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Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study

Abstract Background The rapid reversal of the effects of vitamin K antagonists is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intracranial haemorrhage. Increasingly, four-factor prothrombin complex concentrates (PCCs) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anticoagulation reversal. Both the safety and efficacy of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either perioperatively or in cases of acute trauma. Methods After 15 yr of clinical use, findings of a pharmacovigilance report (February 1996–March 2012) relating to the four-factor PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analysed and are presented here. Furthermore, a review of the literature with regard to the efficacy and safety of four-factor PCCs was performed. Results Since receiving marketing authorization (February 21, 1996), ∼647 250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (one in ∼31 000) is in line with the incidence observed with other four-factor PCCs. Conclusions In general, four-factor PCCs have proven to be well tolerated and highly effective in the rapid reversal of vitamin K antagonists.

Oral anticoagulation therapies such as warfarin are the primary treatment for patients at risk of thrombosis. 1 The highly effective role of vitamin K antagonist administration in the reduction in thromboembolic events has been extensively documented; 2 -5 however, the use of these anticoagulants is coupled with an increased risk of bleeding complications. 6 -9 The annual risk of gastrointestinal and urinary tract bleeding and also intracranial haemorrhage (ICH) is increased in the anticoagulated population, 9 -14 with an annual fatality rate of 1%. 10 15 The potentially serious nature of these complications means that an effective and rapid treatment for vitamin K antagonist reversal is required.
One therapeutic option for the management of vitamin K antagonist reversal is four-factor prothrombin complex concentrates (PCCs). PCCs contain a combination of the coagulation factors which are inhibited by vitamin K antagonists [factors (F) II, VII, IX, and X, and proteins C, S, and Z). 16 PCC administration with concomitant vitamin K is recommended for facilitating the emergency reversal of oral anticoagulation, 17 -20 and has also been used for treating cases of coagulation defects related to liver disease, and also acquired deficiency of vitamin K-dependent coagulation factors in the perioperative setting. 21 -23 The combination of an ageing population and thus the increasing number of anticoagulated patients, and also the increasing administration of PCCs across a wider range of indications, means that the efficacy and safety of these products is currently in focus. 24 25 A growing number of studies have shown that PCCs facilitate the rapid and predictable reversal of vitamin K antagonist therapy in those patients with acute bleeding or requiring emergency surgery. 26 -36 Despite their efficacy, the widespread use of PCCs has been hampered by concerns over their safety. 37 As with all clotting factor concentrates and blood plasma-derived products, thrombogenicity and the potential for pathogen transmission are the primary safety considerations relating to PCC administration. 38 -40 To investigate the safety of treatment since its market authorization, an analysis of pharmacovigilance data related to Beriplex P/N (CSL Behring GmbH, Marburg, Germany) administration is presented here for the first time. These data are updated from those previously presented at the 22nd Congress of the International Society of Thrombosis and Haemostasis. Furthermore, included here is a review of recent studies involving commercially available four-factor PCCs, which was undertaken to establish the efficacy and safety profiles of these products across a range of clinical settings.

Analysis of pharmacovigilance data
Beriplex P/N has been licensed across Europe for a broad range of indications including the reversal of vitamin K antagonist therapy, clotting factor supplementation in severe liver disease, and the treatment of acquired bleeding since February 1996. A retrospective review of the global pharmacovigilance database of CSL Behring between February 1996 and March 2012 was performed [sources: spontaneous reports, case reports from the scientific literature (including published case reports from investigator-initiated clinical trials). and, where applicable, non-interventional postauthorization studies]. Suspected adverse reactions possibly related to Beriplex P/N administration were identified. Information regarding the clinical use of Beriplex P/N including indication and dosage was also collated. Ethical approval was not required for this study.

Review of four-factor PCC efficacy and safety
A literature review was performed to assess the efficacy and safety of commercially available PCCs. Literature searches were performed using the PubMed online search tool; 41 the search terms applied across all search fields were 'prothrombin complex concentrate and safety'; 'prothrombin complex concentrate and efficacy'; 'prothrombin complex concentrate and reversal'; 'prothrombin complex concentrate and thrombosis'; and 'prothrombin complex concentrate and embolism'. Reports of clinical trials reporting adverse events (AEs) between February 1996 and March 2012 were reviewed. Relevant information relating to clinical indication, product efficacy, and AEs related to PCC administration were identified.

Analysis of pharmacovigilance database
A total of 1 294 500 900 IU Beriplex P/N were administered during the observation period. Assuming an average dose of 2000 IU per patient, 647 250 infusions have been performed to treat a number of indications, including vitamin K antagonist reversal and clotting factor supplementation in liver disease. When considering the primary safety concerns related to allogeneic administration, an analysis of the safety review showed that there were no reports of either viral transmission or heparin-induced thrombocytopenia (HIT) type II related to Beriplex P/N administration (Table 1).
A total of 21 cases of suspected thromboembolic events were recorded (Table 2) 33 42 -46 of these, 13 occurred in patients receiving Beriplex P/N for anticoagulant reversal. An analysis of these events revealed that pre-existing or concomitant conditions likely to result in thromboembolism were present in all patients.
Within the context of total infusions performed, a ratio of 1 thromboembolic event per 31 000 infusions was reported.

Review of four-factor PCC safety and efficacy
A review of the literature demonstrated the efficacy and safety profiles of several four-factor PCCs. Their use for the reversal of vitamin K antagonist therapy, the supplementation of coagulation factors in liver disease, and the treatment of trauma-related bleeding was evaluated. A summary of nine prospective studies is shown in Table 3; 22 27 29 32 -35 43 47 48 any incidences of serious AEs were recorded, with cases of viral transmission or thromboembolic events being highlighted. Four cases of thrombotic events were reported in the studies identified; 30 -32 47 of these, two were with Beriplex P/N and are also captured in the analysis of pharmacovigilance data above (Table 2). There were three cases of seroconversion for parvovirus B19 reported after the use of Octaplex w (Octapharma, Lachen, Switzerland). 29 34 An additional three thromboembolic events (cerebral infarction, pulmonary embolism, and an embolism of a brachial artery) which were potentially associated with PCC administration were described in a retrospective pilot study of patients undergoing aortic arch replacement after acute type A aortic dissection. 49 All patients in this study underwent prolonged cardiopulmonary bypass including isolated head perfusion and a phase with deep hypothermic   Table 3) A 70-yr-old male patient with metastatic gastrointestinal cancer and arrhythmia absoluta was treated with marketed Beriplex P/N 1500 IU during a clinical study. The patient had already received the study drug (also Beriplex P/N) when he was in need of a second infusion of PCC, and was thus treated with a marketed batch of Beriplex P/N (not study drug) The patient experienced shortness of breath and died 4 days later. Cause of death was suspected to be pulmonary embolism  No thromboembolic events were reported in the group with thromboelastometry-guided therapy. In all cases, the patients were severely ill and in a potentially pro-thrombotic state. This fact, and the high levels of blood product administration, means the reason for the reported thrombotic events was undetermined; however, PCCs cannot be ruled out as a potential cause. In general, the PCCs reviewed were all found to be effective for the correction of the international normalized ratio (INR) in anticoagulated patients and the cessation of severe bleeding. 22 27 29 31 -34 47 50 51 Within the emergency setting, the rapid correction of vitamin K antagonist therapy is required in patients with major bleeding or before invasive surgery. Evans and colleagues 27 carried out a prospective analysis of 10 anticoagulated patients requiring vitamin K antagonist reversal. PCC administration resulted in the immediate cessation of bleeding and a satisfactory clinical response in all patients. These data were After operation, the patient made a slow neurological recovery. Eight days postoperative, a CT scan showed small peripheral infarcts in the cerebellar hemispheres bilaterally corroborated by a larger prospective study (n¼42), where the correction of INR to ≤1.9 was observed within 20 min of PCC administration. 33 The rapid infusion of PCCs [median dose 22.0 IU kg 21 (+3.0), total infusion time of 3 min] has been used for immediate anticoagulant reversal before neurosurgery in patients with ICH. 35 All patients displayed complete INR correction immediately after PCC bolus, allowing anticoagulated patients to be managed as rapidly as nonanticoagulated patients. 35 Pabinger and colleagues 32 investigated the impact of infusion speed upon the effectiveness of PCC administration for emergency reversal of vitamin K antagonist therapy. Infusion speeds of between 2.0 and 40.0 ml min 21 were used, and the resulting effects on INR and observed thrombogenicity marker pharmacokinetics were recorded. The infusion speed used had no effect upon the INR attained after 30 min, or on the plasma concentrations of thrombogenicity markers. This study provides the first prospective evidence that PCCs can be rapidly infused without impacting safety or efficacy. 32 Clotting defects can result from severe liver damage, due to reduced levels of vitamin K-dependent coagulation factors. 52 Lorenz and colleagues 22 reported the administration of PCCs in 22 patients (median, 25.7 IU kg 21 ) with impaired hepatic function, before urgent surgery or invasive procedure. The in vivo recovery of the substituted coagulation factors (FII, VII, FIX, FX, and protein C) was between 49.7% and 57.4%, with the clinician assessment of efficacy being either very good (76%) or satisfactory (24%). These findings, in conjunction with the lack of observed adverse reactions, led the study authors to conclude PCC administration in this cohort was both effective and well tolerated.

Discussion
During the period from February 1996 to March 2012, the reported number of serious AEs recorded in the Beriplex P/N pharmacovigilance database was low. A review of reported AEs from published clinical studies detailing Beriplex P/N administration shows that its use was associated with no anaphylaxis or allergic reactions, no virus transmission (6 months posttreatment), no cases of HIT type II, and a low incidence of clinically overt thromboembolic complications. 27 31 -33 47 These figures are in line with the generally low incidence of AEs reported after the administration of other four-factor PCCs.

Thrombogenicity
PCCs are potent pro-coagulants, a property which has seen their increase in use in the emergency setting for anticoagulant reversal and the treatment of life-threatening bleeding. However, these products have historically carried a risk of thrombogenic events. 38 39 Three main risk factors that influence thrombotic potential in patients receiving PCCs for reversal of vitamin K-dependent anticoagulation have been identified. 39 First, predisposing factors including both preexisting and current conditions can influence thrombosis. Since patients receiving PCCs to reverse anticoagulation therapy have an underlying tendency to thrombosis, such reversal is likely to increase the risk of thromboembolic events. Secondly, therapeutic factors such as concomitant surgery or the level of PCC dosing administered can increase risk. Finally, thrombogenesis may be influenced by the quality of the PCC preparation used, with the exclusion of activated coagulation factors and inclusion of anticoagulant agents (proteins C, S, Z, antithrombin, and heparin) of particular importance. 39 Based on animal studies, the presence of heparin and antithrombin is suggested to be important for the effective neutralization of the activated forms of FIX and FX. 53 An in vitro analysis of the clotting factor constituents of PCCs found that FII (prothrombin) was the primary thrombogenic component present. 54 Moreover, the ratio of prothrombin administered relative to other coagulation factors was identified as a major determinant of thrombotic risk. 54 The coagulation factors present in PCCs differ in their half-lives, with prothrombin having by far the longest (50 -80 h). 55 Consequently, a recent review of PCC thrombogenicity by Sørensen and colleagues 40 concluded that prothrombin accumulation associated with repeat doses of PCCs is the primary determinant of thrombotic risk. A biochemical comparison of several commercially available PCCs identified Beriplex P/N as well balanced for all four of coagulation factors present, containing the highest concentration of the therapeutic protein FX, while also being the most pure of all the products tested and possessing the greatest thrombin inhibition potential. 16 A clinical evaluation monitored the pharmacokinetics of PCC coagulation factors in healthy volunteers (n¼15) post-Beriplex P/N administration. Large increases in clotting factors (II, VII, IX, and X) and anticoagulant proteins C and S were observed. Importantly, no increase in the thrombogenicity marker D-dimer was observed, nor was there any clinical evidence of thrombosis.
The current article represents an update to the data previously reviewed by Sørensen and colleagues, as more cases of thromboembolic events potentially associated with PCC administration are included. A total of 21 cases of thromboembolic events possibly related to PCC administration have been reported during the observation period reported here. In all of these 21 cases, patients were severely ill and a prothrombotic status is assumed. Even if a direct causal relationship between PCC administration and these thromboembolic events was supposed, the number is small with respect to the number of treatments (one in 31 000). A recent meta-analysis of both three-and four-factor PCCs administered for the reversal of vitamin K antagonist therapy identified a low but quantifiable risk of thromboembolic complications associated with such therapy. 56 Overall, the rate of thromboembolic events across all studies was 1.4% [95% confidence interval (CI): 0.8-2.1], although this was slightly increased in patients receiving four-factor PCCs [1.8% (95% CI: 1.0-3.0)]. Reported thrombosis rates, even in those patients receiving anticoagulant therapies, can be as high as 24.4%, for example, after orthopaedic surgery. 57 It is therefore important to consider why the incidence of thromboembolic events reported in this pharmacovigilance database is lower than others reported. The most likely explanation for the disparity relates to the under-reporting of such events in patients receiving PCC therapy. It is very important that physicians report any events they consider may be related to PCC administration to build the evidence base. One problem with such reporting is that it is often difficult to distinguish between thromboses resulting from PCC administration and those due to the pre-existing, unmasked prothrombotic condition for which patients were often receiving anticoagulant therapy originally. 58 It is important to balance the low risk of thromboembolism associated with PCC administration with its efficacy in treating life-threatening bleeding. A recent prospective study (n¼160) analysed the efficacy and safety of PCCs [Beriplex P/N, Octaplex, or Prothromplex w (Baxter, Deerfield, IL, USA)] administered for the emergency reversal of vitamin K antagonist therapy due to bleeding or the need for urgent surgery. The clinical efficacy of PCC therapy was considered good in 91% of patients, while their administration was associated with a low risk of thromboembolic complications [3.8% (95% CI: 1.4-8.0%)]. 58 From a clinician's point of view, one might say that a way to reduce the risk of thromboembolic events could be a carefully reduced application of PCCs according to the clinical bleeding situation. Since regularly dosing is calculated by laboratory results, administration after clinical signs for bleeding might be favourable and full correction of INR seems not to be necessary in most cases. Furthermore, recently published data support the use of goal-directed therapy based on point-of-care thromboelastometric testing to reduce thromboembolic events. 21 49 59 Pathogen transmission Viral, bacterial, and prion protein transmission are important considerations in the transfusion of blood products, especially in the period after the widespread transmission of human immunodeficiency virus (HIV) and the emergence of variant Creutzfeldt -Jakob disease. 60 Dentali and colleagues 56 described an overall risk of viral transmission associated with PCC administration of 1.9% (95% CI: 0.3-4.9). It should be noted that the only incidences of viral transmission reported during this meta-analysis related to four cases of parvovirus B19 infection observed during two studies documenting Octaplex administration. Since receiving marketing authorization, no cases of pathogen transmission linked to Beriplex P/N administration have been reported. A two-step pathogen removal process during the manufacture of Beriplex P/N comprises both the pasteurization and nanofiltration of the concentrate, facilitating both viral inactivation and elimination, respectively. 61 These processes eliminate all viruses which have been tested for, most notably influenza virus (H5N2, H7N1, H1N1 . Monitoring of prion proteins during the purification process showed these to be significantly reduced. 61 In summary, pharmacovigilance data, in connection with published clinical studies and an assessment of purification processes, show Beriplex P/N to be well tolerated in relation to transfusion-transmitted pathogens. 22 27 31 -33 47 61 62 Efficacy PCC infusion has also been shown to be more efficacious for the correction of INR compared with the established clinical practice of administering FFP. 28 30 Although not discussed in detail here, it is important to note that two of the major drawbacks related to FFP infusion are the high administration volumes required and the consequent slow rate of infusion. 32 63 Given the critical care settings in which PCCs are utilized, and the acute complications associated with anticoagulation therapy, the speed at which treatment can be administered is of paramount consideration. The treatment of traumarelated bleeding is one such setting where the administration of PCCs is increasing. 64 65 A retrospective analysis of trauma patients receiving PCC therapy in conjunction with fibrinogen concentrate revealed improved survival rates compared with those predicted by both the trauma injury severity score and the revised injury severity classification score. 65 In view of these initial results, there is a clear requirement for more prospective studies to further elucidate the efficacy of PCC administration as a therapeutic option in the treatment of trauma-related bleeding.
In conclusion, there exists broad agreement across published studies that four-factor PCCs are an efficacious and well-tolerated method of correcting coagulation factor deficiency in cases of vitamin K-dependent anticoagulation reversal and severe liver disease. A pharmacovigilance report detailing the 15 yr administration of Beriplex P/N across clinical settings shows this product to be both well tolerated and effective. After 647 250 infusions, no cases of virus transmission or HIT type II possibly related to Beriplex P/N administration have been reported. Extensive data have demonstrated that the risk of thromboembolic events is low. These data are further supported by clinical data for the other commercially available four-factor PCCs. The low incidence of serious thromboembolic and other AEs is mitigated by their efficacy, in particular, the speed at which they are able to cessate bleeding in life-threatening situations.
Tem International GmbH, Munich, Germany. C.J. is an employee of CSL Behring GmbH, Marburg, Germany. K.G. has received honoraria for consulting and scientific lectures from CSL Behring GmbH, Marburg, Germany, Tem International GmbH, Munich, Germany, and Octapharma AG, Lachen, Switzerland. K.G. is also the Clinical Director of Tem International.