Label Update for Bivalirudin Warns of Acute Stent Thrombosis With PCI for STEMI, Recommends Continued Infusion

Prescribing information for bivalirudin has been updated in the United States to reflect the higher rate of acute stent thrombosis rates among patients receiving the direct thrombin inhibitor for STEMI, as compared to patients treated with heparin, the FDA’s MedWatch program notes. 

The changes to the Warnings and Precautions and the Adverse Reactions sections of the label for bivalirudin (Angiomax Lyophilized Powder for Injection, The Medicines Company) were noted in the FDA’s March 2016 Drug Safety Labeling Changes list released today. A company spokesperson confirmed that a letter explaining the changes was sent to healthcare providers this week.

Numbers cited in the Warnings and Precautions section come from a 2015 pooled analysis of the HORIZONS-AMI and EUROMAX trials, although the study itself is not referenced. According to the new label, acute stent thrombosis occurring within 4 hours of PCI has been observed at a higher rate in STEMI patients who are bivalirudin-treated (1.2%; 36/2889) compared with heparin-treated (0.2%, 6/2911). The label advises that patients treated with bivalirudin should be monitored for 24 hours following their procedure, at a facility capable of managing ischemic complications.

New dosing information has also been added to the label, which notes that bivalirudin infusion “may be continued following PCI/PTCA for up to 4 hours postprocedure at the discretion of the treating physician” and, in the case of STEMI, “should be considered to mitigate the risk of stent thrombosis.”

This should be done at an infusion rate of 1.75 mg/kg/h for up to 4 hours, with an additional IV infusion at a rate of 0.2 mg/kg/h for up to 20 hours if needed.

Bob Laverty, VP for Global Communications at The Medicines Company, told TCTMD that the company had submitted new data from EUROMAX, HEAT-PPCI, BRIGHT, and MATRIX and requested a label change endorsing the prolonged full-dose infusion. “FDA agreed, and that is reflected in the new language,” Laverty said in an email.

A prolonged infusion was used in the EUROMAX study and was credited by the study authors as a possible reason for the improved drug safety. A similar impact of prolonged infusion was seen in the BRIGHT trial, which used the post-PCI infusion regimen now recommended by the FDA. The overall MATRIX trial found no benefit of a prolonged infusion for the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events, although a supplementary analysis looking only at patients receiving the FDA-recommended dosing regimen (1.75 mg kg/h) did find a benefit. No continued infusion was used in HEAT-PPCI.

In one more addition to the label, a new section has been added to the Warnings and Precautions stating that bivalirudin can affect the International Normalized Ratio (INR). “Therefore, INR measurements made in patients who have been treated with Angiomax may not be useful for determining the appropriate dose of warfarin,” it states.

• Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER). March 2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020873s036lbl.pdf. Published on: April 15, 2016. Accessed on: April 16, 2016.

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