MATRIX Provides Support for Radial Access, Mixed Results for Bivalirudin

SAN DIEGO, CA—Among ACS patients undergoing invasive management, the use of radial vs femoral access improves outcomes, driven by reductions in major bleeding and mortality, according to trial results from the MATRIX program. Also, bivalirudin does not improve composite outcomes compared with unfractionated heparin, despite apparent beneficial effects on mortality and major bleeding.Take Home: MATRIX Provides Support for Radial Access, Mixed Results for Bivalirudin

The findings were presented by Marco Valgimigli, MD, PhD, of Erasmus Medical Center (Rotterdam, the Netherlands), on March 16, 2015, at the American College of Cardiology/i2 Scientific Session, with those related to vascular access simultaneously published online ahead of print in the Lancet.

The MATRIX program included ACS patients with or without STEMI who were undergoing invasive management at 78 centers in Italy, the Netherlands, Spain, and Sweden between October 2011 and November 2014. Patients were randomized to radial or femoral access before angiography and then—only if scheduled for PCI—to bivalirudin (Angiomax; The Medicines Company) or unfractionated heparin. Bailout glycoprotein IIb/IIIa inhibitor (GPI) use was allowed in the bivalirudin arm, and either planned or bailout use was allowed in the heparin arm.

Participating operators needed to have expertise in both transradial and transfemoral access, with performance of at least 75 radial interventions (not including diagnostic procedures) and at least 50% of ACS interventions via the radial approach in the year before the study.

Access Program

Overall, 8,404 patients (mean age 67 years; about 73% male) were randomized to radial or femoral access. There were roughly equal proportions of patients with STEMI (48%) and NSTEMI (46%), while a small percentage of patients had unstable angina (6%). PCI was attempted in 80%, CABG was performed in 3.7%, and 12% received medical therapy alone.

Crossover from one access route to the other was more common among patients initially assigned to radial access (5.8% vs 2.3%; P < .001), but there was no difference in the rate of PCI failure (6.3% vs 6.1%; P = .77).

There were 2 coprimary endpoints, each measured at 30 days:

  • MACE (death, MI, or stroke)
  • Net adverse clinical events (NACE; defined as MACE plus BARC 3 or 5 bleeding) 

The MACE rate was lower with radial than with femoral access (8.8% vs 10.3%; RR 0.85; 95% CI 0.74-0.99), although the difference did not meet a stricter standard for statistical significance used because of the presence of 2 primary endpoints.

The NACE rate also was reduced in the radial group, and the difference met criteria for statistical significance (9.8% vs 11.7%; RR 0.83; 95% CI 0.73-0.96). The number needed to treat was 53.

Looking at the components of the endpoints, there were no differences between groups in MI or stroke, but all-cause mortality was lower with radial access (1.6% vs 2.2%; RR 0.72; 95% CI 0.53-0.99). BARC 3 or 5 bleeding occurred less frequently in the radial arm (1.6% vs 2.3%; RR 0.67; 95% CI 0.49-0.92), driven by reductions in bleeding at the access site (P = .0004) and in BARC 3 (P = .0098) bleeds.

Radial access was associated with only numerically higher rates of definite stent thrombosis (1.0% vs 0.6%; P = .69) and definite/probable stent thrombosis (1.3% vs 1.0%; P = .66).

In subgroup analyses, there were interactions in which the radial approach was associated with greater reductions in both NACE and mortality at centers performing at least 80% of their PCIs through the radial artery. Assignment to bivalirudin or heparin did not influence the results.

The researchers incorporated the MATRIX results into an updated meta-analysis that included both pre- and post-RIVAL studies and RIVAL itself. Among more than 19,328 ACS patients, the radial approach was associated with reductions in non-CABG major bleeding (RR 0.58; 95% CI 0.46-0.72), the composite of death, MI, or stroke (RR 0.86; 95% CI 0.77-0.95), and death (RR 0.72; 95% CI 0.60-0.88).

“Our results, in conjunction with the updated meta-analysis, suggest that [the] radial approach should become the default access for patients with ACS undergoing invasive management,” Dr. Valgimigli said.

Antithrombin Program

The antithrombin part of MATRIX included the 7,213 patients (mean age 65.4 years; about three-quarters male) who had PCI planned after diagnostic catheterization. More than half (56%) had STEMI, 40% had NSTEMI, and almost 5% had unstable angina. PCI was attempted in 95% of patients, with about 5% ultimately receiving medical treatment and less than 1% undergoing CABG. GPI use was 5 times more frequent in the heparin arm than in the bivalirudin arm (25.8% vs 4.6%).

There were no differences between the bivalirudin and heparin groups in either MACE (10.3% vs 10.9%; RR 0.94; 95% CI 0.81-1.10) or NACE (11.2% vs 12.4%; RR 0.89; 95% CI 0.78-1.10).

Among the individual components, however, there were reductions with bivalirudin in all-cause mortality (1.7% vs 2.3%; RR 0.71; 95% CI 0.51-0.99)—driven by fewer cardiovascular deaths—and BARC 3 or 5 bleeding (1.4% vs 2.5%; RR 0.55; 95% CI 0.39-0.78), with an impact on bleeds not related to the access site and both BARC 3 and 5 bleeds individually. TIMI major or minor bleeding and GUSTO moderate or severe bleeding also were less frequent with bivalirudin.

Dr. Valgimigli said results for the composite endpoints were neutral despite differences in death and bleeding because most events were MIs, which occurred at similar rates with bivalirudin and heparin (8.6% vs 8.5%). And most of the MIs, he added, were periprocedural.

The rate of definite stent thrombosis was higher in the bivalirudin group (1.0% vs 0.6%; RR 1.71; 95% CI 1.00-2.93), with a trend toward more definite/probable stent thrombosis.

Findings were consistent across various subgroups and did not vary by vascular access site.

Radial as Default Strategy

Prior studies examining the effects of radial vs femoral access for ACS patients have provided mixed evidence as to whether the reductions in bleeding and vascular complications seen with the radial approach can improve clinical outcomes.

After Dr. Valgimigli’s presentation, panelist David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), suggested that MATRIX helps clarify that issue. “I think this will further support radial access as the default method. It’s becoming part of a quality standard in many cath labs,” he said, noting that radial access is growing more popular in the United States but still used in fewer than 20% of PCIs.

A remaining question, he said, is what mechanism explains the link between lower bleeding and less mortality, given that fatal bleeding was not reduced with radial access in MATRIX.

To answer that, Dr. Valgimigli referred to a nested case-control study within MATRIX that showed that BARC 3 bleeding (requiring transfusion or intervention) was associated with a 2.7-fold greater risk of death. “Bleeding per se does drive mortality…,” he said.

Panelist Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), asked whether the difference in outcomes between MATRIX and RIVAL (which was neutral) had to do with refinement of techniques or differences in definitions or study design.

Dr. Valgimigli responded that it was likely a combination of those factors, noting that in MATRIX, patients were higher risk and more stringent criteria were used to select operators experienced with transradial procedures. 

Potential Bivalirudin Benefits Hypothesis Generating Only

After Dr. Valgimigli’s presentation on bivalirudin vs heparin, panelist Gilles Montalescot, MD, PhD, of Centre Hospitalier Universitaire Pitié-Salpêtrière (Paris, France), cautioned that because both primary endpoints failed to show a difference between groups, any further analyses should be considered exploratory and hypothesis generating only.

That said, he expressed his surprise that mortality was lower in the bivalirudin group and asked how that could be reconciled with the findings of HEAT-PPCI and EUROMAX, which showed no such benefit.

Dr. Valgimigli pointed to the differences in size between the studies, as HEAT-PPCI included about 1,800 patients and EUROMAX about 2,200 patients. With those patient numbers, he said, it would be “almost impossible” to detect a mortality signal.

Asked to defend the differential use of GPIs between the bivalirudin and heparin arms, Dr. Valgimigli noted that HEAT-PPCI took criticism for having no planned GPI use in either arm. In that trial, bailout GPIs were used in 13% of bivalirudin-treated patients and 15% of heparin-treated patients.

Current standard of care, however, is unfractionated heparin with some use of GPIs, he said. Thus, MATRIX, which was designed to be a pragmatic study, left the decision on how to use GPIs in the heparin group to the treating physician.


1. Valgimigli M, Gagnor A, Calabró P, et al. Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial. Lancet. 2015;Epub ahead of print.
2. Valgimigli M. Bivalirudin infusion compared to unfractionated heparin in patients with acute coronary syndromes undergoing invasive management: results from the Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) antithrombin program. Presented at: American College of Cardiology/i2 Scientific Session; March 16, 2015; San Diego, CA.


  • The MATRIX program was sponsored by the Gruppo Italiano Studi Emodinamica, a nonprofit organization, and received grant support from Terumo and The Medicines Company.
  • Dr. Valgimigli reports receiving grants from Terumo and The Medicines Company during the study; grants and personal fees from AstraZeneca; personal fees and nonfinancial support from The Medicines Company; and personal fees from Abbott Vascular, Alvimedica, Correvio, St. Jude Vascular, and Terumo.
  • Dr. Kandzari reports receiving consulting fees/honoraria from Boston Scientific, Medtronic, Micell Technologies, and Thoratec.
  • Dr. Rao reports receiving consulting fees/honoraria from Terumo and The Medicines Company and research grants from Bellerophon.
  • Dr. Montalescot reports relationships with multiple pharmaceutical and device companies.

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