Evidence regarding the comparative efficacy of the different modalities to determine the significance of coronary stenoses in the catheterization laboratory is lacking. We aimed to compare all available modalities guiding the decision to perform percutaneous coronary intervention (PCI). We searched Medline, Embase, and CENTRAL until October 5, 2023. We included trials that randomized patients with greater than 30% stenoses undergoing potential PCI and reported major adverse cardiovascular events (MACE). We performed a frequentist random-effects network meta-analysis and assessed the certainty of evidence using the GRADE approach. We included 15 trials with 16,333 participants with a mean weighted follow-up of 34 months. The trials contained a median of 49.3% (IQR 32.6%, 100%) acute coronary syndrome (ACS) participants. Quantitative flow ratio (QFR) was associated with a decreased risk of MACE compared to coronary angiography (CA) (Risk ratio (RR) 0.68, 95% Confidence Interval (CI) 0.56, 0.82; high certainty), fractional flow reserve (FFR) (RR 0.73, 95%CI 0.58, 0.92; moderate certainty), and instantaneous wave-free ratio (iFR) (RR 0.63, 95%CI 0.49, 0.82; moderate certainty), and ranked first for MACE (88.1% probability of being the best). FFR (RR 0.93; 95%CI 0.82, 1.06; moderate certainty) and iFR (RR 1.07, 95%CI 0.90, 1.28; moderate certainty) likely did not decrease the risk of MACE compared to CA. Intravascular imaging (IVI) may not be associated with a significant decrease in MACE compared to CA (RR 0.85; 95%CI 0.62, 1.17; low certainty) when used to guide the decision to perform PCI. In conclusion, a decision to perform PCI based on QFR was associated with a decreased risk of MACE compared to CA, FFR and iFR in a mixed stable coronary disease and ACS population. These hypothesis-generating findings should be validated in large, randomized, head-to-head trials.