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- Cummings, J., et al.
(author)
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Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial
- 2021
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 83:4, s. 1703-1715
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Journal article (peer-reviewed)abstract
- Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer's disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic "readers" that may distort normal gene expression and contribute to chronic disorders. Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score >= 26 (normal performance), MoCA score 25-22 (mild cognitive impairment), and MoCA score <= 21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of <= 21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.
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- Gaipov, Abduzhappar, et al.
(author)
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Acute kidney injury following coronary revascularization procedures in patients with advanced CKD.
- 2019
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In: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 34:11, s. 1894-1901
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Journal article (peer-reviewed)abstract
- Background: Previous studies reported that compared with percutaneous coronary interventions (PCIs), coronary artery bypass grafting (CABG) is associated with a reduced risk of mortality and repeat revascularization in patients with mild to moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). Information about outcomes associated with CABG versus PCI in patients with advanced stages of CKD is limited. We evaluated the incidence and relative risk of acute kidney injury (AKI) associated with CABG versus PCI in patients with advanced CKD.Methods: We examined 730 US veterans with incident ESRD who underwent a first CABG or PCI up to 5 years prior to dialysis initiation. The association of CABG versus PCI with AKI was examined in multivariable adjusted logistic regression analyses.Results: A total of 466 patients underwent CABG and 264 patients underwent PCI. The mean age was 64 ± 8 years, 99% were male, 20% were African American and 84% were diabetic. The incidence of AKI in the CABG versus PCI group was 67% versus 31%, respectively (P < 0.001). The incidence of all stages of AKI were higher after CABG compared with PCI. CABG was associated with a 4.5-fold higher crude risk of AKI {odds ratio [OR] 4.53 [95% confidence interval (CI) 3.28-6.27]; P < 0.001}, which remained significant after multivariable adjustments [OR 3.50 (95% CI 2.03-6.02); P < 0.001].Conclusion: CABG was associated with a 4.5-fold higher risk of AKI compared with PCI in patients with advanced CKD. Despite other benefits of CABG over PCI, the extremely high risk of AKI associated with CABG should be considered in this vulnerable population when deciding on the optimal revascularization strategy.
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- Gaipov, Abduzhappar, et al.
(author)
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Predialysis coronary revascularization and postdialysis mortality
- 2019
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In: Journal of Thoracic and Cardiovascular Surgery. - : MOSBY-ELSEVIER. - 0022-5223 .- 1097-685X. ; 157:3, s. 976-
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Journal article (peer-reviewed)abstract
- Objectives: Coronary artery bypass grafting (CABG) is associated with better survival than percutaneous coronary intervention (PCI) in patients with mild-to-moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, the optimal strategy for coronary artery revascularization in patients with advanced CKD who transition to ESRD is unclear. Methods: We examined a contemporary national cohort of 971 US veterans with incident ESRD who underwent first CABG or PCI up to 5 years before dialysis initiation. We examined the association of a history of CABG versus PCI with all-cause mortality following transition to dialysis using Cox proportional hazards models adjusted for time between procedure and dialysis initiation, sociodemographics, comorbidities, and medications. Results: In total, 582 patients underwent CABG and 389 patients underwent PCI. The mean age was 64 +/- 8 years, 99% of patients were male, 79% were white, 19% were African American, and 84% had diabetes. The all-cause post-dialysis mortality rates after CABG and PCI were 229 per 1000 patient-years (95% confidence interval [CI], 205-256) and 311 per 1000 patient years (95% CI, 272-356), respectively. Compared with PCI, patients who underwent CABG had 34% lower risk of death (multivariable adjusted hazard ratio, 0.66; 95% CI, 0.51-0.86, P = .002) after initiation of dialysis. Results were similar in all subgroups of patients stratified by age, race, type of intervention, presence/absence of myocardial infarction, congestive heart failure, and diabetes. Conclusions: CABG in patients with advanced CKD was associated lower risk of death after initiation of dialysis compared with PCI.
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- Kulikowski, E, et al.
(author)
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Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease
- 2018
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In: Kidney & blood pressure research. - : S. Karger AG. - 1423-0143 .- 1420-4096. ; 43:2, s. 449-457
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Journal article (peer-reviewed)abstract
- <b><i>Background/Aims:</i></b> The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. <b><i>Methods:</i></b> A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m<sup>2</sup>, who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. <b><i>Results:</i></b> Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m<sup>2</sup>) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m<sup>2</sup>) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. <b><i>Conclusion</i></b>: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients. This is being examined in the phase III trial BETonMACE.
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