Regular Article
Efficacy and safety of a prothrombin complex concentrate (Octaplex®) for rapid reversal of oral anticoagulation

https://doi.org/10.1016/j.thromres.2004.04.004Get rights and content

Abstract

Bleeding is the most serious adverse event of oral anticoagulants and is a major cause of morbidity and mortality in such patients. Rapid reversal of anticoagulation in bleeding patients or prior to urgent surgery is mandatory. The therapeutic options in these situations include administration of fresh frozen plasma (FFP), and recently of prothrombin complex concentrates (PCCs). However, viral safety and thrombogenicity of PCCs remain issues of concern.

In the present study, we administered Octaplex®, a new solvent/detergent (S/D) treated and nanofiltered PCC, to excessively anticoagulated bleeding patients or to anticoagulated patients facing urgent surgery.

Ten excessively anticoagulated patients with major bleeding and 10 anticoagulated patients awaiting surgery (median age 72.5 (43–83) years, 9 females) received a median dose of 26.1 IU/kg body weight (BW) of Octaplex® for reversal of anticoagulation. Response to Octaplex® was rapid with decline of INR within 10 min after Octaplex® administration (from 6.1±2. to 1.5±0.3). Clinical response was graded as good in most patients (85%) and as moderate in the rest. Octaplex® administration was uneventful in all patients. Following Octaplex® administration, a small increase in F1+2 levels was observed in bleeding patients, whereas D-dimer level did not change significantly.

We conclude that Octaplex® is effective and safe in situations where rapid reversal of anticoagulation is needed.

Introduction

Oral anticoagulant therapy (OAT) is increasingly employed in recent years for both therapeutic and prophylactic purposes in patients with an increased risk of thrombosis. The most feared adverse event of OAT is major bleeding. This, undesirable complication is not infrequently encountered with a reported incidence of 1.3–2.7 major bleeds per 100 patients years [1], [2], [3]. Bleeding can result in permanent organ damage and may lead to death. Major bleeding is related to a number of characteristics but mainly to patient's age and the magnitude of INR deviation from the desired therapeutic range [1], [2], [3], [4]. Therefore, in these situations, rapid reversal of anticoagulation status back to normal values is required [4], [5]. In addition, rapid reversal of anticoagulation is indicated in patients awaiting urgent surgery, in whom operation while being anticoagulated may result in increased bleeding.

The therapeutic options in these serious situations include administration of fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs) in addition to intravenous vitamin K [4], [5]. Fresh frozen plasma is a potentially effective mode of treatment but carries the risks of volume overload and potential transmission of infective agents and usually requires prolonged administration time. In contrast, PCCs were proved to be highly effective and to require short time for administration [5], [6]. Furthermore, FFP was found to be inferior to PCC regarding restoration of the INR back to normal levels in warfarin-treated patients with major and life-threatening bleeding episodes [6]. However, the main drawback of PCCs, precluding their routine use in such situations, has been their potential for thrombogenicity and transmission of infective agents [4], [7], [8], although quality assurance and strict control of manufacturing process with the implementation of effective inactivation steps to remove infective agents resulted in significantly improved PCCs in terms of potential thrombogenicity and virus safety. Therefore, administration of PCC is currently still done after careful consideration of risks and benefits on an individual basis either for major or life-threatening bleeding or in anticoagulated patients who are facing immediate surgery.

Octaplex® is a new solvent/detergent (S/D) treated and nanofiltered PCC containing factors II, VII, X and proteins C and S at concentration of 10–40 IU/ml, Factor IX (20–31 IU/ml) and heparin 0.2–0.5 IU/IU factor IX [9]. Thus, Octaplex® offers a balanced concentrate with the potency of contributing to coagulation while limiting its activity to a physiological meaningful level due to the presence of the regulating proteins C and S.

The present prospective multicenter study was a phase II study undertaken to establish the efficacy and safety of Octaplex® as a potential treatment for the immediate reversal of OAT in patients presenting either with major bleeding or facing urgent surgery.

Section snippets

Overall design and plan of the study

This study was a prospective, non-randomized, non-controlled, open-labeled, multicenter, phase II study held in five centers in Israel and Russia.

Study objectives

The primary study objective was to assess efficacy of Octaplex®. This was done by measurement of prothrombin time (PT) shortening post Octaplex® administration as a primary endpoint and by measuring the plasma activity of coagulation factors II, VII, IX, X and proteins C and S together with an efficacy evaluation by the treating physician as secondary

Patients

Between July 2000 and February 2001, 20 patients (9 females) maintained on stable chronic oral anticoagulant therapy (warfarin—14 patients, marcumar—1 patient and pheninidione—5 patients) with a median age of 72.5 (43–83) years were included in the study. In most patients (9/20), the indication for chronic anticoagulant therapy was atrial fibrillation while the rest received therapy for venous thromboembolism (5/20), prosthetic heart valves (4/20), coronary heart disease (1/20) and cardiac left

Discussion

Administration of PCCs for urgent reversal of anticoagulation is becoming increasingly accepted.

In this study, we tested Octaplex® as a new potential PCC for treatment of such patients. Being in a phase II study, investigators were asked to follow closely the decline of INR values following Octaplex® administration. However, investigators were also asked to evaluate the clinical efficacy of Octaplex®. Indeed, Octaplex® was found to be highly effective in lowering INR levels and as early as 10

Acknowledgements

The study was supported by Octapharma who also supplied Octaplex®. The sponsor had no role in collection, analysis or interpretation of data as well as on the decision to submit the manuscript for publication.

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