Prophylaxis in real life scenarios
Prophylaxis has become the standard mantra of care for those individuals with severe haemophilia A and B. Primary prophylaxis is advocated to prevent the occurrence of symptomatic acute spontaneous haemarthroses and to preserve joint structure and function. Typically, twice or thrice weekly infusions of factor VIII or IX concentrates are integral to this treatment approach. Secondary prophylaxis is initiated after the relentless cycle of progressive joint damage has been triggered by prior haemarthroses and is intended to preserve existing joint health by preventing additional spontaneous bleeding events. Event-driven prophylaxis involves the administration of clotting factor concentrates to prevent acute traumatic bleeds, which are anticipated to occur in association with surgical or physical trauma. This regimen enhances the effectiveness of primary or secondary prophylaxis protocols or on-demand approaches to replacement therapy. Besides the marked reduction in the so-called annual bleed rate, prophylaxis regimens frequently increase personal self-confidence to embark on a more active and physical lifestyle; however, in reality, prophylaxis must be individualized in accordance with bleeding phenotypes, with the unique pharmacokinetic profile of administered replacement clotting factor concentrates, with the specific clinical scenario, and with the degree of intensity anticipated for any physical activity. The introduction of extended half-life replacement products will also influence how these prophylaxis regimens will be accomplished. The following scenarios will discuss how prophylaxis regimens can be implemented to protect the individual from developing spontaneous and activity-induced acute bleeding complications and to maintain an improved quality of life.
Intermediate-dose vs. high-dose prophylaxis for severe haemophilia
Since its introduction in 1958 by Professor Nilsson in Sweden , many long-term observational studies [2-5], two paediatric [6, 7] and two adult [8, 9] randomized controlled trials have shown that prophylactic replacement therapy for severe haemophilia prevents bleeds, and subsequent haemophilic arthropathy. Prophylaxis, initiated before the onset of arthropathy is the recommended treatment for boys with severe haemophilia A and B [10-12].
In spite of the high costs of prophylaxis, most countries have followed the successful Swedish prophylactic regimen. This regimen originally aimed at maintaining trough levels of 1–2% clotting factor activity by using doses of 25–40 IU kg−1 three times a week for haemophilia A . In the Netherlands, however, prophylaxis was introduced in 1968 , using lower doses, aiming at preventing spontaneous joint bleeds without targeting on trough levels of factor VIII (FVIII) or FIX. Although treatment was intensified over the years in both countries [3, 14], the difference in dosing has remained considerable: today, a typical adult Dutch haemophilia A patient uses 3 × 1000 IU of FVIII per week, whereas a typical adult Swedish patient uses 1500–2000 IU every other day. Both groups have followed their patients for decades and reported favourable long-term results. As the optimum regimen is not established and the pressure on healthcare budgets is considerable, the question arose as to what the incremental gains of high-dose prophylaxis are .
Aim of the study
An observational study was performed to compare long-term outcomes and costs between the Dutch intermediate-dose and the Swedish high-dose prophylactic regimen in severe haemophilia .
Patients and methods
All patients with severe haemophilia (FVIII/IX <1% or <1 IU dL−1), born between 1 January 1970 and 1 January 1994, treated at the participating centres, with life-long access to care and treatment data available were eligible for this study. Patients with a history of inhibitors (titres >0.6 BU with decreased recovery) were excluded. Diagnosis and onset of joint bleeding were collected from the files. In addition, the full history of treatment, including all prophylactic regimens used until evaluation was collected.
For the last 5 years before evaluation, annual clotting factor consumption, number of (joint) bleeds, number of visits to the centre, hospital admissions, and days lost from work/school were documented.
The primary outcome parameter was clinical joint status, assessed by the centre's physiotherapist, using the Haemophilia Joint Health Score (HJHS version 1.0) [17, 18]. The HJHS is based on physical examination of elbows, knees, and ankles. The total score ranges from 0, signifying perfect joint health, to 144. Secondary outcome parameters were the annual number of joint bleeds, self-reported activities (Haemophilia Activities List-HAL [19-21] and International Physical Activity Questionnaire-IPAQ ), and health-related quality of life (Euroqol-EQ5D ). Treatment costs and lost production were compared using Dutch prices for the year 2010. Costs were translated to USD (1 euro = 1.326 USD).
A total of 78 Dutch (intermediate-dose) and 50 Swedish (high-dose) patients were included and assessed during regular clinic visits. Patients were evaluated at a mean age of 24.5 years (range 14–37).The majority (90%) of patients had haemophilia A. Treatment and outcome according to prophylactic regimen are shown in Table 1. Overall, the prophylactic treatment regimens were very different: patients treated with the Dutch intermediate-dose regimen started prophylaxis later, and used a significantly lower dose throughout life. During evaluation, 78% of Dutch and 96% of Swedish patients were on full-time prophylaxis. Both cohorts showed normal physical activity levels (data not shown). Differences in outcome were small but statistically significant: patients treated with the intermediate-dose regimen had slightly higher HJHS scores (median 7.0 vs. 4.0 points out of 144) and reported slightly more bleeding (7–8 additional joint bleeds in 5 years) and more limitations in daily activities (median HAL scores of 93/100 vs. 99/100). These small differences in outcome did not result in a difference in quality of life or employment status. For the 5-year period, median total costs per patient were 73% higher for high-dose prophylaxis. Clotting factor consumption accounted for >97% of costs.
Table 1. Treatment and outcome according to prophylactic regimen.
| N ||78||50|| |
|Age at evaluation, years||24.8 (19.3–30.2)||23.2 (18.7–28.0)||0.47|
| Treatment history |
|Age at diagnosis, years||0.7 (0.04–1.2)||0.6 (0.3–0.9)||0.55|
|Age at start prophylaxis, years||4.5 (3.2–6.0)||1.5 (1.1–2.5)||<0.01|
| Treatment during the last 5 years |
|Typical regimen||3 × 1000 IU||3.5 × 1500–2000 IU|| |
|Weekly dose, IU kg−1||46 (34–55)||88 (61–113)||<0.01|
|Annual consumption, IU kg−1 year−1b||2100 (1400–2900)||4000 (3000–4900)||<0.01|
| Outcome |
|Joint function (HJHS, 0–144 pts)||7.0 (3.0–15.8)||4.0 (1.0–6.0)||<0.01|
|HJHS >10 points||37%||9%||<0.01|
|Joint bleeds per year, n||1.3 (0.8–2.7)||0 (0.0–2.0)||<0.01|
|Joint bleeds in 5 years, n||10 (4–18)||2.5 (0–9.3)||<0.01|
|Limitated activities (HAL, 100–0 pts)||93 (81–98)||99 (93–100)||<0.01|
|Quality of life, (EQ-5D, 1-0)||0.84 (0.81–1.00)||1.00 (0.81–1.00)||0.93|
| 5-year costs |
|Total costs, million USD||0.852 (0.659–1.094)||1.475 (1.155–1.787)||<0.01|
This study showed a statistically significant but small improvement in outcome at age 24 after nearly doubling the annual prophylactic dose. This small incremental benefit was observed in all outcome parameters, except quality of life. This may reflect the limited clinical effects of one additional joint bleed per year, or the inability of the generic Euroqol questionnaire to pick up small differences. In addition, it must be noted that these joint bleeds were treated at a very early stage, usually requiring only a single infusion of FVIII/IX. From a life-long perspective, it is expected that differences in outcome between these two cohorts will increased in the next decades. However, we do not know the clinical and functional implications of such an increase.
Is the difference attributable to dose difference only? One of the drivers of the slightly better outcome in the high-dose group may be the earlier start of prophylaxis, as was shown in both Swedish and Dutch patients [24, 25]. Multivariable regression analysis of these data suggested that the effect of dose was more important than the effect of early initiation of prophylaxis.
For clinical practice, it will always be important to prevent bleeding, especially in the joints. Overall, these favourable results support the need for an early start of prophylaxis and continuing this treatment in adults with severe haemophilia. At patient level, the data on joint outcome suggest that a proportion of patients are equally well-off with intermediate-dose prophylaxis, while others need a high-dose regimen to control their bleeding. Pharmacokinetic information  in combination with bleeding frequency and individual circumstances, such as sports participation , can be used to assist decisions on prophylactic dosing.
Continued follow-up of these cohorts will provide us with some of the answers needed. Until then, personalizing prophylactic treatment, including lower dosed regimens, appears the most cost-effective treatment strategy.
Prophylaxis in patients with inhibitors
Regular factor infusions to prevent bleeding have become the mainstay of treatment for many patients with haemophilia. Numerous observational studies and one randomized controlled trial have documented that the efficacy of prophylaxis started early in life reduces bleeding and prevents joint damage [6, 28-30]. Even when instituted later in life, after joint damage has occurred, prophylactic factor therapy can significantly reduce the number of bleeds including into joints, although data on long-term joint outcomes are still limited [8, 9, 30]. These results have raised the question of whether prophylaxis could be effective in patients with haemophilia and inhibitors to FVIII or FIX. This question has been addressed in case reports, case series, and in randomized trials.
Patients with haemophilia and persistent inhibitors are more likely to have disabling haemophilic arthropathy and other sequelae of bleeding . While the use of bypassing agents [recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrates (aPCC)] has advanced care of patients with inhibitors, these products are not as effective overall as factor replacement therapy and bleeding results in persistent adverse effects. If prophylactic therapy with bypassing agents could prevent bleeding, there is the potential for even more benefit in the inhibitor population from this approach.
Multiple reports have relayed successful use of either rFVII or aPCC in a prophylactic regimen, although with varying dosing and treatment intervals [27, 32, 33]. In general, these reports document decreased bleeding, improved quality of life, and often the ability to support a rehabilitation regimen, albeit in small numbers of patients.
Three randomized controlled trials which evaluated prophylaxis in inhibitor patients have now been reported, one with rFVIIa and two with aPCC [34-36]. In the study subjects, generally patients with a history of frequent bleeding episodes, there was a significant decrease in bleeding with prophylactic therapy. There were no thrombotic complications and two allergic reactions to the aPCC. All studies had some persistence of bleeding, likely due to the lack of complete correction of haemostasis with these bypassing agents and the severity of haemophilic arthropathy in the patient populations studied.
For the rFVIIa trial, patients who bled frequently (>12 times over the preceding 3 months) were randomized to receive rFVIIa 90 μg kg−1 or 270 μg kg−1 daily for 3 months . Bleeding during the treatment phase was compared to that reported for the 3 months prior to and following the 3 month prophylaxis treatment period. During the non-prophylactic treatment phases, subjects used their standard treatment with rFVIIa or other therapies. During prophylactic therapy, the 22 subjects experienced a 45% and 59% decrease in bleeding with the 90 and 270 μg kg−1 doses, respectively, which was primarily in joint bleeding. The bleeding frequency remained decreased during the 3 months follow-up phase.
The Pro-FEIBA trial was a crossover design where patients with high titre inhibitors were randomized to receive either prophylactic aPCC therapy at 85 units kg−1 on three non-consecutive days per week or on-demand therapy for 6 months . They then received on-demand therapy for 3 months, followed by crossover to the opposite treatment arm. In the 26 patients completing both treatments, there was a 62% reduction in all bleeding and a 61% reduction in haemarthroses with prophylaxis compared to the on-demand arm. As with the rFVIIa trial, there was improvement in short-term measures of quality of life, such as decreased hospital visits and time missed from school and work [34-36].
More recently, a randomized open label study of aPCC treatment at 85 units kg−1 every other day was compared to on-demand therapy . The 17 patients receiving prophylaxis had a reduced annualized bleeding rate of 7.9 compared to 28.7 in the on-demand treatment arm.
Whether prophylaxis should be routinely adopted for inhibitor patients is controversial. The regimens are very costly and, for rFVIIa, treatment intense. The treatment options to date do not completely eliminate bleeding; a likely reason that prophylaxis has been applied to targeted inhibitor patient populations. One area of application is in patients with newly developed inhibitors, where prophylaxis could prevent bleeding while awaiting response to immune tolerance therapy (ITI). This has generally been applied to the periods before starting ITI and in regimens using lower factor doses. Prophylaxis was part of early reported ITI regimens, including the Bonn protocol . However, in the international immune tolerance study, where prophylaxis was left up to the investigator, only 9% of patients were given bypassing agent prophylaxis . This may be, in part, because of a haemostatic effect of factor VIII infusions, even when given in the presence of an inhibitor.
Patients with frequent bleeding are another group where the application of prophylaxis can result in significant improvements in functionality and quality of life. These are the patients best represented in the case reports and randomized trials. Dosing can be informed by results of the randomized trials. Limited data from a retrospective observational study suggest that rFVIIa infused less frequently than daily may be effective when used as prophylaxis . The FENOC study documented individual variation in response to aPCC vs. rFVIIa for treatment of joint bleeding . A similar variation in response is likely true for prophylaxis and thus until we have better laboratory measures of haemostasis, personalized dosing regimens are needed. aPCC contain FIX and thus rFVIIa is preferred as prophylaxis in those haemophilia B patients with inhibitors. As aPCCs also contain some FVIII, they are generally not recommended in the pre-ITI setting when awaiting a decline in the factor VIII inhibitor titre .
New products under development may result in more effective therapy for treatment of patients with inhibitors. These include longer acting and novel bypassing agents. If we can achieve improved haemostasis in patients with haemophilia and inhibitors with these agents, they will be excellent candidates for studies in prophylaxis applications.
Haemophilia and sports
The widespread availability of prophylactic clotting factor has made many sports possible for persons with haemophilia (PWH) living in developed countries. Prior to this, the perceived risks associated with most sports, particularly those with the potential for contact or collision, were thought to be unacceptable.
Fitness and physical activity
Early studies in PWH report impairments in aerobic fitness and strength, consistent with previous advice restricting sports participation [41-46]. Most studies also reported a trend towards overweight and obesity in children with haemophilia [46, 47]. More recent studies, however, in settings where prophylaxis is widespread, have demonstrated comparable fitness and strength in children with haemophilia compared with their healthy peers [48, 49]. Similarly, high levels of physical activity and sports participation have recently been reported in studies performed in countries with widespread availability of prophylactic clotting factor [50, 51].
Advantages of physical activity and sport
The benefits of physical activity have been well described in children . In addition to the short-term benefits, there is now substantial evidence for physical activity in extending life expectancy and reducing the risk of a number of chronic illnesses [53-56]. Regular physical activity has also been shown to improve well-being in children and young people . These benefits may be even more important in PWH to address reported impairments in aerobic fitness, strength, and bone mineral density [41, 42, 44, 58, 59]. Physical activity and sport may also have a role in maintenance of joint health in PWH through improving muscle strength and proprioception, although the evidence for this is currently lacking.
Risks of sport for children with haemophilia
The benefits of sport and physical activity in children with haemophilia need to be balanced against the risk of bleeding episodes and the potential for detrimental effects on joint health. In a recent study of young people with haemophilia in the United States, 60% reported that they avoided or limited physical activity as a way of managing their disease . The perceived risk of bleeding associated with sport, however, may be overstated.
To date three studies have examined the association between physical activity and bleeding outcomes in children with haemophilia [27, 61, 62]. Two studies found no association between level of physical activity and bleeding rates or joint outcomes [61, 62]. A further study which examined the temporal relationship between physical activity and bleeding and adjusted for clotting factor levels in the blood found a moderate transient increase in bleeding risk associated with vigorous physical activity (odds ratio 2.7 for ‘moderate-risk sports’ and 3.7 for ‘high-risk sports’) .
Table 2  denotes sporting activities according to their relative risks of bleeding when compared with the inactive state or light activity such as walking. As the proportion of time spent in vigorous activity is usually relatively small compared to the total number of hours in a week, the increase in absolute bleeding risk associated with physical activity is likely to be small. It is possible, however, that sporting activity impacts on joint health in the absence of clinically detectable bleeds. To date, this association has not been determined. As expected, rates of bleeding are inversely related to pre-existing levels of clotting factor activity.
Table 2. Sporting activities according to relative risk of bleeding.
|Walking/jogging/sprinting||Walking, jogging, sprint races, bushwalking, cross country running||1.0|
|Swimming||Breaststroke, freestyle, backstroke, butterfly||1.0|
|Non-contact sports||Archery, darts, lawn bowls, golf, fishing, tai chi, pool, snooker, table tennis, badminton, ten pin bowling||1.0|
|Dancing||Hip hop, jazz, ballroom, contemporary, Latin American, Irish, Scottish, folk dancing||1.0|
|Gym activities||Lifting weights, gym equipment, cardio, rowing ergometer||1.0|
|Structured throwing activities||Shot put, javelin, discus||1.0|
|Water activities (low risk)||Swimming in surf, sailboarding, snorkeling, scuba diving, boogie boarding, rowing, canoeing||1.0|
|Water activities (mod risk)||Surfing, surf lifesaving, water-skiing, competition diving, white water rafting, sailing||2.7|
|Gymnastics||Gymnastics – artistic, rhythmic, acrobatics, competitive trampolining||2.7|
|Riding activities (low risk)||Bike riding, track & road cycling, riding scooter, riding horse, motor bike riding, rollerblading, roller-skating, BMX lite||2.7|
|Wilderness||Rock climbing, abseiling||2.7|
|Hard ball games/training||Baseball, softball, cricket, t-ball||2.7|
|Running games/jumping||Long jump, high jump, hurdles||2.7|
|Racquet sports||Tennis, squash||2.7|
|Mod-low contact sports||Soccer, netball, basketball, touch football, Oz tag, water polo, volleyball, European handball, field hockey||2.7|
|Snow sports||Skiing, ice-skating, tobogganing, snowboarding||3.7|
|Martial arts||Karate, Kung Fu, Tae Kwon Do, Judo||3.7|
|Contact/collision sports||Tackle football including rugby union, rugby league, AFL, American football, ice hockey, wrestling, boxing||3.7|
|Riding activities (mod risk)||Skateboarding, rip-stick, BMX hard core||3.7|
While the reporting of relative risk may help PWH balance the benefits and risks of sports participation, assessing bleeding risk involves more than just odds ratios. All bleeds are not equal. Take the example of an adolescent boy who wants to play rugby union. While the transient increase in risk of bleeding with this sport is comparable to a sport such as ice skating, the possibility of a serious intra-cerebral bleed is likely to be greater in rugby so this risk might be considered to be unacceptable vs. ice skating which has the same relative risk.
Mitigating risk of joint deterioration and bleeding episodes with sport
The only evidence-based preventative strategy to reduce bleeding episodes in sport is the administration of prophylactic clotting factor. For every 1% increase in clotting factor level, there is a 2% reduction in bleeding risk . There is still debate regarding optimal prophylactic schedules and dosing. In practice, many PWH schedule their prophylaxis around periods of high activity or sport. The efficacy and cost-effectiveness of this approach vs. standard prophylactic dosing regimens needs to be further evaluated in a randomized control trial. Unfortunately, much of the world's population still has no access to prophylactic clotting factor and this is reflected in the low rates of sports participation and poor fitness levels among PWH in these countries .
The impact of the extended half-life products, currently undergoing clinical trials, is cause for optimism in PWH who play sport. The reduction in bleeds risk associated with an increase in factor level previously observed with shorter acting products is likely to be sustained over a longer period. This will need to be verified empirically and future studies examining the role of longer acting products in PWH who are physically active are needed.
Maintaining optimal body weight
Overweight and obesity are associated with a more rapid decline in joint health in young males with haemophilia. A 10-year longitudinal study involving more than 6000 males with severe haemophilia under the age of 21 years, demonstrated a significant increase in limitation of lower limb joint range of motion in those who were overweight and obese compared to those with a normal BMI . Maintaining body weight within the normal range therefore appears important to minimize the risk of joint deterioration.
Other injury prevention strategies
With the exception of prophylaxis, there are currently no evidence-based sports injury prevention strategies for children with haemophilia. While haemarthroses can occur in the absence of acute joint derangements, prevention of sports injury is paramount. Advice to children with haemophilia is, therefore, based on guidelines in healthy children and there are relatively few evidence-based injury prevention strategies in children and adolescents.
To date, research on sports injury prevention in young healthy populations has focussed largely on the use of protective equipment and training programmes . There has been little emphasis on rule changes and behavioural change in sport injury prevention research. The other limitation in injury prevention research is that most interventions have been directed at a particular sporting population or preventing a particular injury, for example, anterior cruciate ligament prevention programmes. This makes it difficult to devise widespread evidence-based injury prevention strategies.
Proprioceptive and neuromuscular training programmes have been shown to reduce lower limb injuries in sport . Randomized control trials involving balance training alone or in combination with strength and plyometric training, have shown a significant decrease in reported lower limb injuries in adolescents and young adults, with training programmes that range from once weekly to seven times weekly and which run for a duration of 3–12 months [66-70]. While these training programmes reduce injury during the timeframe of the research study, injury rates often return to pretrial levels following conclusion of the studies highlighting the difficulty of putting effective training strategies in to practice .
Protective equipment has an important role for PWH competing in certain sports. There are two broad categories of protective equipment that reduce risk of injury. One type is for joint stabilization, for example, ankle taping or bracing, while the other type is designed to disperse contact forces, for example, shin pads and bicycle helmets. While there is evidence for both types of protective equipment in the prevention of sports injury, the difficulty is in modifying behaviour to ensure utilization of this equipment through education and other strategies [72, 73]. Helmet use has been shown to significantly reduce risk of head injury in skiing and yet only a small proportion of skiers use helmets .
There has been little research examining the role of behaviour in sports injury prevention . Despite growing evidence for a number of injury prevention strategies, behavioural change on the part of the sportsperson, the coach and sometimes the adjudicators of sport, is required to prevent injury .
Safe sports participation for PWH involves balancing the benefits and risks of particular activities and, where possible, ensuring adequate clotting factor levels in the blood. The focus now should be on evaluating the role of injury prevention strategies including optimal prophylactic schedules, protective equipment and preparticipation exercise programmes on bleeds risk and ensuring that proven injury prevention strategies are adopted at a community level.
KF has received speaker's fees from Baxter, CSL Behring, Pfizer, Novo Nordisk, Biotest; performed consultancy for Bayer, Baxter, Biogen, Novo Nordisk and Pfizer; and has received research support from Bayer, Wyeth/Pfizer, Baxter, and Novo Nordisk. BK has received research support from Baxter Bioscience, Biogen-Idec Hemophilia, Novo Nordisk and Octapharma, and has acted as a consultant for CSL-Behring, Pfizer, Baxter Bioscience and Biogen-Idec Hemophilia. CB has no conflicts to declare. CMK has not declared any conflicts.