Research Spotlight

Copeland, L. A., J. E. Zeber, L. V. Thibodeaux, R. T. McIntyre, E. M. Stock and A. K. Hochhalter (2018). “Postdischarge Correlates of Health Literacy Among Medicaid Inpatients.” Popul Health Manag. Mar 29. [Epub ahead of print].

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Health literacy may represent a target for intervention to improve hospital transitions. This study analyzed the association of health literacy with postdischarge utilization among Medicaid patients treated in an integrated health care system. Discharged inpatients covered by Medicaid (N = 112) participated in this observational study set in a single 600-bed hospital in a private, nonprofit, integrated health care system in the southwestern United States. Participants completed surveys within 15 days of discharge, self-reporting demographics, self-care behaviors, and 2 measures of health literacy (REALM-SF [Short Form of the Rapid Estimate of Adult Literacy in Medicine] and Chew [health literacy screen from Chew et al]). Electronic medical records data were incorporated to determine occurrence of 30-day/90-day postdischarge emergency visits and readmission. Half the respondents (54%) scored at the high-school grade equivalent on REALM-SF, while 46% scored adequate health literacy on the Chew. Forty percent (40%) experienced either emergency care or readmission within 90 days post discharge. Patients who were younger, female, or living with children had relatively better health literacy. Health literacy itself was not associated with readmission or postdischarge emergency care, although African American race was. Although Medicaid patients varied considerably on health literacy, this factor was not associated with adverse health care outcomes. Future work should better identify individuals requiring supportive transition services to reduce problems following hospital discharge.

Charlton, M., J. Levitsky, B. Aqel, J. O’Grady, J. Heimbach, M. Rinella, M. Ghabril, R. Thomason, P. Burra, E. Coelho Little, M. Berenguer, A. Shaked, J. Trotter, J. Roberts, M. Rodriguez-Davalos, M. Rela, E. Pomfret and F. Saliba (2018). “International Liver Transplant Society Consensus Statement on IMMUNOSUPPRESSION IN LIVER TRANSPLANT RECIPIENTS.” Transplantation Mar 20. Epub ahead of print].

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The steady improvement in patient and graft survival rates following liver transplantation has been related to many factors, including improved efficacy of immunosuppression. Effective immunosuppression management is central to achieving optimal outcomes in liver transplant recipients. The advent of more specific, potent immunosuppression agents has, while greatly reducing graft losses through acute and chronic rejection, been associated with an increasing burden of toxicities. While dosing guidelines are available for individual immunosuppression agents, the overall approach to immunosuppression varies widely between transplant centers. The ILTS convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists and pharmacologists to develop guidelines on key aspects of immunosuppression management. Summaries of the evidence were presented to the entire group of panelists. Six broad areas of immunosuppression were addressed by the consensus panel. These topics were addressed through a critical review of the literature, followed by working group proposals and subsequent consensus, which was reviewed by the whole group. As for other ILTS guidelines, the GRADE (Grading of Recommendations Assessment Development and Evaluation) approach was used to determine the grade of the evidence and the strength of the recommendations. Quality of evidence, benefits to risk ratio, resource use and cost effectiveness were all considered in developing guidelines. Recommendations were rated according to quality of the evidence (rated as very low, low, moderate or high) and strength (rated as strong or conditional (weak)) and reflect perceived probability of benefit likely to be gained by adherence to guidance. The consensus findings and recommendations of the International Liver Transplant Society Consensus guidelines on immunosuppression in liver transplant recipients are presented in this document. The guidance, which will be updated to reflect new evidence as it becomes available, is intended for healthcare providers caring for patients before and after liver transplantation. This guidance is also intended to assist third parties in decision-making regarding access to immunosuppression regimens. (Excerpt from text, p. 5-6, in press; no abstract available.)

Chandra, A., E. F. Lewis, B. L. Claggett, A. S. Desai, M. Packer, M. R. Zile, K. Swedberg, J. L. Rouleau, V. C. Shi, M. P. Lefkowitz, T. Katova, J. J. V. McMurray and S. D. Solomon (2018). “Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial.” JAMA Cardiol. Apr 4. [Epub ahead of print].

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Importance: Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Objective: To examine the effects of sacubitril/valsartan on physical and social activities. Design, Setting, and Participants: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017. Interventions: Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily. Main Outcomes and Measures: Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied. Results: At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P = .002); both persisted through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60], P < .001; and 2.36 [95% CI, 1.01-3.71], P = .001, respectively). Conclusions and Relevance: In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01035255.

Cella, D., B. Escudier, N. M. Tannir, T. Powles, F. Donskov, K. Peltola, M. Schmidinger, D. Y. C. Heng, P. N. Mainwaring, H. J. Hammers, J. L. Lee, B. J. Roth, F. Marteau, P. Williams, J. Baer, M. Mangeshkar, C. Scheffold, T. E. Hutson, S. Pal, R. J. Motzer and T. K. Choueiri (2018). “Quality of Life Outcomes for Cabozantinib Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma: METEOR Phase III Randomized Trial.” J Clin Oncol 36(8): 757-764.E

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Purpose In the phase III METEOR trial (ClinicalTrials.gov identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive cabozantinib or everolimus. The cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study. The nine-item FKSI-Disease-Related Symptoms (FKSI-DRS), a subset of FKSI-19, was also investigated. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size greater than or equal to 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or greater than or equal to 4-point decrease from baseline in FKSI-DRS. Results The QoL questionnaire completion rates remained greater than or equal to 75% through week 48 in each arm. There was no difference over time for FKSI-19 Total, FKSI-DRS, or EQ-5D data between the cabozantinib and everolimus arms. Among the individual FKSI-19 items, cabozantinib was associated with worse diarrhea and nausea; everolimus was associated with worse shortness of breath. These differences are consistent with the adverse event profile of each drug. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline. Conclusion In patients with advanced renal cell carcinoma, relative to everolimus, cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.

Carpenter, J. P., J. S. Lane, 3rd, J. Trani, S. Hussain, C. Healey, C. J. Buckley, H. Hashemi and R. Cuff (2018). “Refinement of anatomic indications for the Nellix System for endovascular aneurysm sealing based on 2-year outcomes from the EVAS FORWARD IDE trial.” J Vasc Surg. Mar 30. [Epub ahead of print].

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BACKGROUND: The Nellix System (Endologix, Inc, Irvine, Calif) for endovascular aneurysm sealing (EVAS) is a novel approach to abdominal aortic aneurysm treatment and conceptually different from endovascular aneurysm repair, whereby polymer is employed to fill and actively manage the abdominal aortic aneurysm sac. One-year safety and effectiveness results of the Nellix pivotal trial demonstrated encouraging outcomes with very low morbidity and mortality and high procedural and treatment success. Two-year imaging revealed a signal of migration, leading to a field safety notification issued by the manufacturer on October 21, 2016, and a dedicated root cause analysis, resulting in refinements to the instructions for use (IFU). We report the 2-year results of the investigational device exemption pivotal trial stratified according to the new and original criteria for selection of patients. METHODS: Comprehensive engineering evaluations, statistical analyses, and clinical assessments were conducted looking at patients enrolled in the pivotal trial (N = 150), roll-in cohort (N = 29), and continued access program (N = 154). All patients in all cohorts were treated on-IFU at the time of enrollment. Logistic regression models supported the mechanism that migration with Nellix is associated with a small aortic flow lumen relative to a large aneurysm thrombus burden and large aortic neck diameters. Based on these findings, refinements to the IFU criteria were applied, excluding patients with a thrombus index (maximum aneurysm sac/maximum flow lumen diameter) >1.4, aortic neck diameter >28 mm, and aortic neck conicity (>10% diameter change along the infrarenal neck) and requiring a 10-mm distal seal zone in the iliac artery. RESULTS: Freedom from all-cause mortality at 2 years was 94%. Patient outcomes were then stratified on the refined morphologic criteria and analyzed retrospectively. Two-year freedom from composite endoleak was high among both cohorts (95% on-IFU vs 92% off-IFU). Freedom from migration was 97.7% on-IFU vs 93.2% off-IFU (P = .0125). Freedom from aneurysm enlargement was 98.1% on-IFU vs 93.5% off-IFU (P value is not available because of failure of log-rank test assumptions). Composite freedom from migration, type IA endoleak, or aneurysm expansion was 95.9% among the on-IFU cohort vs 85.1% in the off-IFU cohort (P = .0017). CONCLUSIONS: Consistent with the introduction of a novel therapy, the presentation of failure modes of EVAS over time was inevitable. Using detailed imaging as well as engineering and statistical analysis, we were able to understand risk factors for adverse events specific to EVAS and defined those patients best suited for Nellix. With this EVAS-specific approach to defining IFU, on-IFU patients were identified as those with large aneurysms with little thrombus that would be prone to type II endoleaks and sac expansion with traditional devices. When treated with Nellix, these patients were predicted to experience exceptional results, especially with regard to a low composite endoleak rate and low all-cause mortality.