MATRIX Antithrombin: Bivalirudin Fails to Reduce Net Adverse Events vs Heparin in ACS Patients Undergoing PCI

LONDON, England—In ACS patients receiving PCI, bivalirudin reduces major bleeding and mortality but not net adverse clinical events (NACE) vs heparin, according to results presented September 1, 2015, at the European Society of Cardiology Congress and simultaneously published in the New England Journal of Medicine. In addition, a prolonged infusion appears to have no impact on either stent thrombosis or bleeding.

Take Home: MATRIX Antithrombin: Bivalirudin Fails to Reduce Net Adverse Events vs Heparin in ACS Patients Undergoing PCI

“Our results reinforce the concept that reducing the rate of major bleeding events among patients with acute coronary syndromes who are treated with PCI does not necessarily affect the risk of major ischemic adverse cardiovascular events,” write Marco Valgimigli, MD, PhD, of Erasmus Medical Center (Rotterdam, the Netherlands), and colleagues.

Full results of the MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial—published in the Lancet in March—showed both that radial vs femoral access improves outcomes in ACS patients and that bivalirudin (Angiomax; The Medicines Company) does not improve composite outcomes compared with unfractionated heparin, despite apparent beneficial effects on mortality and major bleeding.

For MATRIX Antithrombin, the investigators randomized 7,213 patients with STEMI (55.6%) or NSTE-ACS (44.4%) slated for PCI between October 2011 and November 2014 to receive either bivalirudin (n = 3,610; 0.75 mg/Kg plus 1.75 mg/Kg infusion per hour) or unfractionated heparin (n = 3,603; 70-100 units/Kg; 50-70 units/Kg for those given glycoprotein IIb/IIIa inhibitiors [GPIs]). After PCI, those in the bivalirudin group were randomized to receive (n = 1,799) or not receive (n = 1,811) an additional infusion of bivalirudin (full dose for up to 4 hours or 0.25 mg/Kg per hour for up to 6 hours).

Overall, 95.3% and 96.4% of the patients in the bivalirudin and heparin groups, respectively, underwent PCI. One-quarter of patients in the heparin arm and 4.6% of those in the bivalirudin arm received GPIs.

At 30 days, there were no differences in rates of MACE (all-cause death, MI, or stroke) or NACE (non-CABG-related major bleeding and MACE) between the study arms. Bivalirudin was associated with lower all-cause and cardiac mortality than heparin, but there were no differences in MI or stroke. Also, bivalirudin-treated patients had less major bleeding but more definite stent thrombosis than the heparin arm (table 1).

MATRIX Antithrombin: Bivalirudin Fails to Reduce Net Adverse Events vs Heparin in ACS Patients Undergoing PCI

Rates of fatal bleeding, TIMI major or minor bleeding, and GUSTO severe or moderate bleeding were also lower with bivalirudin compared with heparin.

There was no difference in MACE among the patients in the bivalirudin group who did or did not receive the drug after PCI (11.0% vs 11.9%; P = .34). Nor did prolonged infusion reduce overall definite stent thrombosis; it was, in fact, associated with more subacute definite stent thrombosis. In addition, there were no differences between the arms in bleeding, except for BARC 2, which was higher with continued bivalirudin, and BARC 3 or 5 and GUSTO, which were lower.

Results were consistent across subgroups, including access site.

How Does This Fit In?

The discrepant findings seen in this study compared with those of the  ACUITY and HORIZONS-AMI trials “may reflect the way in which nonfatal periprocedural ischemic events (which appear unaffected by the type of antithrombin agent) and bleeding events (which appear to be lower with bivalirudin than with heparin) were defined, since the definition of these events ultimately drives the relative contribution of each within the composite outcome,” the study authors write.

Although consistent with current practice, the fact that the study protocol included 2 different regimens of post-PCI bivalirudin and discretionary GPI use “makes the study results more difficult to interpret,” they say.

But in an email with TCTMD, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), said the MATRIX Antithrombin results “are actually highly consistent with those from ACUITY and HORIZONS-AMI. Specifically, there was a reduction in mortality in patients with STEMI from 3.1% to 2.1% in both MATRIX and HORIZONS—a remarkable equivalence in more than 7,600 patients with STEMI. There was a 40% to 50% reduction in bleeding, and the MATRIX study has now confirmed the results from EUROMAX and BRIGHT in that a 3- to - hour post-PCI infusion of bivalirudin at the PCI dose eliminates any increased risk of acute stent thrombosis.”

MATRIX did not meet its primary endpoint, he continued, because of the use of a “very sensitive troponin definition to diagnose periprocedural MI, which has no clinical relevance. Thus… this trial should remove any doubts that bivalirudin is the optimal antithrombin in patients with acute coronary syndromes compared to heparin with or without [GPIs].”

A Matter of Cost

In an editorial accompanying the study, Peter B. Berger, MD, of the North Shore-Long Island Jewish Health System (Great Neck, NY), adds that the study is confounded because “many patients in the bivalirudin group also received heparin, either upstream (in 32.3% of patients) or in or after the catheterization laboratory (in 6.9%) of patients.”

Additionally, he asks, “What are we to make of the fact that the rates of death from any cause and from cardiovascular causes were significantly lower in the bivalirudin group than in the heparin group?” Since “dozens” of endpoints were included in the study, Dr. Berger writes, the play of chance is inevitable and the fact that the researchers did not correct for multiple comparisons makes the mortality finding “less convincing.”

Nevertheless, the trial “provides the best evidence to date on the question of whether prolonging the infusion of bivalirudin after the end of the PCI procedure is beneficial,” he says, noting that neither the primary endpoint nor any component of it was reduced with a prolonged infusion.

Discussing the study at the meeting, Dr. Stone said that even though the results represent real-world practice, “when we have 1 patient in front of us, we have to make a decision.”

Dr. Valgimigli responded that the secondary endpoints “pretty much favor bivalirudin,” although the question remains as to “whether this advantage… is significant enough to justify the difference in price between the 2 drugs.” As a generic option, he added, prolonged bivalirudin will be the best choice to control bleeding in these patients.


1. Valgimigli M, Frigoli E, Leonardi S, et al. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med. 2015;Epub ahead of print.

2. Berger PB. Finding the proper context for the MATRIX trial [editorial]. N Engl J Med. 2015;Epub ahead of print.

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  • The MATRIX trial was funded by Terumo Medical and The Medicines Company.
  • Dr. Valgimigli reports receiving fees for serving on advisory boards for AstraZeneca and St. Jude Vascular; lecture fees from Abbott Vascular, Alvimedica, AstraZeneca, Correvio, Terumo Medical, The Medicines Company, and St. Jude Vascular; travel support from The Medicines Company; and institutional grant support from AstraZeneca.
  • Dr. Berger reports receiving consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb/Sanofi, and Medicure; and research funding from Accumetrics, AstraZeneca, Corgenix/Aspirinworks, Haemoscope, Helena,, Novartis, Tethys, The Medicines Company, and Thrombovision.