臺灣博碩士論文加值系統

研究背景：
根據Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)的調查，在得到糖尿病20年後，將近99%第一型糖尿病以及60%第二型糖尿病的病人會發展出糖尿病視網膜病變。
糖尿病引起的黃斑部水腫的主流治療方法為玻璃體內注射抗血管內皮細胞生長因子(anti-vascular endothelial growth factor)藥物，但Lucentis® (ranibizumab)、Eylea® (aflibercept)在市面上非常昂貴，另外也有相對便宜但仍為仿單標示外使用(off label use)的藥物Avastin® (bevacizumab)可以使用。

研究目的：
本研究比較糖尿病黃斑部水腫之病人，在玻璃體內注射三種抗血管內皮細胞生長因子藥物之後的藥物療效，以及藥物半衰期對結果的影響；另外，探討其他可能影響藥物療效的因子。

材料和方法：
本研究將分析成大醫院2015至2017為期三年的病患資料，並分析糖尿病黃斑部水腫病患接受三種玻璃體內注射抗血管內皮細胞生長因子藥物：ranibizumab、aflibercept和bevacizumab治療後的效果，包括(1)最佳矯正視力(best corrected visual acuity, BCVA)(2)最小分辨角之對數視力(logarithm minimal angle resolution, LogMAR)以及(3)視網膜中央黃斑部厚度(central macular thickness, CMT)與平均黃斑部厚度(average macular thickness, AMT)的改變。
以混合效果模型(mixed effect model)分析，分成兩個模型：一為探討藥物半衰期之影響，設計以不同藥物在同次注射前後治療效果的測量值之差值為依變項的分析；二為不含藥物半衰期，以不同藥物在每次藥物注射後治療效果的測量值為依變項，並加入三種藥物分別與治療歷經時間的交互作用於可能的影響因子之中。

結果：
當納入藥物半衰期分析時，每次注射前後三種藥物於最佳矯正視力與最小分辨角之對數視力的改善皆無顯著差異。三種藥物每次注射對於中央黃斑部厚度皆有顯著改善ranibizumab：101微米(P=0.003)、aflibercept：102微米(P=0.002)、bevacizumab：79微米(P=0.014)。三種藥物每次注射對於平均黃斑部厚度皆有顯著改善ranibizumab：42微米(P=0.002)、aflibercept：42微米(P=0.002)、bevacizumab：34微米(P=0.011)。
當不考慮藥物半衰期，治療開始之前時，與ranibizumab比較起來，aflibercept在最佳矯正視力差了0.114(P〈0.001)、最小分辨角之對數視力差了0.165(P〈0.001)、中央黃斑部厚度多了20微米(P=0.026)；平均黃斑部厚度則無顯著差異。治療開始之前時，與ranibizumab比較起來，bevacizumab在最小分辨角之對數視力差了0.079(P=0.015)、中央黃斑部厚度多了32微米(P=0.001)、平均黃斑部厚度多了12微米(P=0.008)；最佳矯正視力則無顯著差異。每經過一個時間單位(月)，aflibercept與ranibizumab比較起來，病患平均最佳矯正視力改善0.0002，平均最小分辨角之對數視力改善0.004(-0.008+0.004)，平均中央黃斑部厚度多下降 3.002微米，平均黃斑部厚度多下降 1.523微米。

結論：
本研究分析成大醫院2015至2017三年間的糖尿病視網膜黃斑部水腫在眼內注射抗血管內皮細胞生長因子的治療效果。當納入藥物半衰期分析時，每次注射前後三種藥物於最佳矯正視力與最小分辨角之對數視力的改善皆無顯著差異。於中央黃斑部厚度與平均黃斑部厚度卻都有顯著改善，而三組間厚度改善的比較則需進一步檢定。
當不考慮藥物半衰期時，三種藥物aflibercept比ranibizumab好， bevacizumab與ranibizumab比無顯著差異。有接受全視網膜雷射(panretinal photocoagulation, PRP)的病人，會有略微下降的視力及較厚的平均黃斑部厚度。有牽引型黃斑部水腫(tractional macular edema)的病人，在中央黃斑部厚度的治療改善程度較差。

SUMMARY
The study analyzes the patient data from the Department of Ophthalmology in National Cheng Kung University Hospital from 2015 to 2017. Three anti–vascular endothelial growth factor (anti-VEGF) medications are Lucentis (ranibizumab), Eylea (aflibercept) and Avastin (bevacizumab). The purposes of the study are comparing the effect of three anti-VEGF medications in treating the patient with diabetic macular edema, finding out the effect of drug half-life, and the possible risk factors which can influence the effect of treatment.
The result showed that the effect of drug half-life may be little. Aflibercept is better than ranibizumab in improving best corrected visual acuity (BCVA), logarithm minimal angle resolution (LogMAR), central macular thickness (CMT), and average macular thickness (AMT). There is no significant difference between bevacizumab and ranibizumab. Patients with panretinal photocoagulation may have decline in BCVA and LogMAR and thicker AMT. Patients with tractional macular edema have worse improvement in CMT.

INTRODUCTION
In the Wisconsin Epidemiologic Study of Diabetic Retinopathy cohort, after 20 years of diabetes mellitus, nearly 99% of patients with type 1 and 60% with type 2 disease demonstrated some degree of diabetic retinopathy.
Nowadays, the mainstream treatment for diabetic macular edema is intravitreal anti-VEGF. However, ranibizumab and aflibercept are really expensive. There is another choice: bevacizumab, which is off-label use but much cheaper than ranibizumab and aflibercept.
The three goals for this study are as follows: First, compare the effect of three anti-VEGF medications in treating the patients with diabetic macular edema. Second, find out the effect of drug half-life. Third, find out the possible risk factors which can influence the effect of treatment.

MATERIALS AND METHODS
The study analyzes the patient data from the Department of Ophthalmology in National Cheng Kung University Hospital from 2015 to 2017. Three anti-VEGF medications are ranibizumab, aflibercept and bevacizumab. The study compares the change of visual acuity and macular thickness in different anti-VEGF medications.
The study adopts mixed effect model and analyzes the data in two ways. One is to find out the effect of drug half-life. The dependent variable is the difference of data measured before and after the injection. The other is to find out the effect of interaction between three medications and treatment duration time without drug half-life effect. The dependent variable is the data measured after the injection.

RESULTS AND DISCUSSION
In the model with drug half-life, there is no significant difference in BCVA and LogMAR per injection. In CMT, ranibizumab decreases 101um (P=0.003), aflibercept decreases 102um (P=0.002)、bevacizumab decreases 79um (P=0.014) per injection. In AMT, ranibizumab decreases 42um (P=0.002), aflibercept decreases 42um (P=0.002)、bevacizumab decreases 39um (P=0.011) per injection.
In the model without drug half-life, before the treatment start, aflibercept is worse 0.114 in BCVA (P〈0.001), worse 0.165 in LogMAR (P〈0.001), thicker 20 um (P=0.026) in CMT than ranibizumab and no significant difference in AMT with ranibizumab. Bevacizumab is worse 0.079 in LogMAR (P=0.015), thicker 32 um (P=0.001) in CMT, thicker 12 um (P=0.008) in AMT than ranibizumab and no significant difference in BCVA with ranibizumab.
The interaction between aflibercept and treat duration time is better than the interaction between ranibizumab and treat duration time in BCVA 0.0002, LogMAR 0.004 (-0.008+0.004), CMT 3.002 um and AMT 1.523 um per month.

CONCLUSION
In the model with drug half-life, there is no significant difference in BCVA and LogMAR per injection but significant macular thickness decline in CMT and AMT. The difference of macular thickness decline between three drugs needs further test.
In the model without drug half-life, aflibercept is better than ranibizumab in improving BCVA, LogMAR, CMT and AMT. There is no significant difference between bevacizumab and ranibizumab.
Patients with panretinal photocoagulation may have decline in BCVA and LogMAR and thicker AMT. Patients with tractional macular edema have worse improvement in CMT.

第一章 前言 1
1.1. 研究目的 2
第二章 文獻回顧 3
2.1. 糖尿病視網膜病變 3
2.1.1. 糖尿病視網膜病變之簡介 3
2.1.2. 全視網膜雷射 4
2.1.3. 糖尿病黃斑部水腫 4
2.2. 抗血管內皮細胞生長因子(anti-VEGF) 5
2.2.1. 抗血管內皮細胞生長因子眼內注射藥物半衰期 7
2.3. 糖尿病黃斑部水腫治療之相關研究 7
2.3.1. 抗血管內皮細胞生長因子與黃斑部局部雷射治療比較 7
2.3.2. 抗血管內皮細胞生長因子與安慰劑組比較 7
2.3.3. ranibizumab的藥物研究試驗 8
2.3.4. aflibercept的藥物研究試驗 8
2.3.5. bevacizumab、ranibizumab的藥物相互比較研究試驗 8
2.3.6. aflibercept、bevacizumab和ranibizumab的藥物比較研究試驗 9
2.3.7. aflibercept、bevacizumab和ranibizumab的現實世界研究 10
2.3.8. 糖尿病黃斑部水腫藥物研究成果小結 11
2.4. 抗血管內皮細胞生長因子之藥物成本效益分析 11
2.5. 糖尿病黃斑部水腫之治療現況 11
第三章 材料與方法 13
3.1. 研究問題 13
3.2. 研究資料來源 13
3.3. 研究設計 13
3.3.1. 研究對象選取 13
3.3.2. 研究對象之可能危險因子 14
3.3.3. 研究設計 15
3.3.4. 研究變項 16
3.4. 資料分析 19
3.4.1. 三種藥物治療成果圖 19
3.4.2. 描述性統計 19
3.4.3. 分析性統計 20
(A) 含有藥物半衰期的分析(依變項為注射前後測量值之差) 20
(B) 不含藥物半衰期的分析(依變項為注射後測量值) 20
3.4.4. 藥物半衰期估算 20
第四章 結果 22
研究樣本特值分析 22
4.1. 含有藥物半衰期的分析(依變項為注射前後測量值之差) 25
4.2. 不含藥物半衰期的分析(依變項為注射後測量值) 28
第五章 討論 31
5.1. 分析結果討論 31
5.1.1. 含有藥物半衰期的分析(依變項為注射前後測量值之差) 31
5.1.2. 不含藥物半衰期的分析(依變項為注射後測量值) 32
5.1.3. 藥物價格之成本比較 33
5.2. 過去文獻比較與相關機轉討論 34
5.2.1. 藥物療效比較 34
5.2.2. 糖尿病黃斑部水腫的危險因子 34
5.2.3. 藥物成本比較效果 34
5.3. 研究優勢與限制 35
5.3.1. 研究優勢 35
5.3.2. 研究限制 35
第六章 結論 36
第七章 參考文獻 37
附錄(三種藥物治療成果圖) 40
圖一、最佳矯正視力(BCVA) - Lucentis(ranibizumab) 40
圖二、最佳矯正視力(BCVA) - Eylea(aflibercept) 40
圖三、最佳矯正視力(BCVA) - Avastin(bevacizumab) 41
圖四、最小分辨角對數視力(LogMAR) - Lucentis(ranibizumab) 41
圖五、最小分辨角對數視力(LogMAR) - Eylea(aflibercept) 42
圖六、最小分辨角對數視力(LogMAR) - Avastin(bevacizumab) 42
圖七、中央黃斑部厚度(CMT) - Lucentis(ranibizumab) 43
圖八、中央黃斑部厚度(CMT) - Eylea(aflibercept) 43
圖九、中央黃斑部厚度(CMT) - Avastin(bevacizumab) 44
圖十、平均黃斑部厚度(AMT) - Lucentis(ranibizumab) 44
圖十一、平均黃斑部厚度(AMT) - Eylea(aflibercept) 45
圖十二、平均黃斑部厚度(AMT) - Avastin(bevacizumab) 45

1.Jiang YD, Chang CH, Tai TY, Chen JF, Chuang LM. Incidence and prevalence rates of diabetes mellitus in Taiwan: analysis of the 2000-2009 Nationwide Health Insurance database. J Formos Med Assoc. 2012 Nov;111(11):599-604.
2.Klein R, Lee KE, Gangnon RE, Klein BE. The 25-year incidence of visual impairment in type 1 diabetes mellitus the wisconsin epidemiologic study of diabetic retinopathy. Ophthalmology. 2010 Jan;117(1):63-70.
3.Varma R, Bressler NM, Doan QV, Gleeson M, Danese M, Bower JK, et al. Prevalence of and risk factors for diabetic macular edema in the United States. JAMA Ophthalmol. 2014 Nov;132(11):1334-40.
4.Virgili G, Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev. 2014 Oct 24(10):CD007419.
5.Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991 May;98(5 Suppl):766-85.
6.Masahiko Shimura, Kanako Yasuda, Toru Nakazawa, Tetsuya Kano, Satsuki Ohta, Tamai M. Quantifying alterations of macular thickness before and after panretinal photocoagulation in patients with severe diabetic retinopathy and good vision. Ophthalmology. 2003 (110):2386–94.
7.Soman M, Ganekal S, Nair U, Nair K. Effect of panretinal photocoagulation on macular morphology and thickness in eyes with proliferative diabetic retinopathy without clinically significant macular edema. Clin Ophthalmol. 2012;6:2013-7.
8.Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol. 1999 Jun;127(6):688-93.
9.Vujosevic S, Varano M, Egan C, Sivaprasad S, Menon G, Erginay A, et al. Relevance of Retinal Thickness Changes in the OCT Inner and Outer Rings to Predict Progression to Clinical Macular Edema: An Attempt of Composite Grading of Macular Edema. Ophthalmic Res. 2015;55(1):19-25.
10.Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, Lopez-Galvez M, Navarro-Gil R, Verges R. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. J Diabetes Res. 2016;2016:2156273.
11.Clarke JM, Hurwitz HI. Understanding and targeting resistance to anti-angiogenic therapies. J Gastrointest Oncol. 2013 Sep;4(3):253-63.
12.Fogli S, Mogavero S, Egan CG, Del Re M, Danesi R. Pathophysiology and pharmacological targets of VEGF in diabetic macular edema. Pharmacol Res. 2016 Jan;103:149-57.
13.Central Health Insurance Agency, Ministry of Health and Welfare, National Health Insurance Drug Payment Regulations. Amendment Section 14 Ophthalmic preparations. 2013 Feb 1. 衛生福利部中央健康保險署「全民健康保險藥品給付規定」修正規定第 14 節眼科製劑(Ophthalmic preparations) 102年2月1日.
14.Central Health Insurance Agency, Ministry of Health and Welfare, National Health Insurance Drug Payment Regulations. Amendment Section 14 Ophthalmic preparations. 2016 Dec 1. 衛生福利部中央健康保險署「全民健康保險藥品給付規定」修正規定第 14 節眼科製劑(Ophthalmic preparations). 105年11月1日.
15.Park SJ, Choi Y, Na YM, Hong HK, Park JY, Park KH, et al. Intraocular Pharmacokinetics of Intravitreal Aflibercept (Eylea) in a Rabbit Model. Invest Ophthalmol Vis Sci. 2016 May 1;57(6):2612-7.
16.Krohne TU, Liu Z, Holz FG, Meyer CH. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol. 2012 Oct;154(4):682-6 e2.
17.Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol. 2008 Oct;146(4):508-12.
18.Avery RL, Castellarin AA, Hanley WD. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Ophthalmology Retina. 2017;37:1847–58.
19.Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr;119(4):789-801.
20.Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013 Oct;120(10):2013-22.
21.Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology. 2015 Oct;122(10):2044-52.
22.Heier JS, Korobelnik JF, Brown DM, Schmidt-Erfurth U, Do DV, Midena E, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology. 2016 Nov;123(11):2376-85.
23.Ekinci M, Ceylan E, Cakici O, Tanyildiz B, Olcaysu O, Cagatay HH. Treatment of macular edema in diabetic retinopathy comparison of the efficacy of intravitreal bevacizumab and ranibizumab injections. Ophthalmology. 2014;9(2):139–43
24.Nepomuceno AB, Takaki E, Paes de Almeida FP, Peroni R, Cardillo JA, Siqueira RC, et al. A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema. Am J Ophthalmol. 2013 Sep;156(3):502-10.
25.Diabetic Retinopathy Clinical Research N, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015 Mar 26;372(13):1193-203.
26.Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016 Jun;123(6):1351-9.
27.Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E. Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis. Cochrane Database Syst Rev. 2018 Oct 16;10:CD007419.
28.Ciulla TA, Bracha P, Pollack J, Williams DF. Real-world Outcomes of Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema in the United States. Ophthalmol Retina. 2018 Dec;2(12):1179-87.
29.Rasmussen A, Bloch SB, Fuchs J, Hansen LH, Larsen M, LaCour M, et al. A 4-year longitudinal study of 555 patients treated with ranibizumab for neovascular age-related macular degeneration. Ophthalmology. 2013 Dec;120(12):2630-6.
30.Ross EL, Hutton DW, Stein JD, Bressler NM, Jampol LM, Glassman AR, et al. Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment: Analysis From the Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Trial. JAMA Ophthalmol. 2016 Aug 1;134(8):888-96.
31.Stone T. ASRS 2016 Preferences and Trends Membership. American Society of Retina Specialists. 2016.
32.Central Health Insurance Agency, Ministry of Health and Welfare, National Health Insurance Drug Payment Regulations. Amendment Section 14 Ophthalmic preparations. 2019 Apr 1. 衛生福利部中央健康保險署「全民健康保險藥品給付規定」修正規定第 14 節眼科製劑(Ophthalmic preparations) 108年4月1日