Abstract

• Haemophilia A is an inherited bleeding disorder due to factor VIII deficiency. Patients with moderate or severe haemophilia A are treated by replacing the deficient factor VIII. However, factor VIII administration induces the production of factor VIII inhibitors (anti-factor VIII antibodies) in some patients, rendering the treatment ineffective. In this situation, one option is to use a "bypassing" agent (activated factor VII or activated prothrombin complex), administered "on demand" or as continuous prophylaxis. Another option is an "immune tolerance induction" protocol, in which high doses of factor VIII are administered daily or several times a week for several months or several years, often successfully suppressing the production of factor VIII inhibitors.
   
• Emicizumab is a monoclonal antibody that has the same effect as activated factor VIII in the coagulation cascade. It has been authorised in the European Union for patients with haemophilia A and factor VIII inhibitors.
   
• Emicizumab has not been compared directly with continuous prophylaxis with a bypassing agent. Nor has it been evaluated in the prevention of bleeding associated with surgery. In a 24-week non-blinded randomised trial versus no prophylaxis in 53 adults and adolescents who received bypassing agents on demand before and during the trial, the bleeding rate in the group receiving continuous emicizumab prophylaxis was 5.5 bleeds per patient per year, versus 28.3 in the group without prophylaxis.
   
• In two non-comparative trials in children and adults with frequent bleeds despite continuous prophylaxis with a bypassing agent, the bleeding rate was greatly reduced after patients were switched from the bypassing agent to emicizumab.
   
• A few cases of microangiopathy and thrombosis have been observed in patients receiving emicizumab. They were all also receiving high doses of activated prothrombin complex. Emicizumab’s other adverse effects are mainly injection site reactions. Hypersensitivity reactions are likely to occur. Emicizumab’s effect on the development of children or adolescents is unknown.
   
• As the prothrombotic effects of emicizumab and activated prothrombin complex are probably additive, their concomitant use is best avoided, particularly at high doses. This complicates the management of bleeding in patients receiving emicizumab. Emicizumab interferes with the results of some coagulation tests.
   
• Emicizumab is administered by subcutaneous injection once a week for 4 weeks, and one to four times per month thereafter. Emicizumab prophylaxis is far less burdensome than prophylaxis with bypassing agents, which are administered intravenously at least several times a week in this situation.

•   A REAL ADVANCE  Emicizumab prophylaxis is a first-choice treatment for patients with haemophilia A in whom factor VIII is no longer effective due to the development of factor VIII inhibitors. It greatly reduces the incidence of bleeding. It is much more convenient to use than prophylaxis with a bypassing agent. These advantages should be weighed against the lack of long-term data, the lack of evaluation in certain clinical situations, and the risk of thrombosis, especially when used with activated prothrombin complex. Another option is immune tolerance induction, the only treatment known to restore the efficacy of factor VIII in three-quarters of patients..

©Prescrire 1 December 2019

"Emicizumab (Hemlibra°) in haemophilia A. A first-choice preventive treatment for patients with factor VIII inhibitors" Prescrire Int 2019; 28 (210): 285-289. (Pdf, subscribers only).

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