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Apabetalone and Hospitalization for Heart Failure in Patients Following an Acute Coronary Syndrome: a Prespecifed Analysis of the Betonmace Study Stephen J

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Apabetalone and Hospitalization for Heart Failure in Patients Following an Acute Coronary Syndrome: a Prespecifed Analysis of the Betonmace Study Stephen J Nicholls et al. Cardiovasc Diabetol (2021) 20:13 https://doi.org/10.1186/s12933-020-01199-x Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecifed analysis of the BETonMACE study Stephen J. Nicholls1*, Gregory G. Schwartz2, Kevin A. Buhr3, Henry N. Ginsberg4, Jan O. Johansson5, Kamyar Kalantar‑Zadeh6, Ewelina Kulikowski5, Peter P. Toth7,8, Norman Wong5, Michael Sweeney5 and Kausik K. Ray9 on behalf of the BETonMACE Investigators Abstract Background: Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra‑terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable efects on pathways related to myocardial struc‑ ture and function and therefore could impact subsequent heart failure events. The efect of apabetalone on heart failure events after an ACS is not currently known. Methods: The phase 3 BETonMACE trial was a double‑blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecifed secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied. Results: Patients (age 62 years, 74.4% males, 90% high‑intensity statin use, LDL‑C 70.3 mg/dL, HDL‑C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal fnding of a lower rate of frst hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38–0.94], P 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27–0.83], P 0.01) and the combination= of cardiovascu‑ lar death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI =0.53–0.98], P 0.04). = Conclusion: Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to defne the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS. Keywords: BET inhibitors, Acute coronary syndrome, Diabetes, Heart failure, Clinical trial, Cardiovascular disease, Epigenetics, Atherosclerosis Introduction Despite current evidence-based treatment, patients with diabetes and acute coronary syndromes (ACS) have a *Correspondence: [email protected] high risk of experiencing subsequent cardiovascular 1 Monash Cardiovascular Research Centre, Monash University, 246 Clayton events, including those related to congestive heart failure Road, Clayton, VIC 3168, Australia [1]. Observational studies have reported that congestive Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea‑ tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo‑ main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Nicholls et al. Cardiovasc Diabetol (2021) 20:13 Page 2 of 9 heart failure develops in up to 25% of patients who have Statistical analysis experienced an ACS within the preceding 12 months, Baseline characteristics were summarized as percent- particularly among those with diabetes [2, 3]. Te clinical ages for dichotomous data and means (SDs) for approx- signifcance of this complication is evidenced by frequent imately normal or medians (IQRs) for non-normal hospitalizations, increased mortality and a substantial continuous data. Hypothesis test for change in bio- increase in the use of health care resources [4–6]. As a chemical parameters used ANCOVA models with base- result, a therapy that reduces the development of heart line biomarker value, statin, and country as covariates; failure after ACS would have considerable health and results were summarized using least-squares means health economic benefts. with 95% confdence intervals. For non-normal data, a Development of heart failure after an ACS may result Wilcoxon test was used with results summarized using from ischemic myocardial injury, and also may refect a Hodges–Lehmann pseudo-median and 95% boot- longer term progression of underlying coronary athero- strap confdence intervals. Te time-to-event analyses sclerosis and/or diabetic cardiomyopathy [2]. Patients used log-rank tests to calculate P-values and Cox pro- with diabetes comprise about one third of cases of ACS portional hazards model to estimate the hazard ratio globally and have an elevated risk of heart failure, with (HR) with 95% confdence interval (CI) and to test for or without concurrent coronary disease [7]. Accordingly, treatment-subgroup interactions. Tese analyses were there is an unmet need for new therapies that may be ini- stratifed by statin and country. Kaplan–Meier curves tiated following an ACS to prevent heart failure compli- were also produced. Overall type 1 error control was cations in diabetic patients. provided by a sequential gate-keeping procedure that Apabetalone is a selective inhibitor of bromodomain included testing of the primary end point followed by and extra-terminal (BET) proteins. Preclinical studies key secondary time-to-event end points. Analyses were have implicated BET proteins in the regulation of infam- performed with SAS software, versions 9.2 or higher mation, calcifcation, thrombosis, and lipid and lipopro- (SAS Institute), and R software, version 3.5.1 or higher tein metabolism, all of which participate in atherogenesis (R Foundation for Statistical Computing). P-values less [8–12]. Each of these pathways have been shown to be than 0.05 were considered statistically signifcant. modulated by apabetalone [13–21]. In addition, apabetal- one may attenuate the development of cardiac hyper- trophy [22] and cardiac fbrosis [23]. A recent Phase 3 Results clinical trial in patients with type 2 diabetes and recent Clinical characteristics and medication use ACS demonstrated a trend towards fewer ischemic car- Te clinical characteristics of patients are summarized diovascular events with apabetalone, compared with in Table 1. Groups were well balanced by randomiza- placebo [24]. Te impact of apabetalone on hospitaliza- tion. Te median age was 62 years and the majority of tion for heart failure, however, has not been evaluated in patients were male. Te index ACS event was myocar- detail. dial infarction in 75% of patients and unstable angina in 25%. Nearly four in fve patients underwent percutaneous Methods coronary intervention for the index ACS, prior to rand- Study design omization. All patients had a diagnosis of type 2 diabetes Te principal results of the BETonMACE study have and most had additional risk factors such as hypertension been described previously [25]. Eligible patients were at and dyslipidemia. Fifteen percent of patients had a prior least 18 years of age, had an ACS within the preceding clinical history of heart failure, before the index ACS. Te 7–90 days, low HDL cholesterol levels, and a diagnosis median time from presentation with ACS to randomiza- of type 2 diabetes. Concomitant treatment with high- tion was 38 days in both treatment groups. intensity statin therapy, defned as either atorvastatin Concomitant medication use is summarized in Table 1. 40–80 mg or rosuvastatin 20–40 mg daily, was required. Established cardioprotective therapies for ACS were Eligible patients were randomized to treatment with apa- widely used in both groups, including high-intensity betalone 100 mg twice daily or matching placebo. Te statin and dual anti-platelet therapy, beta-blockers and trial continued until a blinded clinical events committee inhibitors of the renin–angiotensin–aldosterone sys- determined that at least 250 primary events (cardiovas- tem. Te average duration of diabetes was 8.5 years. cular death, non-fatal myocardial infarction or non-fatal Te majority of patients were treated with metformin stroke) had occurred. Additional prespecifed endpoints and more than one third with insulin. Te use of anti- measured in the trial included hospitalization for heart diabetic agents demonstrated to have cardiovascular failure, including both the frst and all subsequent events beneft (SGLT2 inhibitors, GLP1 receptor agonists) was for each patient. relatively low, consistent with reports of slow uptake of Nicholls et al. Cardiovasc Diabetol (2021) 20:13 Page 3 of 9 Table 1 Baseline patient characteristics and medication use Characteristic Placebo (N 1206) Apabetalone = (N 1212) = Age (years)a 62
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