Treatment of Congenital Hemophilia A and B

Remarks

• The use of prophylaxis has a large benefit in reducing the risk of bleeding with minimal adverse events.
• Cost and access to prophylactic concentrates remain the main barriers for implementation of this recommendation.
• Increased uptake and adherence to prophylaxis in disadvantaged populations may help reduce current health equity gaps.
• This recommendation may apply to patients with hemophilia A with a severe bleeding phenotype even when they have factor VIII plasma levels ≥ 2 IU/dL.

Remarks

• Emicizumab may offer a lower treatment burden for patients, given its weekly, biweekly, or every 4-week schedule and subcutaneous administration.
• There is still uncertainty on the long term safety and efficacy of emicizumab in infants with hemophilia A.
• This recommendation may apply to patients with hemophilia A with a severe bleeding phenotype even when they have factor VIII plasma levels ≥ 2 IU/dL.

• Extended half-life recombinant factor VIII concentrates may offer a lower treatment burden for patients due to less frequent injections, and may enable the achievement of higher trough levels.
• This recommendation may apply to patients with hemophilia A with a severe bleeding phenotype even when they have factor VIII plasma levels ≥ 2 IU/dL.

Remarks:

• Standard regimens of prophylaxis are the best option in settings with adequate access to factor VIII concentrates.
• However, low-dose factor VIII prophylaxis decreases the risk of bleeding compared with no prophylaxis and is therefore preferable over episodic treatment.
• This recommendation may apply to patients with hemophilia A with a severe bleeding phenotype even when they have factor VIII plasma levels ≥ 2 IU/dL.

Remarks:

• Initial prophylaxis refers to the first 50 exposure days to factor VIII.
• This recommendation is based on evidence that the use of standard half-life recombinant factor VIII in previously untreated individuals may be associated with an increased risk of inhibitor development compared with plasma-derived factor VIII. However, the risk of developing inhibitors may vary with different recombinant and plasma-derived factor VIII concentrates.
• Although risk of transmission of blood-borne pathogens is minimized with current plasma-derived factor VIII concentrates, some patients or caregivers may prefer to avoid plasma-derived factor VIII.
• Extended half-life factor VIII concentrates were not evaluated in the supporting study for this recommendation, and therefore, are not part of this recommendation.
• All plasma-derived factor VIII concentrates should meet current safety standards.

• Likely, there is no important difference in the efficacy of continuous or bolus infusion of plasma-derived or standard half-life recombinant factor VIII concentrates before, during, or after an invasive procedure for patients with severe hemophilia A.
• This recommendation applies to patients undergoing major general and orthopedic surgeries.
• Continuous infusion tends to consume lower amounts of factor VIII, which could be relevant in setting with constrained resources.
• This recommendation does not apply to extended half-life recombinant factor VIII concentrates, as no comparative study was found for this class of factor VIII concentrates.

• Emicizumab may be both more effective and less costly than bypassing agents to prevent bleeding events. Furthermore, emicizumab may offer a lower treatment burden for patients, given its weekly, biweekly, or every 4-week schedule and subcutaneous administration.

Remarks:

• Both dose regimes may have similar effects in achieving immune tolerance, but low-dose regimens may be preferable in settings with limited access to factor VIII.
• A low-dose regimen may be associated with a higher bleeding risk in comparison with a high-dose regimen.
• This recommendation applies to plasma-derived and standard half-life recombinant factor VIII concentrates, since there have been no randomized controlled trials performed on immune tolerance induction with extended half-life recombinant factor VIII concentrates.
• Studies informing this recommendation were conducted before the advent of emicizumab.

• In patients who are on prophylaxis with emicizumab, recombinant factor VIIa is preferred due to potential thrombotic complications with concomitant use of emicizumab and activated prothrombin complex concentrate.
• Most individuals included in the clinical trials informing this recommendation had high-responding inhibitors.
• The evidence comparing recombinant factor VIIa with activated prothrombin complex concentrate is limited to small cohort studies including different types of surgery. It is unknown whether one alternative is more effective than the other.
• Recombinant factor VIIa requires more frequent administration and is generally more expensive than activated prothrombin complex concentrate, which may limit its feasibility in some scenarios.
• Eptacog beta was not evaluated in the supporting studies for this recommendation, and therefore, is not part of this recommendation.
• Patients with low-titer inhibitors (in general, below 2 BU), may have a good factor VIII recovery after higher than conventional doses of factor VIII. Therefore, these patients may be treated with factor VIII concentrates.

• The limited available evidence does not suggest superiority of one option over the other in treating joint, muscle and mucocutaneous bleeding events.
• The single-dose regimen may be associated with a lower treatment burden for patients and providers.
• However, with the three-dose scheme, if the bleeding is stopped quickly, some patients may not need to complete the full regimen (with three doses) and some resources may be saved.
• Studies informing this recommendation were conducted before the advent of emicizumab.

• The use of prophylaxis has a large benefit in reducing the risk of bleeding with minimal adverse events.
• Cost and access to prophylactic concentrates remain the main barriers for implementation of this recommendation.
• Promoting uptake and adherence to prophylaxis in disadvantaged populations may help to reduce current health equity gaps.
• This recommendation may apply to patients with hemophilia B with a severe bleeding phenotype even when they have factor IX plasma levels ≥ 2 IU/dL.
• No comparative study on the effect of prophylaxis versus episodic treatment of bleeding in previously untreated patients with hemophilia B was found.

• Extended half-life recombinant factor IX concentrates may offer a lower treatment burden for patients due to less frequent injections.
• Although the risk of transmission of blood-borne pathogens is minimized with current plasma-derived factor IX concentrates, some patients or caregivers may prefer to avoid plasma-derived factor IX.
• This recommendation does not include the use of prothrombin complex concentrates. Furthermore, the use of prothrombin complex concentrate may increase the risk of thrombosis.
• This recommendation may apply to patients with hemophilia B with a severe bleeding phenotype even when they have factor IX plasma levels ≥ 2 IU/dL.
• All plasma-derived factor IX concentrates should meet current safety standards.