MATRIX: Is There A Benefit From Longer Bivalirudin Infusion?

September 01, 2015

LONDON, UK — Prolonging the infusion of bivalirudin (Angiomax/Angiox, the Medicines Company) for several hours after the completion of PCI did not reduce the composite outcome of ischemic and bleeding end points in the MATRIX trial[1].

Presenting the results at the European Society of Cardiology (ESC) 2015 Congress, Dr Marco Valgimigli (Swiss Cardiovascular Center, Bern, Switzerland) noted that a nonrandomized exploratory analysis did suggest that prolonging the infusion at a higher dose may show better results.

The comparison of prolonged bivalirudin vs stopping the infusion at the end of the PCI procedure is the last of three questions being addressed by the MATRIX study. The other two parts of the trial addressed the issue of radial vs femoral access for PCI (finding a significant advantage with radial access); and whether to use heparin or bivalirudin as the antithrombotic of choice (showing similar effects on the primary outcome with both agents).

The results of the heparin-vs-bivalirudin comparison and the short vs long infusion of bivalirudin were published together today in the New England Journal of Medicine to correspond with the ESC presentation.

In an accompanying editorial[2], Dr Peter Berger (North Shore-Long Island Jewish Health System, Great Neck, NY) concludes that the trial did not produce a clear winner in the comparison of the two antithrombotics or in the comparison of in-laboratory or prolonged bilvalirudin.

Dr Marco Valgimigli

For the bivalirudin-infusion comparison, 3610 ACS patients were randomized to receive bivalirudin either during PCI only (n=1188) or both during and after the procedure (n=1799).

The drug was administered according to the product labeling, with a bolus of 0.75 mg/kg followed immediately by an infusion of 1.75 mg/kg per hour until completion of PCI.

For patients receiving prolonged treatment, the post-PCI dose could be either the full dose for up to 4 hours or a reduced dose of 0.25 mg/kg per hour for at least 6 hours, at the discretion of treating physicians. About one-third of patients receiving prolonged infusions were given the higher shorter treatment, with the remaining two thirds given the lower-dose longer infusion.

Results of the main comparison of showed no significant difference between stopping bivalirudin at the end of PCI or longer infusions on the primary composite end point of urgent target vessel revascularization (TVR), definite stent thrombosis, and net adverse clinical events (death/MI/stroke/major bleed) at 30 days.

MATRIX: Prolonged Bivalirudin vs No Post-PCI Infusion

Outcome Prolonged bivalirudin infusion (%) No post-PCI bivalirudin (%) P
Urgent TVR, definite stent thrombosis, and net adverse clinical events (primary end point) 11.0 11.9 0.34
Death 1.6 1.8 0.53
MI 8.6 8.6 0.99
Stroke 0.3 0.4 0.79
Urgent TVR 1.7 1.2 0.16
Stent thrombosis 1.3 0.7 0.09
Bleeding (BARC 3 or 5) 1.0 1.8 0.03

Valgimigli commented. "I believe the option to prolong or stop bivalirudin infusion after PCI remains open for clinicians, who will have to decide based on the ischemic and bleeding risk of individual patients as well as perhaps based on type of acute coronary syndrome, timing of loading dose, and type of oral P2Y12 inhibitors."

However, an exploratory analysis comparing the two different dose regimens used for the prolonged infusion showed interesting results, with much better outcomes with the higher-dose infusion.

Exploratory dose analysis

Outcome Low-dose bivalirudin infusion (%) High-dose bivalirudin infusion (%) No post-PCI bivalirudin (%)
Urgent target vessel revascularization, definite stent thrombosis, and net adverse clinical events 11.9 4.4 14.7
Death 1.8 0.8 1.8
Definite stent thrombosis 2.1 0.2 0.7
Bleeding (BARC 3 or 5) 1.4 0.3 1.8

On the exploratory analysis, Valgimigli said. "I would like to caution against the overinterpretation of these results, as the choice of post-PCI bivalirudin regimen was not randomized, but rather left to the discretion of the investigators. However, taking these words of caution into great account, what we saw is that the full-dose regimen may be able to significantly reduce stent-thrombosis risk without increasing bleeding. This may be in keeping with previous observations from the EUROMAX trial."

To heartwire from Medscape,he added: "The hypothesis was that prolonging infusion would reduce thrombotic complications without increasing bleeding risk, but we didn't see that in the main analysis. However, we think the higher dose might have worked better, as it gave complete inhibition of the thrombin pathway. We have to be careful in this interpretation, as this was not a randomized comparison, but it is consistent with what we have seen before in EUROMAX."

On the observation that the bleeding rate in the exploratory analysis was actually lower with the high-dose infusion vs the low-dose infusion, Valgimigli said: "My personal interpretation is that the low dose might have had more bleeding as it was continued for a lot longer than the high dose."

Asked about his own practice, he commented: "I will not use low-dose bivalirudin infusion any more. If I do use bivalirudin I will prolong the infusion for a few hours at the full dose."

Dr Pamela Douglas

Commenting on the data for heartwire , Dr Pamela Douglas (Duke University, Durham, NC) said she found the results intriguing. "I found the exploratory analysis quite provocative. The higher dose looks good. But it's hard to say anything definitive based on these nonrandomized data."

Pointing out that the earlier comparison of bivalirudin with heparin did not show differences in the primary end point, Dr Douglas said: "This would suggest bivalirudin is not necessary. But I suppose from this exploratory analysis if I were going to use it I would continue at the high dose."

Further data on continuing bivalirudin after PCI will come from the Swedish trial—VALIDATE HEART—which is comparing unfractionated heparin with bivalirudin, with all bivalirudin patients receiving prolonged infusion with the full-dose regimen up to the end of the vial. "I think this study will be very important to confirm our results," Valgimigli stated.

The MATRIX trial was s upported by the Medicines Company and Terumo Medical. Valgimigli has served as a speaker, advisor, or consultant for both companies. Disclosures for the coauthors are listed in the article. Berger reports grant support from Novartis, Tethys, Thrombovision, Helena, Accumetrics, AstraZeneca, Haemoscope, the Medicines Company, and Corgenix/Aspirinworks and personal fees from Boehringer Ingelheim, Medicure, and Bristol-Myers Squibb/Sanofi outside the submitted work.

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