Category: Fellows Posters
Purpose: A recent possibility of protamine shortage prompted an inquiry for available alternatives for unfractionated heparin reversal. An evidence based approach for managing drug shortages allows clinicians to provide safe and effective patient care. Protamine is the only FDA approved reversal agent for heparin. Use of protamine alone produces a weak anticoagulation effect but when used in combination with heparin, a strong acid, a salt is formed which neutralizes the compound’s activity. This literature review provides currently available alternatives for protamine when the use of unfractionated heparin is unavoidable.
Methods: An inquiry was submitted to the Christy Houston Drug Information Center (DIC) at the Belmont University College of Pharmacy in July 2019 regarding alternatives to protamine for unfractionated heparin reversal during a protamine shortage. A literature search was conducted during the month of July 2019 in Medline, Embase, and International Pharmaceutical Abstracts using the following search terms: “heparin,” “antidote,” “protamine,” "cardiopulmonary bypass,” “reversal,” “unfractionated heparin,” and ''alternative.” Studies evaluating possible alternatives for the reversal of protamine were included in this review.
Currently, there is no FDA approved alternative to protamine; however, multiple products have been considered for potential use. Based on the available literature, the following compounds have been investigated as alternatives: hexadimethrine bromide, heparinase, platelet factor 4 (PF4), heparin removal devices, synthetic protamine variants, methylene blue, vancomycin, tolonium chloride, ciraparantag, universal heparin reversal agent (UHRA), Dex40-GTMAC3, histidine-rich glycoprotein (HRG) plus zinc, and recombinant inactive antithrombin (riAT), low molecular weight protamine (LMWP), quaternized chitosan derivative. Of the agents listed, the following are currently under investigation in pre-clinical studies: heparinase, UHRA, riAT, Dex40-GTMAC3, HRG plus zinc, quaternized chitosan derivative, and LMWP. With no promising leads, alternatives to the heparin and protamine combination were also considered. Bivalirudin is currently available as an anticoagulant and eliminates the need for an antidote, due to its short half-life of 25 minutes. The pegnivacogin/anivamersen combination along with FIXa aptamer antidote pair are promising alternatives currently in the pipeline for patients undergoing cardiac surgery.
Protamine remains as the only reversal agent for unfractionated heparin. Unfortunately, there are no alternatives readily available for use in the occurrence of a protamine shortage. Substitutions for the heparin/protamine combination such as bivalirudin should be considered in appropriate procedures due to lack of protamine alternatives. There are potential alternatives in the pipeline currently being investigated in pre-clinical studies.