Importance  Postoperative red blood cell transfusion guidelines recommend transfusion for hemoglobin levels less than 7 g/dL. However, the safety of this strategy in patients at high risk of cardiac events undergoing major operations remains unclear.

Objective  To evaluate the risk of death or major ischemic events within 90 days after a liberal transfusion strategy compared with a restrictive transfusion strategy in patients at high risk of cardiac events who had undergone major vascular or general surgery operations and developed postoperative anemia.

Design, Setting, and Participants  This parallel, single-blind, randomized clinical superiority trial included 1428 veterans (≥18 y) at high cardiac risk undergoing major vascular or general surgery operations. Participants were enrolled from February 2018 to March 2023 across 16 Veterans Affairs Medical Centers in the US.

Interventions  Seven hundred fourteen participants with postoperative hemoglobin less than 10 g/dL were randomized to a liberal strategy (transfusion trigger at hemoglobin level <10 g/dL) and 714 to a restrictive strategy (transfusion trigger at hemoglobin <7 g/dL).

Main Outcomes and Measures  The primary end point was a composite of all-cause death, myocardial infarction, coronary revascularization, acute kidney failure, or ischemic stroke within 90 days after randomization. Secondary end points included a composite of cardiac complications other than myocardial infarction (arrhythmias, heart failure, and nonfatal cardiac arrest).

Results  Of the 1424 analyzed veterans (mean age, 69.9 [SD, 7.9] years; 1393 male [97.8%]; 268 Black [18.8%]; 48 Hispanic [4.1%]; 1071 White [75.2%]), 1297 (91.1%) underwent vascular surgical procedures. The mean hemoglobin difference between transfusion strategies was 2.0 g/dL on day 5 after randomization. The primary outcome rate in the liberal group was 9.1% (61 of 670) compared with 10.1% (71 of 700) in the restrictive group (relative risk, 0.90; 95% CI, 0.65-1.24). The secondary end point of cardiac complications without myocardial infarction, which was 1 of 5 secondary end points, occurred in 5.9% (38 of 647) of patients in the liberal group and 9.9% (67 of 678) of patients in the restrictive group (relative risk, 0.59; 99% CI, 0.36-0.98).

Conclusions and relevance  After major vascular or general surgery operations among patients at high risk of a cardiac event, a liberal transfusion strategy did not reduce 90-day death or major ischemic outcome rates compared with a restrictive strategy.