Research Spotlight

Hughes, D. A., K. Nicholls, S. P. Shankar, G. Sunder-Plassmann, D. Koeller, K. Nedd, G. Vockley, T. Hamazaki, R. Lachmann, T. Ohashi, I. Olivotto, N. Sakai, P. Deegan, D. Dimmock, F. Eyskens, D. P. Germain, O. Goker-Alpan, E. Hachulla, A. Jovanovic, C. M. Lourenco, I. Narita, M. Thomas, W. R. Wilcox, D. G. Bichet, R. Schiffmann, E. Ludington, C. Viereck, J. Kirk, J. Yu, F. Johnson, P. Boudes, E. R. Benjamin, D. J. Lockhart, C. Barlow, N. Skuban, J. P. Castelli, J. Barth and U. Feldt-Rasmussen (2016). “Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in fabry disease: 18-month results from the randomised phase iii attract study.” J Med Genet: 2016 Nov [Epub ahead of print].

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BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in alpha-galactosidase (alpha-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of alpha-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of alpha-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.

McCullough, P. A., T. Ball, K. M. Cox and M. D. Assar (2016). “Use of oral anticoagulation in the management of atrial fibrillation in patients with esrd: Pro.” Clin J Am Soc Nephrol 11(11): 2079-2084.

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Warfarin has had a thin margin of benefit over risk for the prevention of stroke and systemic embolism in patients with ESRD because of higher bleeding risks and complications of therapy. The successful use of warfarin has been dependent on the selection of patients with nonvalvular atrial fibrillation at relatively high risk of stroke and systemic embolism and lower risks of bleeding over the course of therapy. Without such selection strategies, broad use of warfarin has not proven to be beneficial to the broad population of patients with ESRD and nonvalvular atrial fibrillation. In a recent meta-analysis of use of warfarin in patients with nonvalvular atrial fibrillation and ESRD, warfarin had no effect on the risks of stroke (hazard ratio, 1.12; 95% confidence interval, 0.69 to 1.82; P=0.65) or mortality (hazard ratio, 0.96; 95% confidence interval, 0.81 to 1.13; P=0.60) but was associated with increased risk of major bleeding (hazard ratio, 1.30; 95% confidence interval, 1.08 to 1.56; P<0.01). In pivotal trials, novel oral anticoagulants were generally at least equal to warfarin for efficacy and safety in nonvalvular atrial fibrillation and mild to moderate renal impairment. Clinical data for ESRD are limited, because pivotal trials excluded such patients. Given the very high risk of stroke and systemic embolism and the early evidence of acceptable safety profiles of novel oral anticoagulants, we think that patients with ESRD should be considered for treatment with chronic anticoagulation provided that there is an acceptable bleeding profile. Apixaban is currently indicated in ESRD for this application and may be preferable to warfarin given the body of evidence for warfarin and its difficulty of use and attendant adverse events.

Packer, M., R. Holcomb, W. T. Abraham, S. Anker, K. Dickstein, G. Filippatos, H. Krum, A. P. Maggioni, J. J. McMurray, A. Mebazaa, C. O’Connor, F. Peacock, P. Ponikowski, F. Ruschitzka, D. J. van Veldhuisen and J. Holzmeister (2016). “Rationale for and design of the true-ahf trial: The effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure.” Eur J Heart Fail: 2016 Nov [Epub ahead of print].

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The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure.

Arsalan, M., G. Filardo, W. K. Kim, J. J. Squiers, B. Pollock, C. Liebetrau, J. Blumenstein, J. Kempfert, A. Van Linden, A. Arsalan-Werner, C. Hamm, M. J. Mack, H. Moellmann and T. Walther (2016). “Prognostic value of body mass index and body surface area on clinical outcomes after transcatheter aortic valve implantation.” Clin Res Cardiol 105(12): 1042-1048.

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BACKGROUND: Inverse associations between Body Mass Index (BMI) and Body Surface Area (BSA) with mortality in patients after Transcatheter Aortic Valve Implantation (TAVI) have been reported. This “obesity paradox” is controversial, and it remains unclear which parameter, BMI or BSA, is of greater prognostic value. The aim of this study was to investigate the association of BMI and BSA on short- and mid-term outcomes after TAVI. METHODS AND RESULTS: This prospective, observational study consisted of 917 consecutive patients undergoing TAVI at our center from 2011 to 2014. The association between BMI/BSA and mortality (at 30 days and 1 year) was assessed using restricted cubic spline functions in propensity-adjusted (by Society of Thoracic Surgeons (STS) risk factors) logistic and Cox proportional models, respectively. The median age of the patients was 82.6 years, with a mean STS Predicted Risk of Mortality (STS-PROM) of 6.6 +/- 4.3 %. Throughout the study period (mean follow-up time was 297 days), 150 (16.4 %) patients died; 72 (7.9 %) patients died within 30 days of TAVI. After risk adjustment, the association between body constitution and 30-day mortality was not significant for either measure (BMI p = 0.25; BSA p = 0.32). However, BMI (p = 0.01), but not BSA (p = 0.13), was significantly associated with 1-year survival. There was no association between stroke, vascular complications, or length of stay with BMI or BSA. CONCLUSIONS: BMI was associated with survival at 1-year after TAVI. Despite the trend towards implementing BSA in risk score calculation, BMI may be more suitable for the assessment of TAVI patients.

Aiken, T., A. Garber, D. Thomas, N. Hamon, R. Lopez, R. Konjeti, A. McCullough, N. Zein, J. Fung, M. Askar and B. V. John (2016). “Donor ifnl4 genotype is associated with early post-transplant fibrosis in recipients with hepatitis c.” PLoS One 11(11).

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BACKGROUND AND AIMS: Early post-transplant hepatic fibrosis is associated with poor outcomes and may be influenced by donor/recipient genetic factors. The rs368234815 IFNL4 polymorphism is related to the previously described IL28B polymorphism, which predicts etiology-independent hepatic fibrosis. The aim of this study was to identify the impact of donor and/or recipient IFNL4 genotype on early fibrosis among patients transplanted for hepatitis C (HCV). METHODS: Clinical data were collected for 302 consecutive patients transplanted for HCV. 116 patients who had available liver biopsies and donor/recipient DNA were included. 28% of these patients with stage 2 fibrosis or greater were compared to patients without significant post-transplant fibrosis with respect to clinical features as well as donor/recipient IFNL4 genotype. RESULTS: The IFNL4 TT/TT genotype was found in 26.0% of recipients and 38.6% of donors. Patients who developed early post-transplant fibrosis had a 3.45 adjusted odds of having donor IFNL4 TT/TT genotype (p = 0.012). Donor IFNL4 TT/TT genotype also predicted decreased overall survival compared to non-TT/TT genotypes (p = 0.016). CONCLUSIONS: Donor IFNL4 TT/TT genotype, a favorable predictor of spontaneous HCV clearance pre-transplant, is associated with increased early post-transplant fibrosis and decreased survival.