Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor®): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety.

From 1997, plasma-derived C1-inhibitor concentrate (Cetor®) has been available to HAE and AAE patients. Recently, a virus reducing 15 nm nanofiltration step has been introduced in the production process. A randomized, double-blind controlled cross-over study was performed to compare the pharmacokinetics (PK) of nanofiltered (C1-INH-NF) with conventional C1-inhibitor (C1-INH). Efficacy and safety were investigated in an open-label, on-demand and a prophylactic study. No differences in pharmacokinetic parameters between C1-INH and C1-INH-NF were found (13 non-symptomatic HAE patients). Both C1-inhibitor products equally increased plasma C4 levels. In the on-demand study, 14 acute angioedema attacks in 8 patients were analyzed. In the prophylactic study, 1 AAE and 5 HAE patients experienced in total 31 attacks during 748 observation days. In total 180,000 units of C1-INH-NF were administered. No product-related adverse events occurred, and no anti-C1-antibodies were induced. Nanofiltration in the production process of C1-inhibitor did not affect the pharmacokinetics, efficacy, and safety.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.

Haemovigilance: an effective tool for improving transfusion practice.

Haemovigilance is a tool to improve the quality of the blood transfusion chain, primarily focusing on safety. In this review we discuss the history and present state of this relatively new branch of transfusion medicine as well as some developments that we foresee in the near future. The top 10 results and conclusions are: (1) Haemovigilance systems have shown that blood transfusion is relatively safe compared with the use of medicinal drugs and that at least in Europe blood components have reached a high safety standard. (2) The majority of the serious adverse reactions and events occur in the hospital. (3) The majority of preventable adverse reactions are due to clerical errors. (4) Some adverse reactions such as anaphylactic reactions often are not avoidable and therefore have to be considered as an inherent risk of blood transfusion. (5) Well-functioning haemovigilance systems have not only indicated how safety should be improved, but also documented the success of various measures. (6) The type of organisation of a haemovigilance system is of relative value, and different systems may have the same outcome. (7) International collaboration has been extremely useful. (8) Haemovigilance systems may be used for the vigilance and surveillance of alternatives for allogeneic blood transfusion such as cell savers. (9) Haemovigilance systems and officers may be used to improve the quality of aspects of blood transfusion other than safety, such as appropriate use. (10) Haemovigilance systems will be of benefit also for vigilance and surveillance of the treatment with other human products such as cells, tissues and organs.

Efficacy and safety of a nanofiltered liquid intravenous immunoglobulin product in patients with primary immunodeficiency and idiopathic thrombocytopenic purpura.

BACKGROUND AND OBJECTIVES: In the production process of a new 5% liquid intravenous immunoglobulin (IVIG-L) product (Nanogam(®) ), a combined pepsin/pH 4·4 treatment/15-nm filtration (pH 4·4/15NF) step and a solvent-detergent (SD) treatment step were incorporated to improve the virus inactivating/reducing capacity of the manufacturing process. Two prospective uncontrolled multicentre studies were performed to evaluate the safety and efficacy of this product. MATERIALS AND METHODS: Efficacy, including pharmacokinetics, of IVIG-L was studied for 6 months in 18 primary immunodeficiency (PID) patients, succeeded by a long-term follow-up study (mean 2·2 years, n=17). Second, in 24 patients with idiopathic thrombocytopenic purpura (ITP), IVIG-L was studied for efficacy for 14 days. In both studies, adverse events and vital signs were recorded to study safety. RESULTS: In PID patients treated with IVIG-L, 0·60 and 0·38 severe infections per patient per year were reported during, respectively, the short-term and long-term follow-up. Pharmacokinetic studies resulted in an IgG half-life of 30·9 ± 11·3 days and a mean IgG trough level of 6·8 ± 1·2 g/l. In the ITP study, all patients showed an increase in platelet counts after infusion with IVIG-L, and 20/24 patients responded with a platelet count >50 × 10(9) /l (83·3%) within 1 week. IVIG-L infusions did not cause clinical relevant changes in laboratory parameters or vital signs. CONCLUSIONS: In clinical studies, IVIG-L (Nanogam®) demonstrated to be efficacious, well tolerated and safe.

Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study.

BACKGROUND: Fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC) reverse oral anticoagulants. We compared PCC and FFP intraoperative administration in patients undergoing heart surgery with cardiopulmonary bypass (CPB). METHODS: Forty patients [with international normalized ratio (INR)≥ 2·1] assigned semi-urgent cardiac surgery were randomized to receive either FFP (n = 20) or PCC (n = 20). Prior to CPB, they received either 2 units of FFP or half of the PCC dose calculated according to body weight, initial INR and target INR ( ≤ 1·5). After CPB and protamine administration, patients received either another 2 units of FFP or the other half PCC dose. Additional doses were administered if INR was still too high ( ≥ 1·5). RESULTS: Fifteen minutes after CPB, more patients reached INR target with PCC (P = 0·007): 7/16 patients vs. 0/15 patients with FFP; there was no difference 1 h after CPB (6/15 patients with PCC vs. 4/15 patients with FFP reached target). Fifteen minutes after CPB, median INR (range) decreased to 1·6 (1·2-2·2) with PCC vs. 2·3 (1·5-3·5) with FFP; 1 h after CPB both groups reached similar values [1·6 (1·3-2·2) with PCC and 1·7 (1·3-2·7) with FFP]. With PCC, less patients needed additional dose (6/20) than with FFP (20/20) (P < 0·001). Both groups differed significantly on the course of factor II (P = 0·0023) and factor X (P = 0·008) over time. Dilution of coagulation factors was maximal at CPB onset. Safety was good for both groups, with only two related oozing cases with FFP. CONCLUSION: PCC reverses anticoagulation safely, faster and with less bleeding than FFP.

Is haemovigilance improving transfusion practice?--The european experience.

Improving transfusion practice for a donor means a safer donation process and maximal use of the donation. From the clinical perspective, it includes the production of the right type of blood component of adequate quality, administered at the right dose at the right moment to the right patient in order to obtain the expected or anticipated effect in absence of harm. Transfusion practice involves not only the complete blood chain, i.e. from the donation to clinical usage, but also the input from the competent authority that bears responsibility for the concepts of improving health care practice. In Europe, experience has shown that haemovigilance offers an effective tool in improving transfusion practice.

Emergency reversal of oral anticoagulation through PPSB-SD: the fastest procedure in Belgium.

OBJECTIVE: To corroborate results obtained in The Netherlands with PPSB-SD, showing a safe acute reversal of anticoagulation within 15 minutes of administration. MATERIAL AND METHODS: PPSB-SD is a concentrate prothrombin complex containing a relatively constant high level of vitamin K-dependant coagulation factors II, VII, IX and X. PPSB-SD was administered to 14 patients treated with oral anticoagulants, according the patient's weight, the initial and the target INR (< 2.0 for moderate haemorrhage and abdominal surgery, or < 1.5 for severe haemorrhage and cardio-vascular interventions). INR values were measured with the Coagucheck Pro (Roche Diagnostics) upon admission and at 15 minutes, 1, 3 and 5 hours after treatment, and confirmed by the hospitals' laboratory. RESULTS: Within 15 minutes 11 patients out of 12 reached their INR target (data were missing for 2 patients). INR decreased rapidly, then remained stable for the next 5 hours. All patients had a favourable outcome: bleeding was stopped and no haemorrhage occurred during surgery. Only one adverse event was reported, but it was not related to the PPSB-SD treatment. No sign of disseminated intravascular coagulation was observed during this study. The administration of PPSB-SD along with vitamin K and dosed according to body weight and initial and target INR allowed for optimal reversal of anticoagulation, as no second infusion was necessary. The recommended dosing worked also very well for patients with high initial INR (9.2 to 22.8) who were brought down to normal values (0.9 to 1.1) within 15 minutes. CONCLUSION: PPSB-SD can safely be used for the rapid reversal of anticoagulation as needed in emergency situations.

PPSB as first choice treatment in the reversal of oral anticoagulant therapy.

In the treatment of reversal of oral anticoagulant therapy, a number of treatment modalities is available and depends on the severity of the clinical situation and the degree of the coagulopathy. FFP and PPSB (PCC) are commonly used in the treatment and/or in combination with cessation of oral anticoagulant therapy and administration of Vitamin K. The double viral inactivated plasma product PPSB-SD is the first choice treatment in this indication because of the relatively constant, high concentrated level of the Vitamin K dependent coagulation factors II, VII, IX and X, compared to FFP.

Continuous 48-h C1-inhibitor treatment, following reperfusion therapy, in patients with acute myocardial infarction.

AIMS: Complement inhibition by C1-inhibitor has been shown to reduce myocardial ischaemia-reperfusion injury in animal models. We therefore studied the effects of intravenous C1-inhibitor, following reperfusion therapy, in patients with acute myocardial infarction. METHODS AND RESULTS: C1-inhibitor therapy was started not earlier than 6h after acute myocardial infarction, in order to prevent interference with thrombolytic therapy. A loading dose of C1-inhibitor was followed by a continuous infusion for 48 h, using three escalating dosage schemes. Efficacy of complement inhibition was estimated from C4 activation fragments. Plasma concentrations of myocardial proteins were compared to values measured in matched control patients. In 22 patients, C1-inhibitor was well tolerated and drug-related adverse events were not observed. Target plasma levels of C1-inhibitor were reached, with values of 48.2 ml.kg(-1) for distribution space and 35.5h for the half-life time of C1-inhibitor. A dose-dependent reduction of C4 fragments was found P=0.005). In 13 patients who received early thrombolytic therapy, release of troponin T and creatine kinase-MB(mass) was reduced by 36% and 57%P =0.001), compared to 18 controls. CONCLUSION: Continuous 48-h treatment with C1-inhibitor provides safe and effective inhibition of complement activation after reperfused acute myocardial infarction and may reduce myocardial injury.

In vivo recovery and safety of human factor VIII product AAFACT in patients with haemophilia A.

AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT, were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe.