MATRIX: Bivalirudin Not Superior to UFH on MACE End Point in ACS, but Benefits Observed

March 20, 2015

SAN DIEGO, CA — An antithrombotic regimen consisting of bivalirudin (Angiomax, the Medicines Company) in ACS patients undergoing invasive management failed to significantly reduce the 30-day risk of major adverse cardiac events (MACE) or net adverse clinical events, a co–primary end point including MACE and major bleeding, when compared with patients who received unfractionated heparin[1].

Treatment with bivalirudin did significantly reduce all-cause mortality, however, including a statistically significant 30% relative reduction in the risk of cardiovascular death and a 32% reduction in the risk of cardiac death. In addition, the use of bivalirudin did result in a significant reduction in non–access-site bleeding, bleeding requiring a blood transfusion, fatal bleeding, and other bleeding measures.

These are the conclusions of the MATRIX study, a trial that included ACS patients with and without ST-segment elevation MI (STEMI), presented earlier this week at the American College of Cardiology (ACC) 2015 Scientific Sessions. The MATRIX study, which also tested transfemoral vs transradial coronary angiography and PCI in the same patients, previously showed a significant advantage with radial access.

Dr Marco Valgimigli

Reporting the results of the antithrombotic arm of the study, lead investigator Dr Marco Valgimigli (Erasmus Medical Center, Rotterdam, the Netherlands) said previous studies testing unfractionated heparin against bivalirudin in ACS patients "have come to conflicting results in terms of ischemic, bleeding, and combined clinical outcomes."

Last year, as reported by heartwire on Medscape, the How Effective Are Antithrombotic Therapies in Primary PCI (HEAT-PPCI) investigators, led by Drs Adeel Shahzad and Rod Stables (Liverpool Heart and Chest Hospital, UK), shook the field up when they presented data showing a significantly lower rate of MACE in the heparin-treated patients at 28 days and no differences in bleeding complications.

In HEAT-PPCI, the MACE end point, defined as all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularization (TLR), occurred in 8.7% of bivalirudin-treated patients and in 5.7% of heparin-treated patients, an absolute increased risk of 3%. The increased risk was driven primarily by an increased risk of TLR and reinfarction.

"I think the community perhaps overreacted to HEAT-PPCI one year ago at this conference," said Valgimigli.

The trial has drawn a lot of controversy over its methodologies and perceived limitations, including that it was conducted at a single center; but it has been both criticized and praised.

The MATRIX Antithrombin Arm

In MATRIX, patients were first considered for the "access" program (radial vs femoral-access PCI). Depending on the planned revascularization strategy, they were then included in the antithrombin component of the trial. Under the assumption that PCI would occur in the vast majority of patients, 7213 participants were enrolled 1:1 to bivalirudin with bailout GP IIb/IIIa inhibitors or to unfractionated heparin with planned or bailout GP IIb/IIIa inhibitor use. Overall, 26% of patients in the unfractionated-heparin arm and 4.6% of patients in the bivalirudin arm received a GP IIb/IIIa inhibitor.

Overall, the MACE end point, a composite end point that included death, MI, or stroke, was not statistically different between the two treatment regimens. Mortality at 30 days, however, was 2.3% in the unfractionated-heparin arm and 1.7% in the bivalirudin arm, a difference that was statistically significant. As noted, the mortality benefit was driven by reductions in cardiovascular and cardiac death.

The rate of definite stent thrombosis was significantly higher in the bivalirudin group—1% vs 0.6% (relative risk 1.71; 95% CI 1.00–2.93)—with a trend toward more definite/probable stent thrombosis.

Regarding the net-clinical-event end point—a composite end point that included death, MI, stroke, and major bleeding—there was no significant difference between the two antithrombin regimens. Bleeding rates were significantly reduced with bivalirudin. In MATRIX, there was a 47% relative reduction in non–access-site bleeding, a 39% relative reduction in Bleeding Academic Research Consortium (BARC) 3, a measure of bleeding requiring blood transfusions, and a 69% relative reduction in BARC 5 bleeding (fatal bleeding). TIMI and GUSTO bleeding measures were also significantly reduced.

"The critical question is how to explain that we have a significant mortality reduction, we have a significant bleeding reduction, and MI and stroke rates are almost identical in the two study groups," said Valgimigli. Despite the observed reductions in mortality and bleeding, the MACE and net adverse clinical event end point was not significantly different between treatments. "The most reasonable and likely explanation at this state is that death, stroke, and even bleeding, per se, contributed relatively very little to the co–primary end points, whereas the MI rate was much higher than expected," said Valgimigli. "It literally dominated the composite end point."

The Experts Respond to MATRIX

Commenting on the study results, in particular how MATRIX fits in with the divergent HEAT-PPCI results, Valgimigli told heartwire the primary MACE end points differed between the two studies. Most important, he was critical of how HEAT-PPCI was interpreted last year, noting that the primary end point in the trial was statistically significant on the basis of the P value but the 95% confidence intervals were wide.

"HEAT-PPCI is a relatively small study performed at a single center where bivalirudin was used, for whatever reason, in an off-label manner, whereas MATRIX is a much broader patient population study where bivalirudin is used as per the label," said Valgimigli. In HEAT–PPCI, a prolonged infusion of bivalirudin post-PCI was not allowed, which is part of the label, he said. As a result, the bivalirudin might have been underdosed.

As for the overall MATRIX results, Valgimigli said the study missed both its primary end points, and by a "pure" definition of clinical-trial analysis, it is a negative trial. However, as Dr Sanjit Jolly (McMaster University, Hamilton, ON) pointed out, "Not all components of the primary end point are equal." Jolly, who was not involved in the study, told the media that "mortality is the most important primary outcome." The mortality benefit observed in MATRIX is hypothesis-generating at this point, but hopefully a meta-analysis of the various bivalirudin studies will confirm the finding.

"If the totality of the data supports that, people will go back after they stopped using bivalirudin after HEAT-PPCI and use bivalirudin again," said Jolly.

Dr Gilles Montalescot (Pitié-Salpêtrière University Hospital, Paris, France), who was not involved in the trial, agreed the mortality reduction must be considered in the context of the negative co–primary end points. He pointed out that EuroMAX and HEAT-PPCI did not show a reduction in deaths among the patients who received bivalirudin. For Valgimigli, however, the reason for the lack of mortality benefit in those previous trials comes down to numbers—they were just too small to detect a difference.

"It would be almost impossible to detect any signal" in a trial with just 2000 patients," said Valgimigli.

Dr Roxana Mehran (Icahn School of Medicine at Mount Sinai, New York) said the MATRIX study is consistent with the HORIZONS-AMI study, a trial that also showed a mortality reduction with bivalirudin in STEMI patients, as well as a large reduction in bleeding. "The magnitude of bleeding benefit was not huge [in MATRIX], so perhaps that's why you missed the MACE end point," she speculated during the late-breaking clinical-trials discussion.

Valgimigli reports grants from the Medicines Company and Terumo during the study; grants and personal fees from AstraZeneca, personal fees and nonfinancial support from the Medicines Company, and personal fees from Terumo, St Jude Vascular, Alvimedica, Abbott Vascular, and Correvio, outside the submitted work. He is on the speaker's bureau for Abbott, AstraZeneca, CID Vascular, and IROKO.

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