Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism,Annals of Internal Medicine

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Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism
Annals of Internal Medicine ( IF 19.6 ) Pub Date : 2021-09-14 , DOI: 10.7326/m21-1094
Faizan Khan ₁ , Tobias Tritschler ₂ , Miriam Kimpton ₃ , Philip S Wells ₃ , Clive Kearon ₄ , Jeffrey I Weitz ₄ , Harry R Büller ₅ , Gary E Raskob ₆ , Walter Ageno ₇ , Francis Couturaud ₈ , Paolo Prandoni ₉ , Gualtiero Palareti ₉ , Cristina Legnani ₉ , Paul A Kyrle ₁₀ , Sabine Eichinger ₁₀ , Lisbeth Eischer ₁₀ , Cecilia Becattini ₁₁ , Giancarlo Agnelli ₁₁ , Maria Cristina Vedovati ₁₁ , Geert-Jan Geersing ₁₂ , Toshihiko Takada ₁₂ , Benilde Cosmi ₁₃ , Drahomir Aujesky ₂ , Letizia Marconi ₁₄ , Antonio Palla ₁₄ , Sergio Siragusa ₁₅ , Charlotte A Bradbury ₁₆ , Sameer Parpia ₁₇ , Ranjeeta Mallick ₁₈ , Anthonie W A Lensing ₁₉ , Martin Gebel ₁₉ , Michael A Grosso ₂₀ , Kednapa Thavorn ₁ , Brian Hutton ₁ , Gregoire Le Gal ₃ , Dean A Fergusson ₂₁ , Marc A Rodger ₂₂ ,

Affiliation

University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (F.K., K.T., B.H.).
Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (T.T., D.A.).
Ottawa Hospital Research Institute, University of Ottawa, and The Ottawa Hospital, Ottawa, Ontario, Canada (M.K., P.S.W., G.L.).
McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (C.K., J.I.W.).
Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands (H.R.B.).
University of Oklahoma Health Sciences Center, Hudson College of Public Health, Oklahoma City, Oklahoma (G.E.R.).
University of Insubria, Varese, Italy (W.A.).
Brest University Hospital, Brest, France (F.C.).
Arianna Foundation on Anticoagulation, Bologna, Italy (P.P., G.P., C.L.).
Medical University of Vienna, Vienna, Austria (P.A.K., S.E., L.E.).
University of Perugia, Perugia, Italy (C.B., G.A., M.C.V.).
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (G.G., T.T.).
Sant'Orsola-Malpighi University Hospital, Bologna, Italy (B.C.).
University of Pisa, Pisa, Italy (L.M., A.P.).
University of Palermo, Palermo, Italy (S.S.).
University of Bristol, Bristol, United Kingdom (C.A.B.).
McMaster University, Hamilton, Ontario, Canada (S.P.).
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (R.M.).
Bayer, Wuppertal, Germany (A.W.L., M.G.).
Daiichi Sankyo, Basking Ridge, New Jersey (M.A.G.).
University of Ottawa, Ottawa Hospital Research Institute, and The Ottawa Hospital, Ottawa, Ontario, Canada (D.A.F.).
Ottawa Hospital Research Institute, Ottawa, Ontario, and McGill University, Montreal, Quebec, Canada (M.A.R.).

Background:

The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain.

Purpose:

To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups.

Data Sources:

MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021.

Study Selection:

Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment.

Data Extraction:

Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies.

Data Synthesis:

Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs.

Limitation:

Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs.

Conclusion:

In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE.

Primary Funding Source:

Canadian Institutes of Health Research. (PROSPERO: CRD42019128597)

中文翻译：

首次无端静脉血栓栓塞延长口服抗凝治疗期间大出血的长期风险

背景：

对于首次无诱因静脉血栓栓塞 (VTE) 接受延长（超过最初的 3 至 6 个月）抗凝治疗的患者发生大出血的长期风险尚不确定。

目的：

确定首次无诱因 VTE 患者总体和临床重要亚组在长达 5 年的延长抗凝治疗期间大出血的发生率。

数据源：

MEDLINE、Embase 和 Cochrane 对照试验中央登记册从开始到 2021 年 7 月 23 日。

研究选择：

随机对照试验 (RCT) 和前瞻性队列研究报告了在完成至少 3 个月的初始抗凝治疗后将接受至少 6 个月口服抗凝治疗的首次无诱因 VTE 患者的大出血。

数据提取：

两名评审员独立提取数据并评估研究质量。分析所需的未发表数据来自纳入研究的作者。

数据合成：

在纳入分析的 14 项 RCT 和 13 项队列研究中，9982 名患者接受了维生素 K 拮抗剂 (VKA)，7220 名患者接受了直接口服抗凝剂 (DOAC)。每 100 人年的大出血发生率为 1.74 次事件（95% CI，1.34 至 2.20 次），VKA 和 DOAC 分别为 1.12 次（CI，0.72 至 1.62 次）。VKA 的 5 年累积大出血发生率为 6.3%（CI，3.6% 至 10.0%）。在接受 VKA 或 DOAC 的患者中，65 岁以上或肌酐清除率低于 50 mL/min、有出血史、同时使用抗血小板治疗或血红蛋白水平低于 100 g/L。VKA 组大出血的病死率为 8.3%（CI，5.1% 至 12.2%），DOAC 组为 9.7%（CI，3.2% 至 19.2%）。