Preventing Gastroduodenal Bleeding in Oral Anticoagulant Users

描述(申请人提供)：华法林是心血管药物治疗的主要药物，也是美国最常用的处方药之一。然而，大出血是使用华法林的常见和潜在的破坏性并发症，每年影响大约3%的患者。与华法林相关的严重出血最常发生在胃肠道(GI)，约占大出血的三分之一。这表明质子泵抑制剂(PPI)可能会提高华法林的安全性。这一假说得到了我们对华法林相关出血的病理生理学以及其他促出血药物的研究的支持。对于许多有其他胃肠道出血危险因素的华法林使用者来说，PPI联合治疗的好处将是最大的。然而，PPI预防华法林相关的严重胃肠道出血的假设虽然看似合理，但尚未得到检验。现有证据在很大程度上是间接的，本身不能支持向华法林患者推荐PPI共疗法。事实上，现代的抗凝剂指南没有提到PPI。组胺-2受体拮抗剂(H2RAs)也可能被认为可以预防华法林相关的严重胃肠道出血，尽管它们可能不如PPI有效。新型口服抗凝剂比华法林使用更方便，将在口服抗凝剂的使用中占据越来越大的比例。然而，这些药物也会导致严重的胃肠道出血；一些药物的风险比华法林更大。因此，PPI可能具有显著提高新型抗凝剂安全性的潜力。我们将在田纳西州医疗补助和全国5%医疗保险样本中进行一项大型历史队列研究，评估口服抗凝剂使用者同时服用PPI/H2RA是否降低了严重消化道出血的风险，这是提高这些广泛使用的药物安全性的关键数据。我们将检验两个假设：目标1：在田纳西州医疗补助华法林使用者中，同时使用PPI或H2RA可降低因胃十二指肠出血而住院的风险。目的2：在Medicare样本中的新型口服抗凝剂使用者中，同时使用PPI或H2RA可降低因胃十二指肠出血而住院的风险。对于这些目标中的每一个，我们还将测试对PPI的保护作用是否大于对H2RAs的保护作用，以及绝对益处是否因GI出血危险因素的数量而异。

DESCRIPTION (provided by applicant): Warfarin is a mainstay of cardiovascular pharmacotherapy and one of the most frequently prescribed medications in the U.S. However, major bleeding is a frequent and potentially devastating complication of its use, affecting approximately 3% of patients annually. Serious warfarin-related bleeding most commonly occurs in the gastrointestinal (GI) tract, accounting for about 1/3 of major bleeds. This suggests proton-pump inhibitors (PPIs) might improve warfarin safety. This hypothesis is supported by our understanding of the pathophysiology of warfarin-related bleeding as well as by studies of other pro-hemorrhagic drugs. A benefit for PPI cotherapy would be greatest for the many warfarin users with other risk factors for GI bleeding. However, the hypothesis that PPIs prevent serious warfarin-related GI bleeding, although plausible, has not been tested. The available evidence is largely indirect and cannot, by itself, support recommending PPI cotherapy to warfarin patients. Indeed, contemporary anticoagulant guidelines do not mention PPIs. Histamine-2 receptor antagonists (H2RAs) also might be considered to prevent serious warfarin-related GI bleeding, although they may be less effective than PPIs. Novel oral anticoagulants, more convenient to use than warfarin, will account for a growing proportion of oral anticoagulant use. However, these also cause serious GI bleeding; some have risk greater than that of warfarin. Thus, PPIs may have the potential to markedly improve the safety of novel anticoagulants. We will conduct a large historical cohort study in Tennessee Medicaid and the national 5% Medicare sample assessing whether concurrent PPI/H2RA in oral anticoagulant users reduces risk of serious GI bleeding, critical data to improve the safety of these widely used medications. We will test two hypotheses: Aim 1: In Tennessee Medicaid warfarin users, concurrent PPI or H2RA use decreases risk of hospitalizations for gastroduodenal bleeding. Aim 2: In novel oral anticoagulant users in the Medicare sample, concurrent PPI or H2RA use decreases risk of hospitalizations for gastroduodenal bleeding. For each of these aims, we also will test whether the protective effect is greater for PPIs than for H2RAs as well as whether the absolute benefit varies according to number of GI bleeding risk factors.