By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCE: Valgimigli M, et al. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med 2015;373:997-1009.
In patients requiring percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS), determining an optimal anticoagulation strategy has been an elusive goal. Maximizing anti-ischemic efficacy while minimizing bleeding risk is still the ultimate measure of success. Despite the prior publication of 14 clinical trials (and the requisite meta-analysis) comparing bivalirudin to unfractionated heparin in support of PCI, no clear winner has emerged, and several important questions have remained unanswered.
The MATRIX trial, recently presented at the ESC conference and published concurrently in The New England Journal of Medicine, was a large multicenter European study that was designed to address three essential issues. The portion of the trial comparing outcomes between transfemoral and transradial access has been previously presented and published. Foremost in the current iteration was the question of whether bivalirudin is superior to heparin with discretionary glycoprotein (GP) IIb/IIIa use in terms of ischemic outcomes and bleeding risk. Several trials have suggested that bivalirudin poses an additional hazard in terms of early stent thrombosis risk, and prolonged post-PCI infusion of bivalirudin has been posited as a potential solution to this problem. The MATRIX trial, therefore, sought to test the efficacy of this practice.
MATRIX analyzed 7213 patients with ACS at 78 centers in Europe. Of these, 55.6% presented with ST segment elevation myocardial infarction (STEMI), while 44.4% were non-ST segment elevation myocardial infarction (NSTEMI), and more than 94% of the total underwent percutaneous coronary intervention (PCI). Patients were randomly assigned to receive either bivalirudin or unfractionated heparin. Interestingly, GP IIb/IIIa inhibitors could be administered at the start of the procedure to any patient in the unfractionated heparin group at the discretion of the operator, but was only to be given in the bivalirudin group as part of a bailout strategy for ischemic complications after PCI. This direction resulted in a large difference in GP inhibitor use between groups — 25.9% of patients in the heparin group, compared with 4.6% in the bivalirudin group. Among patients receiving bivalirudin, patients were assigned 1:1 to either stop the infusion at the end of the procedure or to continue the infusion for several hours afterward in accordance with the manufacturer’s directions.
Patients were evaluated at 30 days for the co-primary outcomes — major adverse cardiovascular events (MACE), which was a composite of all-cause death, myocardial infarction, or stroke, and net adverse clinical events, which encompassed MACE plus major bleeding. At 30 days, MACE occurred in 10.3% of patients in the bivalirudin group, and 10.9% of the heparin group (P = 0.44). Net adverse clinical events were also not significantly different, at 11.2% and 12.4% (P = 0.12). However, analysis of the pre-specified secondary outcomes did show some differences. Rates of major bleeding were significantly lower among bivalirudin patients (1.4% vs 2.5%, P < 0.001), and this translated into lower rates of all-cause death and cardiovascular death (1.7% vs 2.3%, and 1.5% vs 2.2%, respectively). On the other hand, prior observations of higher definite stent thrombosis with bivalirudin were confirmed (1% in the bivalirudin group vs 0.6% in the heparin group, P = 0.048). Analysis of the data comparing duration of bivalirudin infusion showed no difference in the primary outcomes with prolonged infusion. Disappointingly, definite stent thrombosis was not lower in the prolonged infusion group. The authors concluded that among patients with ACS referred for percutaneous intervention, bivalirudin did not lower rates of MACE or net adverse clinical outcomes as compared with unfractionated heparin. In addition, the use of prolonged infusions of bivalirudin did not significantly alter the outcomes, including rates of bleeding and stent thrombosis.
COMMENTARY
The bivalirudin story in acute coronary syndromes in many ways started with two pivotal trials — ACUITY in NSTEACS patients and HORIZONS-AMI in a STEMI population. Both trials are at least partially built on the premise that unfractionated heparin alone is inferior to heparin plus a GP IIb/IIIa inhibitor for supporting PCI in ACS patients. This position by nature prioritizes ischemic over bleeding complications, and preceded much of the more-recent recognition of the morbidity and mortality associated with pathologic bleeding. Therefore, the major comparisons in these trials were between bivalirudin and heparin + GP IIb/IIIa. Put simply, bivalirudin monotherapy was non-inferior to the combination of heparin plus GP inhibitors for ischemic outcomes, and superior with respect to bleeding. HORIZONS in particular reported a benefit in terms of mortality, while also showing a small-but-significant increase in early stent thrombosis with bivalirudin. The message of these studies was upended last year with the presentation of the HEAT-PPCI trial, which compared heparin with bivalirudin in a large single-center study of STEMI patients. HEAT, which used GP IIb/IIIa inhibitors in a similar-but-low percentage of both heparin and bivalirudin cases, ascribed an advantage to heparin in terms of MACE and stent thrombosis, and showed no significant difference in major bleeding.
Does the MATRIX study act as a “tiebreaker” to parse the conflicting results of prior studies? MATRIX does present the clearest direction regarding prolonged post-PCI infusion of bivalirudin, where no advantage was seen. Even here, however, the failure of the trial to mandate a consistent post-PCI infusion regimen (participants were able to choose one of two quite different dosing schedules that are described on the product label) creates uncertainty that even this question has been answered with finality.
MATRIX was designed to be a pragmatic real-world study, and therefore left the decision about GP inhibitor use up to the operator, at least in heparin-treated patients. This resulted in a large disparity in use of these adjunctive agents between the heparin and bivalirudin groups. In the current environment of aggressive P2Y12 inhibitor use and declining GP inhibitor penetration (GP IIb/IIIa inhibitor use was approximately 15% in each group in the more real-world HEAT study, for example), the disproportionate use of GP inhibitors in the heparin group is one of several confounders of this study, clouding both the bleeding and ischemia outcomes. The mortality advantage ascribed to bivalirudin is an interesting point. The authors analyzed dozens of endpoints, and the lack of correction for multiple comparisons means that this finding is hypothesis-generating, but not conclusive. For now, bivalirudin without a prolonged post-procedure infusion remains a viable alternative to unfractionated heparin for the support of PCI in ACS patients, but cannot claim an advantage with respect to a composite of adverse clinical events.
