Pattern of bleeding in a large prospective cohort of haemophilia A patients: A three‐year follow‐up of the AHEAD (Advate in HaEmophilia A outcome Database) study

Introduction

Outcome data on treatment of patients with haemophilia A spanning several years of real‐world evidence collection are currently very limited.

Aim and methods

The global prospective long‐term Advate^® Haemophilia A Outcome Database (AHEAD) cohort study collects real‐world data from patients with severe and moderate haemophilia. We report an interim data read‐out after three years of observation.

Results

A total of 522 patients were enrolled from 21 countries: 334 completed year 1 follow‐up, 238 completed year 2 and 136 completed year 3, with an overall follow‐up of 811 patient‐years. Median annual bleeding rates (ABR) were 1.7 in the prophylaxis group and 8.9 in the on‐demand group at year 1 visit, 1.6 and 13.0, respectively, at year 2 visit and 2.2 and 10.3, respectively, at year 3 visit. Moreover, about 42% of patients on prophylaxis vs 12% of patients on on‐demand had zero annual joint bleeding rates (AJBR). Effectiveness of prophylaxis and on‐demand treatment was deemed excellent/good in the majority of cases. Octocog alfa (Advate^®) was well tolerated. The inhibitors that developed in nine patients all disappeared spontaneously. Three patients had been previously exposed to FVIII for ≤50 exposure days (EDs), 3 for >50 EDs and 3 showed a borderline positive inhibitory activity (≤0.6 BU/mL).

Conclusions

These data confirm that the goal of zero bleeds is achievable, although not yet achieved in all patients. Understanding reasons behind the lower response to standard prophylaxis regimens in some patients and personalizing prophylactic treatment may further improve outcome in patients with haemophilia A.     

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.     

Real‐world comparative analysis of bleeding complications and health‐related quality of life in patients with haemophilia A and haemophilia B

Introduction

Clinical severity and impact of haemophilia on quality of life have been generally considered to be lower for haemophilia B (HB) compared with haemophilia A (HA) patients.

Aims

To compare annual bleeding rate (ABR), target joint development and health‐related quality of life (HRQoL) between adult (≥18 years) severe HA and HB patients using recent data from the Cost of Haemophilia in Europe: a Socioeconomic Survey (CHESS) study.

Methods

Multivariate generalized linear models (GLM) were constructed to assess the relationship between haemophilia type, ABR, HRQoL (derived from EQ‐5D index scores) and the presence of target joints while controlling for covariates.

Results

Of the 1225 patients included, 77% (n = 949) had HA and 23% (n = 278) had HB. Of the 514 patients who completed the EQ‐5D, 78% (n = 405) had HA, and 22% (n = 110) had HB. Unadjusted mean ABR was 3.79 in HA and 4.60 in HB. The presence of ≥1 target joint was reported in 59% and 54% of patients with HA and HB, respectively. Unadjusted mean EQ‐5D index score was 0.78 in HA and 0.76 in HB. Haemophilia type was not a significant predictor of ABR, target joints or HRQoL when adjusted for confounding factors such as BMI, age and replacement therapy regimen.

Conclusion

Data suggest comparable ABR, incidence of target joints and HRQoL between patients with HB and HA indicating comparable clinical severity and disease impact on patient quality of life.     

A sensitive venous bleeding model in haemophilia A mice: effects of two recombinant FVIII products (N8 and Advate®)

Summary. Haemostatic effect of compounds for treating haemophilia can be evaluated in various bleeding models in haemophilic mice. However, the doses of factor VIII (FVIII) for normalizing bleeding used in some of these models are reported to be relatively high. The aim of this study was to establish a sensitive venous bleeding model in FVIII knock out (F8‐KO) mice, with the ability to detect effect on bleeding at low plasma FVIII concentrations. We studied the effect of two recombinant FVIII products, N8 and Advate^®, after injury to the saphenous vein. We found that F8‐KO mice treated with increasing doses of either N8 or Advate^® showed a dose‐dependent increase in the number of clot formations and a reduction in both average and maximum bleeding time, as well as in average blood loss. For both compounds, significant effect was found at doses as low as 5 IU kg^?1 when compared with vehicle‐treated F8‐KO mice. Normalization of maximum bleeding time was found at doses equal to or above 10 IU kg^?1 N8 or Advate^®, corresponding to plasma concentrations of approximately 10% of the level in wild type mice. The present study adds a new model to the armamentarium of bleeding models used for evaluation of pro‐coagulant compounds for treatment of haemophilia. Interestingly, the vena saphena model proved to be sensitive towards FVIII in plasma levels that approach the levels preventing bleeding in haemophilia patients, and may, thus, in particular be valuable for testing of new long‐acting variants of e.g. FVIII that are intended for prophylaxis.     

Randomized comparison of prophylaxis and on‐demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors

Factor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti‐inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high‐titre inhibitors or low‐titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1‐year period, 17 subjects were treated prophylactically (85 ± 15 U kg^?1 every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on‐demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms (P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode‐free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on‐demand therapy than prophylaxis (P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on‐demand treatment, and the safety of prophylaxis is comparable to that of on‐demand treatment.     

Secondary prophylaxis treatment versus on‐demand treatment for patients with severe haemophilia A: comparisons of cost and outcomes in Taiwan

Summary. This study compared secondary prophylaxis treatment with on‐demand treatment for severe haemophilia A in Taiwan. Fifty patients from one medical centre were evaluated over a 5‐year period. Differences in annual bleed rates and factor VIII (FVIII) utilization were assessed between patients receiving secondary prophylaxis and patients receiving FVIII concentrates on‐demand. Results were then used as inputs in a pharmacoeconomic model to predict outcomes of future haemophilia therapy strategies in Taiwan. The median annual number of total bleeding episodes was significantly lower in the 13 (26%) patients who received secondary prophylaxis than in the 37 patients who received FVIII on‐demand (7.76 vs. 31.91, P < 0.0001). The between‐group difference in median annual factor VIII utilization was statistically significant (1824.41 IU kg^?1 for the prophylaxis group and 1324.81 IU kg^?1 for the on‐demand group, P < 0.01). It was estimated that approximately $2 million (USD) per year would be added to the cost of treatment by having all severe haemophilia A patients in Taiwan receive secondary prophylaxis instead of on‐demand therapy while 12 566 bleeding will be prevented. It is recommended that National Health Insurance officials utilize these data to evaluate the benefits of enhanced treatment strategies and before making substantial policy changes to haemophilia care in Taiwan.