Research Spotlight

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.

Vasudevan, A., J. W. Choi, G. A. Feghali, A. Y. Kluger, S. R. Lander, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, R. C. Stoler, R. C. Vallabhan, C. E. Velasco, A. Yoon and P. A. McCullough (2019). “First and recurrent events after percutaneous coronary intervention: implications for survival analyses.” Scand Cardiovasc J Jul 25: 1-6. [Epub ahead of print].

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Objectives. Using composite endpoints and/or only first events in clinical research result in information loss and alternative statistical methods which incorporate recurrent event data exist. We compared information-loss under traditional analyses to alternative models. Design. We conducted a retrospective analysis of patients who underwent percutaneous coronary intervention (Jan2010-Dec2014) and constructed Cox models for a composite endpoint (readmission/death), a shared frailty model for recurrent events, and a joint frailty (JF) model to simultaneously account for recurrent and terminal events and evaluated the impact of heart failure (HF) on the outcome. Results. Among 4901 patients, 2047(41.8%) experienced a readmission or death within 1 year. Of those with recurrent events, 60% had >/=1 readmission and 6% had >4; a total of 121(2.5%) patients died during follow-up. The presence of HF conferred an adjusted Hazard ratio (HR) of 1.32 (95% CI: 1.18-1.47, p < .001) for the risk of composite endpoint (Cox model), 1.44 (95% CI: 1.36-1.52, p < .001) in the frailty model, and 1.34 (95% CI:1.22-1.46, p < .001) in the JF model. However, HF was not associated with death (HR 0.87, 95% CI: 0.52-1.48, p = .61) in the JF model. Conclusions. Using a composite endpoint and/or only the first event yields substantial loss of information, as many individuals endure >1 event. JF models reduce bias by simultaneously providing event-specific HRs for recurrent and terminal events.

Spitler, C. A., E. R. Row, W. E. Gardner, 2nd, R. E. Swafford, M. J. Hankins, P. J. Nowotarski and D. W. Kiner (2019). “Tranexamic Acid Use in Open Reduction and Internal Fixation of Fractures of the Pelvis, Acetabulum, and Proximal Femur: A Randomized Controlled Trial.” J Orthop Trauma 33(8): 371-376.

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OBJECTIVE: To assess the safety and efficacy of tranexamic acid (TXA) use in fractures of the pelvic ring, acetabulum, and proximal femur. DESIGN: Prospective, randomized controlled trial. SETTING: Single Level 1 trauma center. PATIENTS: Forty-seven patients were randomized to the study group, and 46 patients comprised the control group. INTERVENTION: The study group received 15 mg/kg IV TXA before incision and a second identical dose 3 hours after the initial dose. MAIN OUTCOME MEASUREMENTS: Transfusion rates and total blood loss (TBL) [via hemoglobin-dilution method and rates of venous thromboembolic events (VTEs)]. RESULTS: TBL was significantly higher in the control group (TXA = 952 mL, no TXA = 1325 mL, P = 0.028). The total transfusion rates between the TXA and control groups were not significantly different (TXA 1.51, no TXA = 1.17, P = 0.41). There were no significant differences between the TXA and control groups in inpatient VTE events (P = 0.57). CONCLUSION: The use of TXA in high-energy fractures of the pelvis, acetabulum, and femur significantly decreased calculated TBL but did not decrease overall transfusion rates. TXA did not increase the rate of VTE. Further study is warranted before making broad recommendations for the use of TXA in these fractures. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Spechler, S. J. (2019). “Eosinophilic esophagitis: novel concepts regarding pathogenesis and clinical manifestations.” J Gastroenterol Jul 24. [Epub ahead of print].

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This report explores two hypotheses regarding eosinophilic esophagitis (EoE): (1) that the use of proton pump inhibitors (PPIs) might contribute to the pathogenesis of EoE by preventing peptic digestion of food allergens, by increasing gastric mucosal permeability to enable gastric absorption of those undegraded food allergens, and by causing microbial dysbiosis, and (2) that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms, and that the muscle-predominant form of EoE might cause a variety of esophageal motility disorders including achalasia.