臨床療效及安全性之主動監測系統

Abstract

儘管隨機對照試驗被認為是新藥批准的標準研究方法，但仍無法檢測到所有不良藥物事件。由於許多嚴重的藥物不良反應，許多藥物在市場批准後仍被撤回。因此，藥品核可後，病人的藥品使用安全性和有效性的持續性監測和評估是非常重要的。 為了了解病人群對藥品使用安全性、有效性、即時性與持續性監測，並提供臨床效果研究資料的取得與應用。我們開發了基於網路服務的臨床安全監測系統，此系統基於台大醫院的醫療整合資料庫，實作了一系列的以電子病歷資料的擷取自動化流程，方便醫療研究人員在系統介面設計自己的研究參數，指定藥品安全監測分析方法，進而透過此平台產生監測之報告。為了驗證系統的結果，我們在該研究中建立了兩個臨床應用。我們研究了骨質疏鬆性骨折患者的醫療指引的順從性。 第二個應用我們調查了NOACs和warfarin在非瓣膜性心房顫動患者中的有效性和安全性的差異。 根據醫療指引我們透過系統檢索了2010至2014年間，識別出2,193新罹患骨質疏鬆性骨折的病人，藉由系統的進一步的篩選功能，共找出了1,808位病人(82.44%, 1,808/2,193)在三個月內有回到臺大醫院繼續接受治療，其中僅有464位病人 (21.16%, 464/2,193) 在一年內有根據醫療指引服用抗骨質疏鬆的藥物。 我們在2010年至2015年期間識別出2,357名的病患，為新使用口服抗凝劑的非瓣膜性房顫患者，並進一步分析了缺血性中風作為臨床療效的比較與顱內出血作為安全性的比較。在缺血性中風的結果中，與服用warfarin病患相比，NOACs用戶在調整意向治療（ITT）分析中，罹患缺血性中風的風險顯著降低（P = 0.01）。在治療（AT）分析中具有風險則沒有差異（P = 0.12）。 在顱內出血安全性比較，NOACs病患在ITT分析為（P = 0.68）和AT分析為（P = 0.15）其風險並沒有差異。 由此可知，臨床安全監測系統提供了可參數化的設計，研究人員可以專注於解決臨床研究問題，此系統則可以進行資料自動擷取，並進一步產生監測報告。此系統可以加速臨床研究的流程，並提供決策者基於電子病歷的證據，以協助醫院或醫事人員進行決策。

Although the randomized control trial is considered as a gold standard research approach for the new drug approval, such a trial may fail to detect all the adverse drug events. Numerous drugs were still withdrawn after the market approval because of the unexpected severe adverse drug reaction. Therefore, it is a critical issue to establish a well-design effective and convenient active post-marketing drug surveillance system, which is the process of continuous monitoring and evaluation of the drug safety and effectiveness after their listing. We implemented a web-based clinical surveillance system, the National Taiwan University Hospital Clinical Surveillance System (NCSS) that can integrate the workflow of cohort identification to accelerate the survey process of disease and medication prescription patterns and provide a high reusability infrastructure for a computerized workflow to capture relevant longitudinal clinical data and make those data repositories reusable. In order to valid the result of NCSS, we established two clinical applications in the study. The first application of the NCSS, we looked at the identification of osteoporotic fracture patients and their utilization in pharmacological therapy. The second application, we investigated the difference of effectiveness and safety between NOACs and warfarin in the patients with non-valvular atrial fibrillation. By applying the NCSS, we efficiently identified 2,193 patients who were newly diagnosed with a hip or vertebral fracture between 2010 and 2014 at NTUH. By adopting the filter function, we identified 1808 (82.44%, 1808/2,193) patients who continued their follow-up at NTUH, and 464 (21.16%, 464/2,193) patients who have prescribed anti-osteoporosis medications (AOMs), within 3 and 12 months post the index date of their fracture, respectively. On average, only 35% of female and 28% of male osteoporotic fracture patients initiated AOM therapy to prevent a subsequent fracture. More effort is warranted to improve the quality of care with these patients. We demonstrated the practical example of investigating the difference of effectiveness and safety between NOACs and warfarin in the patients with non-valvular atrial fibrillation at NCSS. We efficiently identified 2,357 non-valvular AF patients with newly prescribed oral anticoagulant between 2010 and 2015 and further developed one main cohort and two sub-cohorts for measuring ischemic stroke as clinical effectiveness outcome and intracranial hemorrhage as safety outcome separately. In ischemic stroke, compared to warfarin users, NOACs users have a significantly lower risk of ischemic stroke after adjusting for age, sex, comorbidity and co-medication in intention-to-treat (ITT) analysis (P = 0.01) but have a comparable risk in as-treated (AT) analysis (P = 0.12) after the 2-year follow-up. In intracranial hemorrhage, NOACs users have a comparable risk of ICH both in ITT (P = 0.68) and AT analysis (P = 0.15). The NCSS systems can integrate the workflow of cohort identification to accelerate the survey process of clinically relevant problems and provide decision support in the daily practice of clinical physicians, thereby making the benefit of evidence-based medicine a reality.