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Abstract

Objective:

This study explores the efficacy of recombinant factor VIII (rFVIII) low-dose prophylaxis in Chinese pediatric patients with severe hemophilia A from the Retrospective Study in Chinese Pediatric Hemophilia A Patients With rFVIII Contained Regular Prophylaxis (ReCARE) population.

Methods:

This is additional analysis of the multicenter, retrospective ReCARE study, in which the annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and safety of >12-week, low dose (10-30 IU/kg/wk) rFVIII prophylaxis divided into primary, secondary, and tertiary groups based on the joint status and joint bleeding history were analyzed.

Results:

A total of 57 patients (median age: 8.2 [0.4-17.3] years) from the ReCARE study receiving primary (n = 3), secondary (n = 21), and tertiary (n = 33) prophylaxes were included. Low-dose prophylaxis had significant bleeding reduction in all 3 groups compared to the baseline (S = 408.5, P < .001), with median ABR rates of −4.0 (−8.0 to −3.1), −4.0 (−24.0 to 8.0), and −13.9 (−110.6 to 20.6) in the primary, secondary, and tertiary groups, respectively, with a significant difference between the secondary and tertiary groups (P = .008). Median AJBR reduction rates were −2.3 (−6.3 to 8.4) and −14.9 (−61.5 to 19.1) in the secondary and tertiary groups, respectively. But there was no significant difference in AJBRs between the secondary and tertiary groups (P = .061), which was related to damaged joint status. Hence, longer prophylaxis was associated with better prevention of joint bleeding (P = .024).

Conclusion:

Despite significant ABR/AJBR reduction in all 3 groups, the efficacy of the primary prophylaxis was better than the secondary and tertiary prophylaxes.

Keywords

severe hemophilia A low-dose prophylaxis China rFVIII-FS annual bleeding rate annual joint bleeding rate

Introduction

The prevalence rate of hemophilia A (HA) in China is remarkably high, with an estimate of 65 000 to 130 000 cases in 2011.¹ As per the Chinese National Hemophilia Registry, the rate of HA in children <14 years of age is as high as 52.3%.² Severe HA is manifested by spontaneous or traumatic joint bleeding episodes, especially in the index joints followed by muscle bleeds, due to deficient factor VIII (FVIII: C <1 IU/dL) activity. Lack of appropriate treatment for recurrent bleeding results in intra-articular changes that culminate in progressive joint destruction, irreversible arthropathy, chronic pain, and overall deterioration of disability. Loss of opportunities, school absenteeism, frequent hospital visits, poor quality of life (QoL), stress, and economic burden are other drawbacks associated with the disease.³ The World Health Organization, World Federation of Hemophilia (WFH), and many national medical/scientific organizations recommend prophylaxis as the first-choice gold standard of treatment.⁴ Early prophylaxis is found to be superior to on-demand treatment in reducing the risk of arthropathy and fosters better joint outcomes and improved QoL.^4
–6 The WFH standardized the definitions and standards of prophylaxis and classified it into primary, secondary, and tertiary stages according to the age of onset and index joints status. Prophylaxis initiated before 2 years of age has been reported to provide better outcomes than that initiated at 3 to 5 years or 6 to 9 years of age.^6

–9 Recombinant antihemophilic factor (Kogenate FS, Bayer Healthcare, Whippany, NJ, USA), the first marketed recombinant factor VIII (rFVIII) in China since 2007, is the routinely used prophylactic drug to prevent or reduce the incidence of hemorrhages in adults (25 IU/kg thrice a week) and children (25 IU/kg every alternate day) with HA as well as to reduce the risk of joint damage in children without preexisting joint damage.¹⁰ Recent economic and medical advancements have resulted in increasing the number of children with HA receiving prophylaxis. Furthermore, there is an increase in the incidence of arthropathy with increasing age.¹¹ Nevertheless, the rate of hemophilia control is limited in China because of limited economy and inadequate treatment availability. Several studies considered very low-dose prophylaxis (10 IU/kg twice a week) as a feasible option^1,12,13 although the outcomes were limited by the number of patients and the focus being on just tertiary prophylaxis.^12
–14 To date, sufficient data do not exist regarding the comparison of treatment effect of low-dose prophylaxis among various prophylactic stages (primary, secondary, and tertiary prophylaxes). Considering the high proportion of HA in China, inadequate control with FVIII prophylaxis, and associated economic concerns with the therapy, the authors wanted to explore the effect of low-dose prophylaxis on HA in China. Thus, ReCARE was the first retrospective study conducted across 12 hemophilia treatment centers in China to determine the real-life choice of rFVIII as regular prophylactic treatment (NCT02263066) from November 2007 to May 2013. The study revealed that most patients had been on low-dose prophylactic regimen (10-30 IU/kg/wk) irrespective of the primary, secondary, or tertiary prophylaxis.¹⁵ This study aimed to further explore the data from the ReCARE trial and evaluate the efficiency of low-dose prophylactic rFVIII in the primary, secondary, and tertiary prophylaxes in children with severe HA in China.

Materials and Methods

Study Design and Patient Population

This multicenter, retrospective, phase IV, noninterventional study is an additional supplemental analysis of the ReCARE¹⁵ conducted in china to evaluate the efficiency of rFVIII low-dose prophylaxis in reducing bleeding rates of hemophilia and/or to describe the treatment condition of patients during the usage of rFVIII-FS. The trial was approved by independent ethic committees or institutional review boards of all participating sites after the approval of signed informed consents from all patients or their legal guardians, and the study protocol conformed to the declaration of Helsinki and its subsequent revisions. Patients were included in the study if they had severe HA (defined as the presence of FVIII: C<1 IU/dL, except von Willebrand disease and acquired coagulation factor VIII deficiency¹⁶), received regular rFVIII prophylaxis (administration of ≥2 injections per week, accounting for ≥80% of the prophylactic period¹⁷) for more than 12 weeks, received low-dose (10-30 IU/kg/wk) prophylactic regimen, and had complete medical records in the clinic. Patients were excluded if they had a documented history or the presence of positive inhibitors (≥0.6 BU by Bethesda assay at 2 different time points), their prophylactic regimen was beyond the low dose (<10 or >30 IU/kg/wk), regular prophylaxis was less than 12 weeks, or their medical records were incomplete. However, patient’s incomplete records with sufficient relevant data to be analyzed were included in the study.

Definitions of the 3 Prophylactic Groups

All patients were divided into primary, secondary, and tertiary prophylactic groups based on the index joints status. The primary prophylaxis was referred to the treatment initiated in the absence of evident joint disease and before the second clinically recognized joint bleed, and before 3 years of age. The secondary prophylaxis referred to the treatment initiated after ≥2 bleeds but before the onset of joint disease as documented by physical examination and/or imaging studies, and/or >3 years of age. Tertiary prophylaxis was the treatment started after ≥2 bleeds or the onset of joint disease at any age.⁶ Baseline data were obtained 6 months prior to the initiation of prophylactic therapy.

Study Outcomes

Primary outcomes included the reduction in annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) during the 3 prophylactic periods and their comparison to the baseline. Adverse drug reactions and inhibitor levels were monitored throughout the prophylaxis period and were measured as secondary outcomes.

Statistical Analysis

The SAS-based statistical software JMP Clinical (version 5; SAS Institute Inc, Cary, North Carolina) was used for data analysis. The age, age at first diagnosis, age at first FVIII exposure, duration of diagnosis to starting regular rFVIII prophylactic treatment, ABR, and AJBR were described by median (min-max) for not meeting normal distribution. Factor VIII consumption was described by mean ± standard deviation (SD). Statistical analyses of baseline data (age, age at first diagnosis, age at first FVIII exposure, duration of diagnosis to starting regular rFVIII prophylactic treatment, first regular prophylactic treatment time, and FVIII consumption) among the 3 groups were carried out by Kruskal-Wallis rank sum test. The paired Wilcoxon rank sum test was used to compare the difference between the baseline and the treatment period of ABR and AJBR. The differences between the secondary and tertiary prophylactic groups in ABR and AJBR, considering the unbalance of the baseline in the 2 groups and nonnormality of data, were carried out by rank-based analysis of covariance (CANOVA). Differences were considered as statistically significant when P < .05.

Results

The ReCARE study included 183 patients who underwent regular prophylactic treatment from 2007 to 2013. Two patients were excluded due to protocol deviation as one of them received regular rFVIII prophylaxis for less than 10 weeks, and another patient was >18 years of age. Finally, 181 patients were included of whom 68 were excluded due to the unavailability of regimen records (n = 14); received non low-dose prophylaxis <10 IU/kg/wk, which cannot be regarded as prophylactic replacement therapy (n = 11); received moderate-dose prophylaxis of 30 to 75 IU/kg/wk (n = 42); and standard prophylaxis of ≥75 IU/kg/wk (n = 1). Overall, there were 113 (72.4%) patients who had received low-dose prophylaxis (10-30 IU/kg/wk). Excluding 56 patients without joint bleeding records, data of 57 patients (primary prophylaxis, n = 3; secondary prophylaxis, n = 21; tertiary prophylaxis, n = 33) were finally analyzed (median age: 8.20 years [0.4-17.3]). Details are shown in Figure 1.

Figure 1.

Study flow chart.

Clinical baseline data are reported in Table 1. No statistical significance was observed between the first regular prophylactic treatment time among the 3 groups (P = .322), indicating an equilibrium distribution of treatment duration between the groups; furthermore, there was no statistical significance between the ages of first diagnosis between the 3 groups (P = .133). However, there were statistical significances in the age of first rFVIII exposure (P = .045), duration of diagnosis to start regular rFVIII prophylactic treatment (P = .002), and FVIII consumption (P = .030). All 3 groups started FVIII and regular prophylaxis at different ages—the primary group started treatment at a young age, and a delay in treatment transferred children with hemophilia to tertiary prophylaxis. Furthermore, the rFVIII consumption in the 3 groups was 1157.9 ± 219.7, 1063.5 ± 332.0, and 1303.8 ± 312.1 (IU/kg/y; data not shown), indicating that the factor consumption in low-dose prophylaxis was significantly less than moderate- and high-dose prophylaxis.

Table 1.

Baseline Characteristics of 57 Patients in the Study.

Parameter	Primary Prophylaxis (n = 3)	Secondary Prophylaxis (n = 21)	Tertiary Prophylaxis (n = 33)	P Value
Age, years
n	3	21	33	.002
Median (min-max)	0.9 (0.4-2.2)	6.1 (1.4-17.3)	10.6 (2.6-16.1)	.002
Age at first diagnosis, years
n	3	21	32	.133
Median (min-max)	0.4 (0.3-0.5)	1.1 (0.0-7.9)	0.9 (0.0-5.6)	.133
Age at first FVIII exposure, years
n	3	19	27	.045
Median (min-max)	0.4 (0.3-0.5)	1.2 (0.1-7.8)	1.3 (0.2-10.3)	.045
Duration of diagnosis to starting regular rFVIII prophylactic treatment, months
n	3	21	32	.002
Median (min-max)	0.8 (0.1-1.9)	5.5 (0.1-14.1)	9.3 (0.6-15.5)	.002
First regular prophylactic treatment time
<24 weeks, n (%)	1 (33.3)	8 (38.1)	19 (57.6)	.322
>24 weeks, n (%)	2 (66.7)	13 (61.9)	14 (42.4)	.322
FVIII consumption, IU/kg/y
n	3	21	33	.030
Mean ± SD	1157.9 ± 219.7	1063.5 ± 332.0	1303.8 ± 312.1	.030
Annual bleeding rate
Median baseline (min-max)	4.0 (4.0-8.0)	8.0 (0.0-24.0)	20.0 (0.0-128.0)
Median prophylactic period (min-max)	0.0 (0.0-0.9)	1.9 (0.0-12.6)	9.0 (0.0-50.3)
Annual joint bleeding rate
Median baseline (min-max)	0.0 (0.0-0.0)	4.0 (0.0-12.0)	20.0 (0.0-68.0)
Median prophylactic period (min-max)	0.0 (0.0-0.0)	0.8 (0.0-9.7)	5.1 (0.0-45.2)

Abbreviations: ABR, annual bleeding rates; AJBR, annual joint bleeding rates; FVIII, factor VIII; min, minimum; max, maximum; rFVIII, recombinant FVIII; SD, standard deviation.

Annual Bleeding Rate

Wilcoxon matched-pairs signed rank test revealed a significant difference in ABR between the prophylactic period and baseline (S = 408.5, P < .001). Low-dose prophylaxis had a significant effect on bleeding at different prophylactic stages. Annual bleeding rate was lesser in patients who were receiving regular low-dose prophylaxis than the baseline (primary prophylaxis: 0 vs 4.0 [4.0-8.0]; secondary prophylaxis: 1.9 [0.0-12.6] vs 8.0 [0.0-24.0]; tertiary prophylaxis: 9.0 [0.0-50.3] vs 20.0 [0.0-128.0]). Compared to the baseline, the median reduction of annual bleeding rate was −4.0 (−8.0 to −3.1), −4.0 (−24.0 to 8.0), and −13.9 (−110.6 to 20.6) in the primary, secondary, and tertiary groups, respectively (Table 1). Compared to the baseline values, the reduction in ABR with the primary prophylaxis was greater than the secondary and tertiary prophylaxes. Because there were only 3 patients in the primary prophylactic group, we analyzed the secondary and tertiary prophylactic groups using rank-based CANOVA (Table 2 and Figure 2). Compared to the baseline, there was a significant difference in bleeding rates between the secondary and tertiary prophylactic groups (P = .008), indicating that the tertiary prophylaxis had a higher bleeding rate compared to the secondary prophylaxis. Positive correlation in the baseline and prophylactic period in ABR (Table 2 and Figure 2) revealed that the treatment effect of the secondary prophylaxis was not significantly better than tertiary prophylaxis with a similar low-dose prophylactic treatment period.

Table 2.

Rank-Based CANOVA to ABR and AJBR Between Secondary and Tertiary Prophylactic Groups.^a,b,c

Parameter	Parameter Evaluation	Standard Error	T Value	P Value
ABR
Group (tertiary)	12.34	4.42	2.79	.008
RABR0	0.26	0.14	1.83	.074
Weeks (tertiary)	−10.23	4.27	−2.40	.024
RABR0	0.25	0.15	1.61	.120
Weeks (secondary)	2.26	6.05	0.37	.713
RABR0	0.14	0.29	0.48	.634
AJBR
Group (tertiary)	8.49	4.39	1.94	.061
RAJBR0	0.33	0.19	1.78	.083
Weeks (tertiary)	0.20	0.23	0.87	.398
RABR0	−4.55	4.42	−1.03	.317
Weeks (secondary)	0.43	0.38	1.15	.267
RABR0	1.30	5.54	0.23	.817

Abbreviations: ABR, annual bleeding rates; AJBR, annual joint bleeding rates; CANOVA, analysis of covariance.

^aGroup (tertiary): the comparison result between tertiary and secondary prophylaxes after correction for ABR and AJBR in baseline.

^bWeeks (tertiary) and weeks (secondary): the comparison result between >24- and <24-week treatment periods of tertiary and secondary prophylaxes.

^cRABR0 and RAJBR0: the effect of baseline on the prophylactic period of ABR and AJBR.

Figure 2.

Rank-based CANOVA analyzing ABR and AJBR between the secondary and tertiary prophylactic groups. The difference between the secondary and tertiary prophylactic groups in ABR and AJBR were carried out by rank-based CANOVA for the unbalance of the baseline and nonnormality distribution, which means the data in the baseline and during prophylactic period were ranked first and then CANOVA was performed for the ranked values. RABR0 and RAJBR0 mean the rank of ABR and AJBR in the baseline; RABR1 and RAJBR1 mean the rank of ABR and AJBR during the prophylactic period. The closed symbols and broken line indicate the tertiary group, whereas the open symbols and straight line indicate the secondary group. ABR indicates annual bleeding rates; AJBR, annual joint bleeding rates; CANOVA, analysis of covariance.

Annual Joint Bleeding Rates

In the primary prophylactic group, there were no joint bleeding events during the baseline and prophylactic treatment. On comparing the baseline and prophylactic period results of ABR using Wilcoxon matched-pairs signed rank test (S = 237.0, P < .001), the results were similar to ABR results. During the regular low-dose prophylaxis, AJBR was less than the baseline throughout the primary, secondary (4.0 [0.0-12.0] vs 0.8 [0.0-9.7]), and tertiary prophylaxes (20.0 [0.0-68.0] vs 5.1 [0.0-45.2]). Compared to the baseline, the median reduction of AJBR was −2.3 (−6.3 to 8.4) and −14.9 (−61.5 to 19.1) in the secondary and tertiary prophylactic groups, respectively. The results showed that joint bleeding was effectively controlled or improved in the primary prophylactic group, followed by the secondary and tertiary prophylactic groups. We analyzed the secondary and tertiary prophylactic groups using only the rank-based CANOVA (Table 2 and Figure 2). Compared to baseline values, there was no significant difference between the AJBRs of the secondary and tertiary prophylactic groups (P = .061). Similar to ABR, a positive correlation was observed between the baseline and prophylactic period in AJBR. Therefore, initiating low-dose prophylaxis at the earliest could reduce joint bleeding events more efficiently; however, further studies are warranted to know whether the primary prophylaxis can control joint bleeding altogether.

Treatment Periods (>24 Weeks vs <24 Weeks)

The primary, secondary, and tertiary prophylaxes were analyzed between the treatment periods of >24 and <24 weeks. There was only significant difference in ABR between the secondary and tertiary prophylaxes (P = .024). None of the patients reported inhibitor levels or adverse events during the entire prophylactic period.

Discussion

Early prophylaxis has better outcomes in preventing life-threatening and spontaneous bleeding and maintaining joint status with improvement in the QoL compared to episodic treatment.^6,18 Children receiving FVIII therapy as a routine preventative treatment demonstrated 8 times fewer joint bleeds in a year than those receiving enhanced on-demand treatment.^19,20 In addition, initiating early prophylaxis may help prevent inhibitor formation.²¹ Based on the administration guidelines of standard FVIII prophylaxis, FVIII must be infused at 25 to 40 U/kg every 48 hours to maintain FVIII trough levels at more than 1 IU/dL; however, hemophilia medical professionals have been attempting new treatment regimens and individualized prophylaxis such as moderate-dose prophylaxis (10-15 IU/kg, once every 48 hours), low-dose prophylaxis (10-15 IU/kg/, 2 times a week), or escalated regimen. A study by Valentino et al reported that standard and pharmacokinetic-tailored prophylaxis intended to maintain FVIII trough levels at or above 1% and that the prophylaxis significantly reduces bleeding compared to on-demand treatment.²²

The present study was a further analysis of the ReCARE trial.¹⁵ Data from the ReCARE trial revealed that low-dose prophylaxis accounted for a major proportion of patients (72.4%; n = 113). The number of patients receiving median- and standard-dose prophylaxes was lower than that receiving low-dose prophylactic treatment, which represents the current status of FVIII prophylactic therapy in China. Furthermore, patients in the ReCARE study received regular rFVIII prophylaxis for more than 12 weeks. Therefore, analyzing the data from the ReCARE trial will help in understanding the effect of using low-dose rFVIII as prophylaxis (primary, secondary, and tertiary prophylaxes) in Chinese children with severe HA across geographically well-distributed centers in China.

Because high cost of the primary prophylaxis is a major limitation in developing countries, most patients from China and other developing countries prefer to receive low-dose prophylaxis. Multiple studies have evaluated the effect of low-dose prophylaxis on joint function and the QoL compared to on-demand treatment in children with hemophilia.^{1,13,21

–27} Few studies in China have shown better effect of low-dose prophylaxis on joint bleeding compared to on-demand treatment.^1,13 A control study of low-dose secondary prophylaxis (currently defined as tertiary prophylaxis) and on-demand treatment by Wu et al revealed that both long- and short-term low-dose tertiary prophylaxes can significantly improve joint bleeds and functions compared to on-demand treatment.¹¹ Another study revealed a 6-fold (85%) reduction in the risk of joint damage in children with hemophilia receiving prophylaxis (25 IU/Kg every other day) than those receiving intensive on-demand treatment.²⁸ In their study, Nilsson et al demonstrated that patients receiving a prophylactic regimen of 10 to 20 IU/Kg every 3 to 5 days initiated at an age of 3 to 13 years had only 1.6 to 16 joint bleeds/year with a radiologic score of 0 to 41.²⁹ Prophylaxis has shown minimal/no bleeds at all if initiated at an age of less than 3 years.^1,7,30 In a recent study by Verma et al, it was found out that very low-dose FVIII prophylaxis (10 IU/kg twice a week) was effective in the joint and overall bleeding preventions, in addition to being cost-effective.²⁷ In the current study, there was an age-dependent trend of prophylaxis regimen in which the youngest patients had the primary prophylaxis followed by the secondary and the oldest children had the tertiary prophylaxis, which means children diagnosed early with hemophilia were on primary prophylaxis and those who had delayed diagnosis due to varied reasons had ultimately turned to tertiary prophylaxis after the onset of joint status.

In the current study, after at least 12 weeks of observation, we found that low-dose prophylaxis could significantly reduce bleeding times for each of the groups, with the highest reduction being observed in the primary prophylactic group, indicating that primary prophylaxis also prevented bleeding from further aggravation of the disease. The median ABR of the primary prophylactic group was 0 times (range: 0-0.9), indicating that the bleeding events of the primary prophylactic group were majorly controlled, whereas the other groups demonstrated a significant reduction. Overall, low-dose prophylaxis demonstrated an effective bleeding control in children with hemophilia receiving primary prophylaxis, thereby showing better results than the secondary and tertiary prophylaxes. We observed that low-dose prophylaxis prevents bleeding from further aggravation and improves joint status. According to our results, although ABR of the secondary group was significant less than that of the tertiary group, there was no significant difference in AJBR between the 2 groups. This is likely as the secondary prophylaxis can prevent bleeding and delay the joint damage but is unable to completely prevent the joint damage. Therefore, as compared to tertiary prophylaxis, there is no significant difference on joint bleeding improvement for the secondary prophylaxis.

It is noticeable that ABR and AJBR were positively correlated in the baseline and prophylactic period with low-dose prophylactic treatment. Severe lesions will have poor prognosis, and therefore, bleeding and joint disease cannot be fully improved. This study strengthens the findings from previous studies that concluded that early diagnosis and initiation of prophylaxis, especially the primary and secondary prophylaxes, can be more effective in the prevention of bleeding in children with hemophilia and will delay further progress of the joint disease. Furthermore, this study also supports a multinational study involving 477 patients, in which prophylaxis was associated with significant reduction of arthropathy compared to on-demand treatment, which was directly associated with decreased direct and indirect health-related costs and significant reductions in the number of hospital admissions and school absenteeism with a favorable psychological development in hemophilia children.³¹ Furthermore, we inferred that only longer treatment period resulted in lesser bleeding in the tertiary prophylactic group, representing that longer prophylactic duration will have better prognosis in already established target joint status. Hence, as standard therapy, prophylaxis should be given regularly as early as possible before the onset of joint disease. Furthermore, we also observed that FVIII consumption was significantly less in low-dose prophylaxis regimen compared to moderate-dose and high-dose prophylaxis regimens, which meant that low-dose prophylaxis could have an economic as well as an acceptable short-term outcome.

Therefore, low-dose prophylaxis will have a direct impact on the cost factor and will make treatment an affordable option in developing countries, thus yielding better control rates of HA. Although the total cost of high-dose factor prophylaxis is 66% higher, the outcomes are only slightly better than intermediate-dose prophylaxis.²⁷ We suggest for low-dose prophylaxis, patients with severe HA in developing countries could receive 10 to 15 IU/KG, 1 or 2 times per week to avoid frequent bleeding to keep their normal QoL as much as possible. Our study has certain limitations. First, the retrospective design of the study demands future confirmation of the findings by prospective, randomized, large-group studies. Second, data collection from different centers was inconsistent and there was a large amount of missing data. Third, data of only 57 patients were analyzed. Evaluation for joint structures using ultrasound, X-ray, and MRI test for index joints and the evaluation of function using tools such as Hemophilia Joint Health Score (HJHS) were not available because of the retrospective nature of the study. One of the major limitations was that data of only 3 patients in the primary prophylactic group were analyzed due to the lack of awareness of Chinese families about hemophilia resulting in late initiation of prophylaxis, thereby resulting in increased proportion of the secondary and tertiary prophylaxes, which suggested that we need to strengthen public awareness and education as one of the aims in the future. Furthermore, the prophylactic period in the present study was short and further validation is needed.

Conclusion

Low-dose prophylaxis significantly reduced the frequency of bleeding and joint bleeding. Initiating early prophylaxis for a longer duration will result in better prevention of joint damage. However, further randomized prospective research is warranted to support this conclusion, including assessment of the joint structures and functions by assessment tools in a longer prophylactic duration study cohort.

Footnotes

Acknowledgments

The authors thank Dr Amit Bhat and Miss Navya Reddy from Indegene Pvt Ltd, Bangalore, India for providing medical writing assistance to this study.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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The Efficacy of Recombinant FVIII Low-Dose Prophylaxis in Chinese Pediatric Patients With Severe Hemophilia A: A Retrospective Analysis From the ReCARE Study

Abstract

Objective:

Methods:

Results:

Conclusion:

Keywords

Introduction

Materials and Methods

Study Design and Patient Population

Definitions of the 3 Prophylactic Groups

Study Outcomes

Statistical Analysis

Results

Annual Bleeding Rate

Annual Joint Bleeding Rates

Treatment Periods (>24 Weeks vs <24 Weeks)

Discussion

Conclusion

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Funding

References