PROTECT, ASCEND-HF, TRUE-HF, and RELAX-AHF-2. This article reviews how this practice in trials began and summarizes the reasons why such a brief exposure of any novel therapy has failed to reduce the end points of rehospitalization or death. Future trials should consider acute and extended use of novel agents to better match the pathophysiology of decompensation and recovery from acute HF.

Mooney, J., S. L. Sellers, P. Blanke, P. Pibarot, R. T. Hahn, D. Dvir, P. S. Douglas, N. J. Weissman, S. K. Kodali, V. H. Thourani, H. Jilaihawi, O. Khalique, C. R. Smith, S. H. Kueh, M. Ohana, R. Grover, C. Naoum, A. Crowley, W. A. Jaber, M. C. Alu, R. Parvataneni, M. Mack, J. G. Webb, M. B. Leon and J. A. Leipsic (2017). “Ct-defined prosthesis-patient mismatch downgrades frequency and severity, and demonstrates no association with adverse outcomes after tavr.” JACC Cardiovasc Interv: 2017 Jul [Epub ahead of print].

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OBJECTIVES: This study sought to determine if indexed effective orifice area (EOAi), using left ventricular outflow tract measured from computed tomography (EOAiCT), reclassified prosthesis-patient mismatch (PPM) compared with conventional echocardiogram-defined measurements (EOAiTTE). BACKGROUND: PPM does not predict mortality following transcatheter aortic valve replacement (TAVR). However, it is unknown if the EOAiCT of the left ventricular outflow tract improves risk stratification. METHODS: A total of 765 TAVR patients from the PARTNER II (Placement of Aortic Transcatheter Valves II) trial S3i cohort were evaluated. EOAi was calculated using the continuity equation, and the left ventricular outflow tract area was derived from baseline computed tomography. Traditional echocardiographic categories defined PPM: absent (>0.85 cm2/m2), moderate (>/=0.65 and

Tecson, K. M., E. Erhardtsen, P. M. Eriksen, A. O. Gaber, M. Germain, L. Golestaneh, M. L. A. Lavoria, L. W. Moore and P. A. McCullough (2017). “Optimal cut points of plasma and urine neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury among critically ill adults: Retrospective determination and clinical validation of a prospective multicentre study.” BMJ Open 7(7): 1-9.

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OBJECTIVES: To determine the optimal threshold of blood and urine neutrophil gelatinase-associated lipocalin (NGAL) to predict moderate to severe acute kidney injury (AKI) and persistent moderate to severe AKI lasting at least 48 consecutive hours, as defined by an adjudication panel. METHODS: A multicentre prospective observational study enrolled intensive care unit (ICU) patients and recorded daily ethylenediaminetetraacetic acid (EDTA) plasma, heparin plasma and urine NGAL. We used natural log-transformed NGAL in a logistic regression model to predict stage 2/3 AKI (defined by Kidney Disease International Global Organization). We performed the same analysis using the NGAL value at the start of persistent stage 2/3 AKI. RESULTS: Of 245 subjects, 33 (13.5%) developed stage 2/3 AKI and 25 (10.2%) developed persistent stage 2/3 AKI. Predicting stage 2/3 AKI revealed the optimal NGAL cutoffs in EDTA plasma (142.0 ng/mL), heparin plasma (148.3 ng/mL) and urine (78.0 ng/mL) and yielded the following decision statistics: sensitivity (SN)=78.8%, specificity (SP)=73.0%, positive predictive value (PPV)=31.3%, negative predictive value (NPV)=95.7%, diagnostic accuracy (DA)=73.8% (EDTA plasma); SN=72.7%, SP=73.8%, PPV=30.4%, NPV=94.5%, DA=73.7% (heparin plasma); SN=69.7%, SP=76.8%, PPV=32.9%, NPV=94%, DA=75.8% (urine). The optimal NGAL cutoffs to predict persistent stage 2/3 AKI were similar: 148.3 ng/mL (EDTA plasma), 169.6 ng/mL (heparin plasma) and 79.0 ng/mL (urine) yielding: SN=84.0%, SP=73.5%, PPV=26.6%, NPV=97.6, DA=74.6% (EDTA plasma), SN=84%, SP=76.1%, PPV=26.8%, NPV=96.5%, DA=76.1% (heparin plasma) and SN=75%, SP=75.8%, PPV=26.1, NPV=96.4%, DA=75.7% (urine). CONCLUSION: Blood and urine NGAL predicted stage 2/3 AKI, as well as persistent 2/3 AKI in the ICU with acceptable decision statistics using a single cut point in each type of specimen.

Adelmann, D., K. Kronish and M. A. Ramsay (2017). “Anesthesia for liver transplantation.” Anesthesiol Clin 35(3): 491-508.

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The provision of anesthesia for a liver transplant program requires a dedicated team of anesthesiologists. Liver transplant anesthesiologists must have an understanding of liver physiology and anatomy; the spectrum of clinical disease associated with liver dysfunction; the impact of warm and cold ischemia times, surgical techniques in liver transplantation, and the impact of ischemia-reperfusion syndrome; and optimal practices to protect the liver. The team must provide a 24-hour service, be actively involved in the selection committee process, and stay current with advances in the subspecialty.