Research Spotlight

Goker-Alpan, O., N. Longo, M. McDonald, S. P. Shankar, R. Schiffmann, P. Chang, Y. Shen and A. Pano (2016). “An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with fabry disease who are naive to enzyme replacement therapy.” Drug Des Devel Ther 10: 1771-1781.

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BACKGROUND: Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naive children with Fabry disease. METHODS: In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged >/=7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life. RESULTS: Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes. CONCLUSION: Fifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.

Edwards, F. H., V. A. Ferraris, P. A. Kurlansky, K. W. Lobdell, X. He, S. M. O’Brien, A. P. Furnary, J. S. Rankin, C. M. Vassileva, F. L. Fazzalari, M. J. Magee, V. Badhwar, Y. Xian, J. P. Jacobs, M. C. Wyler von Ballmoos and D. M. Shahian (2016). “Failure to rescue rates after coronary artery bypass grafting: An analysis from the society of thoracic surgeons adult cardiac surgery database.” Ann Thorac Surg: 2016 Jun [Epub ahead of print].

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BACKGROUND: Failure to rescue (FTR) is increasingly recognized as an important quality indicator in surgery. The Society of Thoracic Surgeons National Database was used to develop FTR metrics and a predictive FTR model for coronary artery bypass grafting (CABG). METHODS: The study included 604,154 patients undergoing isolated CABG at 1,105 centers from January 2010 to January 2014. FTR was defined as death after four complications: stroke, renal failure, reoperation, and prolonged ventilation. FTR was determined for each complication and a composite of the four complications. A statistical model to predict FTR was developed. RESULTS: FTR rates were 22.3% for renal failure, 16.4% for stroke, 12.4% for reoperation, 12.1% for prolonged ventilation, and 10.5% for the composite. Mortality increased with multiple complications and with specific combinations of complications. The multivariate risk model for prediction of FTR demonstrated a C index of 0.792 and was well calibrated, with a 1.0% average difference between observed/expected (O/E) FTR rates. With centers grouped into mortality terciles, complication rates increased modestly (11.4% to 15.7%), but FTR rates more than doubled (6.8% to 13.9%) from the lowest to highest terciles. Centers in the lowest complication rate tercile had an FTR O/E of 1.14, whereas centers in the highest complication rate tercile had an FTR O/E of 0.91. CONCLUSIONS: CABG mortality rates vary directly with FTR, but complication rates have little relation to death. FTR rates derived from The Society of Thoracic Surgeons data can serve as national benchmarks. Predicted FTR rates may facilitate patient counseling, and FTR O/E ratios have promise as valuable quality metrics.

Copeland, L. A., E. P. Finley, M. J. Bollinger, M. E. Amuan and M. J. Pugh (2016). “Comorbidity correlates of death among new veterans of iraq and afghanistan deployment.” Med Care: 2016 June [Epub ahead of print].

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BACKGROUND: Veterans of the wars in Iraq and Afghanistan who receive care in the Veterans Health Administration (VA) have high disease burden. Distinct comorbidity patterns have been shown to be differentially associated with adverse outcomes, including death. This study determined correlates of 5-year mortality. MATERIALS AND METHODS: VA demographic, military, homelessness, and clinical measures informed this retrospective analysis. Previously constructed comorbidity classifications over 3 years of care were entered into a Cox proportional hazards model of death. RESULTS: There were 164,933 veterans in the cohort, including African Americans (16%), Hispanics (11%), and whites (65%). Most were in their 20s at baseline (60%); 12% were women; 4% had attempted suicide; 4% had been homeless. Having clustered disorders of pain, posttraumatic stress disorder, and traumatic brain injury was associated with death [hazard ratio (HR)=2.0]. Mental disorders including substance abuse were similarly associated (HR=2.1). Prior suicide attempt (HR=2.2) or drug overdose (HR=3.0) considerably increased risk of death over 5 years. CONCLUSIONS: As congressional actions such as Veterans Choice Act offer more avenues to seek care outside of VA, coordination of care, and suicide prevention outreach for recent veterans may require innovative approaches to preserve life.

Cizenski, J., J. Griffin and A. Menter (2016). “Image gallery: Cutaneous t-cell lymphoma mimicking a gyrate erythema.” Br J Dermatol 174(5): e42.

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A 22-year-old white man was evaluated for a mildly pruritic scaly rash of 6 years’ duration, which began on his chest and recently spread to the axillae and back. He initially presented to his primary doctor, who provided him with topical steroids without benefit. The eruption never ulcerated. Examination revealed pink annular and polycyclic patches on the chest, axillae and flanks without nodules, tumours or adenopathy. There was very faint scale at the borders of the lesions. A potassium hydroxide stain was negative for dermatophytes. Two biopsies revealed a CD8 predominant epidermotropic infiltrate of atypical lymphocytes with a clonal T-cell receptor rearrangement. Complete staging revealed stage IA disease. The indolent behaviour is consistent with mycosis fungoides with aberrant CD8+ phenotype. Current treatment includes a potent topical corticosteroid and close follow-up.

Coleman, K. J., C. Stewart, B. E. Waitzfelder, J. E. Zeber, L. S. Morales, A. T. Ahmed, B. K. Ahmedani, A. Beck, L. A. Copeland, J. R. Cummings, E. M. Hunkeler, N. M. Lindberg, F. Lynch, C. Y. Lu, A. A. Owen-Smith, C. M. Trinacty, R. R. Whitebird and G. E. Simon (2016). “Racial-ethnic differences in psychiatric diagnoses and treatment across 11 health care systems in the mental health research network.” Psychiatr Serv 67(7): 749-757.

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OBJECTIVE: The objective of this study was to characterize racial-ethnic variation in diagnoses and treatment of mental disorders in large not-for-profit health care systems. METHODS: Participating systems were 11 private, not-for-profit health care organizations constituting the Mental Health Research Network, with a combined 7,523,956 patients age 18 or older who received care during 2011. Rates of diagnoses, prescription of psychotropic medications, and total formal psychotherapy sessions received were obtained from insurance claims and electronic medical record databases across all health care settings. RESULTS: Of the 7.5 million patients in the study, 1.2 million (15.6%) received a psychiatric diagnosis in 2011. This varied significantly by race-ethnicity, with Native American/Alaskan Native patients having the highest rates of any diagnosis (20.6%) and Asians having the lowest rates (7.5%). Among patients with a psychiatric diagnosis, 73% (N=850,585) received a psychotropic medication. Non-Hispanic white patients were significantly more likely (77.8%) than other racial-ethnic groups (odds ratio [OR] range .48-.81) to receive medication. In contrast, only 34% of patients with a psychiatric diagnosis (N=548,837) received formal psychotherapy. Racial-ethnic differences were most pronounced for depression and schizophrenia; compared with whites, non-Hispanic blacks were more likely to receive formal psychotherapy for their depression (OR=1.20) or for their schizophrenia (OR=2.64). CONCLUSIONS: There were significant racial-ethnic differences in diagnosis and treatment of psychiatric conditions across 11 U.S. health care systems. Further study is needed to understand underlying causes of these observed differences and whether processes and outcomes of care are equitable across these diverse patient populations.