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Postprocedure bivalirudin infusion for primary percutaneous coronary intervention

We appreciate Chen and colleagues' thoughtful letter about our article, “Bivalirudin with post-procedure infusion versus heparin monotherapy for the prevention of stent thrombosis”. It is true that the current evidence is not robust regarding the efficiency and safety of the prolonged bivalirudin infusion after percutaneous coronary intervention (PCI). The only true randomized clinical trial (RCT) on this subject was the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial, in which the bivalirudin group was randomly assigned, at a 1:1 ratio, to receive either a post-PCI bivalirudin infusion or no post-PCI infusion. In that trial, the post-PCI bivalirudin infusion did not decrease the acute stent thrombosis (AST) risk in the overall post-PCI bivalirudin group compared to the no-infusion group. Unfortunately, the MATRIX investigators let the individual practitioners choose the bivalirudin dosages (high vs. low) for the post-PCI infusion, despite post hoc analysis from the European Ambulance Acute Coronary Syndrome Angiography Trial that suggested that only high-dose bivalirudin infusions decrease the risk of AST. Due to practitioner choice, the majority of the patients received low-dose bivalirudin infusions for the post-PCI infusion, which explains the lack of benefit. The MATRIX investigators pointed out this issue as one of their study limitations, and the post hoc subgroup analyses did suggest that continuing full-dose bivalirudin infusions after the procedure would significantly decrease the risk of AST. Similarly, a meta-analysis using data from the subgroup of RCTs showed that the increased risk of AST with bivalirudin can be mitigated by continuing full-dose bivalirudin infusions after the procedure. We do agree with Chen and colleagues that the best evidence in this field will be obtained by doing high-quality RCTs with enough power to show a difference for AST between post-procedure highdose bivalirudin infusions versus no infusion. However, in 2016, the Food and Drug Administration updated the bivalirudin package insert and began recommending high-dose bivalirudin infusions for 4 hr after primary PCI based on the current evidence. Similarly, the current guidelines do recommend up to 4 hr of full-dose bivalirudin infusions after primary PCI. Therefore, in contemporary practice, an RCT comparing postprocedure bivalirudin infusions versus no infusion may be difficult, both logistically and ethically, as AST is a catastrophic event. Conversely, in contemporary practice, more and more interventionists are using heparin monotherapy (without Glycoprotein IIb-IIIa inhibitors [GPI]) for primary PCI. In the most recent RCT trial on this topic (the VALIDATE-SWEDEHEART [Bivalirudin versus Heparin in STSegment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated according to Recommended Therapies Registry]), a trend toward lower AST risk was observed with a postprocedure infusion of bivalirudin compared to heparin monotherapy (without the routine use of GPI), which was confirmed in our meta-analysis. Thus, a RCT that compares heparin monotherapy with full-dose, postprocedure bivalirudin infusions during primary PCI may be a more pragmatic trial. The incidence of definite stent thrombosis was 0.5% in the heparin monotherapy group (without routine GPI use) and 0.2% in the bivalirudin group (with postprocedure infusion at full PCI does) in the MATRIX trial. Therefore, a trial will necessitate the inclusion of at least 6,082 patients in each study group to yield a power of 80% to detect a difference at a two-sided alpha level of .05.