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研究生：	趙若雁 Chao, Jo-Yen
論文名稱：	探討血液透析病患使用活性維生素D與死亡率及其他預後之相關性 Assessing the effect of activated vitamin D on all-cause mortality and clinical outcomes in hemodialysis patients
指導教授：	高雅慧 Yang, Yea-Huei Kao
學位類別：	博士 Doctor
系所名稱：	醫學院 - 臨床藥學與藥物科技研究所 Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	91
中文關鍵詞：	活性維生素D 、末期腎病、血液透析、死亡、心肌梗塞、缺血性中風、截肢、感染
外文關鍵詞：	activated vitamin D, end-stage renal disease, hemodialysis, mortality, myocardial infarction, ischemic stroke, amputation, infection
相關次數：	點閱：106 下載：2
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中文摘要
研究背景：
台灣的慢性腎衰竭與尿毒症之發生率與盛行率目前仍名列世界第一。尿毒症病患有很高的死亡率，最常見的死因為心血管疾病及感染。目前活性維生素D仍是慢性腎衰竭之次發性副甲狀腺亢進與腎骨病變的主要治療藥物。除此之外，活性維生素D有許多潛在的好處，包括抑制腎素生合成、抑制血管鈣化、以及調控免疫反應。然而，腎衰竭病患常有高血磷、高血鈣甚或血管鈣化等問題，因此，活性維生素D之使用常會因此受限，導致處方使用率偏低。目前活性維生素D藥物處方型態在台灣未有探討，且活性維生素D之治療與尿毒症病患整體預後之關聯性仍未釐清，此等研究需長期追蹤，無法以短期小規模隨機對照試驗得知，因此，世代追蹤觀察性研究仍有相當之價值。
研究目的：
探討我國血液透析病患使用活性維生素D之比例，並將探討活性維生素D之使用對於血液透析病患預後之影響。
研究方法：
首先，我們使用全民健保資料庫來分析2001至2010年我國血液透析病患使用活性維生素D之處方現況，分析活性維生素D使用者與非使用者之各種差異。先使用多變數存活分析及傾向分數匹配來評估活性維生素D之使用對於死亡率之影響，並使用軌跡分析將使用劑量高低分組，進而分析維生素D之使用與預後之相關是否有劑量反應。之後，我們使用競爭風險存活分析，個別分析活性維生素D之使用與心肌梗塞、缺血性中風、下肢截肢，與感染之相關性。
結果：
在2001至2010年，新發生之長期血液透析病患之門診與住院處方申報資料中，約25%病患在追蹤期間有處方活性維生素D，處方率於醫學中心最高、區域醫院次之、地區醫院最低，而醫院所在位置亦有差別：於都會區最高、郊區次之、鄉村醫院最低。這些有處方活性維生素D之病患當中，四成以上是於進入透析一年後才被處方該藥物。考量腎衰竭病患之高死亡率，以進入透析後的360天內有無處方活性維生素D來分類使用者與非使用者，可發現活性維生素D之使用者較為年輕、較少共病症。
多變量存活分析顯示，活性維生素D之使用者有較低的全死因死亡風險，風險比：0.91 (95% 信賴區間0.87-0.95)；經傾向分數匹配，活性維生素D之使用者仍有較低的全死因死亡風險，風險比：0.94 (95% 信賴區間0.90-0.98)。使用軌跡分析來分類，有93%之活性維生素D使用者使用一般處方劑量，其餘7%為較高劑量使用者，而較高劑量使用者相較於一般劑量使用者或非使用者來說，經多變量因子校正，仍有較低的死亡風險。
在各種常見的臨床事件以競爭風險存活分析，並以死亡作為競爭風險事件，活性維生素D使用者相較於非使用者，並沒有較低的心肌梗塞或缺血性中風之風險，但有較低的截肢或因感染而住院之風險。
在次族群分析部分則發現，年紀較輕、無心衰竭病史之活性維生素D使用者其死亡風險的降低較年長、有心衰竭者顯著。而在活性維生素D對於截肢與感染發生的風險探討，在年齡、性別、有無糖尿病或心血管疾病之次族群分析則發現均有好處且無顯著差異。

結論：
相較於其他國家，活性維生素D在我國慢性腎衰竭尿毒症之病患使用率偏低，而低使用率可能源自於較多的含鈣之磷結合劑使用，或擔憂高血鈣、高血磷，與血管鈣化之風險。由我們的資料庫研究可發現，活性維生素D之使用者伴隨有較低的死亡風險，且高劑量使用者有更低的死亡風險。
更進一步，活性維生素D之使用，雖未觀察到降低急性心肌梗塞或缺血性中風之風險，但卻伴隨著有較低的下肢截肢與因各種感染而需住院之風險。
血液透析病患之死亡原因多元且複雜，且常伴隨罹患各種心血管疾病或感染等，並非單一藥物或處置即能扭轉。活性維生素D有多重潛在好處、不昂貴且相對安全，在血液透析病患之臨床照顧中，尤其是年輕族群，若無處方禁忌症，實應考慮廣泛處方。

Abstract
Background:
The reported incidence rate of end-stage renal disease (ESRD) patients receiving dialysis therapy in Taiwan remained highest across the world and the number of prevalent dialysis patients continued to rise. Patients with ESRD have a high mortality rate that far exceeds the mortality rate for the general population. The most common causes of death are cardiovascular disease and infection. Activated vitamin D plays an important role in the treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) which encompasses vitamin D deficiency, derangement of mineral metabolism, hyperparathyroidism, renal osteodystrophy, and vascular calcification. In addition, many potential benefits of activated vitamin D have been suggested, including suppression of renin synthesis, inhibition of vascular calcification, and modification of immune response. However, tertiary hyperparathyroidism, hypercalcemia, and vascular calcification, all confine the prescriptions of activated vitamin D to patients with relatively normal serum calcium and phosphorus levels. The utilization pattern of activated vitamin D has not been determined in Taiwan. The long-term impact of activated vitamin D use on clinical hard outcomes is still controversial.

Objective:
We aimed to determine the real world prescribing pattern, patient characteristics, hospital accreditation levels, and urbanizations which may influence prescription of activated vitamin D in incident hemodialysis patients in Taiwan. Then we evaluated the effect of activated vitamin D use on overall survival and the associated clinical hard outcomes in these patients.
Method:
The national survey of oral activated vitamin D for hemodialysis patients was done using the National Health Insurance Research Database from 2000 through 2010. We used the registry of catastrophic illness certificate to confirm the ESRD status of these incident hemodialysis patients. Then we used multivariate Cox proportional hazard regression to assess the association of activated vitamin D use with all-cause mortality in these patients. We also used competing risk analysis to evaluate the impact of activated vitamin D use on the hazards of acute myocardial infarction, ischemic stroke, amputation, and infection, respectively.

Results:
Of 61,485 incident hemodialysis patients from 2001 through 2010, 25% received activated vitamin D over the follow-up period. The prescription of activated vitamin D was more prevalent in medical centers than in regional or district hospitals, and more in urban than in suburban or rural hospitals. The first time of activated vitamin D prescription varied widely. There were 8,151 vitamin D users and 44,606 non-users according to prescription of vitamin D or not before the 360th day of hemodialysis initiation. Patients prescribed vitamin D were younger and had fewer baseline comorbidities.
Vitamin D users were associated with a significantly lower risk of death in the multivariate adjusted Cox model (HR 0.91 [95% CI, 0.87-0.95]) and propensity score matching analysis (HR 0.94 [95% CI, 0.90-0.98]), respectively. High dose users were associated with a lower risk of death compared with conventional dose users and non-users.
The result of competing risk analysis using subdistribution hazard regression with death as competing events showed that vitamin D users were associated with a lower risk of amputation (subdistribution hazard ratio, SHR 0.84 [95% CI, 0.74-0.96]) and infection (SHR 0.91 [95% CI, 0.88-0.95]) but not acute myocardial infarction (SHR 1.04 [95% CI, 0.93-1.16]) or ischemic stroke (SHR 0.91 [95% CI, 0.82-1.01]).
In subgroup analyses, the survival advantage associated with activated vitamin D was prominent in younger patients and those without heart failure. The reduced subdistribution hazards of amputation and infection were consistent across all subgroups analyzed. Moreover, a trend toward a lower subdistribution hazard of amputation and infection was observed in high dose users.

Conclusion:
Compared with other countries, activated vitamin D prescribing was less prevalent in Taiwan. Use of activated vitamin D in incident hemodialysis patients is associated with a lower risk of all-cause death, amputation, and infection. Evidence from the real world practice has also suggested survival benefits in the high dose vitamin D users. The cause of death in ESRD patients is complex and multifactorial. Prescription of activated vitamin D is inexpensive and associated with multiple potential benefits. It could be considered an integral part in the care of these patients unless contraindicated.

Contents
Part I. Introduction .......1
1. Prevalence and disease burden of chronic kidney disease ....1
2. Vitamin D and chronic kidney disease ......2
3. Indications of activated vitamin D in end-stage renal disease patients ...4
4. Pleotropic effects of vitamin D .......4
5. Statement of the research question .....5
6. Specific aims and significance ......6
Part II. Prescribing of activated vitamin D use in incident hemodialysis patients in Taiwan .7
1. Introduction ........7
2. Methods ........8
2.1 Data source and study design .......8
2.2 Definition of end stage renal disease .....8
2.3 Definition of activated vitamin D treatment .....9
2.4 Definition of hospital and urbanization levels .... 10
2.5 Statistical analysis ........ 10
3. Results ......... 11
3.1 Prescription of activated vitamin D across hemodialysis patient cohort ... 11
3.2 Prescription timing, dosage, and frequencies ..... 12
3.3 Baseline characteristics of vitamin D users versus non-users .... 14
3.4 Persistence of prescription of vitamin D ...... 15
3.5 Prescription of activated vitamin D in subgroups of hospital-based hemodialysis
patients across urban, suburban, and rural area ...... 15
4. Discussion ......... 17
5. Strength and limitation ....... 19
6. Conclusion ........ 20
Part III. Is activated vitamin D use associated with improved overall survival in incident
hemodialysis patients? ........ 28
1. Introduction ........ 28
2. Methods ....... 29
2.1 Data source ....... 29
2.2 Study design and population ...... 30
2.3 Covariates, exposure, and outcome ....... 30
2.4 Statistical analyses ....... 31
2.5 Propensity score method ....... 31
2.6 Trajectory model........ 32
2.7 Sensitivity analyses ...... 32
2.8 Supplementary analysis ...... 33
3. Results ......... 34
3.1 Baseline characteristics of patients..... 34
3.2 Effect of activated vitamin D use on overall survival .... 34
3.3 Trajectory analysis and dose response relationship .... 35
3.4 Sensitivity analyses ...... 35
3.5 Supplementary analyses ........ 36
4. Discussion ......... 37
5. Limitations ....... 40
6. Conclusion and implications for future studies .... 41
Part IV. Is activated vitamin D use associated with lower risks of acute myocardial infarction,
ischemic stroke, amputation, or infection hospitalization? .... 54
1. Introduction ........ 54
2. Methods ....... 55
2.1 Data source and study design ...... 55
2.2 Activated vitamin D exposure and covariate .... 55
2.3 Outcome measures ....... 56
2.4 Statistical analyses ....... 57
2.5 Sensitivity analysis ....... 58
3. Results ......... 59
3.1 Effects of activated vitamin D use on individual hard outcomes ... 59
3.2 Sensitivity analyses ...... 61
3.3 Post hoc stratified analyses ...... 61
3.4 Dose response relationship ...... 63
4. Discussion ......... 63
5. Limitations ....... 66
6. Conclusion ........ 67
Part V. Summary and implications for future study ..... 75
Part VI. Reference ........ 78
Part VII. Appendices ........ 86
Appendix 1. Details of diagnostic codes to retrieve comorbidity information from baseline
period ........ 86
Appendix 2. Details of prescribed medication during baseline period ... 87
Appendix 3. Details of procedure codes of vascular access type ... 89
Appendix 4. The International Statistical Classification of Diseases and Related Health
problems 9th Revision (ICD-9) codes for AMI, ischemic stroke, and various kinds of
infection ......... 90
Index of Table
Table 1. The number of patients according to time of the first prescription of activated
vitamin D ........ 22
Table 2. Cumulative and average dosage units of vitamin D use in each 120-day period of the
first 360 days of hemodialysis initiation ......23
Table 3. Baseline characteristics of activated vitamin D users versus non-users according to
status by landmark time .......24
Table 4 . The persistence of vitamin D prescription among those who had been prescribed
before the 360th day of dialysis initiation was shown......26
Table 5. The distribution of hemodialysis patients and the percentage of vitamin D
prescription in medical centers, regional hospitals, or district hospitals in urban,
suburban, and rural area......27
Table 6 . Baseline characteristics of activated vitamin D users versus non-users according to
status by landmark time, before and after propensity score (PS) matching ..43
Table 7. Events of death and crude mortality rates by status of vitamin D use on the
landmark time in the entire cohort and subgroup of patients in hospital-based
hemodialysis setting........46
Table 8. Multivariate Cox proportional hazards models examining activated vitamin D
treatment as compared with no treatment by landmark time...48
Table 9. Crude mortality rate and multivariate adjusted hazard ratio for mortality according
to the different dosage categories of oral activated vitamin D based on trajectory
analysis. ..........51
Table 10. Multivariate Cox proportional hazard models examining activated vitamin D
treatment as compared with no treatment by landmark time in hospital-setting
hemodialysis patients........52
Table 11. Hazard ratio for mortality associated with activated vitamin D treatment stratified
by baseline characteristics. ........53
Table 12. The result of competing risk analyses with AMI, ischemic stroke, amputation, and
hospitalization for infection as events of interest, respectively....68
Table 13. Incidence rates of acute myocardial infarction, ischemic stroke, amputation, and
hospitalization for infection after landmark date (the 360th day) and competing events of
death for vitamin D users versus non-users, respectively. ....69
Table 14. The hazard of acute myocardial infarction (AMI), ischemic stroke, amputation, and
hospitalization for infection for vitamin D users compared with non-users in incident
hemodialysis patients using competing risk analysis with subdistribution hazard model
and cause-specific hazard regression models ......71
XII
Table 15. Effects of activated vitamin D on the outcomes of interest including amputation and
infection, according to baseline characteristics.....72
Table 16. Multivariate adjusted competing risk model for events of amputation and infection
according to dosage of activated vitamin D based on trajectory analysis ...74
Index of Figure
Figure 1. Flow diagram shows inclusion of hemodialysis patients for analysis. ..21
Figure 2. The prescribing frequencies and duration of activated vitamin D in the ambulatory
care in incident hemodialysis patients (2001-2010) .....22
Figure 3. Kaplan-Meier Survival curve of activated vitamin D users versus non-users
according to status by landmark time .......47
Figure 4. The distribution of propensity score across vitamin D users and non-users before
and after propensity score matching.....49
Figure 5. Result of group-based trajectory analysis. Trajectory of vitamin D dosage grouping
from initiation of hemodialysis in the first 360 days. .....50
Figure 6. Cumulative incidence curves of acute myocardial infarction (AMI), ischemic stroke,
amputation, and hospitalization for infection for vitamin D users compared with nonusers
.........70
                                    

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