Exercise for hemophilia

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the evidence on the effectiveness and safety of exercise interventions for people with hemophilia.

Background

Description of the condition

Hemophilia is a congenital condition in which the absence or defect of a clotting protein affects the ability of the blood to form a stable clot. The two most common types are hemophlia A and hemophlia B. Hemophilia A is caused by a defect of clotting factor VIII, and hemophilia B (Christmas disease) is caused by a defect of factor IX.

According to the World Federation of Hemophilia (WFH), hemophilia has an expected frequency of approximately one per 10,000 births and there are approximately 400,000 people with hemophilia worldwide (WFH 2012). Hemophilia A is more common than hemophilia B, representing 80% to 85% of the total hemophilia population (WFH 2012). Hemophilia is caused by an inherited X-linked recessive trait. The severity of hemophilia is constant within families and throughout the lifespan of the affected individual.

The frequency and severity of bleeding in hemophilia is generally correlated with the clotting factor level. The severe form accounts for more than 50% of the cases and has factor levels less than 1% IU/mL. It is associated with so-called spontaneous bleeding or bleeding as a result of unknown or unrecognised trauma. The moderate form has factor levels between 1% IU/mL and 5% IU/mL and hemorrhage can follow minor trauma. The mild form has a factor level of more than 5% IU/mL, but less than 40% IU/mL, in which hemorrhage usually occurs only after major trauma or surgery (White 2001).

Males who have the defective X chromosome are affected, while females with the defective gene are carriers of the condition, having one normal and one abnormal X chromosome, and may show symptoms of mild or moderate hemophilia. Each daughter of a female carrier has a 50% chance of also being a carrier; all daughters of men with hemophilia will be carriers. Each son of a carrier female has a 50% chance of being affected; sons of males with hemophilia do not inherit the father’s X chromosome, and are therefore not affected. In approximately one third of new cases, there is no family history, and the condition arises due to a spontaneous genetic mutation in either the mother or the son.

Internal and prolonged bleeding are the main symptoms of hemophilia, and hemorrhagic episodes can occur anywhere in the body. For both hemophilia A and B, hemarthrosis (bleeding into a joint) is the most common site of bleeding and accounts for 70% to 80% of all bleeding episodes; this is followed by muscle bleeds which account for 10% to 20% of bleeding episodes (WFH 2012). Ankles, knees and elbows are the more frequently affected joints. Hips, shoulders, and the small joints of the hands and feet are less commonly affected (Branea 2005). Joint disease affects 90% of people with severe hemophilia and contributes the greatest cost and morbidity in the hemophilia population (Manco-Johnson 2004). Recurrent hemarthrosis and muscular bleedings have serious consequences on the musculoskeletal system and the functional health status of patients.

In an acute hemarthrosis, blood flows from the vessels of the synovial membrane and fills the joint cavity. A few hours after blood enters the joint, the joint capsule becomes distended and there is an acute inflammatory reaction. Clinically, an acute hemarthrosis is characterized by pain, effusion, loss of range of motion, muscle inhibition or weakness and loss of joint proprioception. Once the bleeding has stopped, acute hemarthrosis usually recovers in approximately one week as a result of the digestive action of the synoviocytes of the synovial membrane, which removes the blood. Repeated hemarthroses are common; in its attempts to clear all of the accumulated blood, the synovium becomes hypertrophied, inflamed, villous and highly vascularized (De La Corte-Rodriquez 2013). This begins the vicious cycle of acute hemarthrosis and synovitis, which eventually leads to chronic synvovitis and the destruction of the joint cartilage. Damage to the joint cartilage occurs directly as a result of apoptosis of the chondrocyte cell and indirectly due to destructive enzymes and cytokines that are released from inflammatory cells in the synovial membrane (Rodriquez-Merchan 2012; Roosendaal 2008). In vitro animal studies have shown that the effect of blood on cartilage is accentuated by several factors including the duration of exposure to blood, weight bearing while there is blood in the joint and age; younger cartilage is more susceptible to damage than older cartilage (Roosendaal 2008). Chronic hemophilic arthropathy radiographically presents as synovial thickening, epiphyseal overgrowth, periarticular osteopenia, narrowed joint space, subchondral cysts, and incongruence of the joint surfaces (Pettersson 1980).

Description of the intervention

For the purpose of this review, exercise will encompass "a diverse set of interventions prescribed or planned by a health professional that includes conducting specific activities, postures or movements". Examples of such interventions are general physical fitness, aerobic exercise, strengthening of specific muscles or group of muscles, and various types of flexibility and stretching exercises (Blamey 2010).

How the intervention might work

Exercise programs for people with hemophilia are usually designed and implemented to help manage the recovery after a hemarthrosis or a muscle bleed, or as a tool to help prevent frequent bleeding episodes.

The aims of exercise that are considered to be important for people with hemophilia are to:

  • promote normal neuromuscular development (WFH 2012);

  • preserve or restore range of motion (ROM) and flexibility around joints;

  • increase muscular strength and endurance;

  • maintain or improve co-ordination and balance (WFH 2012);

  • maintain a healthy body weight thus decreasing stress on joints;

  • promote development and maintenance of good bone density (WFH 2012);

  • improve aerobic conditioning;

  • improve function and participation and reduce health risks associated with a sedentary lifestyle (which may also be important for people with hemophilia) (Gomis 2009; Iorio 2010).

Healthier joints will allow individuals with hemophilia to function in their community. Regular physical activity benefits communities by lowering healthcare costs and improving productivity at work and school. A significant proportion of healthcare expenditure and gross domestic product (GDP) is attributed to costs related to the lack of physical activity and obesity. Promoting physical activity can be a highly cost-effective and a sustainable public health intervention (Riske 2007).

The World Health Organization (WHO) and the US Centers for Disease Control and Prevention have produced numerous reports and publications in which scientific evidence demonstrates that regular and appropriate physical activity and sports provides people of all ages and conditions (including disabilities), with a wide range of physical, social and mental health benefits (Benifits Centre for Disease Control 2007).

Why it is important to do this review

Over the past 40 years, the medical treatment for people with hemophilia has evolved from transfusions of whole blood to the use of fractionated blood products and to the use of recombinant technology. The availability and safety of coagulation factor products has allowed a philosophical change in medical care that previously limited activities and exercise for people with hemophilia because of concerns about the induction of bleeding (Riske 2007).

The threats to a healthy musculoskeletal system for people with hemophilia encompass every element of joint and muscle function. Decisions regarding what type of activity to undertake to minimize joint and muscle bleeding, and how to maintain or maximize the structure and function of both the bony and soft tissue elements, require expert physiotherapy care by a professional trained in the management of inherited bleeding disorders. Since therapeutic exercise is an important component of the management of other forms of arthropathy (e.g. osteoarthritis, rheumatoid arthritis), it would appear logical that exercise would be effective for people with hemophilia (Hunter 2009; Stenstrom 2003).

Thus, this review will seek to evaluate the use, safety and efficacy of exercise in preventing bleeding episodes, maintaining and restoring joint and muscle function, and in maintaining the ability of the individual with hemophilia to participate in society.

Objectives

To assess the evidence on the effectiveness and safety of exercise interventions for people with hemophilia.

Methods

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials.

Types of participants

Males of any age group who are diagnosed with hemophilia A and B of any severity (severe, moderate and mild). Patients with inhibitors and any co-morbidity will not be excluded.

Types of interventions

Any exercise intervention considered relevant in the management of hemophilia. If, within any included trials, there are co-interventions, these should be similar in the comparator groups. The relevant exercise interventions include: supervised and unsupervised exercises; aquatic exercises; exercise programmes focusing on muscle strength, cardiovascular fitness, flexibility or combination, proprioceptive and balance training.

Types of outcome measures

Primary outcomes
  1. Bleed frequency (number of major bleeds reported per year, month, or week)

  2. Adverse events (e.g. bleed following exercise, worsening of symptoms)

  3. Quality of life (e.g. assessed through self-administered questionnaires such as the 'Hemo-QOL and SF-36')

Secondary outcomes
  1. Balance or proprioception (or both) (e.g. the 'Berg Balance Test' and the 'Functional Reach Test')

  2. Aerobic activity (measured using submaximal and maximal testing protocols, e.g. the 'Modified Bruce protocol', the 'Six-Minute Walk Test' (6MWT), the 'Wingate Anaerobic Test')

  3. Joint health status (assessing the severity of joint damage and musculoskeletal issue using, e.g. the 'Hemophilia Joint Health Status' (HJHS), the 'World Federation of Hemophilia Score', the 'Gilbert Scale')

  4. Pain intensity (measured using, e.g. the 'Visual Analogue Scale', the 'Numerical Rating Scale')

  5. Functional status (assessing the functional status of the person through questionnaires such as the 'Hemophilia Activity List' (HAL), 'Functional Independence Measure For Hemophilia' (FISH) and the 'Canadian Occupational Performance Measure' (COPM).

Search methods for identification of studies

There will be no language or publication restrictions.

Electronic searches

We will identify relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register using the terms: haemophilia* AND exercise.

The Coagulopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE and the handsearching of one journal - Haemophilia. Unpublished work is identified by searching the abstract books of major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; and the Congress of the World Federation of Hemophilia. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

We will also search for relevant studies from the following electronic databases (with no language or date restrictions):

  • PubMed;

  • Embase (Ovid);

  • CINHAL (EBSCO).

In addition to these searches, we will search the following trials registries: ClinicalTrials.gov (http://www.clinicaltrials.gov/); International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/); and the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu).

Searching other resources

In addition the reference lists of all publications found by the above methods will be searched for any other potentially relevant studies.

Data collection and analysis

Selection of studies

The three authors will independently check the titles and abstracts of the trials identified from the searches. We will obtain the full text of all studies of possible relevance for assessment. The authors will decide which trials fit the inclusion criteria. We aim to resolve any disagreement by discussion. We will contact trial authors for clarification where necessary. We will use consensus to resolve any disagreements. We will assess studies published in languages other than English and include them in the review whenever feasible using English language abstracts, translation tools and services, or review by co-authors and colleagues familiar with the language of publication.

Data extraction and management

The three authors will independently extract data from the included trials using forms provided by the Cochrane Cystic Fibrosis and Genetic Disorders Group. We will extract population characteristics (patient population, source and setting, study inclusion criteria, symptom characteristics, severity, mean age, prophylaxis), intervention characteristics (description and types of exercise, duration and number of treatment sessions, intervention delivery type and co-interventions), comparison characteristics and outcome data. We will extract results for primary outcomes as change scores or final value scores for inclusion in the meta-analyses. We will assess the clinical relevance of each trial with four items: participants described in detail to assess clinical comparability; interventions and treatment settings adequately described to allow repetition; clinically relevant outcomes measured and reported; and whether the likely treatment benefits are worth the potential harms. We will extract data on adverse events, if reported, from each paper.

When information regarding any of the above is unclear, we will contact the trial authors for further details. We will enter data into the RevMan 5.1 software and pool where appropriate (RevMan 2011).

Assessment of risk of bias in included studies

The three authors will independently assess the risk of bias of each included study using the Cochrane Collaboration's risk of bias assessment tool (Higgins 2011a). We plan to resolve any disagreement between the three authors by discussion and consensus.

We will assess the following domains as having either a low, unclear or high risk of bias.

  • Randomization ('low risk': randomization list generated using a computer, random number table, or similar methods; 'unclear risk': described as randomized, but no details given; 'high risk': non-random approach, e.g. alternation, use of case record numbers, dates of birth or day of the week).

  • Concealment of allocation ('low risk': list from a central independent unit, on-site locked computer, identically appearing treatment; 'unclear risk': not described; 'high risk': if allocation sequence was known to, or could be deciphered by the investigators who assigned participants or if an open allocation schedule was used.

  • Blinding ('low risk': if participants, investigators and outcome assessors were blinded, or if any of these were not blinded but outcome assessment was judged not to influence the outcome; 'unclear risk': if this issue was not discussed; 'high risk': if none of the parties involved in the trial were blinded).

  • Incomplete outcome data ('low risk': if any withdrawals were described in full and were equal across groups; 'unclear risk': if insufficient information was given; 'high risk': if the missing data were likely to be directly related to the outcome or if they were uneven across groups).

  • Selective outcome reporting.

  • Other potential sources of bias.

Measures of treatment effect

We will examine continuous outcomes as either a mean difference (MD), in cases where the outcome is measured using the same instrument, or as a standardized mean difference (SMD) when the outcome is measured using different instruments, each with their 95% corresponding confidence intervals (CI). A negative effect size will indicate that exercise is more beneficial than the comparison group. For dichotomous outcomes we will calculate a risk ratio (RR) and the 95% CI. For categorical data the results will be presented as a risk ratio (RR) with 95% CI.

Unit of analysis issues

Cluster-randomized trials

We will include cluster-randomized trials in the analyses along with individually randomized trials. In an attempt to account for any unit of analysis error, we plan to use the methods described in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intra-cluster correlation co-efficient (ICC) derived from the study (if possible), from a similar (in design) study or from a study of a similar population (Higgins 2011b). If we use ICCs from other sources, we will report them and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomized trials and individually-randomized trials, we plan to pool the relevant information. If there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomization unit is considered to be unlikely, we will consider it reasonable to combine the results from both. We will also acknowledge heterogeneity in the randomization unit and perform a sensitivity or subgroup analysis to investigate the effects of the randomization unit.

Cross-over studies

In the event that we identify cross-over trials, we will only analyse first-arm data (collected prior to the cross-over of the intervention) given that an effective washout period is almost impossible to achieve with an exercise program.

Dealing with missing data

The authors will report the numbers and reasons for dropouts and withdrawals in all intervention groups (if described), or if the papers specify that there were no dropouts or withdrawals. The review authors will contact the original Investigators for clarification on any missing information.

In the event that we are unable to contact the original authors, or they are unable to supply missing data, we will impute missing variance scores using the mean variance from studies with similar populations. If data are reported as a median and interquartile range (IQR), for studies with moderate to large sample sizes (n > 25), we will use the median to estimate the mean; for studies with small sample sizes, we will use the formula proposed by Hozo (Hozo 2005). We will calculate the standard deviation (SD) with the width of the IQR equivalent to 1.35 times the SD (Higgins 2002). In studies where a range is presented along with the median instead of an IQR, we will estimate the SD to be one quarter of the range (Higgins 2011c).

For included trials, we will note levels of attrition. For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomized to each group in the analyses, and analyse all participants in the group to which they were allocated, and regardless of whether or not they received the allocated intervention. One author will analyse missing data in consultation with another using RevMan.5.1 (RevMan 2011).

Assessment of heterogeneity

We will assess heterogeneity between trials by inspecting the forest plots and using the Chi2 test and I2 statistic for heterogeneity with a statistical significance level of P < 0.10 and an interpretation of I2 is as follows:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

If any trial protocols are available, we will compare these to the published reports. For primary outcomes, we will investigate any potential reporting biases using a funnel plot, provided a sufficient number of trials are available, i.e. 10 or more (Begg 1994). We will use a linear regression approach to measure funnel plot asymmetry on the logarithm scale of the RR. If we obtain an asymmetrical funnel plot, we will explore alternative causes in addition to publication bias.

Data synthesis

We will perform statistical analysis in accordance with the guidelines developed by the Cochrane Collaboration (Deeks 2011). We will perform our statistical analysis using the RevMan 5.1 software (RevMan 2011). If there is no substantial heterogeneity (less than 50%) we will use the fixed-effect model. In the presence of at least moderate heterogeneity (over 50%) we will use the random-effects model and sensitivity analyses as described below to investigate the source of heterogeneity. We plan to analyse the different interventions separately and plan to group outcome data as follows: four weeks to three months; over three months to six months; and longer than six months. If outcome data were recorded at other time periods consideration would be given to examining those as well.

Subgroup analysis and investigation of heterogeneity

If there is significant heterogeneity we will undertake the following subgroup analyses:

  1. exercise versus other interventions (including no intervention);

  2. comparison of various modes of exercise versus prophylaxis group;

  3. comparison of various modes of exercise versus on-demand group;

  4. long-term and short-term effects of exercise on patients with hemophilia.

Sensitivity analysis

If there are sufficient comparable studies, i.e. 10 or more, we will perform sensitivity analyses excluding trials with clearly inadequate allocation of concealment, randomization, blinding or incomplete outcome data (high risk of bias). As reported above, in reference to cluster randomized trials, if we use ICCs from other sources we will conduct sensitivity analyses to investigate the effect of variation in the ICC.

Contributions of authors

Rojer Michael planned, wrote and co-ordinated the protocol.

Kathy Mulder and Karen Strike were involved in planning the protocol, providing expert opinion, editing and reviewing.

Declarations of interest

Rojer Michael declares no known conflicts of interest.

Kathy Mulder declares no known conflicts of interest.

Karen Strike declares no known conflicts of interest.

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