Can BRIGHT Restore the Glow of Bivalirudin

Bivalirudin, a direct thrombin inhibitor, has been studied as an alternative to heparin for patients undergoing percutaneous coronary intervention (PCI) with stable coronary artery disease,1,2 non–ST-segment elevationacutecoronary syndrome (NSTE-ACS),3,4 and ST-elevation myocardial infarction (STEMI).5,6 These studies found that bivalirudin reducedmajor bleedingwhen comparedwith regimens of heparinplusglycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors.However, many of these trials also found small numerical increases in ischemic events with bivalirudin and increases in acute stent thrombosis, particularly in patients with STEMI.5,6 Over time, the need for routine Gp IIb/IIIa inhibitors for PCI has become less clear. Two trials found that Gp IIb/IIIa inhibitor use to treat NSTE-ACS increased the risk of bleeding without reducing ischemicevents.7,8 P2Y12 antagonists that result inpotent antiplatelet effectshavealsodecreased theneed for additional antiplatelet medications. Thus, practice has shifted and current guidelines recommend thatGp IIb/IIIa inhibitors be reserved as “bailout therapy” for thrombotic complications.9 As a result, there has been a need to readdress the efficacy of bivalirudinwhen comparedwith heparin, such as by studies inwhichGp IIb/IIIa inhibitors areused only on a provisional basis in both treatment groups. The Unfractionated Heparin Versus Bivalirudin in PrimaryPercutaneousCoronary Intervention (HEAT-PPCI) trial,10 performed at a single center in the United Kingdom, randomized 1812 patients with STEMI to receive bivalirudin or heparin.Glycoprotein IIb/IIIa inhibitorswereused infrequentlywith bivalirudin (13%) and heparin (15%). Contrary to prior trials, therewas no difference in bleeding and bivalirudin increased the composite end point of death, stroke, reinfarction, or unplanned target lesion revascularization (8.7% vs 5.7%; relative risk [RR], 1.52; 95% CI, 1.09-2.13; P=.01) and stent thrombosis (3.4% vs 0.9%; RR, 3.91; 95% CI, 1.61-9.52; P=.001). In this issue of JAMA, Han and colleagues11 report the results of the Bivalirudin in Acute Myocardial Infarction vs Heparin and GPI Plus Heparin Trial (BRIGHT), which is the latest clinical trial studying bivalirudin in patients undergoing PCI. The trial was performed in 82 centers in China and randomized 2194 patients with acute MI undergoing PCI into 1 of 2 open-label treatment groups: bivalirudin and provisional Gp IIb/IIIa inhibitors (n=735), heparin and provisional Gp IIb/IIIa inhibitors (n= 729), or heparin and routine Gp IIb/IIIa inhibitors (n=730). The primary end point was a net adverse clinical end point (a composite of death, reinfarction, ischemia-driven revascularization, stroke, or any bleeding event). Patients treatedwithbivalirudinandprovisionalGpIIb/IIIa inhibitors had lower rates of this net composite end point (65 events, 8.8%) than thepatients treatedwitheitherheparinand provisional Gp IIb/IIIa inhibitors (96 events, 13.2%) or heparin and routine Gp IIb/IIIa inhibitor (124 events, 17.0%). The difference between the groups was almost entirely driven by the difference in the any-bleeding category. There was a statistically significant reduction in bleeding at 30 days, but the time-to-eventcurves forbleedingappear toshowthat theseparation in the bivalirudin–provisional Gp IIb/IIIa inhibitor and heparin–provisionalGpIIb/IIIa inhibitorgroupsoccurredsometime around day 10. There were no differences in ischemic events, including stent thrombosis. At first glance, the discordant results of the HEAT-PPCI and BRIGHT trials are somewhat difficult to reconcile. However, these trials have fundamental differences that may explain the difference in results without challenging the validity of either trial. For instance, the trials were performed in countries with different patients, health care systems, and methods of health care, all of which can influence clinical outcomes.12 The studies enrolled different populations—HEAT-PPCI only randomized patients with STEMI undergoing primary PCI (median time from to randomization to symptom onset 2.8 hours) and BRIGHT randomized patients with both STEMI (median time from symptom onset to hospital arrival 6.1 hours) and NSTE-ACS undergoing emergency PCI (of which the largest proportion were STEMI). In addition, there are important differences in the trials with regards to the anticoagulant treatment. In the HEAT-PPCI trial, anticoagulation was started before patients arrived at the catheterization laboratory, whereas in BRIGHT patients did not receive anticoagulation until after arrival into the catheterization lab at which time randomization occurred. The doses of heparin to which bivalirudin and provisional Gp IIb/IIIa inhibitors were compared and the management of bivalirudin following PCI also differed. Finally, the majority of patients in HEAT-PPCI received novel platelet P2Y12 inhibitors, whereas these agents were not available in BRIGHT. TheBRIGHT trial reportedbyHanandcolleagues is an important contribution that raises further questions including what is theoptimal doseofheparin.Despite longstandinguse, the best dose and degree of anticoagulation during PCI remains unclear. Current guidelines support an initial dose of heparin between 70 U/kg (dose used by HEAT-PPCI) and 100 U/kg (dose used in the BRIGHT). As the degree of anticoagulation increases, the risk of bleeding does as well. Is there an optimal dose or is the risk:benefit ratio so variable for each individual that it cannot be determined? Related article page 1336 Opinion