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静脈血栓塞栓症に対する抗凝固療法の継続期間

抗凝固療法の継続期間は静脈血栓を生じた危険因子の種類により判断する。
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1: 日本循環器学会ほか編:肺血栓塞栓症および深部静脈血栓症の診断、治療、予防に関するガイドライン(2017年改訂版).http://www.j-circ.or.jp/guideline/pdf/JCS2017_ito_h.pdf(2019年4月閲覧)班長:伊藤正明、p30、表17、VTEに対する抗凝固療法の継続期間

DVTの検査前臨床確率の評価

DVTの画像検査前の臨床的確率を評価する方法としてWellsスコアがよく知られている。危険因子や症状所見などを点数化してDVTの可能性を評価する方法である。
 
参考文献:
Wells PS, Owen C, Doucette S, et al. Does this patient have deep vein thrombosis? JAMA 2006; 295: 199-207. PMID: 16403932
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VTEの危険因子

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1: Risk factors for venous thromboembolism.
著者: Frederick A Anderson, Frederick A Spencer
雑誌名: Circulation. 2003 Jun 17;107(23 Suppl 1):I9-16. doi: 10.1161/01.CIR.0000078469.07362.E6.
Abstract/Text: Until the 1990s, venous thromboembolism (VTE) was viewed primarily as a complication of hospitalization for major surgery (or associated with the late stage of terminal illness). However, recent trials in patients hospitalized with a wide variety of acute medical illnesses have demonstrated a risk of VTE in medical patients comparable with that seen after major general surgery. In addition, epidemiologic studies have shown that between one quarter and one half of all clinically recognized symptomatic VTEs occur in individuals who are neither hospitalized nor recovering from a major illness. This expanding understanding of the population at risk challenges physicians to carefully examine risk factors for VTE to identify high-risk patients who could benefit from prophylaxis. Factors sufficient by themselves to prompt physicians to consider VTE prophylaxis include major surgery, multiple trauma, hip fracture, or lower extremity paralysis because of spinal cord injury. Additional risk factors, such as previous VTE, increasing age, cardiac or respiratory failure, prolonged immobility, presence of central venous lines, estrogens, and a wide variety of inherited and acquired hematological conditions contribute to an increased risk for VTE. These predisposing factors are seldom sufficient by themselves to justify the use of prophylaxis. Nevertheless, individual risk factors, or combinations thereof, can have important implications for the type and duration of appropriate prophylaxis and should be carefully reviewed to assess the overall risk of VTE in each patient.
Circulation. 2003 Jun 17;107(23 Suppl 1):I9-16. doi: 10.1161/01.CIR.00...

Hokusai-VTE試験の結果

a:VTE再発率。エドキサバン群の従来治療群に対する非劣性が示された。
b:出血イベント発生率。エドキサバン群は従来治療群と比較して有意に低率であった。
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1: Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
著者: Hokusai-VTE Investigators, Harry R Büller, Hervé Décousus, Michael A Grosso, Michele Mercuri, Saskia Middeldorp, Martin H Prins, Gary E Raskob, Sebastian M Schellong, Lee Schwocho, Annelise Segers, Minggao Shi, Peter Verhamme, Phil Wells
雑誌名: N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056/NEJMoa1306638. Epub 2013 Aug 31.
Abstract/Text: BACKGROUND: Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear.
METHODS: In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding.
RESULTS: A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52; 95% CI, 0.28 to 0.98).
CONCLUSIONS: Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.).
N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056/NEJMoa1306638....

DVT患者

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DVT 静脈造影

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下大静脈フィルター

a:回収可能型フィルター 左よりGünther tulip filter(Cook)、OptEase filter(Cordis/Cardinal Health)、 ALN filter(ALN)、Denali filter(Bard)
b:一時留置型フィルター Neuhaus Protect SE filter(東レ)
c:永久留置型フィルター 左よりGreenfield filter(Boston Scientific)、TrapEase filter(Cordis/Cardinal Health)
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DVTの超音波所見

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PTE、下肢DVTのCT所見

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Villaltaスコア

参考文献:
Kahn SR, Partsch H, Vedantham S, et al.: Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost. 2009 May;7(5):879-83. 2009. PMID:19175497.
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弾性ストッキング

血栓後症候群

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静脈血栓塞栓症(VTE):深部静脈血栓症(DVT)と肺血栓塞栓症(PTE)

治療群別にみた静脈血栓症の症候性の拡大または再発の確認症例

経口抗凝固薬acenocoumarol(ビタミンK拮抗薬)単独治療開始群は未分画ヘパリン併用と経口抗凝固薬との併用治療開始群と比較して、1週間後の血栓伸展率が有意に高率に発生していた。また、6カ月以内の血栓伸展、再発も統計学的有意差はなかったものの高率に発生する傾向が示された。
 
参考文献:
Brandjes DP, Heijboer H, Büller HR, de Rijk M, Jagt H, ten Cate JW.:Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1992 Nov 19;327(21):1485-9. PMID:1406880
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試験中に認められた臨床的な転帰

フォンダパリヌクス治療群と低分子量ヘパリン治療群の間で静脈血栓塞栓症の再発率に差はなく、また、大出血、臨床的に意義のある非大出血、死亡の発生頻度に両群間では差は認められなかった。フォンダパリヌクスの従来治療に対する有効性・安全性に関する非劣性が示された。
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1: Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial.
著者: Harry R Büller, Bruce L Davidson, Hervé Decousus, Alexander Gallus, Michael Gent, Franco Piovella, Martin H Prins, Gary Raskob, Annelise E M Segers, Roger Cariou, Oscar Leeuwenkamp, Anthonie W A Lensing, Matisse Investigators
雑誌名: Ann Intern Med. 2004 Jun 1;140(11):867-73.
Abstract/Text: BACKGROUND: The current standard initial therapies for deep venous thrombosis are low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy and a safety profile similar to those of low-molecular-weight heparin (dalteparin).
OBJECTIVE: To evaluate whether fondaparinux has efficacy and safety similar to those of enoxaparin in patients with deep venous thrombosis.
DESIGN: Randomized, double-blind study.
SETTING: 154 centers worldwide.
PATIENTS: 2205 patients with acute symptomatic deep venous thrombosis.
INTERVENTION: Fondaparinux, 7.5 mg (5.0 mg in patients weighing <50 kg and 10.0 mg in patients weighing >100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0.
MEASUREMENTS: The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolic complications. The main safety outcomes were major bleeding during initial treatment and death. An independent, blinded committee adjudicated all outcomes.
RESULTS: 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, -0.15 percentage point [95% CI, -1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively.
LIMITATIONS: Follow-up was incomplete in 0.4% of fondaparinux-treated patients and 1.0% of enoxaparin-treated patients.
CONCLUSIONS: Once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily, body weight-adjusted enoxaparin in the initial treatment of patients with symptomatic deep venous thrombosis.
Ann Intern Med. 2004 Jun 1;140(11):867-73.

短期および長期のアウトカム

カテーテル血栓溶解療法を追加した群では従来治療群と比較して有意に24カ月後の血栓後症候群の発生が抑制された。また、6カ月後の腸骨大腿静脈の開存率の有意に高率であった。
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1: Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
著者: Tone Enden, Ylva Haig, Nils-Einar Kløw, Carl-Erik Slagsvold, Leiv Sandvik, Waleed Ghanima, Geir Hafsahl, Pål Andre Holme, Lars Olaf Holmen, Anne Mette Njaastad, Gunnar Sandbæk, Per Morten Sandset, CaVenT Study Group
雑誌名: Lancet. 2012 Jan 7;379(9810):31-8. doi: 10.1016/S0140-6736(11)61753-4. Epub 2011 Dec 13.
Abstract/Text: BACKGROUND: Conventional anticoagulant treatment for acute deep vein thrombosis (DVT) effectively prevents thrombus extension and recurrence, but does not dissolve the clot, and many patients develop post-thrombotic syndrome (PTS). We aimed to examine whether additional treatment with catheter-directed thrombolysis (CDT) using alteplase reduced development of PTS.
METHODS: Participants in this open-label, randomised controlled trial were recruited from 20 hospitals in the Norwegian southeastern health region. Patients aged 18-75 years with a first-time iliofemoral DVT were included within 21 days from symptom onset. Patients were randomly assigned (1:1) by picking lowest number of sealed envelopes to conventional treatment alone or additional CDT. Randomisation was stratified for involvement of the pelvic veins with blocks of six. We assessed two co-primary outcomes: frequency of PTS as assessed by Villalta score at 24 months, and iliofemoral patency after 6 months. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00251771.
FINDINGS: 209 patients were randomly assigned to treatment groups (108 control, 101 CDT). At completion of 24 months' follow-up, data for clinical status were available for 189 patients (90%; 99 control, 90 CDT). At 24 months, 37 (41·1%, 95% CI 31·5-51·4) patients allocated additional CDT presented with PTS compared with 55 (55·6%, 95% CI 45·7-65·0) in the control group (p=0·047). The difference in PTS corresponds to an absolute risk reduction of 14·4% (95% CI 0·2-27·9), and the number needed to treat was 7 (95% CI 4-502). Iliofemoral patency after 6 months was reported in 58 patients (65·9%, 95% CI 55·5-75·0) on CDT versus 45 (47·4%, 37·6-57·3) on control (p=0·012). 20 bleeding complications related to CDT included three major and five clinically relevant bleeds.
INTERPRETATION: Additional CDT should be considered in patients with a high proximal DVT and low risk of bleeding.
FUNDING: South-Eastern Norway Regional Health Authority; Research Council of Norway; University of Oslo; Oslo University Hospital.

Copyright © 2012 Elsevier Ltd. All rights reserved.
Lancet. 2012 Jan 7;379(9810):31-8. doi: 10.1016/S0140-6736(11)61753-4....

中圧弾性ストッキング群とプラセボストッキング群における血栓後症候群の累積発生率

中圧弾性ストッキング着用群ではプラセボストッキング群と比較して血栓後症候群の発生頻度に差は認められなかった。
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1: Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.
著者: Susan R Kahn, Stan Shapiro, Philip S Wells, Marc A Rodger, Michael J Kovacs, David R Anderson, Vicky Tagalakis, Adrielle H Houweling, Thierry Ducruet, Christina Holcroft, Mira Johri, Susan Solymoss, Marie-José Miron, Erik Yeo, Reginald Smith, Sam Schulman, Jeannine Kassis, Clive Kearon, Isabelle Chagnon, Turnly Wong, Christine Demers, Rajendar Hanmiah, Scott Kaatz, Rita Selby, Suman Rathbun, Sylvie Desmarais, Lucie Opatrny, Thomas L Ortel, Jeffrey S Ginsberg, SOX trial investigators
雑誌名: Lancet. 2014 Mar 8;383(9920):880-8. doi: 10.1016/S0140-6736(13)61902-9. Epub 2013 Dec 6.
Abstract/Text: BACKGROUND: Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS.
METHODS: We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751.
FINDINGS: From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings.
INTERPRETATION: ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT.
FUNDING: Canadian Institutes of Health Research.

Copyright © 2014 Elsevier Ltd. All rights reserved.
Lancet. 2014 Mar 8;383(9920):880-8. doi: 10.1016/S0140-6736(13)61902-9...

抗凝固療法下における、PTEの新規発症に対する早期歩行と安静臥床の比較(メタ解析)

抗凝固療法による治療を行っていれば、急性期に早期歩行をさせても安静臥床を維持させてもPTEの新規発症率に差がなかった。
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1: A meta-analysis of bed rest versus early ambulation in the management of pulmonary embolism, deep vein thrombosis, or both.
著者: Nadia Aissaoui, Edith Martins, Stéphane Mouly, Simon Weber, Christophe Meune
雑誌名: Int J Cardiol. 2009 Sep 11;137(1):37-41. doi: 10.1016/j.ijcard.2008.06.020. Epub 2008 Aug 8.
Abstract/Text: BACKGROUND: Bed rest is often recommended as part of the management of deep vein thrombosis (DVT) and pulmonary embolism (PE), though this recommendation is not clearly evidence-based.
METHODS: Using the Cochrane Central Register of Controlled Trials, Medline, and Embase, this meta-analysis considered all randomized studies and prospective registries that compared the outcomes of patients with DVT, PE, or both, managed with bed rest versus early ambulation, in addition to anticoagulation. For each study, data regarding the incidence of new PE, new or progression of DVT, and death from all causes, were used to calculate relative risks (RR) and 95% confidence intervals (CI).
RESULTS: The 5 studies retained in this analysis included a total of 3048 patients. When compared to bed rest, early ambulation was not associated with a higher incidence of a new PE (RR 1.03; 95% CI 0.65-1.63; p=0.90). Furthermore, early ambulation was associated with a trend toward a lower incidence of new PE and new or progression of DVT than bed rest (RR 0.79; 95% CI 0.55-1.14; p=0.21) and lower incidence of new PE and overall mortality (RR 0.79; 95% CI 0.402-1.56; p=0.50).
CONCLUSIONS: Compared with bed rest, early ambulation of patients with DVT, PE or both, was not associated with a higher risk of progression of DVT, new PE or death. This meta-analysis does not support the systematic recommendation of bed rest as part of the early management of patients presenting with DVT, PE of both.
Int J Cardiol. 2009 Sep 11;137(1):37-41. doi: 10.1016/j.ijcard.2008.06...

DVTの診断手順

DVTの診断手順の1つとして、DVTが疑われたなら、Wellsスコアにて臨床確率を評価する。
低あるいは中臨床確率ならば、まず迅速Dダイマー測定を行い、陰性ならばDVTは否定的であり治療は行わず、陽性ならば静脈エコーで血栓のありなしを評価する。
高臨床確率ならば、DVTである可能性が高く、Dダイマーは測定せず、すぐに静脈エコーを用いて血栓のありなしを評価する。静脈エコーで血栓がない場合にもさらに静脈造影、造影CT、MRヴェノグラフィーのいずれかを用いて再評価を行う。
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下肢DVTの治療アルゴリズム

いずれの下肢DVTに対しても、急性期は禁忌でない限り、基本は抗凝固療法による治療が開始されるべきである。ただし、末梢型DVTに対する抗凝固療法の必要性の是非に関しては十分には確立していない。
有痛性青股腫や有痛性白股腫の患者では動脈阻血を伴うため、抗凝固療法に加えて、積極的治療(外科的血栓摘除術やカテーテルを用いた血栓溶解あるいは血栓吸引治療など)を行い迅速に動脈阻血を解除する必要がある。
発症から2~3週間以内の腸骨大腿静脈領域の広範な静脈血栓で、出血のリスクが低い患者に対しては、カテーテルを用いた血栓溶解あるいは血栓吸引治療を考慮する。
別記の適応に該当する場合には下大静脈フィルター(多くは非永久留置で対応可)の留置を考慮する。
慢性期には危険因子に応じた期間、抗凝固療法を継続する(参照:表[ID0714])。
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DVTの抗凝固療法手順

①、②:リバーロキサバン、アピキサバンでは経口による単剤での治療も可能。基本的にはリバーロキサバンは15 mg 1日2回を3週間投与後、維持用量の15 mg 1日1回投与へ切り換える。アピキサバンは10 mg 1日2回を1週間投与後に、5 mg 1日2回の維持用量に切り換える。
 
③、④:未分画ヘパリンあるいはフォンダパリヌクス(アリクストラ)のいずれかで治療を始める。慢性期にかけてはエドキサバン(リクシアナ)あるいはワルファリン(ワーファリン)に切り替える。
 
③:エドキサバンに切り替える場合には、初期治療で用いた抗凝固薬が未分画ヘパリン持続静注なら中止4±1時間後に、未分画へパリンあるいはフォンダパリヌクスの皮下注なら次回の投薬が予定される時間にエドキサバンを開始する。
 
④:ワルファリンを用いる場合には、ワルファリンを初期治療薬(未分画ヘパリンあるいはフォンダパリヌクス)と併用し、ワルファリン投薬量を調整し、PT-INRが2日間連続で治療域に到達したことを確認の後に、未分画ヘパリンあるいはフォンダパリヌクスを中止する。
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末梢型DVTの治療アルゴリズム

Grade 1B: Strong recommendation, moderate quality evidence
Grade 2C: Weak recommendation, low or very low quality evidence
 
参考文献:
Kearon C, et al.: Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149; 315-352. PMID:26867832
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静脈血栓塞栓症に対する抗凝固療法の継続期間

抗凝固療法の継続期間は静脈血栓を生じた危険因子の種類により判断する。
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1: 日本循環器学会ほか編:肺血栓塞栓症および深部静脈血栓症の診断、治療、予防に関するガイドライン(2017年改訂版).http://www.j-circ.or.jp/guideline/pdf/JCS2017_ito_h.pdf(2019年4月閲覧)班長:伊藤正明、p30、表17、VTEに対する抗凝固療法の継続期間

DVTの検査前臨床確率の評価

DVTの画像検査前の臨床的確率を評価する方法としてWellsスコアがよく知られている。危険因子や症状所見などを点数化してDVTの可能性を評価する方法である。
 
参考文献:
Wells PS, Owen C, Doucette S, et al. Does this patient have deep vein thrombosis? JAMA 2006; 295: 199-207. PMID: 16403932
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