Clotting factor concentrates given to prevent bleeding and bleeding related complications in people with hemophilia A and B
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine whether the preventive use of clotting factor concentrate in hemophilia A and B patients improves short‐term and long‐term outcomes as measured by;
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number of bleeding episodes or bleeding frequency
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clinical joint function
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quality of life measurements
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orthopedic joint score
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radiologic joint score
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clotting factor concentrate levels
Background
Hemophilia is an inherited abnormality in the hemostasis mechanism due to a coagulation factor deficiency. Hemophilia A is an X‐linked recessive bleeding disorder due to decreased blood levels of the functional procoagulant factor VIII. Hemophilia B is also an X‐linked recessive disorder attributable to decreased blood levels of functional procoagulant factor IX. Hemophilia A and B are clinically indistinguishable from each other. Hemophilia is classified according to three groups based on clotting factor level; severe with a baseline coagulation factor level of less than 1% of normal, moderate with clotting factor levels of 1% to 5%, and mild with a clotting factor greater than 5%.
Recurrent bleeding into joints and soft tissues is the hallmark of severe hemophilia A and B. Acute hemarthrosis episodes usually begin as the infant is learning to walk. Prior to availability of clotting factor concentrates most severe haemophiliacs developed crippling musculoskeletal deformities.
The availability of clotting factor concentrates has radically changed the treatment of patients with hemophilia, bringing about a remarkable change in the quality of life and the probability of longevity (Lusher 1997). The early outpatient treatment for acute bleeding episodes is now routine and has produced a decrease in the number of joint deformities since the introduction of clotting factor concentrates (Hilgartner 1974). The focus of managing a person with hemophilia has changed from treating an acute bleeding episode to the comprehensive care of the patient.
The theory is that the use of clotting factor concentrate converts a person with severe hemophilia to a milder form of the disease. The goal is to preserve joint function, by preventing spontaneous bleeding into joints. The preventive use of clotting factor concentrates given at regular intervals has been used for several decades in Sweden (Nilsson 1976).
In 1994, the Medical and Scientific Advisory Council (MASAC), of the United States of America's National Hemophilia Foundation issued guidelines after reviewing the Swedish experience with prophylaxis, stating that preventive therapy be considered the optimal therapy for children with severe hemophilia A and B (NHF 1994). Despite the stated directive, prophylaxis has not been universally adopted because of medical, psychosocial, and cost controversies. Clotting factor concentrate use is the single largest predictor of overall cost in the care of persons with hemophilia. The high cost of clotting factor concentrate may be a reason why hemophilia treatment centres have not implemented prophylaxis.
Objectives
To determine whether the preventive use of clotting factor concentrate in hemophilia A and B patients improves short‐term and long‐term outcomes as measured by;
-
number of bleeding episodes or bleeding frequency
-
clinical joint function
-
quality of life measurements
-
orthopedic joint score
-
radiologic joint score
-
clotting factor concentrate levels
Methods
Criteria for considering studies for this review
Types of studies
Randomized or quasi randomized clinical trials where clotting factor concentrate used in a preventive regime is compared to either placebo or standardized therapy (on‐demand or no placebo).
Types of participants
Children and adults with congenital hemophilia A or B, including all ages and all degrees of severity diagnosed by decreased blood levels of functional procoagulant factor VIII or IX respectively. People with factor VIII inhibitors will be excluded.
Types of interventions
Intravenous clotting factor concentrate in any formulation (fresh frozen plasma, cryoprecipitate, lyophilized plasma derived clotting factor concentrates, or recombinant clotting factor concentrates), any concentration, any frequency and any dose. The duration of treatment must be at least greater than a single treatment. The clotting factor concentrate used in the clinical trial should be the same formulation in both arms of the study.
Types of outcome measures
Primary Outcomes
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number of bleeding episodes or bleeding frequency
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pain scores
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radiologic joint score or radiologic measurements or descriptions of joint damage
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orthopedic joint score or clinical joint function
Secondary Outcomes
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Quality of Life
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clotting factor concentrate levels
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time loss to school or employment
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integration into society
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scales recording feeling of well‐being and global functioning
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cost effectiveness, cost benefit, cost utilization, cost minimization
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any reported adverse effects or toxicity of clotting factor concentrates will be recorded (e.g. inhibitors, reactions, transmission of infection)
Outcome data will be grouped into those measured at one, three, six, twelve months and annually thereafter. If outcome data is recorded at other time periods then consideration will be given to examining those as well.
Search methods for identification of studies
See: Collaboration Review Group search strategy
Relevant clinical trials (RCTs/CCTs) will be identified from the Coagulopathy Specialized Register of Controlled Trials held at the editorial base of the Cochrane Cystic Fibrosis and Genetic Disorders Group. The Coagulopathy Specialized Register was complied by conducting computerized searches of MEDLINE (1966 to present) and CENTRAL/CCTR on the Cochrane Library (updated each new issue). For full details of all searching activities for the Specialized Register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.
Further works will be identified by hand searching through the abstract books of the The American Society of Hematology, The European Journal of Hematology, The British Society of Hematology, the World Federation Of Hemophilia, the American Society of Pediatric Hematology & Oncology, the Society International Pediatric Oncology.
The pharmaceutical companies supplying clotting factor concentrate will be contacted (Aventis Behring, Baxter, Bayer, Genetics Institute/Wyeth‐Ayerst, Speywood).
The bibliographic references of all retrieved studies and reviews will be assessed for additional reports of clinical trials.
Data collection and analysis
Two reviewers (KS and JKMW) will retrieve all randomized or quasi randomized controlled trials to be included in the review and independently extract the data. The methodological quality of each trial will be assessed by the same reviewers who will record details of the methods of concealment and generation of randomization sequences, blinding, whether data was available to analyze on intention to treat basis, and whether all randomized participants were included in the analysis.
Full reports will be sought from authors where trials have been published in abstract form, presented at meetings or reported to the co‐reviewers.
Data will be collected by allocated treatment groups, irrespective of compliance, later exclusion (regardless of cause) or loss to follow‐up in order to allow an intention to treat analysis. Outcomes will be recorded as dichotomous (present or absent), some as categorical (i.e. joint scores), while others will be recorded as continuous variables, either as a mean change from baseline for each group or mean post treatment values and standard deviation for each group. For binary outcomes, we aim to calculate a pooled estimate of the treatment effect for each outcome across studies (the risk of an outcome among treatment allocated patients to the corresponding risk among controls). For continuous outcomes, we will calculate a pooled estimate of treatment effect. Subgroup analysis according to age, type of hemophilia, dosage regimen and setting will be performed where possible. We will also conduct a separate sub‐group analysis of quasi‐randomized studies.
If we find heterogeneity between studies, examination of subgroups may help to explain the reasons for this.
Heterogeneity between trials will be tested for using a standard chi‐squared test or ANOVA as appropriate. In addition we will perform a sensitivity analysis based on the methodological quality of the studies, including and excluding quasi‐randomized studies. Where information is missing, we will contact the primary investigator.
