消化道出血后不再用华法林增加死亡风险

《内科学文献》(Archives of Internal Medicine)9月17日在线发表的一项回顾性队列研究显示，消化道出血后不再重新使用华法林，可导致血栓形成风险增加9倍，死亡风险增加2倍(Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2012.5261])。

在这项研究中，科罗拉多州奥罗拉Kaiser Permanente机构的Daniel M. Witt博士及其同事采用该机构的行政和临床数据库，研究了2005~2009年间因华法林相关消化道出血入院或到急诊科就诊的442例成人患者的血栓形成、复发性出血和全因死亡发生率。这些患者的随访时间为90天，平均年龄为74岁，男女比例各占一半。约半数患者使用华法林预防房颤相关卒中或全身性栓塞，1/4的患者用其治疗或预防复发性静脉血栓形成，10%用其预防人工心脏瓣膜所致的血栓栓塞性并发症，其余患者用其预防其他适应证。在索引消化道出血后，260例(59%)患者再次使用华法林(通常在1周内)，至再次使用华法林的中位时间为4天；41例患者未中断华法林治疗；182例患者中断华法林治疗，并且未再次使用。

在90天随访期间，11例(2.5%)患者发生血栓形成事件。发生6起动脉事件，包括5起卒中和1起全身性栓塞。发生5起静脉事件，包括3起肺栓塞和2起深静脉血栓形成(DVT)。

再次使用华法林的患者的血栓形成事件发生率为0.4%(1起DVT)，而未再次使用华法林的患者为5.5%(5起卒中、1起全身性栓塞、3起肺栓塞和1起DVT)，差异显著。未中断华法林治疗的患者和索引胃出血后14天内再次接受华法林治疗的患者未发生血栓形成事件。

共36例(8.4%)患者出现复发性胃肠道出血。再次使用华法林的患者的复发性胃肠道出血发生率(10%)高于未再次使用华法林的患者(5.5%)，但差异无统计学显著性。校正多种可能混杂因素(包括患者年龄、性别、并发症倾向；入院时INR；消化道出血的急性治疗；消化道出血位置)的多因素分析也显示，再次使用华法林的患者的复发性出血风险并不显著高于未再次使用华法林的患者。

此外，无1例患者因复发性消化道出血而死亡。然而，有3例停用华法林后未再次使用的房颤患者发生致死性卒中。共52例(12%)在随访期间死亡。最常见的死亡原因为恶性肿瘤(占死亡例数的29%)、感染(19%)和心脏病(17%)。再次使用华法林与全因死亡风险降低2倍强烈相关。研究者排除所有在索引消化道出血1周内死亡的患者(没有机会再次接受华法林治疗的患者)，进行事后分析仍发现，再次使用华法林与死亡率降低强烈相关。索引消化道出血15~90天内再次使用华法林者的死亡率最低。

该研究获杰特贝林公司资助。一位研究者声明与多家药企存在联系。

随刊述评：复发性出血的低风险可以接受

Amir K. Jaffer博士

约翰•霍普金斯医院院派医生项目的Daniel J. Brotman博士和迈阿密大学医院医学部的Amir K. Jaffer博士表示，该研究的高质量结果表明，复发性出血的低风险(10%)可以接受，并且无1起复发事件为致死性，同时大部分医生和患者愿意在消化道出血后不久即再次进行抗凝治疗。对于无明显适应证(如近期置入冠状动脉支架)的患者，如果继续合用抗血小板药，可能需要三思。另外，在将这些结果外推至更新型的抗凝药(如达比加群和利伐沙班)时，需持谨慎态度，因为新型抗凝药长期使用时的消化道出血发生率高于华法林，并且这种效应不易逆转。Brotman博士和Jaffer博士均声明与多家药企存在联系(Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2012.4309])。

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By: MARY ANN MOON, Cardiology News Digital Network

Deciding not to resume warfarin therapy after an episode of gastrointestinal bleeding raises the risk of thrombosis by a factor of 10 and the risk of death threefold, according to a retrospective cohort study published online September 17 in Archives of Internal Medicine.

"For many patients who have experienced gastrointestinal bleeding, the benefits of resuming warfarin therapy will outweigh the risks," said Daniel M. Witt, Pharm.D., of the clinical pharmacy anticoagulation service at Kaiser Permanente of Colorado, Aurora, and his associates.

"Surprisingly little is known about warfarin therapy and resumption" following a GI bleed, and there is no consensus as to the optimal timing or the risks of restarting anticoagulation. Dr. Witt and his colleagues used Kaiser’s administrative and clinical databases to study the incidence of thrombosis, recurrent bleeding episodes, and death from any cause in 442 adults who presented to a hospital or emergency department with warfarin-associated GI bleeding in 2005-2009 and who were followed for 90 days.

The mean patient age was 74 years, and the study population was equally comprised of men and women. Half of the study subjects were taking warfarin to prevent atrial fibrillation–related stroke or systemic embolization. One-quarter of patients used it to treat or prevent a second venous thrombosis, 10% were on it to prevent thromboembolic complications from prosthetic heart valves, and the remainder took it for other indications.

After an index GI bleed, 260 patients (59%) resumed warfarin therapy, usually within a week. The median time to resumption of warfarin was 4 days. In 41 of these patients, warfarin therapy was never suspended. It was suspended and never resumed in the remaining 182 patients.

During the 90-day follow-up, 11 patients (2.5%) had a thrombotic event. There were six arterial events, including five strokes and one systemic embolus, and five venous events, including three pulmonary embolisms and two deep vein thromboses (DVTs).

The rate of thrombotic events was 0.4% among the patients who resumed warfarin therapy (one DVT), compared with 5.5% among those who did not resume warfarin (five strokes, one systemic embolus, three pulmonary embolisms, and one DVT), a significant difference, the investigators said (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2012.5261]).

"Patients who either never interrupted warfarin therapy or resumed therapy within 14 days of the index GI bleed experienced no thromboses," they added.

GI bleeding recurred in 36 patients (8.4%) overall. A numerically higher proportion of patients who resumed warfarin therapy had recurrent GI bleeding (10%) than those who did not resume warfarin (5.5%), but this difference was not statistically significant.

In addition, a multivariable analysis that accounted for numerous possible confounders – including patient age, sex, propensity for complications; the INR at admission; acute treatment for the GI bleed; and location of GI bleed – also showed that the risk for rebleeding was not significantly greater in patients who resumed warfarin therapy than in those who did not.

Moreover, recurrent GI bleeding was never fatal. Fatal strokes did occur, however, in three patients with atrial fibrillation whose warfarin therapy was withdrawn and never resumed, Dr. Witt and his associates said.

A total of 52 patients (12%) died during follow-up. The most common cause of death was related to malignancy (29% of deaths), infection (19% of deaths), or cardiac disease (17%).

Resumption of warfarin therapy was strongly associated with a threefold decrease in the risk of death from any cause.

The investigators also performed a post hoc analysis excluding all patients who died within 1 week of the index GI bleed to rule out those who may not have had an opportunity to resume warfarin therapy. In this analysis, the strong association between resumption of warfarin and decreased mortality persisted.

Mortality was lowest among patients who resumed warfarin therapy within 15-90 days of the index GI bleed, the researchers said.

"Our results provide some guidance regarding the optimal timing of warfarin therapy resumption following GI bleeding, but clinical judgment remains a critical factor in this difficult decision," they noted.

This study was funded by CSL Behring. Dr. Witt’s associates, but not Dr. Witt, reported ties to numerous industry sources.

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Acceptably Low Risk of Rebleeding

This study provides high-quality, real-world data showing that the risk of recurrent bleeding was acceptably low (10%), none of the episodes of recurrence were fatal, and most physicians and patients were willing to resume anticoagulation soon after GI bleeding, said Dr. Daniel J. Brotman and Dr. Amir K. Jaffer.
     
"We would hesitate to continue concurrent antiplatelet therapy in these patients without a compelling indication to do so (such as a recent coronary stent), and also would caution against extrapolating these findings to newer anticoagulants, such as dabigatran and rivaroxaban, that may be associated with more GI bleeding than warfarin when used long term and whose effects are not easily reversed," they said.

Dr. Brotman is with the hospitalist program at Johns Hopkins Hospital, Baltimore. Dr. Jaffer is with the division of hospital medicine at the University of Miami. Dr. Brotman reported ties to Gerson Lehrman Group, the Dunn Group, Quantia Communications, Siemens Healthcare Diagnostics, and Amerigroup Corporation. Dr. Jaffer reported ties to Sanofi-Aventis, Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceuticals, Canyon Pharmaceuticals, and CSL. These remarks were taken from their invited commentary accompanying Dr. Witt’s report (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2012.4309]).