Research Spotlight

Packer, M. (2019). “Are healthcare systems now ready to adopt sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in chronic heart failure? The culmination of a 20-year journey.” Eur Heart J 40(40): 3353-3355.

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As one of the two principal investigators of the PARADIGM-HF trial, I was dismayed when obstacles were placed in the path of physicians who sought to prescribe neprilysin inhibition to patients with chronic heart failure. As a matter of personal choice, I have had no financial relationship with the manufacturer of sacubitril/valsartan (Novartis) since the publication of the primary papers, and I have not been involved in any efforts to market or give sponsored presentations on behalf of the drug. However, at the same time, I have been an ardent supporter of the findings of the trial, which represented my second chance (after the disappointment of the OVERTURE trial) to finally demonstrate that neprilysin inhibitors can meaningfully potentiate the survival benefits of conventional antagonists of the renin–angiotensin system in patients with heart failure. If the PIONEER-HF trial allows all cardiologists to embrace that conclusion, I am very pleased. If the biomarker data published in this issue are motivating to practitioners to increase their appropriate prescribing of sacubitril/valsartan, I am delighted to hear that. If physicians, healthcare systems, and the manufacturer are prepared to work collaboratively to facilitate affordable unrestricted access to a life-saving treatment for heart failure, I doubt that patients will complain. (Excerpt from text of this editorial, p. 3355; no abstract available. Refers to “Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.” New England Journal of Medicine 381(17): 1609-1620.)

Navia, J. L., H. Elgharably, A. H. Hakim, J. C. Witten, M. J. Haupt, E. Germano, P. L. Houghtaling, F. G. Bakaeen, G. B. Pettersson, B. W. Lytle, E. E. Roselli, A. M. Gillinov and L. G. Svensson (2019). “Long-term Outcomes of Surgery for Invasive Valvular Endocarditis Involving the Aortomitral Fibrosa.” Ann Thorac Surg 108(5): 1314-1323.

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BACKGROUND: Reconstruction of the intervalvular fibrosa (IVF) for invasive double-valve infective endocarditis (IE) is a technically challenging operation. This study presents the long-term outcomes of two surgical techniques for IVF reconstruction. METHODS: From 1988 to 2017, 138 patients with invasive double-valve IE underwent surgical reconstruction of the IVF, along with double-valve replacement (Commando procedure, n = 86) or aortic valve replacement with mitral valve repair (hemi-Commando procedure, n = 52). Mean follow-up was 41 +/- 5.9 months. RESULTS: Reoperation was required in 82% of patients, and 34% underwent emergency surgery. Pathologic features included positive blood cultures (90%), prosthetic valve IE (75%), aortic root abscess (78%), mitral annular abscess (24%), and intracardiac fistula (12%). There were 28 hospital deaths: 21 (24%) in the Commando group and 7 (14%) in the hemi-Commando group (P = .12). Overall survival at 1, 5, and 10 years was 67%, 48%, and 37%, respectively. Coronary artery disease, native valve IE, and causative organism (Staphylococcus aureus, coagulase-negative Staphylococcus, and viridans streptococci) were risk factors for late mortality. Freedom from reoperation at 1, 5, and 8 years was 87%, 74%, and 55%, respectively. Freedom from recurrent IE at 1, 5, and 8 years was 90%, 78%, and 67%, respectively. CONCLUSIONS: Although it is technically demanding, surgery for invasive IE involving IVF, which provides the only chance for cure, can be performed with reasonable clinical outcomes. In cases of IE invading the IVF and limited to the anterior mitral valve leaflet, a hemi-Commando procedure that includes mitral valve repair has improved early outcomes.

Meduri, C. U., M. J. Reardon, D. Scott Lim, E. Howard, G. Dunnington, D. P. Lee, D. Liang, R. Gooley, D. O’Hair, M. K. Ng, A. Walton, K. Spargias, D. Blackman, A. Coisne, D. Hildick-Smith, M. De Gouy, S. Chenoweth, S. Kar, P. M. McCarthy, N. Piazza, A. Qasam, R. P. Martin, M. B. Leon, M. J. Mack, D. H. Adams and V. Bapat (2019). “Novel Multiphase Assessment for Predicting Left Ventricular Outflow Tract Obstruction Before Transcatheter Mitral Valve Replacement.” JACC Cardiovasc Interv Oct 11. [Epub ahead of print].

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OBJECTIVES: This study proposes a physiologic assessment of left ventricular outflow tract obstruction (LVOTO) that accommodates changes in systolic flow and accounts for the dynamic neo-left ventricular outflow tract (LVOT). BACKGROUND: Patients considered for transcatheter mitral valve replacement trials often screen-fail because of the perceived risk of LVOTO. In the Intrepid Global Pilot Study, assumed risk of LVOTO was based on computed tomography estimates of the neo-LVOT area computed at end-systole. However, this may overestimate actual risk. METHODS: Retrospective analyses were performed for screen-failed patients for potential LVOTO (n = 33) and treated patients (n = 29) with available dynamic computed tomography. A multiphase assessment of the neo-LVOT area was performed and represented as: 1) multiphase average; and 2) early systolic value. Prospective evaluation was performed in 9 patients approved for enrollment with multiphase and early systole methods that would have previously screen-failed with the end-systolic approach. RESULTS: Of 166 patients screened for possible inclusion; 32 were screen-failed for nonanatomical reasons. Screen failure for assumed LVOTO risk occurred in 37 of 134 (27.6%) patients. Retrospective analysis indicated a potential enrollment increase of 11 of 33 (33.3%) and 18 of 33 (54.5%) patients using multiphase and early systolic assessment methods. In the prospective cohort, there were no clinical observations of LVOTO 30 days post-procedure, despite assumed risk based on end-systolic estimates. CONCLUSIONS: Multiphase, and specifically early systolic, assessment of the neo-LVOT may better determine risk of LVOTO with transcatheter mitral valve replacement compared with end-systolic estimates. This novel approach has the potential to significantly increase patient eligibility, with over one-half of patients previously screen-failed now eligible for treatment.

Meduri, C. U., D. J. Kereiakes, V. Rajagopal, R. R. Makkar, D. O’Hair, A. Linke, R. Waksman, V. Babliaros, R. C. Stoler, G. J. Mishkel, D. G. Rizik, V. S. Iyer, J. Schindler, D. J. Allocco, I. T. Meredith, T. E. Feldman and M. J. Reardon (2019). “Pacemaker Implantation and Dependency After Transcatheter Aortic Valve Replacement in the REPRISE III Trial.” J Am Heart Assoc Nov 5: 8(21). [Epub 2019 Oct 23].

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Background As transcatheter aortic valve replacement expands to younger and/or lower risk patients, the long-term consequences of permanent pacemaker implantation are a concern. Pacemaker dependency and impact have not been methodically assessed in transcatheter aortic valve replacement trials. We report the incidence and predictors of pacemaker implantation and pacemaker dependency after transcatheter aortic valve replacement with the Lotus valve. Methods and Results A total of 912 patients with high/extreme surgical risk and symptomatic aortic stenosis were randomized 2:1 (Lotus:CoreValve) in REPRISE III (The Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus Valve System-Randomized Clinical Evaluation) trial. Systematic assessment of pacemaker dependency was pre-specified in the trial design. Pacemaker implantation within 30 days was more frequent with Lotus than CoreValve. By multivariable analysis, predictors of pacemaker implantation included baseline right bundle branch block and depth of implantation; diabetes mellitus was also a predictor with Lotus. No association between new pacemaker implantation and clinical outcomes was found. Pacemaker dependency was dynamic (30 days: 43%; 1 year: 50%) and not consistent for individual patients over time. Predictors of pacemaker dependency at 30 days included baseline right bundle branch block, female sex, and depth of implantation. No differences in mortality or stroke were found between patients who were pacemaker dependent or not at 30 days. Rehospitalization was higher in patients who were not pacemaker dependent versus patients without a pacemaker or those who were dependent. Conclusions Pacemaker implantation was not associated with adverse clinical outcomes. Most patients with a new pacemaker at 30 days were not dependent at 1 year. Mortality and stroke were similar between patients with or without pacemaker dependency and patients without a pacemaker. Clinical Trial Registration Unique identifier NCT02202434.

McCullough, P. A., M. Ostermann, L. G. Forni, A. Bihorac, J. L. Koyner, L. S. Chawla, J. Shi, J. P. Kampf, P. McPherson and J. A. Kellum (2019). “Serial Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7 and the Prognosis for Acute Kidney Injury over the Course of Critical Illness.” Cardiorenal Med Oct 16: 1-12.[Epub ahead of print].

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INTRODUCTION: Over the course of critical illness, there is a risk of acute kidney injury (AKI), and when it occurs, it is associated with increased length of stay, morbidity, and mortality. The urinary cell-cycle arrest markers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) have been utilized to predict the risk of AKI over the next 12 h from the time of sampling. The aim of this analysis was to evaluate the utility of [TIMP-2] x [IGFBP7] measured serially to anticipate the occurrence of AKI over the first 7 days of critical illness. METHODS: This analysis is from a prospective, blinded, observational, international study of patients admitted to intensive care units. We designed the analysis to emulate a clinician-driven serial testing strategy. Urine samples collected every 12 h up to 3 days from 530 patients were considered for analysis. We evaluated [TIMP-2] x [IGFBP7] results for the first 3 measurements (baseline, 12 and 24 h) and continued to evaluate additional results if any of the first 3 were positive >0.3 (ng/mL)2/1,000. Patients were stratified by number of [TIMP-2] x [IGFBP7] results >0.3 (ng/mL)2/1,000 and number of results >2.0 (ng/mL)2/1,000. The primary endpoint was AKI stage 2-3 defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: The median (interquartile range) age was 64 (53-74) years, 61% were men, and 79% were Caucasian. The median APACHE III score was 71 (51-93), and 82% required mechanical ventilation. Baseline serum creatinine was 0.8 mg/dL and 164/530 (31%) developed the primary endpoint by day 7 with a median time from baseline to stage 2/3 AKI of 26 (8-56) h. In patients with negative values for the first 3 tests (2.0 (ng/mL)2/1,000), the cumulative incidence for the primary endpoint at 7 days was 57.7, 75.0, and 94.4%, respectively, p < 0.001 for trend. There were 3.4% with test results between 0.3 and 2.0 (ng/mL)2/1,000 at all measurements; one third of those patients developed the primary endpoint. We observed a graded increase in the primary endpoint in Kaplan-Meier plots for successively positive test results over time. CONCLUSION: Serial urinary [TIMP-2] x [IGFBP7] at baseline, 12 and 24 h, and up through 3 days are prognostic for the occurrence of stage 2/3 AKI over the course of critical illness. Three consecutive negative values (2.0 [ng/mL]2/1,000] predict very high incidence rates (up to 94.4%) of stage 2/3 AKI. There was a low rate of test results between 0.3 and 2.0 (ng/mL)2/1,000, where the primary endpoint was observed in a third of cases.