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深部静脈血栓症

著者: 山田典一 地方独立行政法人桑名市総合医療センター

監修: 今井靖 自治医科大学 薬理学講座臨床薬理学部門・内科学講座循環器内科学部門

著者校正/監修レビュー済:2021/09/15
参考ガイドライン:
  1. 日本循環器学会、日本医学放射線学会、日本胸部外科学会、日本血管外科学会、日本血栓止血学会、日本呼吸器学会、日本静脈学会、日本心臓血管外科学会、日本心臓病学会、日本肺高血圧・肺循環学会: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)(https://j-circ.or.jp/old/guideline/pdf/JCS2017_ito_h.pdf)
患者向け説明資料

概要・推奨   

  1. 中枢型深部静脈血栓症の抗凝固療法としては、高度腎機能障害や妊娠などがないことを確認のうえで、即効性を有し、用量調整が不要な直接作用型経口抗凝固薬(DOAC)が推奨される(ただし、DOAC単独での治療開始はリバーロキサバンとアピキサバンに限る)(推奨度1)。
  1. 未分画ヘパリンやワルファリンなど採血による用量調整が必要な抗凝固薬による初期治療では早期に治療域内でコントロールすることが重要である(推奨度1)。
  1. 有症候性深部静脈血栓症患者に対する初期治療法としてフォンダパリヌクスの1日1回皮下注は従来治療(未分画ヘパリン+ワルファリン)と同等の効果と安全性を有している(推奨度2)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
山田典一 : 講演料(バイエル薬品株式会社)[2021年]
監修:今井靖 : 講演料(第一三共株式会社)[2021年]

改訂のポイント:
  1. 定期レビューを行い、最近の治療法の変化や新たなエビデンスに応じて加筆修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 静脈血栓症とは、文字どおり静脈に血栓が生じた状態である。静脈血栓は全身のいずれの静脈にも生じ得るが、なかでも頻度が高いのが下肢の静脈に生じる静脈血栓であり、四肢の筋膜より深部を走行する深部静脈に発生するものを深部静脈血栓症(DVT)、浅い表在静脈に発生するものを表在静脈血栓症あるいは静脈炎を伴うことが多いことより表在性血栓性静脈炎と呼ぶ。
 
DVTとPTE

出典

 
  1. DVTの成因を考えるうえで、Virchowの3徴:①血流停滞、②血管内皮障害、③血液凝固能亢進――が重要である。
  1. 下肢DVTでは血栓の存在範囲により、通常、膝窩静脈を含む中枢側にあるものを中枢型(近位型)、膝窩静脈より末梢にあるものを末梢型(遠位型)と分類する。
  1. DVTの重篤な合併症に急性肺血栓塞栓症(PTE)があるが、表在静脈に限局した表在静脈血栓症では頻度は少ないとされる。
  1. 中枢型DVTの40~60%に無症候性も含めPTEが合併する。また、急性PTEの約90%では下肢DVTが塞栓源である。
  1. 慢性期の静脈弁不全に伴う血栓後症候群が問題となる。
  1. DVTは米国の年間発症数は11万6,000~25万例で10万人当たり約50例、日本では2万4,538例で10万人当たり約20例と報告されている。
問診・診察のポイント  
DVT:
  1. 症状:患肢の腫脹、疼痛、緊満感、だるさ、違和感、発赤(多くは片側性)

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文献 

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.).

PMID 23991658  N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056・・・
著者: EINSTEIN Investigators, Rupert Bauersachs, Scott D Berkowitz, Benjamin Brenner, Harry R Buller, Hervé Decousus, Alex S Gallus, Anthonie W Lensing, Frank Misselwitz, Martin H Prins, Gary E Raskob, Annelise Segers, Peter Verhamme, Phil Wells, Giancarlo Agnelli, Henri Bounameaux, Alexander Cohen, Bruce L Davidson, Franco Piovella, Sebastian Schellong
雑誌名: N Engl J Med. 2010 Dec 23;363(26):2499-510. doi: 10.1056/NEJMoa1007903. Epub 2010 Dec 3.
Abstract/Text BACKGROUND: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring.
METHODS: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.
RESULTS: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).
CONCLUSIONS: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

PMID 21128814  N Engl J Med. 2010 Dec 23;363(26):2499-510. doi: 10.105・・・
著者: Giancarlo Agnelli, Harry R Buller, Alexander Cohen, Madelyn Curto, Alexander S Gallus, Margot Johnson, Urszula Masiukiewicz, Raphael Pak, John Thompson, Gary E Raskob, Jeffrey I Weitz, AMPLIFY Investigators
雑誌名: N Engl J Med. 2013 Aug 29;369(9):799-808. doi: 10.1056/NEJMoa1302507. Epub 2013 Jul 1.
Abstract/Text BACKGROUND: Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.
METHODS: In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.
RESULTS: The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.
CONCLUSIONS: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).

PMID 23808982  N Engl J Med. 2013 Aug 29;369(9):799-808. doi: 10.1056/・・・
著者: Giancarlo Agnelli, Harry R Buller, Alexander Cohen, Madelyn Curto, Alexander S Gallus, Margot Johnson, Anthony Porcari, Gary E Raskob, Jeffrey I Weitz, AMPLIFY-EXT Investigators
雑誌名: N Engl J Med. 2013 Feb 21;368(8):699-708. doi: 10.1056/NEJMoa1207541. Epub 2012 Dec 8.
Abstract/Text BACKGROUND: Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism.
METHODS: In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months.
RESULTS: A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group.
CONCLUSIONS: Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).

PMID 23216615  N Engl J Med. 2013 Feb 21;368(8):699-708. doi: 10.1056/・・・
著者: Jeffrey I Weitz, Anthonie W A Lensing, Martin H Prins, Rupert Bauersachs, Jan Beyer-Westendorf, Henri Bounameaux, Timothy A Brighton, Alexander T Cohen, Bruce L Davidson, Hervé Decousus, Maria C S Freitas, Gerlind Holberg, Ajay K Kakkar, Lloyd Haskell, Bonno van Bellen, Akos F Pap, Scott D Berkowitz, Peter Verhamme, Philip S Wells, Paolo Prandoni, EINSTEIN CHOICE Investigators
雑誌名: N Engl J Med. 2017 Mar 30;376(13):1211-1222. doi: 10.1056/NEJMoa1700518. Epub 2017 Mar 18.
Abstract/Text BACKGROUND: Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin.
METHODS: In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding.
RESULTS: A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups.
CONCLUSIONS: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).

PMID 28316279  N Engl J Med. 2017 Mar 30;376(13):1211-1222. doi: 10.10・・・
著者: D P Brandjes, H Heijboer, H R Büller, M de Rijk, H Jagt, J W ten Cate
雑誌名: N Engl J Med. 1992 Nov 19;327(21):1485-9. doi: 10.1056/NEJM199211193272103.
Abstract/Text BACKGROUND: In most countries, heparin is used in the initial treatment of patients with deep-vein thrombosis. Well-designed studies establishing the efficacy of heparin therapy are lacking, however. Treatment with acenocoumarol alone, according to the hypothesis that high dosages of oral anticoagulants obviate the need for heparin, is considered an effective alternative in some countries.
METHODS: In a randomized, double-blind study we compared the efficacy and safety of continuous intravenous heparin plus acenocoumarol with the efficacy and safety of acenocoumarol alone in the initial treatment of outpatients with proximal-vein thrombosis. The principal study end point was a confirmed symptomatic extension or recurrence of venous thromboembolism during six months of follow-up. In addition, we assessed asymptomatic extension or pulmonary embolism by repeating venography and lung scanning after the first week of treatment. The incidence of major bleeding was determined during three months of follow-up.
RESULTS: The study was terminated early by the Data Safety and Monitoring Committee because of an excess of symptomatic events in the group that received acenocoumarol alone (in 12 of 60 patients [20 percent], as compared with 4 of 60 patients [6.7 percent] in the combined-therapy group by intention-to-treat analysis; P = 0.058). Asymptomatic extension of venous thrombosis was observed in 39.6 percent of the patients in the acenocoumarol group and in 8.2 percent of patients treated with heparin plus acenocoumarol (P < 0.001). Major bleeding complications were infrequent and comparable in the two groups.
CONCLUSIONS: Patients with proximal-vein thrombosis require initial treatment with full-dose heparin, which can safely be combined with acenocoumarol therapy.

PMID 1406880  N Engl J Med. 1992 Nov 19;327(21):1485-9. doi: 10.1056/・・・
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.
PMID 22172244  Lancet. 2012 Jan 7;379(9810):31-8. doi: 10.1016/S0140-6・・・
著者: Ylva Haig, Tone Enden, Ole Grøtta, Nils-Einar Kløw, Carl-Erik Slagsvold, Waleed Ghanima, Leiv Sandvik, Geir Hafsahl, Pål Andre Holme, Lars Olaf Holmen, Anne Mette Njaaastad, Gunnar Sandbæk, Per Morten Sandset, CaVenT Study Group
雑誌名: Lancet Haematol. 2016 Feb;3(2):e64-71. doi: 10.1016/S2352-3026(15)00248-3. Epub 2016 Jan 6.
Abstract/Text BACKGROUND: Post-thrombotic syndrome is a common complication after acute proximal deep vein thrombosis (DVT) and is associated with reduced quality of life and a substantial cost burden. In the 2-year results of the CaVenT study, additional catheter-directed thrombolysis reduced the risk of post-thrombotic syndrome by 14% compared with conventional therapy, but did not affect quality of life. In this study we report results at the 5-year follow-up, aiming to assess whether findings for post-thrombotic syndrome and quality of life have persisted.
METHODS: Between Jan 3, 2006, and Dec 22, 2009, we recruited patients aged 18-75 years with a first-time high proximal leg DVT from 20 hospitals in the Norwegian southeastern health region. With sealed envelopes, participants were randomly assigned (1:1) to standard treatment with compression stockings and anticoagulants (control group) or to standard treatment plus catheter-directed thrombolysis with alteplase within 21 days from symptom onset. Pre-specified outcomes in this analysis were post-thrombotic syndrome at 5 years as assessed with the Villalta score and scores for quality of life at 5 years with EQ-5D and the disease-specific VEINES-QOL/Sym. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00251771.
FINDINGS: At 5 year follow-up (last date Oct 14, 2014), data were available for 176 patients (84% of the 209 patients originally randomised)--87 originally assigned to catheter-directed thrombolysis and 89 originally assigned to the control group. 37 patients (43%; 95% CI 33-53) allocated to catheter-directed thrombolysis developed post-thrombotic syndrome, compared with 63 (71%; 95% CI 61-79) allocated to the control group (p<0·0001), corresponding to an absolute risk reduction of 28% (95% CI 14-42) and a number needed to treat of 4 (95% CI 2-7). Four (5%) patients assigned to catheter-directed thrombolysis and one (1%) to standard treatment had severe post-thrombotic syndrome (Villalta score ≥ 15 or presence of an ulcer). Quality-of-life scores with either assessment scale did not differ between the treatment groups.
INTERPRETATION: Additional catheter-directed thrombolysis resulted in a persistent and increased clinical benefit during follow-up for up to 5 years, supporting the use of additional catheter-directed thrombolysis in patients with extensive proximal DVT. However, allocation to this therapy did not lead to better quality of life. The optimal endovascular thrombolytic approach needs further investigation.
FUNDING: Southeastern Norway Regional Health Authority, the Research Council of Norway, University of Oslo, Oslo University Hospital.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 26853645  Lancet Haematol. 2016 Feb;3(2):e64-71. doi: 10.1016/S23・・・
著者: Suresh Vedantham, Samuel Z Goldhaber, Jim A Julian, Susan R Kahn, Michael R Jaff, David J Cohen, Elizabeth Magnuson, Mahmood K Razavi, Anthony J Comerota, Heather L Gornik, Timothy P Murphy, Lawrence Lewis, James R Duncan, Patricia Nieters, Mary C Derfler, Marc Filion, Chu-Shu Gu, Stephen Kee, Joseph Schneider, Nael Saad, Morey Blinder, Stephan Moll, David Sacks, Judith Lin, John Rundback, Mark Garcia, Rahul Razdan, Eric VanderWoude, Vasco Marques, Clive Kearon, ATTRACT Trial Investigators
雑誌名: N Engl J Med. 2017 Dec 7;377(23):2240-2252. doi: 10.1056/NEJMoa1615066.
Abstract/Text BACKGROUND: The post-thrombotic syndrome frequently develops in patients with proximal deep-vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter-directed thrombolysis (hereafter "pharmacomechanical thrombolysis") rapidly removes thrombus and is hypothesized to reduce the risk of the post-thrombotic syndrome.
METHODS: We randomly assigned 692 patients with acute proximal deep-vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post-thrombotic syndrome between 6 and 24 months of follow-up.
RESULTS: Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P=0.09). Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanical-thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P<0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups.
CONCLUSIONS: Among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT ClinicalTrials.gov number, NCT00790335 .).

PMID 29211671  N Engl J Med. 2017 Dec 7;377(23):2240-2252. doi: 10.105・・・
著者: Anthony J Comerota, Clive Kearon, Chu-Shu Gu, Jim A Julian, Samuel Z Goldhaber, Susan R Kahn, Michael R Jaff, Mahmood K Razavi, Andrei L Kindzelski, Riyaz Bashir, Parag Patel, Mel Sharafuddin, Michael J Sichlau, Wael E Saad, Zakaria Assi, Lawrence V Hofmann, Margaret Kennedy, Suresh Vedantham, ATTRACT Trial Investigators
雑誌名: Circulation. 2019 Feb 26;139(9):1162-1173. doi: 10.1161/CIRCULATIONAHA.118.037425.
Abstract/Text BACKGROUND: The ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) previously reported that pharmacomechanical catheter-directed thrombolysis (PCDT) did not prevent postthrombotic syndrome (PTS) in patients with acute proximal deep vein thrombosis. In the current analysis, we examine the effect of PCDT in ATTRACT patients with iliofemoral deep vein thrombosis.
METHODS: Within a large multicenter randomized trial, 391 patients with acute deep vein thrombosis involving the iliac or common femoral veins were randomized to PCDT with anticoagulation versus anticoagulation alone (No-PCDT) and were followed for 24 months to compare short-term and long-term outcomes.
RESULTS: Between 6 and 24 months, there was no difference in the occurrence of PTS (Villalta scale ≥5 or ulcer: 49% PCDT versus 51% No-PCDT; risk ratio, 0.95; 95% CI, 0.78-1.15; P=0.59). PCDT led to reduced PTS severity as shown by lower mean Villalta and Venous Clinical Severity Scores ( P<0.01 for comparisons at 6, 12, 18, and 24 months), and fewer patients with moderate-or-severe PTS (Villalta scale ≥10 or ulcer: 18% versus 28%; risk ratio, 0.65; 95% CI, 0.45-0.94; P=0.021) or severe PTS (Villalta scale ≥15 or ulcer: 8.7% versus 15%; risk ratio, 0.57; 95% CI, 0.32-1.01; P=0.048; and Venous Clinical Severity Score ≥8: 6.6% versus 14%; risk ratio, 0.46; 95% CI, 0.24-0.87; P=0.013). From baseline, PCDT led to greater reduction in leg pain and swelling ( P<0.01 for comparisons at 10 and 30 days) and greater improvement in venous disease-specific quality of life (Venous Insufficiency Epidemiological and Economic Study Quality of Life unit difference 5.6 through 24 months, P=0.029), but no difference in generic quality of life ( P>0.2 for comparisons of SF-36 mental and physical component summary scores through 24 months). In patients having PCDT versus No-PCDT, major bleeding within 10 days occurred in 1.5% versus 0.5% ( P=0.32), and recurrent venous thromboembolism over 24 months was observed in 13% versus 9.2% ( P=0.21).
CONCLUSIONS: In patients with acute iliofemoral deep vein thrombosis, PCDT did not influence the occurrence of PTS or recurrent venous thromboembolism. However, PCDT significantly reduced early leg symptoms and, over 24 months, reduced PTS severity scores, reduced the proportion of patients who developed moderate-or-severe PTS, and resulted in greater improvement in venous disease-specific quality of life.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00790335.

PMID 30586751  Circulation. 2019 Feb 26;139(9):1162-1173. doi: 10.1161・・・
著者: R D Hull, G E Raskob, J Hirsh, R M Jay, J R Leclerc, W H Geerts, D Rosenbloom, D L Sackett, C Anderson, L Harrison
雑誌名: N Engl J Med. 1986 Oct 30;315(18):1109-14. doi: 10.1056/NEJM198610303151801.
Abstract/Text We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

PMID 3531862  N Engl J Med. 1986 Oct 30;315(18):1109-14. doi: 10.1056・・・
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.

PMID 18691773  Int J Cardiol. 2009 Sep 11;137(1):37-41. doi: 10.1016/j・・・

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