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Parenteral anticoagulation is essential during percutaneous coronary intervention (PCI) to decrease the risk of periprocedural thrombotic complications. However, the risk of bleeding complications may overshadow its established benefit,1 and risk stratification can be challenging.2,3 This caveat may be true especially in the context of “enrichment factors” for bleeding such as the use of femoral vascular access and potent antiplatelet therapies.4 In the joint guidelines for myocardial revascularization from the EuropeanSocietyof Cardiologyand the European Association for Cardio-Thoracic Surgery, published in 2018, unfractionated heparin is recognized as the reference standard for periprocedural anticoagulation (class I), and a few alternatives with a lower class of recommendation are suggested, including enoxaparin and bivalirudin.5 Bivalirudin displays several potential pharmacodynamic and pharmacokinetic advantages over heparins.6 Nevertheless, in recent years, its use has been largely resized in magnitude. Several reasons may contribute to this tendency, particularly in countries where the use of bivalirudin was more prevalent.7 First, the perception of a bleeding advantage with bivalirudin has become relatively less important in the context of increasing use of radial vascular access and avoidance of upstream infusion of glycoprotein IIb/IIIa inhibitors (GPI).8,9 Second, recent trials and meta-analyses conducted in patients with acute coronary syndromes (ACS) have questioned thesafetyofbivalirudin in lightof theobserved increase in acute stent thrombosis comparedwith heparin.10,11 Indeed, putting the results of bivalirudin trials into perspective is puzzling due to their inherent differences in design, inclusion criteria, methods, and controls.7 With respect to the latter, in particular, major confounding derives from the disparate proportions of GPI used in the heparin arms across the years. Prior investigations comparing bivalirudinwith a combination of heparin and GPI did not allow a clear understanding of the relative merits of bivalirudin compared with heparin, which in turn are best captured bymore contemporary investigations.12 Study-level meta-analyses have attempted over the years to make the best out of bivalirudin data.11,13,14 However, the best that such meta-analyses can actually do to explore sources of inconsistency across trials is to analyze subgroups, runsensitivityanalyses, orundertakemeta-regressions. Therefore, to get more insights into the true merits of bivalirudin and heparin, pooling of patient-level data is required, which enables more sophisticated efforts including identification of independent predictors and examining the temporal relationship between treatments and outcomes. In this issue of Thrombosis and Haemostasis, Bikdeli and colleagues15 publish the protocol of an ongoing attempt to bring the bivalirudin controversy at rest and dissipate current gaps in knowledge bymeans of a definitive patient-level meta-analysis. The authors scrutinized the available literature in search of randomized clinical trials comparing bivalirudin-based and heparin-based regimens in patients with acute myocardial infarction, and contacted the original investigators as contributors. Patients were pooled if PCI was attempted (i.e., using a “modified intention-to-treat” approach), which however introduces some distortion in the randomization scheme and the need for correcting potential new confounders by covariate adjustment. Patients were considered only in the trial arms where GPI were used as a bailout measure in the bivalirudin group and at any time in the heparin group. In addition, the investigators restricted the search to studies enrolling at least 1,000 subjects, in an attempt to decrease the number of smaller investigations using disparate definitions of clinical endpoints. Indeed, only outcomes measures of ischemia and thrombotic complications with acceptably similar definitions were considered, and mortality was elected as the primary efficacy endpoint due to its univocal definition. On the other hand, bleeding definitions were potentially less consistent, which led the authors to electively use prognostically equivalent information from either or both Thrombolysis in Myocardial

Pooling the Evidence at the Patient Level: End of the Bivalirudin Saga?