Research Spotlight

Butler, J., M. Packer, S. J. Greene, M. Fiuzat, S. D. Anker, K. J. Anstrom, P. E. Carson, L. B. Cooper, G. C. Fonarow, A. F. Hernandez, J. L. Januzzi, Jr., M. Jessup, R. R. Kalyani, S. Kaul, M. Kosiborod, J. Lindenfeld, D. K. McGuire, M. S. Sabatine, S. D. Solomon, J. R. Teerlink, M. Vaduganathan, C. W. Yancy, N. Stockbridge and C. M. O’Connor (2019). “Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.” Circulation 140(25): 2108-2118.

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Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

Brouwer, W. P., Q. Zhao, B. E. Hansen, D. Lau, M. Khalili, N. A. Terrault, A. M. Di Bisceglie, R. P. Perrillo, M. W. Fried, D. Wong, J. J. Feld, S. H. Belle and H. L. A. Janssen (2020). “HBV Genotype-Specific Levels of Hepatitis B Surface Antigen Improve HBV Phenotype Definition.” Clin Gastroenterol Hepatol 18(1): 259-261.

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Controversies exist regarding the classification of the different clinical phases of chronic hepatitis B (CHB) because hepatitis B virus (HBV) DNA and alanine aminotransferase levels fluctuate over time. To improve the distinction of clinical phases and the associated spectrum of clinical outcome, hepatitis B surface antigen (HBsAg) levels may be of help. We hypothesize that HBV genotype specific HBsAg levels are needed for the identification of different clinical HBV disease phases.

Baxter, R., J. Squiers, W. Conner, M. Kent, J. Fann, K. Lobdell and J. M. DiMaio (2019). “Enhanced Recovery After Surgery: A Narrative Review of its Application in Cardiac Surgery.” Ann Thorac Surg Dec 23. [Epub ahead of print].

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BACKGROUND: Enhanced recovery after surgery (ERAS) is a perioperative patient management strategy that is being adopted rapidly across surgical specialties worldwide. Components of ERAS work collaboratively throughout the perioperative course to achieve significant benefits for both the patient and the entire healthcare system. The use of ERAS in cardiac surgery (ERAS-C) could lead to similar improvements, but currently use of ERAS-C programs are lacking and not well-defined. METHODS: A search of the literature was performed of the Medline database to capture relevant studies discussing enhanced recovery after cardiac surgery. Key concepts were extracted from these articles and grouped according to appropriate perioperative stages. Supporting literature was also included briefly discussing the historical progression of cardiac surgery to enhanced recovery pathways, potential limitations to these pathways in cardiac surgery, and the first studies evaluating he use of an ERAS program with cardiac surgery patients. RESULTS: Initial results of ERAS-C studies have shown similar benefits to those of other surgical fields including decreased hospital and intensive care unit lengths of stay (1-4 days and 4-20 hours, respectively, improved perioperative pain control (25-60% decreased opioid usage), and improvements in early postoperative mobility and oral diets. Results especially beneficial to cardiac surgery have also been reported such as an 8-14% decreased incidence of postoperative atrial fibrillation. CONCLUSIONS: This manuscript aims to present pertinent current research related to the implementation of ERAS programs in the field of cardiac surgery and provide a call to action for further investigation and adaption of ERAS in cardiac surgery.

Asch, F. M., P. A. Grayburn, R. J. Siegel, S. Kar, D. S. Lim, J. G. Zaroff, J. M. Mishell, B. Whisenant, M. J. Mack, J. Lindenfeld, W. T. Abraham, G. W. Stone and N. J. Weissman (2019). “Echocardiographic Outcomes After Transcatheter Leaflet Approximation in Patients With Secondary Mitral Regurgitation: The COAPT Trial.” J Am Coll Cardiol 74(24): 2969-2979.

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BACKGROUND: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial among patients with heart failure (HF) and moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation, patients treated with transcatheter mitral valve repair (TMVr) through leaflet approximation had reduced rates of HF hospitalization and mortality compared with guideline-directed medical therapy (GDMT) alone. OBJECTIVES: The purpose of this study was to describe the echocardiographic patient qualification process for the COAPT trial, baseline echocardiographic characteristics, changes over time, and the interaction between treatment group and echocardiographic parameters on clinical outcomes. METHODS: A novel echocardiographic algorithm was implemented for grading mitral regurgitation severity during the screening process. Standardized echocardiograms were obtained at baseline and during regular follow-up intervals through 2 years, and were analyzed by a core laboratory. RESULTS: A total of 614 patients were randomized to TMVr plus maximally tolerated GDMT or GDMT alone. Mean baseline left ventricular (LV) ejection fraction was 31.3 +/- 9.3%, LV end-diastolic volume was 192.7 +/- 71 ml, and effective regurgitant orifice area was 0.41 +/- 0.15 cm(2). The beneficial effect of TMVr compared with GDMT alone was consistent in all echocardiographic subgroups, independent of the severity of LV dysfunction, LV dilatation, pulmonary hypertension, severity of tricuspid regurgitation, or individual mitral regurgitation characteristics. The LV ejection fraction decreased and the LV volumes progressively increased in both groups during follow-up, although less after TMVr (p < 0.05). CONCLUSIONS: HF patients in the COAPT trial with 3+ or 4+ secondary mitral regurgitation, selected using strict echocardiographic criteria, benefitted from TMVr with reduced 2-year rates of death and HF hospitalization. Strict application of these echocardiographic criteria should enable the COAPT results to be translated to clinical practice. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).

Ahmad, K. A., M. M. Bennett, S. E. Juul, R. K. Ohls, R. H. Clark and V. N. Tolia (2019). “Utilization of Erythropoietin within the United States Neonatal Intensive Care Units from 2008 to 2017.” Am J Perinatol Dec 13. [Epub ahead of print].

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OBJECTIVE: Little data are available regarding erythropoietin (Epo) utilization patterns within neonatal intensive care units (NICUs). We sought to describe the trends in Epo utilization across a large cohort of U.S. NICUs. STUDY DESIGN: This is a retrospective cohort study of infants discharged from 2008 to 2017 using the Pediatrix Clinical Data Warehouse. RESULTS: We identified 704,159 eligible infants from 358 sites, of whom 9,749 (1.4%) had Epo exposure. For extremely low gestational age newborns (ELGANs), Epo exposure ranged from 7.6 to 13.5%. We found significant site variability in Epo utilization in ELGANs. Among the 299 NICUs caring for ELGANs during the study period, 184 (61.5%) never used Epo for this population, whereas 21 (7%) utilized Epo in 50% or more of eligible infants. Epo was initiated at a median of 25 days in ELGANs. For infants with hypoxic-ischemic encephalopathy (HIE), Epo exposure remained