A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. Evaluation of prophylactic replacement therapy in haemophilia B. An evaluation of the efficacy of postoperative blood salvage after total joint arthroplasty. A prospective randomized trial. A randomized controlled trial of beta-blockers versus endoscopic band ligation for primary prophylaxis: a large sample size is required to show a difference in bleeding rates.
Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia.
                This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period.
                Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 × week) or episodic therapy with ≥25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated.
                Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy.
                This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life.
                © 2011 International Society on Thrombosis and Haemostasis. Effective ways to prevent arthropathy in severe hemophilia are unknown.
                We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).
                Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.
                Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).
                Copyright 2007 Massachusetts Medical Society. Prophylaxis replacement therapy has been assessed for a period of 12 months in 10 patients with severe haemophilia B showing a high incidence of spontaneous bleeding episodes. Two different schedules of administration of a freeze-dried factor IX concentrate were randomly evaluated: according to scheme A, 7.5 U/kg were administrated biweekly, whereas scheme B was based on the weekly infusion of 15 U/kg. On prophylaxis the frequency of bleeding episodes was significantly reduced (P less than 0.005) when compared with that observed in one-year period preceding the trial. Biweekly infusions were superior to weekly infusion (P less than 0.01), and the benefit appeared to be related to the higher number of days in which measurable levels of factor IX were attained in plasma. Range of motion, which was redeced at the start of the trial in 26 joints, was found to have improved in 23. Favourable changes of the joint radiological picture were observed in 6 cases. Hepatitis and factor IX inhibitors did not develop during the trial period. Side effects were rare and mild. The efficacy of a postoperative blood salvage system was assessed in 239 consecutive patients undergoing total knee or total hip arthroplasty. Patients were randomly allocated to either a control group using a standard drainage system or to the study group using the Solcotrans blood salvage canister. The median amount of homologous blood required after operation by the study group was reduced by 74% from the amount required by the control group (mean, 67 ml vs 256 ml, respectively; P less than .0001). Thirteen percent (13%) of the study group required postoperative homologous blood transfusions, as compared to 39% of the control group (P less than .0001). Additionally, patients in the study group had higher hemoglobin levels beginning on the first postoperative day. This study indicates that a postoperative blood salvage system safely and effectively reduces the amount of homologous blood required and sustains higher hemoglobin levels after operation. Primary prophylaxis with nonselective beta-blockers in high-risk subjects has been shown to be effective in reducing both esophageal variceal bleeding and mortality. Recently it has been suggested that band ligation may be a better option for primary prophylaxis. We compared nonselective beta-blockers with band ligation in patients with large varices (F2, F3) and elevated hepatic venous wedge pressure gradient (HVWPG, > or = 12 mm Hg). All patients were prospectively followed for variceal bleeding, mortality, and treatment-related complications. Based on previous published studies, we estimated that 90 patients in each arm would be required to show a difference in bleeding rate. The study was prematurely terminated when we realized that our estimated sample size was inadequate to show a difference based on the observed bleeding rate. At the time of termination, 31 patients (Child A, 11; B, 14; C, 6), with a mean HVWPG of 19 +/- 9.1 mm Hg, were randomized to either band ligation (group A; n = 16) or beta-blockers (group B; n = 15). Baseline demographics of both groups were similar and the mean follow-up period was 27.4 +/- 12.9 months. During the follow-up, two patients in group A and one patient in group B had bleeding. Nine patients (29%; group A, six; group B, three; P = ns) died due to non-bleeding-related causes and five (16%) patients (group A, three; group B, two) underwent liver transplantation. Treatment-related complication were minimal in both groups. Despite the selection of high-risk patients, the observed bleeding rate was much lower than anticipated. Based on our observed bleeding rates, 424 patients would be required in each arm to show a difference between band ligation and beta-blocker therapy.
There is strong evidence from randomised controlled trials and observational trials that prophylaxis preserves joint function in children with hemophilia as compared to on-demand treatment. There is insufficient evidence from randomised controlled trials to confirm the observational evidence that prophylaxis decreases bleeding and related complications in patients with existing joint damage. Well-designed randomised controlled trials and prospective observational controlled studies are needed to establish the best prophylactic regimen and to assess the effectiveness of prophylactic clotting factor concentrates in adult patients.