Abstract Background The optimal chronic oral antispastic medication after coronary artery bypass grafting (CABG) using radial artery (RA) grafts is controversial. Purpose This pilot trial aimed to preliminarily compare the efficacy and safety of nicorandil, isosorbide mononitrate, or diltiazem in patients who underwent CABG using RA grafts. Methods This was a single-center, randomized, open-label, parallel-group pilot trial. Eligible patients who underwent CABG using RA grafts within 3 days were randomized in a 1:1:1 ratio to receive oral doses of nicorandil (15 mg daily), isosorbide mononitrate (50 mg daily), or diltiazem (180 mg daily) for 24 weeks post-CABG. The primary outcomes were RA grafts failure (defined as modified FitzGibbon Grade B, S, or O) at 1- and 24-weeks, assessed by coronary computed tomography angiography (CCTA). The secondary outcomes include major adverse cardiovascular event (MACE, a composite of all-cause death, myocardial infarction, stroke, and unplanned revascularization) and angina recurrence. Results Among 150 randomized participants, 149 patients (full analysis set, mean age 56.8 years, 13.4% females, 83.9% with acute coronary syndrome, 49.7% with diabetes) with 177 RA grafts completed at least once CCTA assessment, including 50 patients with 64 RA grafts in the nicorandil group, 50 patients with 57 RA grafts in the isosorbide mononitrate group, and 49 patients with 56 RA grafts in the diltiazem group, respectively. (Figure 1). At 1-week post-CABG, the RA graft failure rates were numerically lower with nicorandil vs. diltiazem (19.4% vs. 25.0%, difference: -5.6% [95% CI -20.6% to 9.3%]; P = 0.49) and isosorbide mononitrate vs. diltiazem (18.2% vs. 25.0%, difference: -6.8% [95% CI -21.8% to 8.6%]; P =0.41). Nicorandil vs. isosorbide mononitrate showed similar rates (19.4% vs 18.2%, difference: 1.2% [95% CI −13.3% to 15.2%]; P =0.88). At 24 weeks, a numerically trend indicating a larger reduction in RA graft failure rates between nicorandil vs. diltiazem (16.1% vs 27.8%, difference: -11.7% [95% CI -26.6% to 3.4%]; P =0.17), and isosorbide mononitrate vs. diltiazem (12.5% vs 27.8%, difference: -15.3% [95% CI -29.8% to -0.2%]; P =0.06). Nicorandil vs. isosorbide mononitrate remained similar (16.1% vs 12.5%, difference: 3.6% [95% CI -9.6% to 16.4%]; P =0.59). Per-protocol set analysis results were consistent with full analysis set analysis (Table 1). During the follow-up, 6 patients with MACEs and 7 with angina recurrence were observed (MACE: 2 in nicorandil, 2 in isosorbide mononitrate, and 2 in diltiazem; angina recurrence: 1, 3, and 3 in the respective groups). Conclusions In this underpowered pilot trial, treatment with nicorandil or isosorbide mononitrate showed a numerically considerable but not statistically significant benefit on RA grafts outcome compared to diltiazem up to 24-week post-CABG. Larger hypothesis testing trial is warranted.Figure 1:The study flow diagramFigure 2:Primary outcomes in FAS and PP