Research Spotlight

Packer, M. (2016). “Kicking the tyres of a heart failure trial: Physician response to the approval of sacubitril/valsartan in the USA.” Eur J Heart Fail: 2016 Aug [Epub ahead of print].

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Angiotensin receptor-neprilysin inhibition has been shown to be superior to target doses of an ACE inhibitor in reducing the risk of cardiovascular death and clinical disease progression in patients with chronic heart failure and a reduced EF. Nevertheless, although sacubitril/valsartan has been available in the USA for a year, uptake of the drug by practitioners has been slow, in part because of misconceptions about the pivotal trial that demonstrated its efficacy in heart failure (PARADIGM-HF). This review addresses questions that have been raised in the USA about the design of the trial as well as the patients who were studied, the replicability and applicability of the results, and the safety of neprilysin inhibition. The totality of evidence indicates that the PARADIGM-HF trial used an appropriate comparator; enrolled patients typical of those seen in the community with mild to moderate symptoms; yielded highly persuasive and replicable results; and demonstrated benefits that are applicable to patients taking subtarget doses of ACE inhibitors and ARBs. Regulatory review in the USA concluded that the established advantages of sacubitril/valsartan on cardiovascular death and disease progression outweighed hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug. Accordingly, both the new US and European Society of Cardiology heart failure guidelines recommend sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in patients with chronic heart failure who are currently receiving an ACE inhibitor or ARB.

Baber, U., M. E. Farkouh, Y. Arbel, P. Muntner, G. Dangas, M. J. Mack, T. H. Hamza, R. Mehran and V. Fuster (2016). “Comparative efficacy of coronary artery bypass surgery vs. Percutaneous coronary intervention in patients with diabetes and multivessel coronary artery disease with or without chronic kidney disease.” Eur Heart J: 2016 Aug [Epub ahead of print].

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BACKGROUND: The optimal method of coronary revascularization among patients with diabetes mellitus (DM) and multivessel coronary artery disease (CAD) complicated by chronic kidney disease (CKD) remains unknown. PURPOSE: To examine the impact of coronary artery bypass surgery (CABG) vs. percutaneous coronary intervention (PCI) on cardiovascular outcomes in patients with diabetes with and without CKD. METHODS: We conducted an ‘as-treated’ subgroup analysis of the FREEDOM trial to examine the therapeutic efficacy of CABG vs. PCI among patients with DM stratified by the presence (n = 451) or absence (n = 1392) of CKD. We defined CKD as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. Baseline characteristics and clinical outcomes were compared between PCI and CABG groups within each CKD stratum. The primary endpoint was the composite occurrence of all-cause death, stroke or myocardial infarction [major adverse cardiovascular and cerebrovascular events (MACCE)]. Event rates were estimated at 5 years using the Kaplan-Meier approach and hazard ratios (HRs) for CABG (vs. PCI) were generated using Cox regression. RESULTS: Patients with CKD (mean eGFR 47 mL/min/1.73m2) were older and more often female compared to those without renal impairment. Over a median follow-up of 3.8 years, the effect of CABG on MACCE was consistent among those with CKD (26.0% vs. 35.6%; HR [95% CI]: 0.73 [0.50-1.05]) and without CKD (16.2% vs. 23.6%; HR [95% CI)]: 0.76 [0.58-1.00]) with no evidence of interaction (pint = 0.83). Stroke rates were non-significantly higher with CABG whereas rates of MI and repeat revascularization were significantly reduced with CABG in both groups. CONCLUSIONS: Compared to PCI, the effects of CABG on long-term risks for MACCE observed in the FREEDOM trial are preserved among patients with mild to moderate CKD.

McCullough, P. A., E. Bennett-Guerrero, L. S. Chawla, T. Beaver, R. L. Mehta, B. A. Molitoris, A. Eldred, G. Ball, H. J. Lee, M. T. Houser and S. Khan (2016). “Abt-719 for the prevention of acute kidney injury in patients undergoing high-risk cardiac surgery: A randomized phase 2b clinical trial.” J Am Heart Assoc 5(8): 1-11.

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BACKGROUND: Patients undergoing cardiac surgeries with cardiopulmonary bypass (on-pump) have a high risk for acute kidney injury (AKI). We tested ABT-719, a novel alpha-melanocyte-stimulating hormone analog, for prevention of AKI in postoperative cardiac surgery patients. METHODS AND RESULTS: This phase 2b randomized, double-blind, placebo-controlled trial included adult patients with stable renal function undergoing high-risk on-pump cardiac surgery in the United States and Denmark. Participants received placebo (n=61) or cumulative ABT-719 doses of 800 (n=59), 1600 (n=61), or 2100 mug/kg (n=59). Primary outcome was development of AKI based on Acute Kidney Injury Network (AKIN) criteria, measured utilizing preoperative creatinine value and maximum value within 48 hours and urine output within the first 42 hours postsurgery. Secondary outcomes included incidence of AKI based on maximal changes from baseline in novel AKI biomarkers over a 72-hour period after clamp release and length of intensive care unit stays through 90 days postsurgery. A total of 65.5%, 62.7%, and 69.6% of patients in the 800-, 1600-, and 2100-mug/kg groups, respectively, developed AKI (stages 1, 2, and 3 combined) versus 65.5% in the placebo group (for each pair-wise comparison with placebo, P=0.966, 0.815, and 0.605, respectively). Adverse events occurred at a similar rate in all treatment groups. CONCLUSIONS: ABT-719 treatment did not lower AKI incidence using AKIN criteria, influence the elevations of novel biomarkers, or change 90-day outcomes in patients after cardiac surgery.

Kevelam, S. H., M. E. Steenweg, S. Srivastava, G. Helman, S. Naidu, R. Schiffmann, S. Blaser, A. Vanderver, N. I. Wolf and M. S. van der Knaap (2016). “Update on leukodystrophies: A historical perspective and adapted definition.” Neuropediatrics: 2016 Aug [Epub ahead of print].

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Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

Arsalan, M., E. Agricola, O. Alfieri, S. Baldus, A. Colombo, G. Filardo, C. Hammerstingl, M. Huntgeburth, F. Kreidel, K. H. Kuck, G. LaCanna, D. Messika-Zeitoun, F. Maisano, G. Nickenig, B. D. Pollock, B. J. Roberts, A. Vahanian and P. A. Grayburn (2016). “Effect of transcatheter mitral annuloplasty with the cardioband device on 3-dimensional geometry of the mitral annulus.” Am J Cardiol 118(5): 744-749.

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This study was performed to assess the acute intraprocedural effects of transcatheter direct mitral annuloplasty using the Cardioband device on 3-dimensional (3D) anatomy of the mitral annulus. Of 45 patients with functional mitral regurgitation (MR) enrolled in a single arm, multicenter, prospective trial, 22 had complete pre- and post-implant 3D transesophageal echocardiography (TEE) images stored in native data format that allowed off-line 3D reconstruction. Images with the highest volume rate and best image quality were selected for analysis. Multiple measurements of annular geometry were compared from baseline to post-implant using paired t tests with Bonferroni correction to account for multiple comparisons. The device was successfully implanted in all patients, and MR was reduced to moderate in 2 patients, mild in 17 patients, and trace in 3 patients after final device cinching. Compared with preprocedural TEE, postprocedural TEE showed statistically significantly reductions in annular circumference (137 +/- 15 vs 128 +/- 17 mm; p = 0.042), intercommissural distance (42.4 +/- 4.3 vs 38.6 +/- 4.4 mm; p = 0.029), anteroposterior distance (40.0 +/- 5.4 vs 37.0 +/- 5.7 mm; p = 0.025), and aortic-mitral angle (117 +/- 8 degrees vs 112 +/- 8 degrees ; p = 0.032). This study demonstrates that transcatheter direct mitral annuloplasty with the Cardioband device results in acute remodeling of the mitral annulus with successful reduction of functional MR.