16-Year Follow-Up Proves Weekly FVIII Prophylaxis Reduces Bleeding in Hemophilia A

Results from a study recently published in The Lancet Neurology describe in detail a 16-year follow up of patients with hemophilia A who were treated with frequency-escalated prophylaxis.

The study, “Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort,” was conducted by Professor Brian M Feldman, MD of the Division of Rheumatology at The Hospital for Sick Children in Toronto, and colleagues. It was initially funded by grants from the Medical Research Council of Canada/Pharmaceutical Manufacturers Association of Canada Partnership Fund and the Bayer/Canadian Blood Services/Hema-Quebec Partnership Fund.

Hemophilia A is an X-linked bleeding disorder that results from mutations in the gene-encoding coagulation factor VIII (FVIII). Patients with severe hemophilia A are vulnerable to impulsive or triggered bleeding in joints and soft tissue, which can lead to excruciating and incapacitating arthropathy, poor quality of life (QOL), and escalated risks of intracranial hemorrhage and early death.

Commonly referred to as classic hemophilia, hemophilia A is a genetic disorder caused by missing of defective factor VIII. Approximately 1/3 of hemophilia A cases, however, are caused by a spontaneous genetic mutation.

The longitudinal study had 2 specific objectives: first, to estimate the incidence of target joint bleeding in patients with severe hemophilia A treated (for primary prophylaxis) with escalating dose prophylactic factor replacement. The second objective was obtaining accurate estimates of the direct and indirect costs associated with this protocol for use in a cost-effectiveness model, comparing escalating dose with standard prophylaxis and with intermittent therapy.

Fifty-six boys with severe hemophilia A and a factor level less than 2% were enrolled between June 26, 1997 and January 30, 2007. All were followed for a median of 10.2 years (to a maximum of 16.1 years) after they were treated with standard half-life recombinant factor VIII (SHL-rFVIII), beginning as once-weekly prophylaxis with 50 IU/kg and escalating in frequency (with accompanying dose adjustments) in response to breakthrough bleeding as determined by the protocol.

Joint health, as measured by the Colorado Child Physical Examination Scores (CCPES), served as the primary endpoint for the analysis and was evaluated at study end. All analyses were done by intention to treat. The median end-of-study CCPES physical examination score was 1 (IQR 1-3; range 0-12) for the left ankle and 1 (1-2; 0-12) for the right ankle, with all other joints having a median score of 0.

No treatment-related safety events were reported over the duration of the study, including central venous catheter infections. The median annualized index joint bleeding rate was 0.95 per year (IQR 0.44-1.35; range 0.00-13.43), but, at some point during the study, 17 (30%) patients had protocol-defined unacceptable breakthrough bleeding.

“Our study has shown that very good health outcomes within the WHO-ICF domains of body structures and functions, and activities and participation are possible with the use of tailored frequency-escalated prophylaxis, using less SHL-rFVIII than standard full-dose prophylaxis regimens,” Dr. Feldman says in the study.

“Starting treatment with once weekly rather than more frequent infusions allowed most young boys to avoid the placement of a CVC.31 In addition, the use of less SHL-rFVIII has the potential to provide substantial cost savings16 as compared with standard treatment. However, because our tailored frequency-escalated approach was driven by bleeding events, some bleeding did occur that resulted in joint damage in some participants. Our primary outcomes of interest were long-term function and joint health, and we showed that despite some bleeding, our cohort had very good health at the end of the study.“

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References:

Feldman BM. Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort. The Lancet Neurology. 2018;PIIS2352-3026(18)30048-6. doi: 10.1016/ S2352-3026(18)30048-6