| Background and ObjectiveHemophilia A is an X-linked inherited bleeding disorder, pathological mechanism is that the qualitative or quantitative defects in FⅧ production due to mutations in the FⅧ gene. The main clinical manifestations of hemophilia A is repeated spontaneous or post-traumatic bleeding in joints, muscles, organs and deep tissue. Long-term repeated bleeding will lead to joint deformity, muscle atrophy and other complications, seriously affecting the quality of life of patients with hemophilia.To date, there’s no radical method to cure hemophilia A. FⅧ replacement therapy is currently the only effective treatment, which were divided into on-demand treatment and prophylaxis treatment. On-demand treatment is early treatment with F Ⅷ when bleeding, while prophylaxis treatment is preventive injection of FⅧ before bleeding occurred, with the purpose of reducing the bleeding rate, prevent joint damage accumulation as well as bleeding complications.Prophylaxis was pioneered for hemophilia in the late 1950s in Sweden by Nilsson. In recent years, a large number of studies have demonstrated the effectiveness of prophylaxis treatment in reducing bleeding rate, delaying joint damage, improving joint function and quality of life. Although the efficacy of prophylaxis treatment is superior to on-demand treatment, and it is recommended as the preferred treatment for severe hemophilia patients by World Federation of Hemophilia(WFH) and World Health Organization (WHO),however, due to the differences of economic development around the world, only less than 40% severe hemophilia patients is on prophylaxis treatment nowadays.In addition, Europe and the United States and other developed countries have mostly adopted the high-dose regimen (≥75IU/kg/week) for prophylaxis, and it is too expensive to apply to developing countries. For the past few years, some developing countries have practiced low-dose prophylaxis regimen and achieved good outcomes, yet some studies have indicated that the joint damage progression can not be prevent by low-dose regimen.In recent years, our hemophilia treatment centre (HTC) further attempts to implement intermediate-dose regimen. Currently there is no system comparison of low-dose and intermediate-dose regimen in adult patients with hemophilia A in our country, therefore in the first part of this project, we compare the different clinical outcomes of low-dose and intermediate-dose regimen by collecting the date from adult patients with severe hemophilia A receiving prophylaxis treatment in our HTC, to explore a better prophylaxis regimen under current conditions of China to maximize the benefit of the patients.On the other hand, adherence is an important issue in prophylaxis treatment of hemophilia. WHO conducted a survey and the results showed that the adherence of chronic diseases is less than 50%, which is even lower in any prophylaxis treatment. Poor treatment adherence correlates with worse efficacy, and increases the cost of health care. The effectiveness of the prophylaxis treatment depends largely on the patient’s adherence, so in order to reduce the gap between hemophilia treatment and curative effect, research on adherence is necessary. The study results about adherence by Europe and the United States and other developed countries were different due to a variety of evaluation methods, varied from 6% to 90%. There is no data about patients’adherence in China now.On factors affecting patient adherence, age is the primary factor. Some studies showed that adherence was classified according to age, children had higher levels of adherence than adults patients. Adolescence is the crucial time for the transition of adherence. Whether adherence is associated with age in adult patients has not been determined.Recently studies have found that better adherence to prophylaxis is associated with better clinical outcomes and higher quality of life. Although many studies in other countries have focused on the association between adherence and clinical outcomes in hemophilia prophylaxis treatment, but there’s no domestic study about adherence by reason of the slow starting of prophylaxis. In the second part of this project, we access the adherence of adult patients with hemophilia A in prophylaxis treatment in our HTC, and preliminary explore the association between adherence and age or clinical outcomes to further guide the better implementation of the prophylaxis treatments.Though prophylaxis treatment can reduce bleeding rate, but it can’t completely stop all the bleeding. The pattern of breakthrough bleeding in prophylaxis treatment is different among patients. To realize this pattern can guide the prophylaxis treatment dosage and dosing intervals more effectively, so as to further obtain ideal curative effect. In the third part in this project we will access the proportion of breakthrough bleeding occurs in different time period after clotting factor injection, combined with the patient bleeding patterns, to guide the adjustment of prophylaxis regimen.MethodsA retrospective comparative and non-intervention study of curative effect about short-term low-dose and intermediate-dose tertiary prophylaxis treatment in adults patients with hemophilia A1.Collect data from Guangdong Province hemophilia cases registration management center (Nanfang Hospital hemophilia Registration Center) from July 2010 to February 2015, a total of 40 adult patients with hemophilia A who are receiving prophylaxis treatment≥1 year, including 25 patients in low-dose regimen and 15 patients in intermediate-dose regimen. Patients in low-dose regimen received FⅧ 8-15 IU/kg 1-2 times weekly(Weekly<30IU/kg), patients in intermediate-dose regimen received FⅧ 15-20 IU/kg 2-3 times weekly(Weekly≥40IU/kg and<75 IU/kg).Other 25 patients receiving on-demand treatment screening as the control, who were matched by age, weight.2.Data Collection:patients’characteristics, previous condition and treatment, treatment efficacy index(annual bleeding rate, annual joint bleeding rate, number of target joint, annual target joint bleeding rate, annual severe bleeding event, etc.),clotting factor consumption. Use FISH scoring system to evaluate patients’joint status, use the difference between the beginning of this study and one year ago of FISH score to represent the improvement of joint function. According to the number of annual joint bleeding rate(<5 times or>5 times), the patients in prophylaxis treatment groups are divided into two subgroups. To analyze the joint function in various subgroups under persistent prophylaxis treatment. Use SF36 to evaluate patients’quality of life, use the difference between the beginning of this study and one year ago of SF36 score to represent the improvement of quality of life. Related definitions consulted 2012 WFH standards.3.Statistical analysis:curative effect comparison between groups were analyzed by Kruskall-Wallis non-parametric test, application SPSS 13.0 software for statistical analysis.Adherence in adult patients with severe hemophilia A receiving short-term low-dose and intermediate-dose tertiary prophylaxis treatment1.Use "hemophilia bleeding and factor injection record handbook" to collect information about patients’ bleeding and injection record, use HO’s measuring method for adherence to evaluate the 40 patients in prophylaxis treatment. Data of treatment efficacy use previous results in the first part.2. The correlation between treatment efficacy index and adherence were analyzed by multivariate linear regression analysis, application SPSS 13.0 software for statistical analysis.Breakthrough bleeding in adult patients with severe hemophilia A receiving short-term low-dose and intermediate-dose tertiary prophylaxis treatment1. Screening prophylaxis group to find out patients whose dosage and frequency adherence both>75%. The final total of 29 patients, including 15 patients in low-dose regimen and 14 patients in intermediate-dose regimen.2. Use "hemophilia bleeding and factor injection record handbook" to collect information about patients’bleeding and injection record, accurate to the hour. Observe the situation that breakthrough bleeding events occurred in different time period after clotting factors’injection and calculate the proportion of them.3.Differences between groups were analyzed by Kruskall-Wallis non-parametric test, application SPSS13.0 software for statistical analysis.Results:1. Comparison of curative effects and cost efficient:There were 25 adult patients with severe hemophilia A in on-demand treatment group and 40 adult patients in prophylaxis treatment group, while the latter one included 25 patients in low-dose regimen and 15 patients in intermediate-dose regimen. Patients’ characteristics and previous treatment were paralleled among three groups without statistical difference (the range of P-value was 0.221-1.000, P>0.05). The median annual bleeding rate(ABR) of on-demand treatment group, low-dose prophylaxis treatment group and intermediate-dose group were 31,13.5,5 respectively, the differences among three groups were statistically significant (P=0.000<0.05). The median annual joint bleeding rate(AJBR) of three groups were 24,10,4 respectively, the differences among three groups were statistically significant (the range of P-value was 0.000-0.001, P< 0.05). The median annual target joint bleeding rate(ATJBR) of three groups were 18,8,3.5 respectively, the differences among three groups were statistically significant (the range of P-value was 0.000-0.002, P<0.05). The median annual abscent days of three groups were 36,7.5,0 respectively, the differences among three groups were statistically significant (the range of P-value was 0.000-0.005, P<0.05). The above description illustrated that the prophylaxis group’s AJBR,AJBR, ATJBR and annual abscent days were significantly less than the on-demand treatment group, and the intermediate-dose group was significantly superior to the low-dose group (the range of P-value was 0.000-0.002, P<0.05)In terms of median ABR, low-dose group decreased 56% than on-demand group(13.5 vs.31, P=0.000) while intermediate-dose group decreased 63% than low-dose group(5 vs.13.5, P=0.000). In terms of median AJBR, low-dose group decreased 58% than on-demand group(10 vs.24, P=0.000) while intermediate-dose group decreased 60% than low-dose group(4 vs.10, P=0.001). However, in terms of target joint numbers and annual severe bleeding events, there were statistical differences between prophylaxis and on-demand treatment group (the range of P-value was 0.001-0.012, P<0.05), which illustrated that patients in prophylaxis treatment had lower target joint numbers and annual severe bleeding events than patiets in on-demand treatment. Yet there was no statistical differences between low-dose and intermediate-dose group among the above indicators.The total annual usages of clotting factor were statistical differences among three groups(the range of P-value was 0.000-0.001,P<0.05),which illustrated that intermediate-dose prophylaxis group consumed most clotting factor, followed by the low-dose prophylaxis group, the on-demand treatment group at least. The total annual usages of clotting factor of low-dose group increased 71% than on-demand group (1950IU/kg/year vs.1140 IU/kg/year, P=0.001), while the intermediate-dose group increased 35% than low-dose group (2630 IU/kg/year vs.1950 IU/kg/year, P=0.000). Combined with the information of ABR and AJBR, intermediate-dose group decreased 63% ABR and 60% AJBR by increased 35% clotting factors than low-dose group,which inferred that intermediate-dose group got better potency ratio. From another perspective, when compared to on-demand treatment, the intermediate-dose regimen decreased 29% ABR,25% AJBR and 27% ATJBR than the low-dose regimen, and the dosage of coagulation factors for decreasing one bleeding increased 24%,29% and 27% respectively,which had similar proportion and revealed that the dosage of coagulation factors didn’t increase significantly when one bleed decreased, which further inferred that intermediate-dose group got better cost efficient.2. Comparison of joint function:Used FISH scoring system to evaluate patients’joint status, used the difference between the beginning of this study and one year ago of FISH score to represent the improvement of joint function. There was no statistical differences between low-dose group and on-demand group on the improvement of FISH score (P=0.066>0.05),which inferred that there was no obvious difference between these two groups in joint function during one year. There was statistical differences between intermediate-dose group and on-demand group (P=0.000)、 intermediate-dose group and low-dose group(P=0.008),which showed that patients in intermediate-dose group had obvious improvement of joint function, better joint status and independent ability than patients in on-demand or low-dose group.3. Prediction of long-term joint status:The proportion that patients’ annual joint bleeding rate<5 in low dose and intermediate-dose group were 12% and 73.3% respectively, and the latter rate was significantly higher than the former. When AJBR <5,the improvement of Fish of low-dose and intermediate-dose group was 0.33 and 1.18 respectively, which illustrated that the joint function had been improved in prophylaxis group, and the improvement was more obvious in intermediate-dose group than in low-dose group. When AJBR>5, the improvement of Fish of on-demand group, low-dose and intermediate-dose group was -0.52,-0.09 and 1.00, which illustrated that the joint function had been deteriorated in on-demand group and low-dose group, and the deterioration was more obvious in on-demand group,while the the joint function still improved in intermediate-dose group. The above results showed that the intermediate-dose prophylaxis regimen maybe better in long-term curative effect than low-dose regimen.4.Comparison of quality of life:Used SF36 to evaluate patients’quality of life, used the difference between the beginning of this study and one year ago of SF36 score to represent the improvement of quality of life. Prophylaxis group was better than on-demand group on total SF36, role-physical, social functioning and role-emotional(the range of P-value was 0.000-0.023, P<0.05). Only on bodily pain (P=0.965) and vitality (P=0.101) the differences did not exist between intermediate-dose group and low-dose group,beyond that intermediate-dose group were better in other aspects(included total SF36, physical functioning, role-physical, general health, social functioning, role-emotional and mental health) than low-dose group(the range of P-value was 0.000-0.045, P< 0.05),which inferred that the improvement of quality of life was better in patients in intermediate-dose group than in low-dose group.5. Comparison of adherence in prophylaxistreatment:Used HO’s measuring method for adherence to evaluate the 40 patients in prophylaxis treatment. The dosage and dosing intervals adherence of low-dose group were 78.6、88.5 respectively, while the intermediate-dose group were 90.3,95.2 respectively, the differences in dosage and dosing intervals adherence between two groups were statistically significant (P=0.003 <0.05).Poor dosage adherence correlates with more ABR (B=-0.555, P=0.000< 0.05), which meant worse adherence was association with much bleeding, but there was no correlation between dosing intervals adherence and ABR (B=0.171, P=0.507 >0.05).No correlation between age and dosage or dosing intervals adherence was found in adult patients with hemophilia A (P> 0.05)6. Comparison of breakthrough bleeding rate in prophylaxis treatment:The low-dose group had higher proportion of breakthrough bleeding in 24-48h after clotting factors injection, while intermediate-dose group got higher proportion in more than 48h after clotting factors injection,which inferred that the breakthrough bleeding maybe had a relation with the time of FVI less than 1IU/dL. Combine with the late effect of breakthrough bleeding in intermediate-dose group, it can be suggested that once every other day regimen is beneficial to further reduce bleedings in intermediate-dose prophylaxis treatment.Conclusion1.Prophylaxis treatment should be the preferred choice for patients with severe hemophilia A. Compared to on-demand treatment, the bleeding frequency decreases significantly, joint function improves significantly, the quality of life improves obviously.2.Compared to low-dose prophylaxis regimen, the annual bleeding rate, annual joint bleeding rate,annual target joint bleeding rate and annual absent days decreased significantly in patients in intermediate-dose regimen, as well as better joint function and improved quality of life. Besides, intermediate-dose group got better potency ratio.3. Patients’joint function would be improved to some extent when AJBR<5, and that improvement was more obvious in intermediate-dose group than low-dose group.When AJBR>5, patients in low-dose prophylaxis group whose joint function got worse, while patients in intermediate-dose prophylaxis group whose joint function still improved. The above results showed that the intermediate-dose prophylaxis treatment maybe better in long-term effect than low-dose regimen, which could prevent the progress of joint damage.4.Adult patients with severe hemophilia in China have high levels of adherence, and the intermediate-dose group is better than low-dose group. There are negative correlation between dosage adherence and ABR, which means poor adherence lead to more bleeding events, while there’s no correlation between dosing intervals adherence and ABR. No correlation between age and dosage or dosing intervals adherence in adult patients.5.The low-dose group had higher proportion of breakthrough bleeding in 24-48h after clotting factors injection, while intermediate-dose group got higher proportion in more than 48h after clotting factors injection. It can be suggested that once every other day regimen is beneficial to further reduce bleedings in intermediate-dose prophylaxis treatment. |
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