ABSTRACT Background Perioperative hyperoxia may be associated with increased long‐term mortality, whereas perioperative antioxidants may be associated with reduced long‐term mortality. This study aimed to determine if high perioperative inspiratory oxygen fraction (FiO 2 ) (0.80) compared with normal FiO 2 (0.30) would increase mortality, hospital admissions, and myocardial infarction (MI) within 1 year after surgery, and whether antioxidants compared with placebo would reduce this. Methods This was the preplanned 1‐year follow‐up of 600 patients with cardiovascular risk factors, scheduled for noncardiac surgery. They were randomized in a 2 × 2 factorial design to perioperative FiO 2 of 0.80 or 0.30 and to receive antioxidants (vitamin C and N‐acetylcysteine) or matching placebo. The primary 1‐year outcome was all‐cause mortality, and secondary 1‐year outcomes were one or more hospital admissions and MIs, respectively. All outcomes were assessed using medical records and analyzed with the Cox proportional hazards model. Results Follow‐up was completed for 594 patients (99%). Twenty‐five of 298 patients (8.4%) allocated to FiO 2 of 0.80 died within 1 year as compared with 17 out of 296 (5.7%) allocated to FiO 2 of 0.30, HR 1.46 (95% CI, 0.79–2.70), p = 0.23. A total of 260 patients had one or more hospital admissions (44%), and seven patients had MI (1.2%) with no significant difference when comparing FiO 2 of 0.80 with 0.30. Antioxidants had a HR of 0.98 (95% CI, 0.54–1.80), p = 0.96 for all‐cause mortality vs. placebo. The interaction between the FiO 2 and antioxidant administration was statistically significant ( p = 0.04) with fatalities overrepresented in patients given 80% oxygen and placebo. Conclusions Differences in all‐cause mortality, hospital admission, or MI were not statistically significant at 1‐year follow‐up for either oxygen fractions or antioxidant administration in patients undergoing major noncardiac surgery. Editorial Comment In this preplanned long‐term study of the VIXIE trial, no differences in total mortality, hospitalization, or myocardial infarction were found for oxygen fractions of 0.80 compared to 0.30 or antioxidant administration compared to placebo. Interestingly, the study showed a higher rate of fatalities with 80% oxygen which appeared only to be present in patients not given the antioxidant intervention, but this is hypothesis‐generating and needs to be further investigated in new clinical trials. Trial Registration: Clinicaltrials.gov identifier: NCT03494387
Loft et al. (Tue,) studied this question.