Dataset Information

Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.

ABSTRACT:

Importance

Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes.

Objective

To test whether apabetalone significantly reduces major adverse cardiovascular events.

Design, setting, and participants

A randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019.

Interventions

Patients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care.

Main outcomes and measures

The primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke.

Results

Among 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]).

Conclusions and relevance

Among patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events.

Trial registration

ClinicalTrials.gov Identifier: NCT02586155.

SUBMITTER: Ray KK

PROVIDER: S-EPMC7101505 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.

Ray Kausik K KK Nicholls Stephen J SJ Buhr Kevin A KA Ginsberg Henry N HN Johansson Jan O JO Kalantar-Zadeh Kamyar K Kulikowski Ewelina E Toth Peter P PP Wong Norman N Sweeney Michael M Schwartz Gregory G GG

JAMA 20200401 16

<h4>Importance</h4>Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes.<h4>Objective</h4>To test whether apabetalone significantly reduces major adverse cardiovascular events.<h4>Design, setting, and ...[more]

PMID: 32219359

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Project description:Background and objectivesCKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.Design, setting, participants, & measurementsBETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m2 at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure.ResultsMedian follow-up was 27 months (interquartile range, 20-32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure-related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure-related hospitalization. Interaction of CKD on treatment effect was P=0.03 for major adverse cardiovascular events, and P=0.12 for heart failure-related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; P=0.02) in the apabetalone group.ConclusionsApabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease.

Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is common among patients with type 2 diabetes mellitus (T2DM) and is associated with increased risk for coronary atherosclerosis and acute cardiovascular (CV) events. We employed the validated, non-invasive Angulo NAFLD fibrosis score (FS) in an intervention study in patients with T2DM and recent acute coronary syndrome (ACS) to determine the association of FS with CV risk and treatment response to apabetalone. Apabetalone is a novel selective inhibitor of the second bromodomain of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression.MethodsThe Phase 3 BETonMACE trial compared apabetalone with placebo in 2,425 patients with T2DM and recent ACS. In this post hoc analysis, we evaluated the impact of apabetalone therapy on CV risk, defined as a composite of major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction [MI], or stroke) and hospitalization for heart failure (HHF) in two patient categories of FS that reflect the likelihood of underlying NAFLD. Patients were initially classified into three mutually exclusive categories according to a baseline Angulo FS <-1.455 (F0-F2), -1.455 to 0.675 (indeterminant), and >0.675 (F3-F4), where F0 through F4 connote fibrosis severity none, mild, moderate, severe, and cirrhosis, respectively. The composite of ischemic MACE and HHF in the placebo group was higher in indeterminant and F3-F4 categories compared to the F0-F2 category (17.2% vs 15.0% vs 9.7%). Therefore, for the present analysis, the former two categories were combined into an elevated NAFLD CVD risk group (FS+) that was compared with the F0-F2 group (lower NAFLD risk, FS0-2).ResultsIn 73.7% of patients, FS was elevated and consistent with a moderate-to-high likelihood of advanced liver fibrosis (FS+); 26.3% of patients had a lower FS (FS0-2). In the placebo group, FS+ patients had a higher incidence of ischemic MACE and HHF (15.4%) than FS0-2 patients (9.7%). In FS+ patients, addition of apabetalone to standard of care treatment lowered the rate of ischemic MACE compared with placebo (HR = 0.79; 95% CI 0.60-1.05; p=0.10), HHF (HR = 0.53; 95% CI 0.33-0.86; p=0.01), and the composite of ischemic MACE and HHF (HR = 0.76; 95% CI 0.59-0.98; p=0.03). In contrast, there was no apparent benefit of apabetalone in FS0-2 patients (HR 1.24; 95% CI 0.75-2.07; p=0.40; HR 1.12; 95% CI 0.30-4.14; p=0.87; and HR 1.13; 95% CI 0.69-1.86; p=0.62, respectively). Over a median duration of 26.5 months, FS increased from baseline in both treatment groups, but the increase was smaller in patients assigned to apabetalone than to placebo (p=0.04).ConclusionsAmongst patients with T2DM, recent ACS, and a moderate-to-high likelihood of advanced liver fibrosis, apabetalone was associated with a significantly lower rate of ischemic MACE and HHF and attenuated the increase in hepatic FS over time.

Project description:Background & aimsHepatic steatosis has been associated with increased risk of major adverse cardiovascular events (MACE) but it is not clear whether steatosis is independently associated with risk of MACE. We investigated whether steatosis is associated with risk of MACE independently of the presence and extent of baseline coronary artery disease, assessed by comprehensive contrast-enhanced computed tomography angiography (CTA).MethodsWe conducted a nested cohort study of 3756 subjects (mean age, 60.6 years; 48.4% men) who underwent coronary CTA at 193 sites in North America, from July 2010 through September 2013, as part of the PROMISE study, which included noninvasive cardiovascular analyses of symptomatic outpatients without coronary artery disease. Independent core laboratory readers measured hepatic and splenic attenuation, using non-contrast computed tomography images to identify steatosis, and evaluated coronary plaques and stenosis in coronary CTA images. We collected data on participants' cardiovascular risk factors, presence of metabolic syndrome, and body mass index. The primary endpoint was an adjudicated composite of MACE (death, myocardial infarction, or unstable angina) during a median follow-up time of 25 months.ResultsAmong the 959 subjects who had steatosis (25.5% of the cohort), 42 had MACE (4.4%), whereas among the 2797 subjects without steatosis, 73 had MACE (2.6%) (hazard ratio [HR] for MACE in subjects with steatosis, 1.69; 95% CI, 1.16-2.48; P = .006 for MACE in subjects with vs without steatosis). This association remained after adjustment for atherosclerotic cardiovascular disease risk scores, significant stenosis, and metabolic syndrome (adjusted HR, 1.72; 95% CI, 1.16-2.54; P = .007) or obesity (adjusted HR, 1.75; 95% CI, 1.19-2.59; P = .005). Steatosis remained independently associated with MACE after adjustment for all CTA measures of plaques and stenosis.ConclusionsHepatic steatosis is associated with MACE independently of other cardiovascular risk factors or extent of coronary artery disease. Strategies to reduce steatosis might reduce risk of MACE. ClinicalTrials.gov no: NCT01174550.

Project description:BackgroundThe number of models developed for predicting major adverse cardiovascular events (MACE) in patients undergoing percutaneous coronary intervention (PCI) is increasing, but the performance of these models is unknown. The purpose of this systematic review is to evaluate, describe, and compare existing models and analyze the factors that can predict outcomes.MethodsWe adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 during the execution of this review. Databases including Embase, PubMed, The Cochrane Library, Web of Science, CNKI, Wanfang Data, VIP, and SINOMED were comprehensively searched for identifying studies published from 1977 to 19 May 2023. Model development studies specifically designed for assessing the occurrence of MACE after PCI with or without external validation were included. Bias and transparency were evaluated by the Prediction Model Risk Of Bias Assessment Tool (PROBAST) and Transparent Reporting of a multivariate Individual Prognosis Or Diagnosis (TRIPOD) statement. The key findings were narratively summarized and presented in tables.ResultsA total of 5,234 articles were retrieved, and after thorough screening, 23 studies that met the predefined inclusion criteria were ultimately included. The models were mainly constructed using data from individuals diagnosed with ST-segment elevation myocardial infarction (STEMI). The discrimination of the models, as measured by the area under the curve (AUC) or C-index, varied between 0.638 and 0.96. The commonly used predictor variables include LVEF, age, Killip classification, diabetes, and various others. All models were determined to have a high risk of bias, and their adherence to the TRIPOD items was reported to be over 60%.ConclusionThe existing models show some predictive ability, but all have a high risk of bias due to methodological shortcomings. This suggests that investigators should follow guidelines to develop high-quality models for better clinical service and dissemination.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=400835, Identifier CRD42023400835.

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Dataset Information

Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.

Similar Datasets

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