1、 1實證藥學床問題討記表 報告日期： 2008.4.16 床藥師： 謝慧貞 記：謝慧貞 一、問題別： Therapy（治性） Diagnosis（診斷性） Prognosis（預後性） Harm （併發症） 二、背景敘述：顯影劑腎病變是指投予顯影劑後 2 至 7 天內出現急性腎功能化且無其它原因會影響腎臟功能，腎臟功能化的定義是指腎功能指標 Cre 比投予顯影劑前上升0.5mg/dl 或增加 25以上。顯影劑所造成的腎功能化常會導致住院天增加、洗腎、嚴重心血管事件、甚至於死亡而增加醫成本。顯影 劑導致腎病變的機轉目前仍十分清楚，過腎血的改變可能佔有很大的因素。容 造成顯影劑腎病變的危顯因子包括
2、有現存有腎功能常、病、心臟衰竭或 其它可能會低腎灌因素、使用高劑的顯影劑、多發性骨髓瘤增加為腎病變比正常人高。顯影 劑本身也是造成腎病變的危險因子之一，包括滲透壓、是否使用非子型顯影劑 、顯影劑黏稠、及顯影劑使用的。 Hydration是目前最廣泛用預防顯影劑腎病變，其它則包含有 n-acetylcysteine、 vasodilator 等。Fluimucil 是目前最常被用研究顯影劑導致腎病 變，目前仍十分清楚其腎臟保護機制為何，但可能低自由基對腎小管的直接傷害或影響 NO 或 endothelial 途徑導致的血管收縮都有可能。 三、床問題敘述：51 歲性進 PTCA 後出院 ，於三日後
3、再次入院，入院診斷為 acute on chronic renal failure，故醫師懷疑為先前進 PTCA 使用的顯影劑所導致，故開N-acetylcysteine 600mg q.i.d。 P（Patient or problem） ： 進 PTCA 的病患因使用 contrast 而併發腎臟病變 I（Intervention） ：N-acetylcysteine C（Comparison Intervention） ： placebo O（Outcomes） ：Renal function（serum creatinine） 四、關鍵字搜尋（ Key words） ： acetylc
4、ysteine and contrast、 n-acetylcysteine, contrast-induced nephrotoxicity 2五、搜尋之資庫（ MEDLINE、PubMed、Cochrane、NGC、ACP 、DARE or other database） ：PubMed、Cochrane library 、文獻等級與摘要： （ Level 1A：systemic review of RCT；Level 1B：single RCT；Level 2A：systemic review of cohort study；Level 2B：cohort study or poor R
5、 CT；Level 3：case control；Level 4：case series；Level 5：expert opinion） 1. N-acetylcysteine and contrast-induced nephropathy: a meta-analysis of 13 randomized trials Am Heart J. 2006 Jan;151(1):140-5 （ Level 1A） BACKGROUND: Contrast-induced nephropathy (CIN) following coronary angiography increases mor
6、bidity and mortality. Randomized trials of small sample size have evaluated whether N-acetylcysteine (NAC) prevents CIN in patients with renal dysfunction. METHODS: To conduct a meta-analysis of the randomized trials the following databases were searched: MEDLINE (1966-2003), Cochrane Controlled Tri
7、als Register, ACP Journal Club online, published abstracts presented at the major cardiology and nephrology meetings, references from reviews. Two authors independently evaluated all relevant randomized trials. Eligibility criteria were (1) randomized placebo controlled trials of NAC, (2) patients w
8、ith impaired renal function (creatinine 1.2 mg/dL) undergoing coronary angiography, (3) patients receiving intravenous fluids and low-osmolarity nonionic contrast media, (4) the primary outcome was CIN (increases in creatinine of either at least 0.5 mg/dL or 25% from baseline to 48 hours). Of 589 tr
9、ials reviewed 3 disagreements were easily resolved by mutual discussion and 13 were selected. Data extraction included patient characteristics, intravenous fluid regimen, type and dose of contrast media, dosing regimen, creatinine at baseline and 48 hours and CIN requiring dialysis. RESULTS: Four of
10、 the 13 trials reported statistically significant results. In meta-analysis of the 13 trials, which included 1892 patients, the RR was 0.68 (95%CI, 0.46-1.01). The addition of the trial of patients undergoing computerized tomography, which had formulated the hypothesis, yielded a statistically signi
11、ficant reduction (RR 0.64 95%CI 0.42-0.96) as did an earlier meta-analysis of 7 trials. CONCLUSIONS: Our meta-analysis of the most currently available randomized data concerning NAC before coronary angiography to prevent CIN in patients with impaired renal function is neither conclusive nor provides
12、 proof beyond a reasonable doubt to influence clinical practice and public policy. The intervention has minimal toxicity but the width of the 95% CI remains compatible with a range from a large benefit to none at all. In addition, the trials used change in creatinine as the measure of outcome. Furth
13、er randomized trials of large sample size and with clinical outcomes will add importantly relevant information to the totality of evidence 3and allow the most rational clinical decisions for individual patients as well as policy decisions for the health of the general public. 1. In meta-analysis of
14、the 13 trials, which included 1892 pati ents，the RR was 0.68（95CI: 0.46-1.01） 2.CIN requiring dialysis，total 1 3 paients，4 patients in NAC an d 7 patients in placebo 3.Study heterogeneity：與 small size 、dose regimen、contrast volume 或 baseline SCR有關 2. N-acetylcysteine for the prevention of contrast-i
15、nduced nephropathy. A systematic review and meta-analysis. J Gen Intern Med. 2005 Feb;20(2):193-200 （Level 1A） OBJECTIVE: Contrast-induced nephropathy is a common cause of acute renal failure in hospitalized patients. Although patients are often given N-acetylcysteine to prevent renal injury from co
16、ntrast agents, there are no clear guidelines supporting its use. We conducted a systematic review to determine whether administering N-acetylcysteine around the time of contrast administration reduces the risk of contrast-induced nephropathy. DESIGN: We searched MEDLINE, EMBASE, the Cochrane Collabo
17、ration Database, bibliographies of retrieved articles, and abstracts of conference proceedings, and consulted with experts to identify relevant studies. Randomized controlled trials of N-acetylcysteine in hospitalized patients receiving contrast were included. Studies were excluded if they did not r
18、eport change in creatinine or incidence of contrast-induced nephropathy at 48 hours. MEASUREMENTS AND MAIN RESULTS: Nine randomized controlled trials satisfied all inclusion criteria and were included in the analysis. The difference in mean change in creatinine between the N-acetylcysteine-treated g
19、roup and controls was -0.27 mg/dl (95% confidence interval CI, -0.43 to -0.11). The relative risk of developing contrast-induced nephropathy was 0.43 (95% CI, 0.24 to 0.75) in subjects randomized to N-acetylcysteine. Significant heterogeneity existed among studies, suggesting differences in patient
20、populations or study methodology not identified by sensitivity analyses. The incidence of dialysis was rare (0.2%). CONCLUSIONS: Our findings suggest that N-acetylcysteine helps prevent declining renal function and contrast-induced nephropathy. While N-acetylcysteine is inexpensive and nontoxic, und
21、eviating insistence for dosing at least 12 hours in advance of contrast exposure may delay diagnostic and therapeutic procedures. Future studies are needed to address the longer-term clinical outcomes and cost-effectiveness of this agent. 41.用 systemic revi ew 評估投予顯影劑前後給予 NAC 對於腎病變的預防效果 2.共有 9 篇 RCT
22、，NAC 組與控制組 Scr 平均差為-0.27 mg/dl 3.RR 為 0.43（95CI 0.24-0.75） 4.Study heterogeneity：與 patien t population、study methodology 有關 5.洗腎的發生很低：0.2 3. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int. 2004 Apr;65(4):1366-74. （Level 1A） BACKGROUND: The efficacy of N-acety
23、lcysteine (NAC) for preventing contrast nephropathy is uncertain. We performed a systematic review and meta-analysis to assess the efficacy of NAC for preventing contrast nephropathy after administration of intravenous contrast media. METHODS: Data were obtained from searching MEDLINE (1969-2003) an
24、d EMBASE (1988-2003), Cochrane Controlled Clinical Trial Registry (2002, Volume 3), and conference proceedings. We considered all randomized studies that compared changes in renal function between groups that received and did not receive NAC. Studies in which the control group also received active t
25、herapy were excluded, although co-intervention directed at both groups was permitted. Two reviewers independently extracted quantitative and qualitative data. Disagreements were resolved by consensus with the aid of a third party. RESULTS: Fifteen studies with a total of 1776 patients satisfied incl
26、usion and exclusion criteria. Contrast nephropathy was typically defined by an increase in serum creatinine of 0.5 mg/dL within 24 to 48 hours of contrast administration. The pooled random effect relative risk was 0.65 (0.43-1.00, P= 0.049), indicating that NAC significantly reduced the incidence of
27、 contrast nephropathy. However, the effect of NAC was not statistically significant in several prespecified subgroup analyses, and the results were not robust to the addition of hypothetical new or unidentified randomized trials. There was evidence of significant heterogeneity in NAC effect across s
28、tudies (Q = 26.3, P= 0.02). Random effects meta-regression did not implicate identified differences in participant or study characteristics as responsible for the observed heterogeneity. CONCLUSION: NAC may reduce the incidence of acutely increased serum creatinine after administration of intravenou
29、s contrast, but this finding was of borderline statistical significance, and there was significant heterogeneity between trials. Before NAC becomes the standard of care for all patients receiving intravenous contrast, new randomized trials evaluating its effect on clinically relevant outcomes are re
30、quired. 1.用 systemic review 及 meta-analysis 分析 NAC 對於 contrast 產生 nephropathy 的5預防效果 2.共包含有 15 個 RCT，1776 人，study 對於 CIN 的定義為投予 contrast 後 24-48 小時,serum ceatinine 上升 0.5 mg/dl，多的 NAC regimen 為 600 mgxb.i.dx2 day， 最高劑為 1500mgxb.i.dx2day，另有一 study 使用 IV NAC 150mg/kg 後以 50mg/kgx4 hr。 3.RR：0.65（95CI 0.
31、43-1, P =0.049），NAC 明顯低 CIN 的發生，NAC 可能可以預防腎病變，但是統計學上是 bordeline significant，且床研究之間有顯著的質性，建議有多的隨機的床研究評估。 4.N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006 Jun 29;354(26):2773-82. （Level 1B） BACKGROUND: Patients with acute myocardial infarction undergoing p
32、rimary angioplasty are at high risk for contrast-medium-induced nephropathy because of hemodynamic instability, the need for a high volume of contrast medium, and the lack of effective prophylaxis. We investigated the antioxidant N-acetylcysteine for the prevention of contrast-medium-induced nephrop
33、athy in patients undergoing primary angioplasty. METHODS: We randomly assigned 354 consecutive patients undergoing primary angioplasty to one of three groups: 116 patients were assigned to a standard dose of N-acetylcysteine (a 600-mg intravenous bolus before primary angioplasty and 600 mg orally tw
34、ice daily for the 48 hours after angioplasty), 119 patients to a double dose of N-acetylcysteine (a 1200-mg intravenous bolus and 1200 mg orally twice daily for the 48 hours after intervention), and 119 patients to placebo. RESULTS: The serum creatinine concentration increased 25 percent or more fro
35、m baseline after primary angioplasty in 39 of the control patients (33 percent), 17 of the patients receiving standard-dose N-acetylcysteine (15 percent), and 10 patients receiving high-dose N-acetylcysteine (8 percent, P or =1.5mg/dl and/or creatinine clearance or =140ml, or contrast ratio 1) contr
36、ast dose, the event was significantly more frequent in the SD Group. Conclusions Double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially with high volumes of non-ionic, low-osmolality contrast agent. 在低劑顯影劑下，在腎功能化的 發生機沒有明顯差，但在高劑的 contrast 下，投予 double dose 可
37、以明顯減少 CIN 的事件發生比，高劑的 NAC 似乎以標準劑在預防 CIN 的有效，特別是 high volume contrast。 七、關鍵性結： 這些研究之間都存在質性，包括對於顯 影劑引起的急性腎衰竭的定義、急性腎衰竭的基本危險值 （包括腎功能化的嚴重或病的比） 、 NAC 的劑與投予途徑、 IV hydration protocol、 contrast 的種與投予的劑、執手術的種7（ contrast CT、 cardiac catheterization、 or peripheral angiography） 。但都朝向對於 CIN有幫助，特別對於高危險群的病患，有多種同的 re
38、gimen 被討 ,最常的是 600 mg 投予時間為每日 2 次 ,投予 contrast 前一天及進檢查當天。 八、問題與討： Q1.Quality score 是指甚麼？表是如何評估？ weight ？ ANS:進 meta-analysis 常的品質評估功具的內容包括品 質表或品質檢查表等，以reviewer 能系統性的檢查每一選取出的研究文獻， 賦予檢查表每一項目一個分，就成為品質的分表。同時進分析時 必需將研究品質入考因子中，檢驗同的品質水準的對研究效果的影響，當各研究的效果的差性很大時， reviewer 會給予品質較佳的研究較高的權重，依品質水準的高低 賦予各研究同的權重。 R
39、ef: Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials. 1995 Feb;16(1):62-73 Q2.假如非高危險性的病患要使用顯影劑，在床 上是否可以建議需使用 NAC？ ANS:基本上目前在心臟內科進心導 管手術前都會預防性給予 FLUIMUCIL 600mg b.i.dx2 day， fluimucil 的價錢宜又沒有太大的藥物副作用， 床上是遇到必須使用顯影劑的手術過程還是會建議
40、使用。 Q3.是否 only hydration 比較 hydration combined NAC 的 OUTCOME 差性？ ANS：以上所討的文獻多以 HYDRATION 當作 placebo 與 NAC 比較或 NAC combined hydration 比較的結，這些研究的質性差其 一在於研究方法上的藥物 regimen 同甚至 hydation regimen 也有差，有單獨的 RCT 研究結果，但以上這些文獻是將以上 RCT整合分析後分析出的結果。 Q4.有無分析同 subgroup 發生 CIN 的比較？ ANS: 這些 META-ANALYSIS 的研究質性其一是沒有特別針
41、對 subgroup 進分，之後有一些文獻開始研究 CIN 對於 subgroup 在 CIN 的結果，如有一篇研究針對病患進 fluimucil 在 CIN 上的結果發現並如之前的研究提出的建 議，反而認為沒有實質的幫助，本次因為首次進 EBM book reading，所以閱的文獻明顯足，於下次小組會議時會提出建議，故本次只有五篇文獻。 ref: Acetylcysteine In Diabetes (AID): A randomized study of acetylcysteine for the prevention of contrast nephropathy in diabetics ; American Heart Journal. 2006 May Volume 151, Number 5 九、 COMMENT：
