Surgery in patients with haemophilia and high responding inhibitors: Izmir experience

Summary. This report evaluates the haemostatic efficacy of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) in patients with haemophilia and high responding inhibitors who underwent major and minor surgery. Data pertaining to surgeries from 2001 to 2009 at a single centre were retrospectively analysed. During this period, 53 surgical procedures were performed in 30 haemophiliacs with high responding inhibitors. Mean age was 16.2 ± 9.4 years. Eleven major surgeries in 4 patients, 41 radioisotope synovectomies (RS) and one circumcision classified as minor surgery in 28 patients were performed. Among the major surgery procedures, four were treated with rFVIIa, five with APCC and two with sequential use of APCC and rFVIIa. We used rFVIIa at the dosage of 80–120 μg kg^?1 every 2 h and APCC 100 IU kg^?1 every 12 h for the major surgery. When performing RS, we used rFVIIa in 18 patients with 26 target joints and APCC in 9 patients with 15 target joints. Three consecutive doses of rFVIIa (90 μg kg^?1) were used at 2‐h intervals followed by additional three doses at 6‐h intervals. The initial dose of APCC was 75 IU kg^?1 followed by a second and third dose of 50 IU kg^?1 at 12‐h intervals. APCC and rFVIIa demonstrated excellent efficacy in our major and minor surgical interventions [100% (22/22) and 94% (31/33), respectively]. We had only two bleeding complications with rFVIIa. There were no thromboembolic complications. APCC and rFVIIa provide an effective and safe first line haemostatic therapy for inhibitor‐positive haemophiliacs, allowing both major and minor surgery to be successfully performed.     

Elective surgery in patients with congenital coagulopathies and inhibitors: experience of the National Haemophilia Centre of Venezuela

Summary. Elective surgery in patients with congenital haemophilia with inhibitors carries a high risk of bleeding. However, inhibitor patients also have a high risk of haemarthroses and other orthopaedic complications, and surgery could improve their quality of life. Successful elective surgery has been reported in inhibitor patients under haemostatic cover with plasma‐derived activated prothrombin complex concentrate (pd‐aPCC) or recombinant activated factor VII (rFVIIa). Recombinant FVIIa has recently become available in Venezuela and, unlike pd‐aPCC, has not been associated with an anamnestic response. The aim of this study was to assess our experience using rFVIIa as a first‐line and sustained treatment in elective invasive surgical procedures at the National Haemophilia Centre in Venezuela. Surgical procedures were classified as major or minor, under haemostatic cover with rFVIIa. A total of 13 patients (12 with haemophilia A with high‐responding inhibitors and one with von Willebrand’s disease type 3) underwent a total of 19 surgical procedures under rFVIIa cover. Thirteen procedures were classified as major surgeries. Intraoperative haemostasis was achieved in the majority of patients. Only two patients required an additional dose of rFVIIa, at 30 min and 75 min, respectively, with good results. Postoperative haemostasis was considered effective in 16 of 18 (89%) of the procedures in haemophilia A patients. Treatment was considered to be ineffective in two patients because of excessive postoperative bleeding. Data from the study provide no safety concerns, and demonstrate that rFVIIa provides effective haemostatic cover in elective surgery in patients with inhibitors; research is ongoing to determine the optimal dose for such procedures.     

Experience of recombinant activated factor VII usage during surgery in patients with haemophilia with inhibitors

Inhibitor development is one of the most challenging complications of haemophilia management. Haemostatic control in patients with haemophilia with inhibitors can be difficult, and is especially risky in those undergoing surgical interventions. Most haemophilia patients with inhibitors suffer from chronic joint disease requiring surgical correction due to recurrent bleeding episodes. The aim of this study was to assess the use of recombinant activated factor VII (rFVIIa) as haemostatic therapy during orthopaedic surgery in haemophilia patients with inhibitors. A series of case reports was retrospectively collected to describe clinical experience of rFVIIa use in inhibitor patients undergoing a range of orthopaedic surgical procedures at a single centre. All surgeries were performed using standard methods. All patients received rFVIIa at a starting dose of 120 μg kg^?1 with the subsequent regimens depending on the type of surgery. rFVIIa provided effective haemostasis in 23 patients with haemophilia A and inhibitors (15 with high inhibitor titres) undergoing orthopaedic surgery. The majority (70%) of surgical procedures were major (joint and extra‐articular surgery). The doses and intervals of rFVIIa treatment used varied depending on the severity of bleeding, and the type (major or minor) or site of surgery. In all cases, administration of rFVIIa achieved good haemostasis. In all 23 patients with haemophilia with inhibitors, rFVIIa treatment in orthopaedic interventions proved to be an efficient haemostatic agent, providing effective intra‐operative and postoperative haemostasis.     

Combination of FVIII and by-passing agent potentiates in vitro thrombin production in haemophilia A inhibitor plasma

The by-passing agents, recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC), are important tools in the treatment of patients with haemophilia A and high-responding inhibitory antibodies. It has been observed clinically that in some patients undergoing immune tolerance induction the bleeding frequency decreases, hypothetically caused by a transient haemostatic effect of infused FVIII not measurable ex vivo. We evaluated how by-passing agents and factor VIII (FVIII) affect thrombin generation (TG) in vitro using plasma from 11 patients with severe haemophilia A and high titre inhibitors. Samples were spiked with combinations of APCC, rFVIIa and five different FVIII products. Combination of APCC and FVIII showed a synergistic effect in eliciting TG (P<0·005) for four FVIII products. When rFVIIa and FVIII were combined the interaction between the preparations was found to be additive. APCC and rFVIIa were then combined without FVIII, resulting in an additive effect on thrombin production. Each product separately increased TG above baseline. In conclusion, the amount of thrombin formed in vitro by adding a by-passing agent, was higher in the presence of FVIII. Our findings support the use of FVIII in by-passing therapy to optimize the haemostatic effect.     

Cost‐effectiveness of recombinant activated factor VII vs. plasma‐derived activated prothrombin complex concentrate in the treatment of mild‐to‐moderate bleeding episodes in patients with severe haemophilia A and inhibitors in Spain

Several analyses have shown that recombinant activated factor VII (rFVIIa) is a cost‐effective intervention compared with plasma‐derived activated prothrombin complex concentrate (pd‐aPCC) for the on‐demand treatment of mild‐to‐moderate bleeds in haemophilia patients with inhibitors. The aim of the study was to assess the cost‐effectiveness of rFVIIa vs. pd‐aPCC in the treatment of bleeding episodes in severe haemophilia A patients with inhibitors in Spain. A decision analytic model was designed to evaluate the costs and clinical outcomes of using rFVIIa or pd‐aPCC to treat mild‐to‐moderate joint bleeds in children (≤14 years old) and adults with inhibitors. Data were obtained from a published meta‐analysis and a panel of haemophilia experts. The analysis was conducted from the perspective of the Spanish National Healthcare System. One‐way sensitivity analyses were performed to assess the impact of model assumptions on study results. In the Treur meta‐analysis, rFVIIa resulted in cumulative joint bleed resolution of 88% and 95% after 24 and 36 h, respectively, compared with 62% and 76%, respectively, with pd‐aPCC (Treur et al. Haemophilia 2009; 15 : 420–36). Here, the mean cost per bleed was estimated at €8473 and €15 579 in children and adults treated with rFVIIa, vs. €8627 and €15 677 in children and adults treated with pd‐aPCC. rFVIIa treatment was found to be the dominating option (cheaper and more effective). The one‐way sensitivity analysis also confirmed that rFVIIa was less costly than pd‐aPCC. The model suggests that rFVIIa is a cost‐effective option compared with pd‐aPCC for the treatment of mild‐to‐moderate bleeding episodes in a Spanish setting.     

The benefits of prophylactic treatment with APCC in patients with haemophilia and high-titre inhibitors: a retrospective case series

Summary.  Prophylactic infusion of factor concentrates is a safe, effective intervention for preventing arthropathy in patients with haemophilia; on-demand treatment is insufficient to prevent the orthopaedic complications and subsequent haemophilic arthropathy that stem from recurrent joint haemorrhages. The usefulness of prophylaxis in haemophilia patients without inhibitors suggests that patients with haemophilia and inhibitors could derive similar benefits. In patients with haemophilia and high-titre (>5 BU mL⁻¹) inhibitors, bleeding episodes are treated with bypassing agents such as activated prothrombin complex concentrates (APCCs) and recombinant activated factor VII (rFVIIa, N ovo S even ^®; Novo Nordisk A/S, Bagsvaerd, Denmark). It is possible to administer bypassing therapy regularly to prevent haemorrhages, with the goal of limiting arthropathy and serious life- and limb-threatening bleeding. The data evaluating the efficacy and safety of this approach in patients with inhibitors are limited, consisting of results from one prospective trial and retrospective case reports. This report describes our experience with the prophylactic use of the APCC Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA™; Baxter AG, Vienna, Austria). Data from patients at one treatment centre were retrospectively evaluated. Case records of six patients with haemophilia A or B and high-titre inhibitors were identified. When APCC was administered regularly, most patients exhibited a reduction in the numbers of haemorrhages, an improvement in orthopaedic status, and an improvement in quality of life. Prophylaxis with APCC can reduce haemorrhages and halt further joint deterioration in patients with haemophilia and inhibitors.     

Surgical interventions in a cohort of patients with haemophilia A and inhibitors: an experiential retrospective chart review

Strategies for the management of perioperative bleeding in patients with haemophilia and inhibitors have evolved rapidly as a result of the development of the bypassing agents Factor Eight Inhibitor Bypassing Activity, Anti-inhibitor Coagulant Complex (FEIBA) and activated recombinant factor VII (rFVIIa). However, there are currently no established guidelines for perioperative use of bypassing agents, and few controlled clinical studies have been carried out. Thus, case reports, such as those presented here, provide useful anecdotal evidence to guide the treatment of inhibitor patients. The purpose of this report was to describe experiences in the use of bypassing agents in a small cohort of patients with haemophilia A and inhibitors undergoing surgical procedures. Cases from five treatment centres were reviewed. Twenty-two procedures using FEIBA, rFVIIa or a combination of both agents were compiled from seven inhibitor patients (six with an alloantibody inhibitor and one with an acquired autoantibody inhibitor). Eleven procedures used FEIBA monotherapy, two employed rFVIIa monotherapy and nine were performed using combination therapy. Supplemental therapies were required to manage bleeding in some cases. Haemostatic control was achieved in all cases, and treatment regimens were generally well tolerated. One thrombotic adverse event was reported: evidence of disseminated intravascular coagulation (DIC) was found after rFVIIa use in one case, although the direct cause of DIC was unknown. The experiences in this case review demonstrate that both major and minor surgical procedures can be safely performed in patients with haemophilia and high-titre inhibitors under the cover of bypassing agents, with a high expectation of success.     

A cost minimization model for the treatment of minor bleeding episodes in patients with haemophilia A and high-titre inhibitors

Treatment of acute bleeding episodes in patients with haemophilia A and inhibitory antibodies to factor VIII (FVIII) most often involves the use of bypassing haemostatic agents, such as activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa). We constructed a cost minimization model to compare the costs of initial treatment with aPCC vs. rFVIIa in the home treatment of minor bleeding episodes. We developed a clinical scenario describing such a case and presented it to a panel of US haemophilia specialists. For each product class, we asked panellists to provide dosing regimens required to achieve complete resolution of a minor haemarthrosis in a child with high-titre inhibitors, and for the probabilities of success at two time points (8-12 and 24 h). Consensus among the panellists was refined by a second round of the process, and the median values resulting were used as inputs to a decision analysis model. Sensitivity analyses were conducted to determine threshold values for key variables. The base case model found that initial treatment with aPCC would result in a mean cost per episode of 21 000 dollars, compared with 33 400 dollars for initial treatment with rFVIIa. Sensitivity analyses over a range of clinically plausible values for cost, dosing, and efficacy did not change the selection of aPCC as the dominant strategy.     

Ten‐year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.     

Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors

Summary. Some 10–20% of bleeding events in haemophilia patients with high‐responding inhibitors cannot be controlled with bypassing agents. However, sequential combined bypassing therapy (SCBT) has been reported to be successful in five children. To extend this observation, a survey was undertaken by the European Haemophilia Treatment Standardisation Board (EHTSB) in children and adults. Data were collected from all centres belonging to the EHTSB network by a retrospective medical record review. SCBT courses were defined as the administration of both recombinant activated factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within 12 h. A web‐based database was prepared to collect data on SCBT courses in a standardized and anonymous manner from patients’ files. Eleven inhibitor patients underwent SCBT (nine haemophilia A; two haemophilia B). Two children had refractory knee haemarthrosis and one, an unresponsive calf haematoma. Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post‐traumatic upper limb haematoma and haemarthrosis. SCBT administration alternated one APCC dose to 1–3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20–80 U kg^?1) was given every 8–12 h; rFVIIa (90–270 μg kg^?1) was given every 3–12 h. Bleeding control was achieved in 12–24 h in all patients. SCBT was discontinued after 1–15 days. No clinical adverse events were observed, but a significant increase in D‐dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A prospective clinical trial is needed to provide further evidence.     

Major surgery in severe haemophilia A with inhibitors using a recombinant factor VIIa and activated prothrombin complex concentrate hybrid regimen

Major surgery in persons with haemophilia A and inhibitors is increasingly being performed. Both recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC) are used to cover surgery but it remains unclear what the optimal dosing schedules are. We describe the use of a hybrid regimen in four inhibitor patients undergoing eight major surgical procedures using rFVIIa in the initial 2–6 postoperative days followed by FEIBA^® for the remaining period. All patients were also treated with tranexamic acid while receiving rFVIIa. We performed six major orthopaedic procedures, one emergency orchidectomy and one open appendectomy. The dosing schedules were at the higher end of those described in the literature but within the recommendations of the summary of product characteristics. Despite this, we encountered non‐surgical bleeding in four of eight episodes. Three of these occurred in one individual suggesting a patient factor. The overall outcome was good for all episodes. The hybrid regimen combines flexibility of dose and dosing frequency of rFVIIa in the immediate postoperative setting with the advantage of a reduced dosing frequency with FEIBA^® in the subsequent days. This study also emphasizes that surgical procedures in this patient group remain a challenge.     

Economical comparison of APCC vs. rFVIIa for mild‐to‐moderate bleeding episodes in haemophilia patients with inhibitors

Summary. To construct a cost‐minimization model comparing activated prothrombin complex concentrates (APCC) vs. recombinant factor VIIa (rFVIIa) in haemophilia patients with inhibitors from a US third party payer perspective. A literature‐based decision model was used to model inhibitor treatment costs and outcomes. As existing clinical trials fail to demonstrate differences in the relative efficacy or safety of APCC vs. rFVIIa, we assumed the same efficacy for both products in the base‐case. Regimens of APCC (75 IU kg^?1 × 2 doses) and rFVIIa (90 μg kg^?1 × 3 doses) were assumed according to manufacturer recommendations. If the first‐line treatment failed, patients chose to continue the current treatment or switch to another drug. All costs were adjusted to 2009 US dollars. Sensitivity analyses on the infusion frequency, efficacy, unit price, switch rate, re‐bleed rate and body weight were performed to assess model robustness. In the base‐case, the total medical cost to treat a bleed with APCC or rFVIIa as first‐line medication was US$25 969 and US$35 838, respectively. One‐way sensitivity analyses showed that results were insensitive to the efficacy of rFVIIa, unit price of APCC or rFVIIa, switch rate, re‐bleed rate or body weight. The rFVIIa will reach cost neutrality when the efficacy of APCC is as low as 60%, or rFVIIa is infused only twice for each line, or APCC is infused three times for each line. Two‐way sensitivity analyses showed that results were quite sensitive to the assumed infusion frequency for both products. First‐line APCC compared with rFVIIa can be a cost‐saving alternative for home treatment of mild‐to‐moderate bleeds in haemophilia patients with inhibitors.     

Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literature

Summary.  Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven^®) is one of the treatments available for acute life-threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 μg kg⁻¹ bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences.     

Combined treatment with APCC (FEIBA®) and tranexamic acid in patients with haemophilia A with inhibitors and in patients with acquired haemophilia A – a two‐centre experience

The management of bleeding in haemophilia patients with inhibitors can be challenging when using monotherapy with either activated prothrombin complex concentrate (APCC) or recombinant activated FVII (rFVIIa) fail. The antifibrinolytic agent tranexamic acid (TXA) increases clot stability and is used concomitantly with coagulation factor replacement to improve haemostasis in haemophilia patients without inhibitors in many countries in Europe. Combined treatment with TXA and rFVIIa is not contraindicated in haemophilia patients with inhibitors. However, the combined approach of TXA and APCC has not been investigated due to safety concerns of increased risk of thrombosis or disseminated intravasal coagulation (DIC). The aim of this study is to report our experience of concomitant use of APCC and TXA in haemophilia A patients with inhibitor and in patients with acquired haemophilia A with respect to safety and efficacy. Seven (n = 6) haemophilia A patients with inhibitors and one (n = 1) with acquired haemophilia A from Oslo (Norway) and Stockholm (Sweden) were included in the study. The APCC was given at doses consistent to the manufacturers' recommendation. TXA was administered concomitantly either 10 mg kg(-1) every 6-8 h intravenously or 20 mg kg(-1) every 6-8 h orally. Haemostatic response was assessed by thromboelastography (TEG) and thrombin generation assay (TGA) in three of the patients. A total number of three bleeding episodes and two minor and six major surgical procedures were performed under the coverage with APCC and TXA. Haemostatic outcome was rated excellent or good in 10 of 11 (91%) treatment episodes. One episode was rated with poor effect. No episodes of arterial, venous thrombosis or DIC occurred during or after the treatment. Data from TEG and TGA analysis showed no signs of hypercoagulability following the combined treatment. This report demonstrates that, in a limited number of patients, combined treatment with APCC and TXA seemed to be safe, tolerated and relatively effective in management of bleeding episodes and in preventing haemorrhage during surgery in haemophilia patients with inhibitors and in a patient with acquired haemophilia A. Further studies should be performed to confirm these data.     

Surgery in haemophilic patients with inhibitor: 20 years of experience

Summary.  Surgery in haemophilic patients with inhibitor against factor (F)VIII or FIX is high risk. Surgery may be performed with the administration of sufficiently high dose of FVIII in patients with low-response inhibitor or who, despite having a high response, present a low inhibitor titre at the time of surgery. The use of high doses of FX is more complicated in patients with a low-titre FIX inhibitor, as there is a high risk of anaphylactic reactions. In the case of patients with high-titre inhibitors, several treatments have been proposed, such as porcine FVIII, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrate (APCC). We present our 20 years' experience in the treatment and subsequent management of haemophilic patients with inhibitor in surgery and evaluate the results obtained with the products available for haemostatic control in 64 surgical procedures. The efficacy we obtained with FVIII is good in 100% of the cases described; we had no haemorrhagic complication (HC) in the 18 procedures in which it was used (three major and 15 minor surgery). With APCC we obtained excellent results with only one HC in a synoviorthesis in the form of bleeding and haematomas out of 32 procedures. Good results were obtained with rFVIIa with few haemorrhagic episodes. Thus, in major surgery there was one HC out of three cases. In minor surgery, greater efficacy was observed using extremely large doses of rFVIIa (≥ 120 mg kg⁻¹ 2h⁻¹) because of the shorter half-life of this factor in this type of patients.     

Orthopaedic surgery in haemophilic patients with inhibitors: an overview

Our experience and a review of the literature on inhibitors have shown that, with the availability of recombinant factor VIIa (rFVIIa), haemophilic patients with high inhibitor titres requiring elective orthopaedic surgery can undergo such surgery with a high expectation of success. The advent of rFVIIa has made major elective orthopaedic surgery possible in haemophilic patients with high-titre inhibitors, resulting in an improved quality of life. Recombinant FVIIa appears to be an efficient haemostatic product for surgery in patients suffering from haemophilia A and B with inhibitors. The series of major elective orthopaedic surgical procedures using rFVIIa (n=53) is the largest ever reported in haemophilic patients with inhibitors, despite the long-standing presence of other treatment modalities, such as high-dose human factor VIII (FVIII), porcine FVIII (n=8), and prothrombin complex concentrates/activated prothrombin complex concentrates (n=9). Thorough analysis of each case as part of a multidisciplinary team will allow us to perform elective orthopaedic procedures in patients with inhibitors.     

Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and inhibitors

Patients with haemophilia and inhibitors have bleeding episodes that can be refractory to home therapy with either activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa). Sequential therapy with these products has not been widely used because of concern regarding the possibility of thrombosis. This report describes the results of a retrospective chart review of five hospitalized children with severe haemophilia and inhibitors who have been treated with sequential doses of APCC and rFVIIa for refractory bleeding. These patients all had failed home therapy with APCC and rFVIIa alone. A total of 20 admissions were documented covering 170 hospital days, including 91 days of combination therapy. While being closely monitored in the hospital, they received alternating doses of APCC and rFVIIa every 6 h. Anywhere from one to three doses of rFVIIa were given every 2 h between APCC doses. Doses of APCC ranged from 35 to 80 U kg(-1) dose(-1), and doses of rFVIIa ranged from 80 to 225 mcg kg(-1) dose(-1). There was no clinical or laboratory evidence of thrombosis, thrombocytopenia, or disseminated intravascular coagulation (DIC). We found the combination of these factors to be safe and effective for patients with refractory bleeds. However, we recommend this aggressive therapy only in the inpatient setting with careful monitoring of the physical examination and frequent laboratory screening to assess for thrombosis and DIC, and without the concurrent use of antifibrinolytic medications.     

Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres

Many patients with haemophilia develop inhibitors to factor VIII and require bypassing agents to provide haemostatic cover for limb- or life-threatening bleeding episodes. Due to the reduced risk of blood-borne pathogen transmission with recombinant products, on-demand recombinant factor VIIa (rFVIIa; NovoSeven is the treatment of choice for children with inhibitors. In haemophiliac patients without inhibitors, primary prophylaxis has been clinical practice for several years. This paper summarises 13 case histories of rFVIIa secondary prophylaxis for haemophilia patients with inhibitors. This was a retrospective survey of adult and paediatric severe haemophilia patients with inhibitors treated with rFVIIa from ten European Haemophilia Centres. There was a wide variation in administered rFVIIa dose, from 200-250 microg kg(-1) per week to 220 microg kg(-1) daily. In many cases, this was lower than the recommended on-demand dose of rFVIIa. In 12/13 cases, prophylaxis with rFVIIa considerably reduced the number of bleeding episodes compared with previous treatment. Eight/nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life (QoL), all were improved, much improved, or significantly improved. In haemophilia patients with inhibitors, prophylaxis with rFVIIa is highly effective in reducing the number of bleeding episodes and results in good patient compliance and improved QoL. Randomised controlled trials are needed to confirm these findings. Results of a recently completed clinical trial on secondary prophylaxis with rFVIIa in frequently bleeding haemophilia patients with inhibitors are expected in late 2006.     

Rapid rFVIIa enhanced on‐demand dosing in haemophilia inhibitor patients

Recombinant factor VII activated (rFVIIa) is a bypassing agent widely used in haemophilia A and B patients with antibodies against coagulation factors VIII or IX. When used according to the correct doses, rFVIIa may control bleeding, subclinical bleeding and rebleeding, avoiding the effect of neutralising inhibitors. Because of the fast action of the rFVIIa, haemostasis occurs promptly and enables a fast bleeding control with on‐demand treatment in home or in surgical setting. Rapidity is also a distinguishing feature in preparation and injection of rFVIIa to cope the restraining times of busy patients and parents. The effective haemostatic activity of rFVIIa enables a sustained bleeding control, which is implemented with every other day (eod) administration and suited for enhanced on‐demand therapy and short‐term repeated infusions use of rFVIIa to prevent microhaemorrhages or rebleeding. Comprehensive appreciation of these pharmacological and pharmacodynamic’ characteristics will likely be a further stimulus to the wider enhanced on‐demand use of rFVIIa.     

A systematic review of the cost-effectiveness of rFVIIa and APCC in the treatment of minor/moderate bleeding episodes for haemophilia patients with inhibitors

Summary.  The clinical, humanistic and economic consequences associated with haemophilia and inhibitors are considerable. Primary treatment for mild-to-moderate bleeding disorders in such patients is recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (APCC). The aims of this study were to identify, review and evaluate the quality of the published literature on the relative cost-effectiveness of rFVIIa and APCC in treating haemophilia patients with inhibitors. The review concentrates on model type, design and assumptions, and results. The results of this study suggest that rFVIIa may be the cost-effective alternative to treatment with APCC. In seven out of the nine studies, rFVIIa had the lower average treatment cost. The difference in average treatment cost to resolve a bleed, between rFVIIa and APCC in these seven studies, ranged from $3000 to $17 000. The adapted modelling framework is similar in all the economic models reviewed, suggesting clinical acceptability of the approach used. The estimates of efficacy varied between the models, especially for APCC. The efficacy for APCC derived from retrospective studies was lower than reported in the literature. Sensitivity analysis was undertaken in the majority of the economic analyses and the results were found to be robust to realistic parameter variations. Only one of the studies was a cost-utility study, showing the lack of measuring health status within this area. This systematic review showed that models based on different sources of data produced fairly similar robust results despite differences in the estimates of efficacy, average dosage required, and unit costs. However, ideally there should be a systematic approach to identifying the relevant data.