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.     

Cost and effectiveness of treatments for mild-to-moderate bleeding episodes in haemophilia patients with inhibitors in Korea

Summary.  First-line treatment for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Korea is currently activated prothrombin complex concentrate (aPCC) with recombinant activated factor VII (rFVIIa) as second-line therapy or as a last resort. The aim of this study was to estimate the cost and effectiveness of aPCC vs. rFVIIa for treating mild-to-moderate bleeds in inhibitor patients from the Korean reimbursement authorities' perspective. Clinical outcomes and resource utilization data (number of doses, average dose, number of outpatient visits, inpatient stays, ambulance transport and concomitant medications) were collected from an observational study involving four Korean paediatric haemophilia centres. Cost-effectiveness was modelled using a decision analysis approach and sensitivity analyses undertaken. rFVIIa was a more effective haemostatic therapy (87.1% efficacy in bleed resolution) than aPCC (64.0%). rFVIIa effected more rapid haemostasis, resolving bleeding in a mean of 6.6 h vs. 25.2 h for aPCC. Fewer rFVIIa doses were required per bleed vs. aPCC (means 1.7 and 2.3). Mean total direct medical costs from bleed initiation to cessation were estimated at Korean Won (KRW)12 460 thousand (US$12 311) for rFVIIa given as first-line therapy and KRW18 304 thousand (US$18 085) for aPCC given as first-line therapy. Sensitivity analyses confirmed the cost-effectiveness of rFVIIa vs. aPCC given as first-line therapy. In Korea, use of rFVIIa as first-line therapy for treatment of mild-to-moderate bleeding episodes in inhibitor patients is both clinically effective and cost-effective compared with initial aPCC treatment. rFVIIa should be considered as the first-line treatment for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Korea.     

Prediction of the haemostatic effects of bypassing therapy using comprehensive coagulation assays in emicizumab prophylaxis-treated haemophilia A patients with inhibitors

In emicizumab prophylaxis, the concomitant therapy using bypassing agents (BPAs) is required for breakthrough bleeding and invasive procedures with attention to thrombotic complications. To predict coagulant effects of BPAs in emicizumab-treated patients with haemophilia A (PwHA) with inhibitor (PwHAwI), blood samples from emicizumab-treated PwHAwI (n = 8) and PwHA without inhibitor (n = 2) in phase 1/2 and HAVEN 1 study, spiked with activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa) ex vivo, and blood samples from emicizumab-treated PwHAwI-receiving BPAs were analysed by Ca²⁺-triggered rotational thromboelastometry (ROTEM) and ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Spiked aPCC, corresponded to 10–100 U/kg, markedly shortened ROTEM parameters beyond the normal range, while spiked rFVIIa, corresponded to 90–270 μg/kg, shortened them within near-normal range. Each of the spiked BPA-improved adjusted maximum coagulation velocity of CWA to within or near the normal range. In blood samples at post-infusion of aPCC (44–73 U/kg) or rFVIIa (79–93 μg/kg), the parameters of both assays improved to approximately the normal range. Taken together, ex vivo results of spiking tests in ROTEM and CWA, except aPCC spiking test in ROTEM, were relatively consistent with in vivo ones, and could usefully predict the coagulant effects of concomitant bypassing therapy for emicizumab-treated PwHAwI.     

Monitoring bypassing agent therapy – a prospective crossover study comparing thromboelastometry and thrombin generation assay

The aim of this study was to evaluate the capability of thromboelastometry (ROTEM) and thrombin generation assay (TGA) to monitor the treatment response of bypassing agent (BPA) therapy and to study whether one method is superior to another. In a prospective crossover study haemophilia A patients with high titre inhibitors were included to receive a dose of 75 U kg^?1 activated prothrombin complex concentrates (aPCC) intravenously. Blood sampling was performed at baseline, 15, 30 min, 1, 2, 3 and 4 h post‐infusion for TGA and ROTEM analysis. After a washout period of 14 days the subjects received recombinant FVIIa (rFVIIa) at a dose of 90 μg kg^?1 and similar blood sampling was performed. Healthy subjects were used as controls. Six haemophilia A patients with inhibitors were included. We found that TGA parameters endogenous thrombin potential (ETP) and peak thrombin increased 2–3 folds from baseline 15–30 min after infusion. ROTEM parameters MaxVel and maximum clot firmness increased to a level comparable to that of healthy controls. An individual difference in response was observed for different parameters among participants. ETP and peak thrombin were almost two‐fold greater following aPCC infusion compared to rFVIIa, whereas ROTEM parameters showed no difference in response between the two products. The study showed that ROTEM and TGA have a great potential to evaluate the effect of BPA in haemophilia patients with inhibitors. TGA seemed to be more sensitive than ROTEM in reflecting the difference in treatment response between aPCC and rFVIIa. Additional prospective clinical studies are needed to clarify which assay and what parameters are clinically predictive.     

A cost evaluation of treatment alternatives for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil

Summary.  The first-line treatment for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil is currently activated prothrombin complex concentrate (aPCC), with recombinant activated factor VII (rFVIIa) used as second-line therapy or as a last resort. The aim of this study was to determine the cost and effectiveness of these treatments from the perspective of the Brazilian National Health Service. A decision analysis model was constructed to assess total direct medical costs (including drug costs, costs of outpatient or inpatient care, ambulance transportation and cost of concomitant medications) of first-line treatment with aPCC or rFVIIa. Clinical outcome and resource utilization data were obtained both retrospectively and prospectively and validated by the consensus of an expert panel of Brazilian haematologists. A total of 103 bleeds in 25 patients were included in the analysis. rFVIIa resolved bleeds more quickly (4.4 h) than aPCC (62.6 h) and was more effective (100% vs. 56.7% respectively). Mean total direct medical costs (from initiation to cessation of bleed) were estimated to be US$13 500 (aPCC) and US$7590 (rFVIIa). Extensive sensitivity analyses confirmed the cost-effectiveness of rFVIIa. Compared with aPCC, rFVIIa was more effective and less expensive when used as first-line treatment for mild-to-moderate bleeding episodes in patients with haemophilia and inhibitors in Brazil. rFVIIa should be considered a first-line treatment for the management of these patients.     

Thrombin generation and fibrinolysis in anti‐factor IX treated blood and plasma spiked with factor VIII inhibitor bypassing activity or recombinant factor VIIa

Summary. Activated prothrombin complex concentrates (aPCC) and recombinant activated factor VIIa (rFVIIa) are two important therapies in haemophilia patients with inhibitors and improve clot stability. We hypothesized that potential differences in procoagulant and fibrinolytic actions of aPCC and rFVIIa may lie in the clot stability against fibrinolytic activation. We used thrombin generation, fluorescence detection and thromboelastometry in anti‐factor IXa (FIXa) aptamer‐treated whole blood (WB) and plasma to evaluate: (i) generation of thrombin and activated factor X (FXa) and (ii) viscoelastic properties of blood clots in the presence of tissue plasminogen activator (tPA) after addition of aPCC (0.4 U mL^?1) or rFVIIa (60 nm ). Peak thrombin generation increased from 85 ± 19 nm in aptamer‐treated plasma to 276 ± 83 nm and 119 ± 22 nm after addition of aPCC and rFVIIa respectively (P < 0.001). FXa activity increased within 20 min by 87 ± 6% and by 660 ± 97% after addition of aPCC and rFVIIa respectively (P < 0.001). TPA‐induced lysis time increased from 458 ± 378 s in aptamer‐treated WB to 1597 ± 366 s (P = 0.001) and 1132 ± 214 s (P = 0.075), after addition of aPCC and rFVIIa respectively. In this haemophilia model using the anti‐FIXa aptamer, the larger amount of thrombin was generated with aPCC compared with rFVIIa, while FXa generation was more rapidly increased in the presence of rFVIIa. Furthermore, clot formation in anti‐FIXa aptamer‐treated WB was less susceptible to tPA‐induced fibrinolysis after adding aPCC compared with rFVIIa.     

Factor (F)VIII/VIIa enhances global haemostatic function in the co‐presence of bypassing agents and FVIII among patients with haemophilia A with inhibitor

Bypassing therapy is essential for the haemostatic management of patients with haemophilia A with inhibitor (PWHA‐inh), but the therapeutic effects are inconsistent. We previously reported that activated prothrombin complex concentrates (aPCC) activated factor (F)VIIIin vitro, and was mediated mainly by the activated FVII (FVIIa) contained in aPCC. We have extended those studies to assess global coagulation in whole blood from 18 PWHA‐inh in the co‐presence of aPCC and FVIII using Ca²⁺‐triggered rotational thromboelastometry. The clot times (CTs) in the presence of both aPCC (0·05 iu/ml) and recombinant (r)FVIII (1 iu/ml) ex vivo were shortened compared to the aPCC alone (P < 0·01). These enhancing effects of rFVIII were observed, irrespective of recognizing inhibitor epitopes; however, the clot formation time and ‘α’‐angle were not significantly different. In samples from 7 PWHA‐inh post‐infusion of aPCC (70‐80 iu/kg), only the CTs were shortened in the presence of rFVIIIex vivo compared to its absence (P < 0·05), indicating that the enhanced activity centred on the initiation phase of coagulation. Furthermore, experiments in the co‐presence of rFVIIa and rFVIII demonstrated that FVIII accelerated only the CTs. We concluded that FVIII/FVIIa‐related coagulation mechanism enhanced global haemostatic function by the co‐presence of bypassing agents and FVIII in PWHA‐inh.     

Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors

Haemophilia patients with inhibitors require bypassing agents (BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid (TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers (N = 5) and haemophilia inhibitor patients (N = 6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20 mg kg^?1 orally (O.R.) Patients were treated with aPCC 75 IU kg^?1 intravenous (I.V.) on day 1 followed by TXA 20 mg kg^?1 O.R. combined with aPCC 75 IU kg^?1 I.V. on day 2. A 14‐day washout occurred before crossover to rFVIIa 90 μg kg^?1 I.V. ±TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240 min post treatment. Primary outcome was maximum clot firmness (MCF) evaluated by whole blood thromboelastometry using a TF + tissue plasminogen activator‐based assay. Healthy controls showed a 20‐fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF (P < 0.0001) reaching levels indistinguishable from healthy controls treated with TXA (P > 0.05). Infusion of aPCC or rFVIIa alone induced only 3–10 fold increase in MCF from baseline, with a decline in MCF starting after 60–120 min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed.     

IL28RA polymorphism is associated with early hepatitis C virus (HCV) treatment failure in human immunodeficiency virus‐/HCV‐coinfected patients

Due to the poor rate of response to hepatitis C virus (HCV) with pegylated interferon and ribavirin treatment in HCV/HIV coinfected patients, key factors for predicting failure would be useful. We performed a retrospective study on 291 patients on HCV treatment, who had early virological response (EVR) data. IL28B and IL28RA polymorphisms were performed using the GoldenGate^® assay. Unfavourable genotypes at IL28B (rs12980275 AG/GG and rs8099917 GT/GG) and an unfavourable allele at IL28RA (rs10903035 G) were associated with early treatment failure. However, only the rs12980275 AG/GG genotype and rs10903035 G allele remained independently associated with early failure in the overall population (OR = 4.15 (95% CI = 1.64–10.54) and OR = 2.00 (95% CI = 1.19–3.36), respectively) as well as in GT1/4 patients (OR = 5.07 (95% CI = 1.81–14.22) and OR = 2.03 (95% CI = 1.13–3.66), respectively). Next, a decision tree showed early treatment failure increased from 37.1% to 65.5% when the unfavourable rs12980275 AG/GG and rs10903035 AG/GG genotypes and HCV‐RNA≥ 500.000 IU/mL were taken into account in GT1/4 patients. In contrast, the failure rate decreased from 37.1% to 11.9% when the favourable rs12980275 AA and rs10903035 AA genotypes were detected. The percentage of patients correctly classified was 78.4%, and AUROC was 0.802 ± 0.028. Regarding GT3 patients, the presence of the GCGCA haplotype (all unfavourable alleles) was associated with early treatment failure, while no association was observed for the IL28B polymorphisms. In conclusion, the IL28RA polymorphism was associated with early treatment failure independently of the IL28B SNPs. The combination of IL28B and IL28RA polymorphisms might be a valuable tool for predicting early treatment failure before starting HCV treatment.     

Health‐related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti‐inhibitor complex concentrate: results from the Pro‐FEIBA study

Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health‐related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short‐Form (SF)‐36 Health Survey and the EQ‐5D questionnaire in subjects ≥14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on‐demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on‐demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF‐36 dimensions except for vitality/energy and physical functioning. After prophylaxis, ‘good responders,’ defined as patients experiencing ≥50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role – physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ‐5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on‐demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ‐5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on‐demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on‐demand treatment.     

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.     

Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise) registry

Although extremely rare, acquired haemophilia A (AHA) can cause severe bleeding, which may be fatal. The underlying causes of autoantibody development are not fully understood. Treatment goals are bleeding control and autoantibody eradication. At the time of our study, there was no consensus on a standard treatment strategy for AHA. Previous data were mainly retrospective or from single‐centre cohorts. We conducted a prospective, controlled, registry‐based study of patients with AHA in France. The prospective French registry (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise [SACHA]) collected data on prevalence, clinical course, disease associations and outcomes for haemostatic treatment and autoantibody eradication in 82 patients with a 1‐year follow‐up. Similar to earlier studies, the prevalence of AHA was higher in the elderly, with two thirds of patients aged >70 years. Around half of AHA cases were associated with underlying disease, most commonly autoimmune disease and cancer in younger and older patients respectively. Haemostatic treatment was initially administered to 46% of patients. Complete resolution or improvement of initial bleeding occurred in 22/27 (81%) rFVIIa‐treated patients and in all six cases receiving pd‐aPCC. The majority of patients (94%) received immunosuppressive therapy, with complete remission at 3 months in 61% (36/59) and in 98% (50/51) at 1 year. Overall mortality was 33%: secondary to bleeding in only three patients but to sepsis in 10. Bypassing agents were effective at controlling bleeding in patients with AHA. Immunosuppressive therapy should be used early but with caution, particularly in elderly patients.     

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus‐based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90–120 μg/kg is the favoured starting dose in most settings. Initial dosing using 90–180 μg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2‐hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors.     

Presentation and management of acute coronary syndromes among adult persons with haemophilia: results of an international,retrospective, 10‐year survey

Sparse data are available on presentation and management of acute coronary syndromes (ACS), including unstable angina and non‐ST‐ and ST‐elevation myocardial infarction, among persons with haemophilia (PWH). The aim of this study was to determine demographics, bleeding disorder characteristics, cardiovascular risk factors (CRFs), interventions, haemostatic protocol, revascularization outcomes and complications among PWH with ACS. Members of an international consortium comprising >2000 adult PWH retrospectively completed case report forms for episodes of ACS in a >10‐year follow‐up period (2003–2013). Twenty ACS episodes occurred among 19 patients [rate, 0.8% (95% CI 0.4, 1.2)]. Seven patients (37%) were aged <50 years; 10 (53%) had ≥3 CRFs. In 5/20 episodes (25%), the initial ACS management protocol was altered because of the bleeding disorder. None of the eight patients with severe haemophilia underwent coronary artery bypass grafting (CABG), compared with 54.5% of patients with non‐severe disease (P = 0.02). Revascularization with percutaneous coronary intervention (PCI) or CABG was rated successful in 13/13 cases, with no excessive bleeding during initial management. During chronic exposure to antiplatelet agents, secondary haemophilia prophylaxis was more prevalent in patients with severe haemophilia compared with non‐severe haemophilia (85.7% vs. 30%, P = 0.05). No ACS‐related deaths occurred during initial management, but one patient with severe haemophilia A died of undetermined cause 36 months after the ACS event while on aspirin therapy. ACS occurs even among relatively younger PWH, typically in association with multiple CRFs. Revascularization with PCI/CABG is feasible, and antiplatelet agents plus secondary prophylaxis appears to be well tolerated in selected PWH with ACS.     

DMARD combination therapy in rheumatoid arthritis: 5‐year follow‐up results in a daily practice setting

Aim: To evaluate the overall effect of disease modifying anti‐rheumatic drug (DMARD) combination therapy in daily practice. Methods: In a retrospective study, 161 consecutive files of patients who attended regular follow‐up sessions, seen from 1998, were analysed. Their data were extracted at baseline, 6 months, 1, 2, 3, 4 and 5 years. American College of Rheumatology ACR70 criteria was chosen for the evaluation of the global result. DMARD combination was methotrexate (7.5–15 mg weekly) and chloroquine (150 mg daily), with low‐dose prednisolone (less than 10 mg daily). In cases of remission, methotrexate was gradually tapered, then prednisolone. Chloroquine was discontinued after 1 year if no recurrence occurred at low‐dose (150 mg every other day). In cases of recurrence at any stage, the treatment scheme was stepped back. Results: The data of 161 patients were analysed. One hundred and six were rheumatoid factor positive (RF+) (66%). ACR 70 for all patients at 6 months follow‐up was 72.5% (95% CI = 7.0); at 1 year, 75.8% (95% CI = 6.7); at 2 years, 72.2% (95% CI = 7.2); at 3 years, 78.9% (95% CI = 6.6); at 4 years, 78.4% (95% CI = 6.9); and at 5 years, 70.6% (95% CI = 8.5). Conclusion: The classical DMARD combination therapy, when used with adequate low‐dose prednisolone, gave an ACR70 response from 71–79%. The efficacy of the treatment did not fade over time. RF– patients did better than RF+ patients, but the difference was not statistically significant.     

Relevance of hepatitis B surface antigen levels in patients with chronic hepatitis B during 5 year of tenofovir treatment

The role of quantitative hepatitis B surface antigen (HBsAg) levels in patients receiving highly potent oral antiviral therapy is controversial, and here, we determined the HBsAg response in 121 chronic hepatitis B patients treated with tenofovir 300 mg daily. During tenofovir treatment, HBsAg decline of ≥1.0 log from baseline was seen in 16.1%, 16.3%, 18.4%, 34.6%, 36.4% and 11.8%, 15.2%, 14.8%, 28.6%, 20% at years 1, 2, 3, 4, 5 for HBeAg‐positive and HBeAg‐negative patients, respectively. Early decline in HBsAg levels at week 4 was predictive of subsequent significant HBsAg level decline. HBeAg seroconversion occurred in 29.9% of HBeAg‐positive patients. On multinomial logistic regression, HBsAg level decline from baseline at week 4 and week 12 or any time subsequently did not correlate with HBeAg seroconversion and HBV DNA level decline from baseline at week 4 and week 12 (OR = 3.704; 95% CI = 1.511–9.076; P = 0.006 and OR = 1.732; 95% CI = 1.032–2.867; P = 0.037, respectively) was significantly predictive of seroconversion. A small proportion of chronic HBV‐infected patients treated with tenofovir exhibit a significant (≥1.0 log) decline in HBsAg levels. Early decline in HBsAg levels at week 4 was predictive of subsequent and significant HBsAg level decline. The HBsAg decline did not correlate with HBeAg seroconversion in HBeAg‐positive patients. Reduction in HBV DNA levels at week 4 and 12 correlated with seroconversion.     

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.     

Efficacy of recombinant activated factor VII vs. activated prothrombin complex concentrate for patients suffering from haemophilia complicated with inhibitors: a Bayesian meta-regression

Summary.  The optimal on-demand treatment of joint bleeds in haemophilia patients with inhibitors is a source of debate, with studies reporting various efficacy levels for different drugs and dosage regimens. To analyse, in a unified Bayesian meta-regression model, the published efficacy of recombinant activated factor VII (rFVIIa) and/or activated prothrombin complex concentrate (aPCC) as on-demand treatments for joint bleeds in haemophilia patients with inhibitors. A systematic search was carried out to identify studies reporting on dosage and efficacy of rFVIIa and aPCC in the treatment of joint bleeds in the target patient population. Data were abstracted and included in the model and adjusted for potential sources of heterogeneity. Pooled efficacy levels for typical rFVIIa and aPCC regimens were estimated. Seventeen studies, collectively reporting on >2000 joint bleeds, were included. Medication type combined with dosage was the only significant explanatory parameter. The model predicts that a typical regimen of 90 μg kg⁻¹ rFVII repeated every 3 h if needed results in cumulative joint bleed resolution of 66%, 88% and 95% after 12, 24 and 36 h, respectively. In comparison, a typical regimen of 75 IU kg⁻¹ aPCC repeated every 12 h if needed results in cumulative joint bleed resolution of 39%, 62% and 76%, respectively. These differences were statistically significant and were also robust in sensitivity analyses. This analysis suggests that a typical rFVIIa regimen will resolve joint bleeds more effectively than a typical aPCC regimen after 12, 24 and 36 h.     

Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).     

Combined administration of FVIII and rFVIIa improves haemostasis in haemophilia A patients with high‐responding inhibitors – a thrombin generation‐guided pilot study

Treatment of haemophilia A patients with inhibitors is challenging, and may require individually tailored regimens. Whereas low titre inhibitor patients may respond to high doses of factor VIII (FVIII), high‐responding inhibitor patients render replacement therapy ineffective and often require application of bypassing agents. Thrombin generation (TG) assays may be used to monitor haemostasis and/or predict patients' response to bypass agents. In this study we defined by TG, the potential contribution of FVIII to recombinant activated factor VII (rFVIIa)‐induced haemostasis in inhibitor plasma. Based upon results, prospectively designed individual regimens of coadministration of rFVIIa and FVIII were applied. Plasma samples from 14 haemophilia patients with inhibitors (including high titre inhibitors) were tested. The response to increasing concentrations of FVIII, rFVIIa or both was assayed by TG. Eight patients, chosen following consent and at physician's discretion, comprised the combined FVIII–rFVIIa therapy clinical study cohort. Combined spiking with FVIII/rFVIIa improved TG induced by rFVIIa alone in all inhibitor plasmas. Combined rFVIIa and FVIII therapy was applied during bleeding or immune tolerance to eight patients, for a total of 393 episodes. Following a single combined dose, 90% haemostasis was documented and neither thrombosis nor any complications evolved. During study period decline of inhibitor levels and bleeding frequency were noted. Pre‐analytical studies enabled us to prospectively tailor individual therapy regimens. We confirmed for the first time that the in vitro advantage of combining FVIII and rFVIIa, indeed accounts for improved haemostasis and may safely be applied to inhibitor patients.