Objective Recent randomized control trials (RCTs) showed conflicting efficacy and safety between bivalirudin and heparin during percutaneous coronary intervention (PCI). We aimed to perform an updated meta-analysis, including real-world and trial data to examine the factors affecting their risk–benefit ratio. Methods We searched Medline, the Cochrane library, and meeting abstracts for studies comparing bivalirudin versus heparin during PCI. Random-effect meta-analyses for MACE (major adverse cardiovascular events), stent thrombosis (ST) and major bleeding were performed. p-Value < 0.05 was considered statistically significant. Results Meta-analysis of 20 RCTs and 31 observation studies (n = 165,835) showed that bivalirudin and heparin were similar in the risk of MACE in RCTs (OR 1.05, 95% CI 0.97–1.13) and observational studies (OR 0.94, 95% 0.81–1.10). Major bleeding was lower with bivalirudin in both RCTs (OR 0.60, 95% CI 0.51–0.70) and observational studies (OR 0.56, 95% CI 0.47–0.68). However, in the metaregression analysis, every 10% increase of transradial access decreased the bleeding benefit of bivalirudin by 4.9% (p = 0.046, adjusted for GPI and heparin loading dose). ST with bivalirudin was higher with ST-segment elevation myocardial infarction (STEMI) in RCTs (OR 1.51, 95% CI 1.15–1.99) but not in observational studies (p = 0.65). Conclusions In this large meta-analysis, bivalirudin is associated with a lower risk of bleeding compared to heparin in both RCTs and observational studies, however, transradial PCI mitigated most of this bleeding benefit. Heparin should be the preferred agent in transradial PCI given its lower cost and comparable outcomes.