Sex-related differences in functional capacity and its implications in risk stratification before major non-cardiac surgery: a post hoc analysis of the international METS study

Background: Poor functional capacity has been identified as an important modifiable risk factor for postoperative complications. Cardiopulmonary exercise testing (CPET) provides objective parameters of functional capacity (e.g., oxygen consumption at peak exercise, peak VO₂), with significant prognostication for postoperative complications. However, sex-specific thresholds for functional capacity to predict surgical risk are yet to be established. Therefore, we performed a post hoc analysis of the international, multicentre, prospective observational METS (Measurement of Exercise Tolerance before Surgery) study to evaluate if sex-specific thresholds of peak VO₂ improve risk prediction of postoperative complications.

Methods: We undertook a post hoc analysis (HREC/71824/PMCC) of the METS study, which was performed between March 2013 and March 2016. We investigated whether sex-specific differences exist for CPET-derived parameters and associated thresholds for predicting postoperative complications in this large cohort of patients that had major non-cardiac surgery (n = 1266). Logistic regression models were analyzed for the association of low peak VO₂ with moderate-to-severe in-hospital postoperative complications. Optimal sex-specific peak VO₂ thresholds were obtained by maximizing the Youden index of receiver operating characteristic (ROC) curves. Finally, multivariable logistic regression models tested the resulting sex-specific thresholds against the established non-sex-specific peak VO₂ threshold (14 mL kg^-1 min^-1) adjusted for clinically relevant features such as comorbidities and surgical complexity. Models were evaluated by bootstrapping optimism-corrected area under the ROC curve and the net reclassification improvement index (NRI).

Findings: Female patients (n = 480) had a lower mean (SD) peak VO₂ than males (16.7 (4.9) mL kg^-1 min^-1 versus 21.2 (6.5) mL kg^-1 min^-1, p < 0.001) and a lower postoperative complication rate (10.4% versus 15.3%; p = 0.018) than males (n = 786). The optimal peak VO₂ threshold for predicting postoperative complications was 12.4 mL kg^-1 min^-1 for females and 22.3 mL kg^-1 min^-1 for males, respectively. In the multivariable regression model, low non-sex-specific peak VO₂ did not independently predict postoperative complications. In contrast, low sex-specific peak VO₂ was an independent predictor of postoperative complications (OR 2.29; 95% CI: 1.60, 3.30; p < 0.001). The optimism-corrected AUC-ROC of the sex-specific model was higher compared with the non-sex-specific model (0.73 versus 0.7; DeLong's test: p = 0.021). The sex-specific model classified 39% of the patients more correctly than the baseline model (NRI = 0.39; 95% CI: 0.24, 0.55). In contrast, the non-sex-specific model only classified 9% of the patients more correctly when compared against the baseline model (NRI = 0.09; 95% CI: -0.04, 0.22).

Interpretation: Our data report sex-specific differences in preoperative CPET-derived functional capacity parameters. Sex-specific peak VO₂ thresholds identify patients at increased risk for postoperative complications with a higher discriminatory ability than a sex-unspecific threshold. As such, sex-specific threshold values should be considered in preoperative CPET to potentially improve risk stratification and to guide surgical decision-making, including eligibility for surgery, preoperative optimization strategies (prehabilitation) or seeking non-surgical options.

Funding: There was no funding for the present study. The original METS study was funded by Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.