從醫學中心醫療資料探討Warfarin處方劑量與慢性腎臟病之相關性

Abstract

研究背景 以腎臟為主要排除路徑的藥品用於慢性腎臟病（chronic kidney disease，CKD）病人時，仿單往往標示需依照腎臟功能做劑量調整。新近研究文獻另顯示，以肝臟代謝為主要排除途徑的特定藥品，於CKD病人可能因體內尿毒素累積等因素，直接或間接使得藥品之代謝或效用受到影響，因而使用時亦須考量腎功能狀態，以求最適劑量、發揮最佳藥效。Warfarin是由肝臟廣泛代謝的藥品，且為腎功能不良時首選之抗凝血藥品，但目前於亞洲漢人族群中還缺乏腎臟功能對warfarin劑量影響的實證。 研究目的 本研究欲分析warfarin的處方型態，並探討亞洲漢人族群之腎功能與其他變因對於warfarin使用劑量之相關性，並以臨床資訊嘗試建立warfarin劑量預估模型。 研究材料與方法 本研究為一回溯性世代研究，利用醫學中心醫療整合資料，探討2017年度有使用warfarin處方及相關醫療資料，並針對warfarin用藥劑量且INR處於穩定期間者之病歷資訊，包括基本特性、臨床檢驗數值、warfarin適應症、併用藥品等進行分析。本研究分組比較分析正常腎功能組與CKD病人組之間於各變項之異同，其中CKD組更進一步依eGFR值細分為G1&2、G3a、G3b、G4、G5等五組檢定。最後，更以多重線性回歸模型嘗試建立warfarin劑量推估模型。 研究結果 在3741位warfarin用藥病人中，有998位符合本研究納入條件，其中 CKD患者有237人（23.7%）。 腎功能正常組與CKD組的estimated creatinine clearance（eCrCL）分別為80.1  28.8 mL/min與33.1  17.0 mL/min（p-value < 0.0001），而兩組之warfarin平均週劑量分別為26.3  16.7 mg/週與18.9  14.7 mg/週（p-value < 0.0001），warfarin平均週劑量與eCrCL有顯著之正相關（p-value < 0.0001，r  0.2762）。 另外本研究發現臨床上病人間warfarin之處方劑量與使用頻次存在頗大的差異性，warfarin平均週劑量之中位數為21 mg，使用頻次「as order」比例佔研究群體之19.9%。在warfarin平均週劑量之單變項分析中，發現「每日使用相同劑量」較「非每日使用相同劑量」的warfarin平均週劑量少11.8 mg（p-value < 0.0001），是以往較少討論到之新變因。 經過多重線性模型的逐步篩選，最終納入warfarin平均週劑量計算模型之變項有eCrCL、身高、average INR、每日使用相同劑量、使用amiodarone之劑量，此模型之校正後決定係數（coefficient of determination，R2）為0.195。 結論 本研究顯示，對於warfarin劑量穩定期之病人，CKD病人warfarin之平均週劑量較腎功能正常者低，且用藥劑量隨著CKD stage惡化而呈現逐次降低趨勢，且eCrCL與warfarin平均週劑量呈現顯著正相關。本研究受限於觀察性研究與資料庫內容之限制，尚待更多深入研究以更完整釐清CKD對warfarin之藥動學與藥效學的影響。

Background Dosage adjustments are usually required for renally-eliminated medications in patients with chronic kidney disease (CKD). Recent studies have further disclosed that the metabolism or efficacy of certain drugs metabolized chiefly by the liver might still be affected, possible due to direct or indirect effects of accumulated uremic toxins, in CKD sufferers. It is postulated that dose adjustments based on renal function status should also be considered for certain liver metabolizing drugs. Warfarin, mainly metabolized by the liver, is the preferred anticoagulant in patients with impaired renal function. The association between renal function status and warfarin dosage in Han Chinese remain elusive. Study objectives This study aimed to: (1) analyze warfarin prescribing pattern, (2) evaluate possible correlation between renal function status (and/or clinical factors) and warfarin dosage in a dosing-stable cohort, and (3) construct a warfarin dosing algorithm by utilizing a medical-center healthcare data. Methods Patients prescribed with warfarin in 2017 and had a stable INR, defined as two consecutive INR values fell between 1.5 and 3.0, were retrospectively identified from the Integrated Medical Database of a medical center. Warfarin regimen and clinical information, including patient demographics, laboratory data, diagnoses or indications, and relevant co-medications were all collected and analyzed. Group (control vs. CKD sub-cohort) or subgroup (by CKD severity, according to estimated glomerular filtration rate [eGFR]) comparisons were also performed. A multivariate linear regression model was used to construct a warfarin dosing algorithm. Results Of 3741 warfarin users, a cohort of 998 individuals were eligible for the study. The CKD sub-cohort consisted of 237 (23.7%) patients. The estimated creatinine clearance (eCrCL) of the control and CKD groups were 80.1  28.8 mL/min and 33.1  17.0 mL/min (mean  standard deviation, p-value < 0.0001), respectively. The average warfarin weekly dose were 26.3  16.7 mg/week and 18.9  14.7 mg/week (p-value < 0.0001), respectively. A positive correlation between average warfarin weekly dose and eCrCL was observed (p-value < 0.0001, r  0.2762). Moreover, a wide variety in warfarin dosage and use frequency was noticed in the INR-stable cohort. The median average warfarin weekly dose was 21 mg, ranging from 2.5 to 180 mg). The proportion of the “as order” use frequency was 19.9% which consisted of a multitude of special instructions. In univariate analysis of warfarin dosage, a novel variable, “same daily dose of warfarin (SDDW)”, was found to decrease 11.8 mg of average warfarin weekly dose. In a stepwise linear regression with average warfarin weekly dose as the dependent variable, eCrCL as well as height, average INR, SDDW, and the dose of amiodarone were chosen as independent variables. The adjusted coefficient of determination (R2) of the developed algorithm was 0.195. Conclusions The study revealed that the average warfarin weekly dose within the INR-stable cohort was significantly lower in CKD sub-cohort, with a tendency of dosage decline in more advanced CKD stages. Concordantly, eCrCL is positively correlated with the average warfarin weekly dose. As limited by the observational design and single-institution data, further in-depth research is needed to investigate more thoroughly the impacts of CKD on the pharmacokinetics and pharmacodynamics of warfarin.