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To compare the cost - effectiveness of treatment options in three patients with hemophilia A and low titer inhibitors.
Methodology: We used a longitudinal before and after design that was conducted in two phases assessed retrospectively: Phase I was 6 months preceding the introduction of r FVII a , during which patients received on-demand usual care with plasma derived factor VIII regimes, phase 2 was 6 month treatment on r FVII a. We determined the clinical response, and the cost of treatment with NovoSeven in 3 boys with low titer inhibitors to factors VIII compared with other treatment regimes previously used in these patients (Plasma derived factor VIII).
Results: treating hemophilia patients with low titer inhibitors with recombinant activated factor VII is cost - effective compared to treatment with plasma derived factor VIII regimes.
Conclusion: Our results confirm that rFVIIa is clinically effective and resulted in 100% reductions in the number of re-treatment emergency room visits compared with the patients with plasma derived factor VIII.
KEY WORDS: Hemophilia, Inhibitors, rFVIIa.
Inhibitors in hemophilia A against FVIII is problematic, challenging, and difficult to manage. While the frequency of bleeding is not increased in hemophilia patient with inhibitors, once bleeding occurs, its control is more difficult and often unpredictable.1 rFVIIa is a bypassing agent evaluated in compassionate use and investigational studies. rFVIIa appears to be effective in 69-90% of treatment courses encompassing different types of hemorrhages and surgical procedures.2 The administration of exogenous rFVIIa in high concentrations has been found to initiate and maintain hemostasis in hemophilia patients with inhibitors to FVIII/FIX. This effect seems to be due to an increased generation of thrombin on the platelet surface after this has been activated by the thrombin molecules formed through the initial FX activation by the TF-FVIIa complex formed on the TF-bearing cells.3
rFVIIa provides site-specific thrombin generation through pharmacological manipulation of the coagulation mechanism at the site of vessel injury. Endothelial damage is associated with collagen and tissue factor (TF) exposure. Under normal physiological conditions, trace amounts of circulating FVIIa, in the order of 3.58Â ng/mL, bind to form the TFÂ :Â FVIIa complex. This complex has now been recognized as the pivotal activator of the coagulation cascade and results in localized thrombin generation. Through thrombin-mediated platelet activation and feedback up-regulation of the clotting mechanism, haemostatis occurs. At pharmacological concentrations in the order of 50Â nM, rFVIIa has been shown to generate significantly more thrombin in a model simulating normal plasma, compared to haemophilic plasma.4
In the French multicenter study, patients assessed the efficacy of NovoSeven in serious bleeding episodes 8h after an initial dose of rFVIIa (90-120 Âµg/kg/dose). 132 episodes of acute hemarthrosis were treated and analyzed. Hemostasis was judged excellent or effective in 90% of episodes, partially effective in 9%, and ineffective in 0.6% of the bleeding episodes. The mean number of doses was 2.9 per bleeding episode.5
In this paper we analyzed the responses and costs of giving rFVIIa Vs plasma-derived Factor VIII to patients with low-titer inhibitors.
Three men, with severe hemophilia A participated in this study. These patients were attending in the Gorgan treatment center ofIran. Their ages in baseline were 7, 23 and 43 years old. Duration of inhibitors presence was not applicable. Maximum inhibitor levels were 3.8, 2.9, 1.3 Bethesda units respectively (Table-I).
We used a longitudinal before and after design that was conducted in 2 phases. Phase 1 was 6 months preceding the rFVIIa treatment during which all patients were treated with an on-demand plasma derived factor VIII regime. Phase 2 was 6 months of on-demand treatment with rFVIIa. The treatment regime was consisted of intravenous push injection of rFVIIa in a dose of 90 Âµg/Kg and was repeated after 2 hours if bleeding continued.
This study was conducted in the perspective of the Iranian Ministry of Health. Due to the un-availability of other medical resources unit costs, study focused on treatment costs and excluded outpatient and inpatient costs associated with the bleeding episodes.
Effectiveness of treatments was assessed through the need for hospitalisation and necessity for re-treatment (a treatment was considered as effective if bleeding episode could be controlled in the outpatient setting within 24 hours). Clinical response to treatment and therefore need for hospitalisation was assessed by a physician.
All bleeding episodes occurring during one of the two phases of the study were treated first in outpatient setting and, if bleeding episode remained uncontrolled, patients were transferred to hospital. Tables II, III, and IV below describe the bleeding episodes and their individual management for each of the 3 patients involved in the study.
Study results confirm that rFVIIa is clinically effective. Indeed, each bleeding managed with rFVIIa was managed in outpatient setting (i.e. did not require transfer to emergency room visit) within 24 hours.
Table-V describes the total factor consumption and associated cost per patient in each study phase. Study results showed that total cost of treatment with rFVIIa was lower than plasma derived FVIII. Total cost of factor VIII plasma derived was $98600 & total cost of rFVIIa was $77000.
There are many published articles which report the success of different treatments for hemophilia A patients with low titre inhibitors, but very few, if any attempt to compare the result between plasma derived factor VIII and rFVIIa. In published papers, effectiveness of rFVIIa and high dose plasma-derived F VIII data were 89.3% and 71.4% respectively.6 Cost analysis data are now extremely valuable for the development of treatment guidelines where there is debate over the most appropriate treatment in terms of cost-benefit ratio. Cost-effectiveness of using rFVIIa Vs aPCC in patients with high titre inhibitors is well documented worldwide.3-8 This study is actually the first one assessing the cost and effectiveness of giving rFVIIa to patients with low titre inhibitors. It is also one of the only studies (with the exception of Dundar S et al5) comparing the cost and effectiveness of rFVIIa Vs high dose factor VIII.
Looking at the effectiveness and the costs, results from our study actually support the use of rFVIIa Vs plasma derived factor VIII in patients with low titre inhibitors.
Moreover, because this study did not account for outpatient and inpatient costs, but only for drug costs, it is expected that the cost-savings associated with the use of rFVIIa in this patients' population would be even bigger since none of the patients taking rFVIIa were sent to hospital and none of them required re-treatment within 24 h.
Finally, if the health-related quality of life (HRQoL) of patients was not assessed through the use of externally validated questionnaires, it is expected that the HRQoL of patients receiving rFVIIa would actually be improved due to the shorter resolution of bleeding episodes and absence of hospitalisation. Similar study results were actually described in a cost-utility study performed in Australia.9-11
Study limitations include the absence of accounting for outpatient and inpatient costs associated with the bleeding episode, but also time to treatment which might actually significantly impact the total cost of treating bleeding episodes. Further data collection will account for these parameters.