Research Spotlight

Zerhouni, Y. A., J. W. Scott, C. Ta, P. C. Hsu, M. Crandall, S. C. Gale, A. J. Schoenfeld, A. J. Bottiggi, E. E. Cornwell, 3rd, A. Eastman, J. K. Davis, B. Joseph, B. R. H. Robinson, S. Shafi, C. Q. White, B. H. Williams, E. R. Haut and A. H. Haider (2019). “Impact of the Affordable Care Act on trauma and emergency general surgery: An Eastern Association for the Surgery of Trauma systematic review and meta-analysis.” J Trauma Acute Care Surg 87(2): 491-501.

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BACKGROUND: Trauma and emergency general surgery (EGS) patients who are uninsured have worse outcomes as compared with insured patients. Partially modeled after the 2006 Massachusetts Healthcare Reform (MHR), the Patient Protection and Affordable Care Act was passed in 2010 with the goal of expanding health insurance coverage, primarily through state-based Medicaid expansion (ME). We evaluated the impact of ME and MHR on outcomes for trauma patients, EGS patients, and trauma systems. METHODS: This study was approved by the Eastern Association for the Surgery of Trauma Guidelines Committee. Using Grading of Recommendations Assessment, Development and Evaluation methodology, we defined three populations of interest (trauma patients, EGS patients, and trauma systems) and identified the critical outcomes (mortality, access to care, change in insurance status, reimbursement, funding). We performed a systematic review of the literature. Random effect meta-analyses and meta-regression analyses were calculated for outcomes with sufficient data. RESULTS: From 4,593 citations, we found 18 studies addressing all seven predefined outcomes of interest for trauma patients, three studies addressing six of seven outcomes for EGS patients, and three studies addressing three of eight outcomes for trauma systems. On meta-analysis, trauma patients were less likely to be uninsured after ME or MHR (odds ratio, 0.49; 95% confidence interval, 0.37-0.66). These coverage expansion policies were not associated with a change in the odds of inpatient mortality for trauma (odds ratio, 0.96; 95% confidence interval, 0.88-1.05). Emergency general surgery patients also experienced a significant insurance coverage gains and no change in inpatient mortality. Insurance expansion was often associated with increased access to postacute care at discharge. The evidence for trauma systems was heterogeneous. CONCLUSION: Given the evidence quality, we conditionally recommend ME/MHR to improve insurance coverage and access to postacute care for trauma and EGS patients. We have no specific recommendation with respect to the impact of ME/MHR on trauma systems. Additional research into these questions is needed. LEVEL OF EVIDENCE: Review, Economic/Decision, level III.

Wen, P. Y., D. A. Reardon, T. S. Armstrong, S. Phuphanich, R. D. Aiken, J. C. Landolfi, W. T. Curry, J. J. Zhu, M. Glantz, D. M. Peereboom, J. Markert, R. LaRocca, D. M. O’Rourke, K. Fink, L. Kim, M. Gruber, G. J. Lesser, E. Pan, S. Kesari, A. Muzikansky, C. Pinilla, R. G. Santos and J. S. Yu (2019). “A Randomized Double-Blind Placebo-Controlled Phase 2 Trial Of Dendritic Cell Vaccine ICT-107 In Newly Diagnosed Patients With Glioblastoma.” Clin Cancer Res Jul 18. [Epub ahead of print].

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PURPOSE: To evaluate the efficacy of ICT-107. PATIENTS AND METHODS: We conducted a double-blinded randomized phase II trial of ICT-107 in newly-diagnosed glioblastoma (GBM) patients and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1+ and/or -A2+ resected patients with residual tumor 1 cm3 received radiotherapy and concurrent temozolomide. Following completion of radiotherapy 124 patients, randomized 2:1, received ICT-107 (autologous dendritic cells (DCs) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL-13Ralpha2) or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly x 4 followed by twelve months of adjuvant temozolomide. Maintenance vaccinations occurred at one, three, and six months and every six months thereafter. RESULTS: ICT-107 was well-tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the intention-to-treat (ITT) population was significantly increased in the ICT-107 cohort by 2.2 months (p=0.011). Frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated pre-specified subgroups, whereas only HLA-A1 methylated patients had an OS benefit. CONCLUSION: PFSl was significantly improved in ICT-107 treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.

Wood, D. A., Z. Krajcer, J. Sathananthan, N. Strickman, C. Metzger, W. Fearon, M. Aziz, L. F. Satler, R. Waksman, M. Eng, S. Kapadia, A. Greenbaum, M. Szerlip . . . and J. G. Webb (2019). “Pivotal Clinical Study to Evaluate the Safety and Effectiveness of the MANTA Percutaneous Vascular Closure Device.” Circ Cardiovasc Interv 12(7): 1-11 e007258.

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BACKGROUND: Open surgical closure and small-bore suture-based preclosure devices have limitations when used for transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, or percutaneous thoracic endovascular aortic aneurysm repair. The MANTA vascular closure device is a novel collagen-based technology designed to close large bore arteriotomies created by devices with an outer diameter ranging from 12F to 25F. In this study, we determined the safety and effectiveness of the MANTA vascular closure device. METHODS AND RESULTS: A prospective, single arm, multicenter investigation in patients undergoing transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, or thoracic endovascular aortic aneurysm repair at 20 sites in North America. The primary outcome was time to hemostasis. The primary safety outcomes were accessed site-related vascular injury or bleeding complications. A total of 341 patients, 78 roll-in, and 263 in the primary analysis cohort, were entered in the study between November 2016 and September 2017. For the primary analysis cohort, transcatheter aortic valve replacement was performed in 210 (79.8%), and percutaneous endovascular abdominal aortic aneurysm repair or thoracic endovascular aortic aneurysm repair was performed in 53 (20.2%). The 14F MANTA was used in 42 cases (16%), and the 18F was used in 221 cases(84%). The mean effective sheath outer diameter was 22F (7.3 mm). The mean time to hemostasis was 65+/-157 seconds with a median time to hemostasis of 24 seconds. Technical success was achieved in 257 (97.7%) patients, and a single device was deployed in 262 (99.6%) of cases. Valve Academic Research Consortium-2 major vascular complications occurred in 11 (4.2%) cases: 4 received a covered stent (1.5%), 3 had access site bleeding (1.1%), 2 underwent surgical repair (0.8%), and 2 underwent balloon inflation (0.8%). CONCLUSIONS: In a selected population, this study demonstrated that the MANTA percutaneous vascular closure device can safely and effectively close large bore arteriotomies created by current generation transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, and thoracic endovascular aortic aneurysm repair devices. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02908880.

Vijayaraghavan, K., H. M. Szerlip, C. M. Ballantyne, H. E. Bays, S. Philip, R. T. Doyle, Jr., R. A. Juliano and C. Granowitz (2019). “Icosapent ethyl reduces atherogenic markers in high-risk statin-treated patients with stage 3 chronic kidney disease and high triglycerides.” Postgrad Med Jul 25: 1-7. [Epub ahead of print].

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Objective: Patients with chronic kidney disease (CKD) have increased cardiovascular disease (CVD) risk, likely driven by atherogenic and inflammatory markers beyond low-density lipoprotein cholesterol (LDL-C). The objective of this hypothesis-generating post hoc subgroup analysis was to explore the effects of icosapent ethyl at 2 or 4 g/day (prescription pure ethyl ester of the omega-3 fatty acid eicosapentaenoic acid [EPA]) on atherogenic lipid, apolipoprotein, inflammatory parameters (high-sensitivity C-reactive protein [hsCRP], lipoprotein-associated phospholipase A2 [Lp-PLA2]), and oxidative parameters (oxidized-LDL [ox-LDL]) in statin-treated patients from ANCHOR with stage 3 CKD. Methods: The 12-week ANCHOR study evaluated icosapent ethyl in 702 statin-treated patients at increased CVD risk with triglycerides (TG) 200-499 mg/dL despite controlled LDL-C (40-99 mg/dL). This post-hoc analysis included patients from ANCHOR with stage 3 CKD (estimated glomerular filtration rate [eGFR] /=3 months) randomized to icosapent ethyl 4 g/day (n = 19), 2 g/day (n = 30), or placebo (n = 36). Results: At the prescription dose of 4 g/day, icosapent ethyl significantly reduced TG (-16.9%; P = 0.0074) and other potentially atherogenic lipids/lipoproteins, ox-LDL, hsCRP, and Lp-PLA2, and increased plasma and red blood cell EPA levels (+879% and +579%, respectively; both P < 0.0001) versus placebo. Icosapent ethyl did not significantly alter eGFR or serum creatinine. Safety and tolerability were similar to placebo. Conclusions: In patients with stage 3 CKD at high CVD risk with persistent high TG despite statins, icosapent ethyl 4 g/day reduced potentially atherogenic and other cardiovascular risk factors without raising LDL-C, with safety similar to placebo. These findings suggest prospective investigation may be warranted.

Vasudevan, A., J. W. Choi, G. A. Feghali, S. R. Lander, L. Jialiang, J. M. Schussler, R. C. Stoler, R. C. Vallabhan, C. E. Velasco and P. A. McCullough (2019). “Event dependence in the analysis of cardiovascular readmissions postpercutaneous coronary intervention.” J Investig Med 67(6): 943-949.

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Recurrent hospitalizations are common in longitudinal studies; however, many forms of cumulative event analyses assume recurrent events are independent. We explore the presence of event dependence when readmissions are spaced apart by at least 30 and 60 days. We set up a comparative framework with the assumption that patients with emergency percutaneous coronary intervention (PCI) will be at higher risk for recurrent cardiovascular readmissions than those with elective procedures. A retrospective study of patients who underwent PCI (January 2008-December 2012) with their follow-up information obtained from a regional database for hospitalization was conducted. Conditional gap time (CG), frailty gamma (FG) and conditional frailty models (CFM) were constructed to evaluate the dependence of events. Relative bias (%RB) in point estimates using CFM as the reference was calculated for comparison of the models. Among 4380 patients, emergent cases were at higher risk as compared with elective cases for recurrent events in different statistical models and time-spaced data sets, but the magnitude of HRs varied across the models (adjusted HR [95% CI]: all readmissions [unstructured data]-CG 1.16 [1.09 to 1.22], FG 1.45 [1.33 to 1.57], CFM 1.24 [1.16 to 1.32]; 30-day spaced-CG1.14 [1.08 to 1.21], FG 1.28 [1.17 to 1.39], CFM 1.17 [1.10 to 1.26]; and 60-day spaced-CG 1.14 [1.07 to 1.22], FG 1.23 [1.13 to 1.34] CFM 1.18 [1.09 to 1.26]). For all of the time-spaced readmissions, we found that the values of %RB were closer to the conditional models, suggesting that event dependence dominated the data despite attempts to create independence by increasing the space in time between admissions. Our analysis showed that independent of the intercurrent event duration, prior events have an influence on future events. Hence, event dependence should be accounted for when analyzing recurrent events and challenges contemporary methods for such analysis.