Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

XXVIII International Congress of the World Federation of Hemophilia

Istanbul, Turkey / June 1-5, 2008

Patients with severe or moderately severe hemophilia A or B face a serious risk of developing antibodies to factor VIII (FVIII) or factor IX (FIX), respectively. The risk is estimated at 20% to 30% for patients with severe hemophilia A. Inhibitors can develop very early in life and after only nine to 12 treatments in patients with severe disease. While the risk decreases after 200 treatment-days, patients with hemophilia have developed inhibitors even into the sixth decade of life. Patients with inhibitors that are less potent (low-responding) may often be managed with FVIII or FIX replacement products, but those with high-responding inhibitors typically need an alternative approach, known as bypass therapy, to induce coagulation.

On-demand treatment options include an activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa), which bypass the specific requirement for FVIII or FIX in the coagulation process. Although both agents are able to bypass the FVIII- or FIX-dependent step in coagulation, they differ in the mechanisms by which this bypass is achieved. Findings have shown that aPCC may also contain small amounts of residual FVIII that may stimulate further antibody production (Astermark et al. Blood 2007;109(2):546-51).

The use of rFVIIa has also demonstrated efficacy in on-demand treatment of bleeding, prevention of surgical bleeding, and prophylaxis, with fewer episodes of excess blood clotting as compared with aPCC. Since it contains no FVIII or FIX and should theoretically not induce additional FVIII or FIX antibody formation, rFVIIa is also useful in children who may eventually undergo immune tolerance treatment. Both aPCC and rFVIIa are considered by the World Federation of Hemophilia to be useful tools in the management of hemophilic bleeding in the presence of high-titre inhibitors.

Treatment Options

During the scientific sessions, Prof. Hervé Chambost, Centre Régional de Traitement des Hémophiles, Service d’Hématologie Pédiatrique, Centre hospitalier universitaire Timone, Marseilles, France, discussed the improved treatment convenience for patients with FVIII inhibitors who use a single-dose treatment with rFVIIa for the treatment of mild to moderate bleeding episodes. The single-dose approach is more convenient than multiple doses, more adaptable for use in the home setting, reduces the likelihood of missed or delayed infusions, and is better tolerated by both children and patients with restricted venous access.

To evaluate its use in the real world, the Observational Registry of NovoSeven Used as On-Demand Treatment of Bleeds in Patients with Haemophilia A and B with Inhibitors (ONE) was established to compare standard multiple-dose (3 x 90 µg/kg) rFVIIa with single-dose (270 µg/kg) regimens for safety, efficacy and impact on quality of life (QoL) and patient satisfaction. Enrolment for this prospective study began in early 2008, with an anticipated participation of approximately 100 patients from up to 30 European hemophilia centres. The primary efficacy outcomes are the proportion of bleed treatments resulting in effective hemostasis and the proportion resulting in effective pain relief. Secondary outcome measures include treatment satisfaction and convenience, time to hemostasis and pain relief, QoL assessments and adverse events. Interim results are anticipated by the end of 2008.

Dr. Massimo Morfini, Agenzia per l’Emofilia, Azienda Ospedaliero Universitaria Careggi, Florence, Italy, expanded upon the use of bypass therapy to prophylactic treatment in current practice and evidence-based medicine. While primary prophylaxis has been considered standard practice in patients with hemophilia without inhibitors for several years, it has also been explored in patients with inhibitors. Recent publications include a summary of 13 case histories of adults and children with hemophilia with inhibitors who used rFVIIa as secondary prophylaxis. In this series, prophylaxis with rFVIIa was highly effective in reducing the number of bleeding episodes with good patient compliance and improved QoL.

Another recent publication described the results in patients who were initially followed for a preprophylaxis period to confirm high baseline bleeding frequency (Konkle et al. J Thromb Haemost 2007;5(9):1904-13). Twenty-two participants were randomly assigned to receive daily rFVIIa prophylaxis of either 90 or 270 µg/kg for three months, followed by a three-month post-prophylaxis period. Bleeding frequency was reduced significantly during prophylaxis at 45% compared to 59% preprophylaxis (P<0.0001), and well-maintained during the post-prophylaxis period, with participants reporting significantly fewer hospital admissions and days absent from work/school. The most pronounced effect was noted for spontaneous joint bleeds, but all types of bleeds were similarly reduced. These studies demonstrate that clinically relevant reductions in bleeding frequency can be obtained using on-demand therapy with rFVIIa in patients with inhibitors.

Joint Bleed Prevention

Dr. Amy D. Shapiro, Medical Director, Indiana Hemophilia and Thrombosis Center, Indianapolis, explored the potential of joint bleed prevention in patients with hemophilia with inhibitors through the use of prophylaxis with rFVIIa. She and colleagues evaluated the efficacy and safety of rFVIIa and aPCC for controlling joint bleeds in a home-treatment setting. In this study, patients were assigned to receive either single-dose or multiple-dose rFVIIa or multiple-dose aPCC. Efficacy, as assessed by the requirement for additional hemostatics within nine hours, was significantly lower in the single-dose rFVIIa arm at 8.3% compared with 36.4% in the aPCC group (P=0.032). While the percentage of the rFVIIa multi-dose group requiring rescue medication (9.1%) was also lower compared to the aPCC cohort, the results were not statistically significant (P=0.05). No significant differences in treatment response were observed with the global response algorithm (P=0.173) nor were any safety issues identified.

Dr. Shapiro concluded that a single dose of rFVIIa is as safe and effective in these patients as the multiple-dose regimen and that it might be considered a potentially more effective treatment than aPCC for managing joint bleeding in this population.

Assessing Quality of Life

Luciana Scalone, PharmD, Centre of Pharmacoeconomics, University of Milan and University of Naples Federico II, Italy, discussed the need for QoL assessments in patients with hemophilia with inhibitors. “Do not be afraid or skeptical about evaluating QoL in your patients with hemophilia, with or without inhibitors. In the past, the main objective was survival... now, patients live many, many years with their condition.” It is important, she noted, to start following QoL as a parameter for successful therapy.

She and colleagues compared the results of QoL assessments in patients with hemophilia with the general population and found that reports of physical QoL were much lower in the patients, primarily because of arthropathies. The psychological QoL was not affected as severely in patients with hemophilia, however. This would suggest that while overall QoL in patients with hemophilia is relatively good, physical QoL can be improved, particularly with regard to orthopedic functioning. Physicians can best monitor QoL with standardized, well-established instruments chosen to meet the needs of the patient (for example, with regard to age and language). The optimal approach is the use of both a generic QoL instrument and one that is specific for hemophilia. One example of a generic instrument is the EQ-5D assessment tool, a simple six-question instrument.

Another consideration in the selection of the best QoL assessment tool, particularly for evaluations of treatment options, is whether it will allow the estimation of a utility index for health-related QoL. The utility index is very useful in economic evaluations. “Budget constraints are often a barrier against the choice of the best options,” Dr. Scalone emphasized. “It is necessary to consider both benefits and costs.” These include the actual costs of treatment and the costs of not making the investment in a treatment. “For example,” she continued, referring to the treatment of patients with hemophilia and inhibitors, “implementing prophylaxis may meet some barriers because it is, in the short run, more expensive, but evaluations should also include economic consequences of prophylaxis vs. on-demand treatment. Prophylactic treatment to prevent arthropathies may require more investments in the short run, but consider it together with the potential savings in the long run by having healthier populations of patients with hemophilia.”