Individual Patient Data Pooled Analysis of Randomized Trials of Bivalirudin versus Heparin in Acute Myocardial Infarction: Rationale and Methodology

Abstract

Background Individual randomized controlled trials (RCTs) of periprocedural anticoagulation with bivalirudin versus heparin during percutaneous coronary intervention (PCI) have reported conflicting results. Study-level meta-analyses lack granularity to adjust for confounders, explore heterogeneity, or identify subgroups that may particularly benefit or be harmed. Objective To overcome these limitations, we sought to develop an individual patient-data pooled database of RCTs comparing bivalirudin versus heparin. Methods We conducted a systematic review to identify RCTs in which ≥1,000 patients with acute myocardial infarction (AMI) undergoing PCI were randomized to bivalirudin versus heparin. Results From 738 identified studies, 8 RCTs met the prespecified criteria. The principal investigators of each study agreed to provide patient-level data. The data were pooled and checked for accuracy against trial publications, with discrepancies addressed by consulting with the trialists. Consensus-based definitions were created to resolve differing antithrombotic, procedural, and outcome definitions. The project required 3.5 years to complete, and the final database includes 27,409 patients (13,346 randomized to bivalirudin and 14,063 randomized to heparin). Conclusion We have created a large individual patient database of bivalirudin versus heparin RCTs in patients with AMI undergoing PCI. This endeavor may help identify the optimal periprocedural anticoagulation regimen for patient groups with different relative risks of adverse ischemic versus bleeding events, including those with ST-segment and non-ST-segment elevation MI, radial versus femoral access, use of a prolonged bivalirudin infusion or glycoprotein inhibitors, and others. Adherence to standardized techniques and rigorous validation processes should increase confidence in the accuracy and robustness of the results.

Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research

“…Parenteral anticoagulants such as bivalirudin, argatroban, and fondaparinux have been studied in management of patients with acute coronary syndromes, VTE, and heparin-induced thrombocytopenia. 47,48 However, these agents are more expensive than unfractionated heparin or LMWH, and there are limited data about their use in COVID-19.…”

Reperfusion After Fibrinolytic Therapy (RAFT): An open-label, multi-centre, randomised controlled trial of bivalirudin versus heparin in rescue percutaneous coronary intervention

“…Study-level meta-analyses have shown that in patients with STEMI undergoing primary PCI, periprocedural bivalirudin compared with heparin ± glycoprotein IIb/IIIa inhibitors reduces the risk of major bleeding, increases the risk of acute stent thrombosis, and in some studies, a short-term mortality benefit was observed [ 10 , 12 , 32 , 33 ]. Additionally, a recent individual patient-level meta-analysis echoed the latter findings and confirmed a reduced risk of death at 30 days for bivalirudin compared with heparin ± glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI [ 34 , 35 ]. However, individual randomised controlled trials have reported conflicting results reflecting the considerable heterogeneity between trials.…”

“…Subsequent trials used glycoprotein IIb/IIIa inhibitors selectively, with some reporting no bleeding reduction with bivalirudin [ 17 , 38 ], while in others, a reduction in major bleeding was observed irrespective of glycoprotein IIb/IIIa inhibitor use [ 18 , 21 , 39 ]. Considering the totality of the evidence, the bleeding advantage observed with bivalirudin is likely independent of planned glycoprotein IIb/IIIa inhibitor use in the heparin arm, as confirmed in a recent individual patient-level meta-analysis [ 34 , 35 ].…”

Antithrombotic Therapy in Acute Coronary Syndromes: Current Evidence and Ongoing Issues Regarding Early and Late Management

“…43,44 Of note, a large patient-level meta-analysis of eight RCTs comparing bivalirudin without systematic GPI to heparin (UFH or low-molecular-weight heparin) with or without systematic GPI and comprising 27,409 patients with STEMI or non-STEMI (NSTEMI) was recently presented. 45 This study found that in patients with STEMI undergoing PCI, use of bivalirudin was associated with a significant reduction of cardiac mortality (adjusted hazard ratio [aHR]: 0.72. 95% confidence interval [CI]: 0.57-0.91) and serious bleeding (aHR: 0.57, 95% CI: 0.47-0.68) at 30 days, albeit at the cost of increased risk of reinfarction (aHR: 1.29, 95% CI: 1.02-1.64) and stent thrombosis (aHR: 1.45, 95% CI: 1.05-1.91).…”