At the American Heart Association Scientific Sessions 2018, several trials were presented in the field of coronary revascularization with relevance to cardiac surgeons. Topics ranged from optimal revascularization among patients with multi-vessel coronary artery disease (CAD) and diabetes, open versus endoscopic vein harvest during coronary artery bypass grafting (CABG), aggressive anti-platelet therapy after CABG and the role of mesenchymal precursor cells in left ventricular assist device weaning. Below are brief summaries of these major trials:

FREEDOM

CABG remains the most commonly performed operation in cardiac surgery. Growing data support the utilization of heart teams to assist patients in navigating complex decisions on optimal therapy for coronary artery disease. One heavily studied population is patients with multi-vessel CAD and diabetes. In 2012, the FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial showed that CABG reduced all-cause mortality, myocardial infarction (MI) and stroke compared to percutaneous coronary intervention utilizing drug-eluding stents (PCI-DES) at a median follow-up of 3.8 years among patients with diabetes and multi-vessel CAD. While the trial had significant implications in demonstrating the comparative effectiveness of CABG versus PCI-DES in this specific population, questions remained regarding the long-term effectiveness of these revascularization strategies. In this follow-on trial of FREEDOM, which randomized 1,900 patients with diabetes and multi-vessel CAD to CABG versus PCI-DES, all-cause mortality was significant higher in the PCI-DES group at a mean follow-up of 7.5 years (HR 1.39, 95% CI 1.07-1.74).¹ In subgroup analysis, the survival advantage of CABG was particularly evident in younger patients. These results demonstrate that among patients with diabetes and multi-vessel CAD, CABG is superior to PCI in reducing all-cause mortality. With a growing prevalence of diabetes in the US, these results have significant implications in providing evidence to assist patients and heart teams in navigating complex decision-making in coronary revascularization. The FREEDOM follow-on trial supports current recommendations indicating CABG as the preferred treatment strategy for revascularization among patients with multi-vessel CAD and diabetes.

REGROUP

A second major trial in coronary revascularization presented at AHA 2018 was the REGROUP (Randomized Endo-Vein Graft Prospective) trial.² REGROUP randomized 1,150 patients to open versus endoscopic saphenous vein harvest during CABG. The trial was developed as a result of a 2009 sub-study of the PREVENT-IV (Prevention of Autogenous Vein Graft Failure in Coronary Artery Bypass Procedures) trial, which demonstrated reduced graft patency and survival at 18 months in endoscopic versus open saphenous vein harvest techniques. The primary endpoint of REGROUP, which was conducted in Department of Veterans Affairs medical centers, was major adverse cardiovascular events (MACE), defined as composite of death from any cause, nonfatal MI or repeat revascularization. Importantly, the trial required expertise in saphenous vein harvest, defined as >100 endoscopic vein harvest cases, <5% conversion rate, and >2 years of experience. At a median follow-up of 2.8 years, there was no significant difference among patients who underwent open versus endoscopic vein harvest with respect to MACE (HR 1.12; 95% CI 0.83 - 1.51) or any of the components of the composite endpoint. As expected, fewer leg wound adverse events were observed among endoscopic vein harvest patients. The study concluded that endoscopic vein harvest performed by an expert should be considered the preferred vein harvest modality in CABG.

TiCAB

A third major trial in coronary revascularization presented at AHA 2018 was the TiCAB (Study Comparing Ticagrelor With Aspirin for Prevention of Vascular Events in Patients Undergoing CABG) trial. Several retrospective studies have reported a potential benefit of more aggressive antiplatelet therapy after CABG to improve long-term graft patency. In TiCABG, 1,859 patients undergoing CABG were randomized to receive either aspirin monotherapy or ticagrelor post-operatively.³ The primary outcome of the study was a composite of cardiovascular death, MI, stroke or recurrent revascularization at one year. The authors discovered no difference in the primary endpoint (HR 1.19, 95% CI 0.87-1.62). There was also no difference in any of the events that made up the composite endpoint. Additionally, there was no difference in bleeding events between groups. The trial did have several limitations including lower than expected events rates, early termination of funding, and early termination of enrollment at the suggestion of the Data Safety Monitoring Board. The authors concluded that use of ticagrelor monotherapy instead of aspirin after CABG did not significantly influence the rate of major cardiovascular events or bleeding. These results are in concordance with the results of CASCADE (The CArdiovasCulAr Diabetes & Ethanol Trial), which similarly found no difference in vein graft patency at one year among patients receiving aspirin versus aspirin plus clopidogrel.

LVAD-MPC-II

A final major trial from AHA 2018, not in coronary revascularization but with significance to cardiac surgery and potentially ischemic cardiomyopathy management, was the LVAD MPC-II (Safety & Efficacy of Intramyocardial Injection of Mesenchymal Precursor Cells on Myocardial Function in LVAD Patients) trial. This innovative trial by the NHLBI-sponsored Cardiothoracic Surgical Trials Network examined whether immunomodulation by injection of intramyocardial mesenchymal precursor cells (MPCs) could augment cardiac recovery after left ventricular assist device (LVAD) placement. Previous data in a small sample of patients confirmed the safety and potential efficacy of this innovative treatment strategy.⁴ The primary endpoint of the trial was the proportion of successful temporary weans from full to minimal LVAD support out of three planned assessments at 2, 4 and 6 months after randomization. A total of 159 LVAD patients were randomized to receive MPCs or sham control treatment. The authors found no difference in the proportion of successful weans among patients who received MPCs versus those that did not (RR 1.08, 95% CI 0.83-1.41). Specifically, the average proportion of successful temporary weans was 61% in the MPC group and 58% in the control group. In subgroup analysis, the rate of successful weans favored ischemic heart failure patients (RR 1.55, 95% CI 1.01 - 2.36). Importantly, the authors did find that patients who received MPCs had lower rates of gastrointestinal bleeding, a significant post-operative complication after LVAD placement. The trial was limited by a high rate of pump thrombosis that lowered the number of evaluable wean attempts and a heterogenous study population of ischemic and non-ischemic heart failure patients who were receiving LVADs as either destination therapy or a bridge to transplant. Based on these data, future trials may focus specifically on ischemic heart failure patients and further examining the role of MPCs in lowering the risk of gastrointestinal bleeding.

AHA 2018 presented several major trials with relevance to cardiac surgeons. These trials highlight the continued, significant prevalence of coronary heart disease both nationally and internationally as well as several areas in coronary revascularization and ischemic cardiomyopathy that require ongoing investigation in future clinical trials.

References

1. Farkouh ME, Domanski M, Dangas GD, et al. Long-term survival following multivessel revascularization in patients with diabetes (FREEDOM Follow-On Study). J Am Coll Cardiol 2018. [Epub ahead of print]
2. Zenati MA, Bhatt DL, Bakaeen FG, et al. Randomized trial of endoscopic or open vein-graft harvesting for coronary-artery bypass. N Engl J Med 2018. [Epub ahead of print]
3. de Waha A, Sandner S, von Scheidt M, et al. A randomized, parallel group, double-blind study of ticagrelor compared with aspirin for prevention of vascular events in patients undergoing coronary artery bypass graft operation: rationale and design of the Ticagrelor in CABG (TiCAB) trial: an investigator-initiated trial. Am Heart J 2016;179:69-76.
4. Ascheim DD, Gelijns AC. Goldstein D, et al. Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices. Circulation 2014;129:2287-96.

Keywords: AHA Annual Scientific Sessions, AHA18, Saphenous Vein, Aspirin, Retrospective Studies, Blood Platelets, Heart-Assist Devices, Clinical Trials Data Monitoring Committees, Coronary Vessels, Random Allocation, Coronary Artery Bypass, Percutaneous Coronary Intervention, Myocardial Infarction, Adenosine, Coronary Disease, Diabetes Mellitus, Thrombosis, Stroke, Heart Failure, Decision Making, Immunomodulation, Cardiomyopathies, Stents

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