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Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial.

ABSTRACT: Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%-50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).

SUBMITTER: Anttila V

PROVIDER: S-EPMC7369517 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial.

Anttila Vesa V Saraste Antti A Knuuti Juhani J Jaakkola Pekka P Hedman Marja M Svedlund Sara S Lagerström-Fermér Maria M Kjaer Magnus M Jeppsson Anders A Gan Li-Ming LM

Molecular therapy. Methods & clinical development 20200601

Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A<sub>165</sub> mRNA formulated in biocompatible citrate-buffered saline and optimized for high-ef ...[more]

PMID: 32728595

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Project description:BackgroundThe intra aortic balloon pump (IABP) is a mechanical assist device which improves cardiac function. The device has a well-established place in algorithms for managing low cardiac output following cardiac surgery. There is increasing evidence that certain cardiac surgery patients benefit from a period of preoperative augmentation with the intra aortic balloon pump.ObjectivesTo determine the effect of the preoperative intra aortic balloon pump on mortality and morbidity in a number of different patients groups undergoing coronary artery bypass grafting.Search strategyThe Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 3, 2009), MEDLINE (2000 to August 2009), EMBASE (1998 to August 2009), BIOSIS previews (1969 to August 2009) and ISI Proceedings (1990 to August 2009) were searched. References and ongoing registers of studies were checked. No language restrictions were applied.Selection criteriaRandomised controlled trials (RCTs) of any size or length were included.Data collection and analysisPapers were assessed for inclusion by two authors independently and differences were settled by consensus with a third author. Date are presented in the form of odds ratios (OR) and 95% confidence intervals (CI).Main resultsSix trials were included (five on-pump and one off-pump). This update adds the results of one further trial. Data from a total of 255 patients were included in the meta-analysis of mortality outcomes; all on-pump. Generally, the patients were considered as "high risk" and 132 were treated preoperatively with IABP and 123 served as controls. There were four hospital deaths in the intervention arm and 23 in the non-intervention arm (OR 0.18, 95% CI 0.08 to 0.41; P<0.0001). In a subgroup analysis, low cardiac index (<2.0 L/min/m(2)) was noted in 21 out of 105 patients in the treatment arm and 59 patients out of 88 in the non-treatment arm (OR 0.14, 95% CI: 0.08 to 0.25; P<0.00001). An off-pump versus on-pump analysis was not possible due to the limited number of off-pump studies. However a single well-conducted RCT suggested favourable effect of the preoperative IABP in off-pump patients.Authors' conclusionsEvidence suggests that preoperative IABP may have a beneficial effect on mortality and morbidity in specific high risk patient groups undergoing coronary artery bypass grafting, however there are many problems with the quality, validity and generalisability of the trials. However, the available evidence is not robust enough to extend the use of IABP to truly elective, high risk patients. Defining more precisely which patient groups may benefit would be the challenge for the future.

Project description:BACKGROUND:Cardiac troponin T (cTnT) is elevated after coronary artery bypass grafting surgery. The aim of this study was to determine the association between cTnT elevations between 6 and 12 hours after coronary artery bypass grafting and in-hospital outcome. METHODS AND RESULTS:We prospectively studied 1722 patients undergoing isolated coronary artery bypass grafting. We assessed the association between conventional cTnT (749 patients) and high-sensitivity cTnT (hs-cTnT; 973 patients) 6 to 12 hours postoperatively with in-hospital major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause death, myocardial infarction, or stroke. The prespecified secondary outcome was a safety composite of MACCE, resuscitation, intensive care unit readmission or admission ?48 hours, inotrope or vasopressor use ?24 hours, or new-onset renal insufficiency. Among patients with a conventional cTnT measurement, 92 experienced a MACCE (12%) and 146 experienced a safety composite event (19%). Likewise, for hs-cTnT, 114 experienced a MACCE (12%) and 153 experienced a safety composite event (16%). Compared with cTnT ?200 ng/L, each 200-ng/L increment in cTnT was associated with a monotonous increase in the odds of MACCE and the safety composite outcome. Conventional and hs-cTnT demonstrated moderate discrimination for MACCE (areas under the fitted receiver operating characteristics curve, 0.72 and 0.77 for conventional and hs-cTnT, respectively) and the safety composite outcome (areas under the fitted receiver operating characteristics curve, 0.66 and 0.74 for conventional and hs-cTnT, respectively) and resulted in improved prognostic performance when added to the EuroSCORE. At a cutoff of 800 ng/L, conventional and hs-cTnT provided clinically relevant power to rule in MACCE and the safety composite outcome. CONCLUSIONS:cTnT levels assessed between 6 and 12 hours after coronary artery bypass grafting identify patients at increased risk of MACCE or other complications.

Dataset Information

Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial.

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Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial.

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