Mr. Santana is a 67 year old man who presented to the emergency room with chest pain and was found to have ST-elevation myocardial infarction. He was taken to the cardiac catheterization lab for emergent coronary reperfusion. Which anti-thrombotic therapy should the interventional cardiologist use? What factors determine this choice?
Atherosclerotic plaque rupture leads to acute MI. Ruptured plaques are highly thrombotic and accordingly revascularization strategies have focused on reducing and preventing thrombus formation. The use of potent anti-thrombotic therapy during revascularization reduces the risk of future ischemic events but they increase the risk of bleeding. Conflicting evidence exists in regards to which anti-thrombotic therapy to use. If unfractionated heparin, an indirect thrombin inhibitor is used, GPIIb/IIIa inhibitors can be used provisionally by the cardiologist depending on certain clinical factors. When bivalirudin, a direct thrombin inhibitor is used for reperfusion, GPIIb/IIIa inhibitors are generally not used.
In this week’s issue of NEJM, Valgimigli and colleagues present their findings from the MATRIX trial. They asked the question whether the use of bivalirudin during percutaneous coronary intervention in individuals with acute MI is superior to unfractionated heparin, with or without the concomitant use of a glycoprotein IIb/IIIa inhibitor.
In this multi-centered randomized open-label study design, just over 7200 individuals with acute MI were randomized to receive either bivalirudin or unfractionated heparin. The co-primary outcomes were 30-day major adverse cardiovascular events (MACE) or net adverse clinical events (NACE). MACE was defined as the composite of all-cause mortality, myocardial infarction, or stroke. NACE was the composite of non-CABG-related major bleeding (intracranial bleeding or overt bleeding with hemoglobin drop of 3-5 g/dL) or major adverse cardiovascular events.
Bivalirudin, as compared to heparin, did not reduce the rates of 30-day major adverse cardiovascular events (10.3% versus 10.9%; P=0.44) or 30-day net adverse clinical events (11.2% versus 12.4%; P=0.12). However, all-cause mortality (1.7% versus 2.3%; P=0.041) and cardiovascular deaths (1.6% versus 2.3%; P=0.038) were significantly lower with bivalirudin than with heparin. Major bleeding events were also lower with bivalirudin as compared to heparin (1.4% versus 2.5%; P<0.001).
From this study we learn that the two anti-thrombotic regimes used during percutaneous coronary intervention appear to be similar in terms of 30-day composite outcomes. However, the all-cause mortality, cardiovascular deaths, and major bleeding were lower with bivalirudin use than with heparin. Though as noted, in the accompanying editorial by Peter Berger from North Shore Long Island Jewish Healthcare System, “the investigators analyzed dozens of end points, so it is to be expected that at least one end point would be positive by chance. The authors did not correct for multiple comparisons, which makes the finding with respect to mortality less convincing”. The difference with respect to major bleeding is more substantial and more convincing, but is influenced by both the clinically determined rate of use of glycoprotein IIb/IIIa inhibitors and the dose of heparin used. Without glycoprotein IIb/IIIa inhibitors, or with lower doses of heparin, the rates of bleeding might not have differed.
Another issue addressed in the trial is the fact that previous studies (N Engl J Med 2013; 369:2207-2217) have found an increased risk of acute stent thrombosis with the use of bivalirudin. In the MATRIX trial, patients treated with bivalirudin underwent a second randomization to either have bivalirudin stopped at the end of the intervention or to receive additional post-procedure bivalirudin. The investigators had hoped that additional bivalirudin infusion could reduce the risk of acute stent thrombosis. In this study, stent thrombosis occurred more frequently with bivalirudin than with heparin, and those patients given a prolonged course of bivalirudin did not have the hoped-for reduction in stent thrombosis.
In the MATRIX trial, bivalirudin did not reduce the risk of major adverse cardiovascular events compared to unfractionated heparin. Bivalirudin did reduce bleeding compared to the alternate regimen as used in this trial. John Jarcho, a NEJM deputy editor, notes that “clinicians will need to make a judgment, based on the specifics of their own practice, as to which regimen is more suitable for their patients.”