研究背景
血友病是一種性染色體隱性遺傳疾病，會導致罹病的病人缺乏製造凝血因子的功能。可以依照缺乏的凝血因子區分為A型、B型血友病。自從凝血因子製的問世，常規的預防性治療以及醫療照護的進展，提升了血友病病人的壽命及醫療品質。日前，衛生福利部公告，從2014年開始，台灣的血友病病人使用預防性治療將納入健保給付，然而，公告後迄今，尚未有台灣病患使用凝血因子狀況的相關研究。同時，預防性治療對於血友病病人保護關節病變的效果也有待釐清。
研究目的
我們的研究目的分成四個部分：
1 台灣血友病病人之流行病學資料，包括盛行率、發生率、死亡率等。
2 台灣血友病病人之醫療資源以及凝血因子的使用趨勢。
3 台灣血友病病人的健康情形，包括了年化出血次數、關節病變等。
4 台灣血友病病人接受預防性治療與需要性治療保護關節病變之比較效果。

研究方法
本研究利用台灣健保資料庫全入口檔，從2003年到2015年，選取有血友病診斷並且有使用過凝血因子紀錄的病人作為研究對象。我們針對這群病人統計其流行病學資料。再者，我們討論男性病人之醫療資源以及凝血因子的使用趨勢。其三，我們統計A型血友病男性病人的 年化出血次數、關節病變等。最後，我們推估A型男性血友病病人接受預防性治療與需要性治療保護關節病變之比較效果。在分析效果時，我們使用的統計方法為羅吉氏迴歸(Conditional logistic regression)，進行巢式病例對照研究（Nested case control study）, 其指標日期為發生關節病變的日期，回溯比較病例組與對照組使用預防性治療與需要性治療的比例，是否預防性治療有比較好的保護關節病變的療效。
研究結果
在研究的第一部分，我們發現台灣共有1184位血友病病人。 血友病入口數從2003年的1040人略微上升到2015年的1092人。2015年，血友病的盛行率為每十萬人4.6人；若單看男性病患，為每十萬男性7.3人。血友病的發生率為1.9~10.3每十萬個新生兒。死亡人數則落在每年5到12個人的範圍。不論在A型血友病或B型血友病人，標準化死亡比皆為1.8。
男性血友病病人的總醫療化費從10億元上升到33億元，從2003年到2015年。在2015年，A型血友病人及B型血友病人每年的就診次數中位數分別為6次以及7次。血友病病人的藥品花費（第八凝血因子以及繞徑治療藥物）佔了整體醫療花費的96%到98%。此外，A型血友病病人的平均出血次數，2015年為4.5次。平均來說，A型血友病第一次診斷有關節病變的年齡為30.9歲。
在巢式病例對照研究中，我們總共納入了512位案例組病人。分別去配對（取後放回）出512位對照組病人。結果發現，在案例組中，分別有79位為預防性治療、433為需要性治療。我們計算出勝算比為4.44 (95% CI:=0.26-7.63)。進一步將年齡範圍縮小至2到12歲，計算出勝算比為0.7 (95% CI:= 0.27-1.84)。
結論
前三部分的結果都和先前台灣的研究資料相仿。隨著時間經過，血友病病人的總醫療花費以及藥品費用逐年攀升，突顯了預防性治療相關研究的重要性。我們的研究顯示，在全年齡層的病人中，預防性治療沒有顯著的療效。然而，當範圍縮小到年輕的病人族群，可以看到預防性治療可能有療效的趨勢。
關鍵字：血友病、關節病變、凝血因子、預防性治療、巢式病例對照研究

Introduction
Hemophilia is an inherited bleeding disorder resulting from the absence or deficiency of coagulation factors. There are two major types of hemophilia, hemophilia A and hemophilia B. Since the introduction of clotting factor concentrates, regular prophylaxis and more comprehensive care have led to an increased life expectancy of persons with hemophilia (PWH).
The National Health Insurance Program has updated the reimbursement guideline for the use of prophylaxis therapy inpatient with hemophilia in 2014. However, there is no sufficient evidence to support what the implement status nowadays and how treatment behavior changed after new national guideline being introduced. Nonetheless, the effectiveness of prophylaxis regimen of hemophilic arthropathy in Taiwan remains unknown.
Objective
The objectives of the study are as the following:
(1) To investigate population-based epidemiologic data of hemophilia in Taiwan, including prevalence, age distribution, incidence rate and mortality rate of hemophilia patients in Taiwan.
(2) To analyze utilization patterns of coagulation factor for hemophilia patients including the dosage, cost, and utilization of healthcare resource, including the number of visits, and related medical costs.
(3) To study health outcomes of patients with hemophilia including the annual bleeding rate of patients with hemophilia and the time of joint outcomes (e.g., arthropathy and joint replacement) for hemophilia patients from their birth date.
(4) To explore the comparative risk of arthropathy between prophylaxis vs on-demand regimens.
Materials and methods
We used the Taiwan National health Insurance Research databases for the following studies. Firstly, we constructed cohorts from 2003 to 2015 of diagnosed hemophilia patients to explore the epidemiologic data. Secondly, we used data of male patients with hemophilia to conduct the research of utilization pattern of health care resource and factor concentrate. Thirdly, we estimated the health outcome of male patients with hemophilia A. Lastly, we used conditional logistic regression to compare the risk of arthropathy between patients with prophylaxis and patients with on-demand regimen. In this study, we used age and the different dosage group to match case and control.
Results
Firstly, we identified 1184 patients with hemophilia. The number of patients were 1040 in 2003 and increased to 1092 in 2015. The prevalence of patients with hemophilia was estimated 4.6 per 100,000 people, while male patients with hemophilia was estimated 7.3 per 100,000 male in 2015. The newborn incidence ranged from 1.9 to 10.3 per 100,000 newborn, while the male newborn incidence ranged from 3.6 to 19.5 per 100,000 male newborn. The number of deaths ranged from 5 to 12, and the standardized mortality ratio was1.8 in patients with hemophilia A and hemophilia B.
In the second part, the total medical cost of male patients with hemophilia was 1.0 billion NTD to 3.3 billion NTD from 2003 to 2015. The median number of visits using factor concentrate in 2015 was 6 in PWHA and 7 in PWHB. The cost of factor concentrate and bypassing agents (Factor VII and aPCC) accounted for 96% to 98% of total medical cost. In addition, the mean bleeding rate of patients with hemophilia A was 4.5 (SD 12.5)in 2015. The mean age of first diagnosis of arthropathy in patients with hemophilia A was 30.9 (SD 17.9)years old.
In the nested case-control analysis, we included 512 cases and 512 controls with male gender and hemophilia A. We then divided these patients of both cases and controls into prophylaxis groups and on-demand groups. There were 79 and 433 cases in prophylaxis and on-demand groups. We used conditional logistic regression model to compare the odds between cases and controls. We found that the point estimate was 4.44(95% CI:=0.26-7.63). We further analyzed the subgroup study population whose were between 2 and 12 years old, and we found that the point estimate was 0.7 (95% CI:= 0.27-1.84)
Conclusions
The results of the epidemiologic data, utilization pattern and health outcome were consistent with previous studies.
The findings indicated the average ages of patients were older by years, which implicated the increased life expectancy of persons with hemophilia. Therefore, age-related disorders will be the possible issue in the future.We found the use of by passing agents was increase by years, which warrants attention on the effectiveness and related issues. As time passed by, we found the use of factor concentrate and the medical cost increased by years, which highlights the importance for assessing the effectiveness or cost-effectiveness for the replacement therapy.
Although there was no statistical significance, we found prophylaxis regimen tended to have better effectiveness than on-demand regimen in patients aged 2 to 12 years, which may imply that the early use of the prophylaxis regimen may pose some benefits in patients with hemophilia.
Key words: Hemophilia, Coagulant factor, Arthropathy, Prophylaxis regimen, Nested case control study.

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