瑞巴派特、泮托拉唑及其联合用药对接受直接口服抗凝药物的心房颤动患者胃保护作用的比较疗效：随机REGATA研究。
完整摘要 · 中文译文
背景：接受直接口服抗凝药（DOAC）治疗的心房颤动（AF）患者发生胃肠道（GI）黏膜损伤和出血的风险升高。质子泵抑制剂（PPI）是常规的胃黏膜保护剂，但其在下消化道的疗效有限。本研究评估了瑞巴派特单药治疗以及泮托拉唑-瑞巴派特联合（P+R）治疗与泮托拉唑单药治疗相比在该易感人群中的疗效和安全性。方法：在随机、平行分组、开放标签、单中心的REGATA试验中，210例接受DOAC的AF患者被随机（1：1：1）分配至三种胃保护方案（每组n=70），持续24周：泮托拉唑单药治疗、瑞巴派特单药治疗或两药联合治疗。疗效分析在符合方案人群中完成（n=118：泮托拉唑组，n=36；瑞巴派特组，n=39；P+R组，n=43）。主要和次要结局包括复合临床GI事件（按ISTH/BARC分类的出血、溃疡/糜烂和严重消化不良）以及黏膜屏障功能生物标志物（粪便连蛋白和钙卫蛋白）。结果：主要疗效终点事件的发生率在泮托拉唑组为13.9%（n=5；95% CI：3.1-25.7），瑞巴派特组为10.3%（n=4；95% CI：2.3-21.1），P+R组为9.3%（n=4；95% CI：2.1-18.6），成功证实两个试验组在预设的10%界值内均符合非劣效性假设（p<0.05）。多变量回归分析显示，与泮托拉唑单药治疗相比，瑞巴派特单药治疗显示出 得出的比值比（OR）为0.71（95%置信区间：0.18-2.88，p = 0.630），而P + R疗法与OR 0.64相关（95%置信区间：0.16-2.57，p = 0.525）。未发生重大消化道出血事件或死亡；在泮托拉唑组记录到一次消化道出血事件（ISTH轻度/BARC 2型）（2.8%）。粪便钙卫蛋白水平在瑞巴派特组显著下降（下降37.6%，从139降至78 µg/g；p < 0.001），在P + R组也显著下降（下降50.0%，从135降至61 µg/g；p < 0.001），而泮托拉唑组未见显著变化（p = 0.530）。同时，反映肠上皮通透性的粪便连串蛋白水平在瑞巴派特组下降45.1%（从434降至225 ng/mL；p < 0.001），在P + R组下降47.1%（从347降至182 ng/mL；p < 0.001），相比之下泮托拉唑组仅有3.0%的微小波动。结论：尽管主要临床终点方面显示非劣效性，但瑞巴派特单药治疗及联合治疗（P + R）在降低亚临床胃肠道炎症和恢复肠上皮屏障完整性方面均比泮托拉唑单药治疗取得了一定优势。
完整摘要 · 英文原文
Background: Patients with atrial fibrillation (AF) receiving direct oral anticoagulants (DOAC) are at an elevated risk of gastrointestinal (GI) mucosal damage and bleeding. Proton pump inhibitors (PPI) are conventional gastroprotectors, but their efficacy in the lower GI tract is limited. This study evaluated the efficacy and safety of rebamipide monotherapy and combination pantoprazole-rebamipide (P + R) therapy compared to pantoprazole monotherapy in this vulnerable population. Methods: In the randomized, parallel-group, open-label, single-center REGATA trial, 210 AF patients receiving DOAC were randomized (1:1:1) to three gastroprotective regimens (n = 70 each) for 24 weeks: pantoprazole monotherapy, rebamipide monotherapy, or their combination. Efficacy analyses were performed in the per-protocol population (n = 118: pantoprazole, n = 36; rebamipide, n = 39; P + R, n = 43). The primary and secondary outcomes included composite clinical GI events (bleeding classified by ISTH/BARC, ulcers/erosions, and severe dyspepsia) and biomarkers of mucosal barrier function (fecal zonulin and calprotectin). Results: The incidence of primary efficacy endpoint events was 13.9% (n = 5; 95% CI: 3.1-25.7) in the pantoprazole group, 10.3% (n = 4; 95% CI: 2.3-21.1) in the rebamipide group, and 9.3% (n = 4; 95% CI: 2.1-18.6) in the P + R group, successfully confirming the non-inferiority hypothesis for both experimental arms within the pre-specified margin of 10% (p < 0.05). Multivariable regression analysis showed that compared with pantoprazole monotherapy, rebamipide monotherapy demonstrated an odds ratio OR of 0.71 (95% CI: 0.18-2.88, p = 0.630), while the P + R therapy was associated with an OR of 0.64 (95% CI: 0.16-2.57, p = 0.525). No major GI bleeding events or fatalities occurred; a single episode of GI bleeding (ISTH minor/BARC Type 2) was recorded in the pantoprazole arm (2.8%). Fecal calprotectin levels significantly decreased in the rebamipide group (by 37.6%, from 139 to 78 µg/g; p < 0.001) and the P + R group (by 50.0%, from 135 to 61 µg/g; p < 0.001), while no significant changes were observed in the pantoprazole group (p = 0.530). Concurrently, fecal zonulin levels, reflecting intestinal epithelial permeability, fell by 45.1% in the rebamipide arm (from 434 to 225 ng/mL; p < 0.001) and by 47.1% in the P + R arm (from 347 to 182 ng/mL; p < 0.001) compared to a minimal 3.0% fluctuation in the pantoprazole group. Conclusions: While demonstrating non-inferiority regarding primary clinical endpoints, both rebamipide monotherapy and combination (P + R) therapy achieved some advantages over pantoprazole monotherapy in decreasing subclinical GI inflammation and restoring intestinal epithelial barrier integrity.