Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Joseph Ornelas, PhD; Allen Blaivas, DO, FCCP; David Jimenez, MD, PhD, FCCP; Henri Bounameaux, MD; Menno Huisman, MD, PhD; Christopher S. King, MD, FCCP; Timothy A. Morris, MD, FCCP; Namita Sood, MD, FCCP; Scott M. Stevens, MD; Janine R. E. Vintch, MD, FCCP; Philip Wells, MD; Scott C. Woller, MD; and COL Lisa Moores, MD, FCCP BACKGROUND: We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics. METHODS: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence. RESULTS: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava lter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C). CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research. KEY WORDS: antithrombotic therapy; evidence-based medicine; GRADE approach; venous thromboembolism FOR EDITORIAL COMMENT SEE PAGE 293 ABBREVIATIONS: AT9 = 9th Edition of the Antithrombotic Guideline; AT10 = 10th Edition of the Antithrombotic Guideline; CHEST = American College of Chest Physicians; CDT = catheter-directed thrombolysis; COI = con ict of interest; CTEPH = chronic thrombo- embolic pulmonary hypertension; CTPA = CT pulmonary angiogram; GOC = Guidelines Oversight Committee; INR = International Normalized Ratio; IVC = inferior vena cava; LMWH = low-molecular- weight heparin; NOAC = non-vitamin K oral anticoagulant; PE = pulmonary embolism; PTS = postthrombotic syndrome; RCT = ran- domized controlled trial; UEDVT = upper extremity deep vein thrombosis; US = ultrasound; VKA = vitamin K antagonist AFFILIATIONS: From McMaster University (Drs Kearon and Akl), Hamilton, ON; American University of Beirut (Dr Akl), Beirut, Lebanon; CHEST (Dr Ornelas), Glenview, IL; VA New Jersey Health Care System (Dr Blaivas), Newark, NJ; Hospital Ram n y Cajal and Instituto Ram n y Cajal de Investigaci n Sanitaria, Universidad de Alcala (Dr Jimenez), Madrid, Spain; University of Geneva (Dr Bou- nameaux), Geneva, Switzerland; Leiden University Medical Center (Dr Huisman), Leiden, Netherlands; Virginia Commonwealth University (Dr King), Falls Church, VA; University of California (Dr Morris), San Diego, CA; The Ohio State University (D. Sood), Columbus, OH; Intermountain Medical Center and the University of Utah (Drs Stevens and Woller), Murray, UT; Harbor-UCLA Medical Center (Dr Vintch), Torrance, CA; The University of Ottawa and Ottawa Hospital Research Institute (Dr Wells), Ottawa, ON; Uniformed Services University of the Health Sciences (Dr Moores), Bethesda, MD. [ Evidence-Based Medicine ] Note on Shaded Text: In this guideline, shaded text with an asterisk (shading appears in PDF only) indicates recommendations that are newly added or have been changed since the publication of Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis (9th edition): American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Recommendations that remain unchanged since that edition are not shaded. The order of our presentation of the non-vitamin K oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban) is based on the chronology of publication of the phase 3 trials in VTE treatment and should not be interpreted as the guideline panel s order of preference for the use of these agents. Summary of Recommendations Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant 1. In patients with proximal DVT or pulmonary embolism (PE), we recommend long-term (3 months) anticoagulant therapy over no such therapy (Grade 1B). *2. In patients with DVT of the leg or PE and no cancer, as long-term ( rst 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apix- aban, or edoxaban over vitamin K antagonist (VKA) therapy (all Grade 2B). For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, we suggest VKA therapy over low-molecular weight heparin (LMWH) (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. *3. In patients with DVT of the leg or PE and cancer ( cancer-associated thrombosis ), as long-term ( rst 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2B), dabigatran (Grade or edoxaban (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. *4. In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the rst 3 months (Grade 2C). Remarks: It may be appropriate for the choice of anticoagulant to change in response to changes in the patient s circumstances or preferences during long-term or extended phases of treatment. Duration of Anticoagulant Therapy 5. In patients with a proximal DVT of the leg or PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B), or (iii) extended therapy (no scheduled stop date) (Grade 1B). 6. In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) and (ii) treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B). We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B), and recommend treatment for 3 months over extended therapy if there is a high risk of bleeding (Grade 1B). Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). DISCLAIMER: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://www.chestnet. org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/ CHEST-Guidelines. FUNDING/SUPPORT: This guideline was supported solely by internal funds from The American College of Chest Physicians. ENDORSEMENTS: This guideline is endorsed by the American Asso- ciation for Clinical Chemistry, the American College of Clinical Pharmacy, the International Society for Thrombosis and Haemostasis, and the American Society of Health-System Pharmacists. CORRESPONDENCE TO: Elie A. Akl, MD, MPH, PhD, Department of Internal Medicine, Faculty of Medicine, American University of Beirut, PO Box 11-0236, Riad-El-Solh Beirut 1107 2020, Lebanon; e-mail: Copyright 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. 316 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] 7. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor, we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C), we recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B), and we recommend treatment with anticoagulation for 3 months over extended therapy (no scheduled stop date) (Grade 1B). Remarks: Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants. 8. In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B). Remarks: After 3 months of treatment, patients with unprovoked DVT of the leg or PE should be evaluated for the risk-bene t ratio of extended therapy. Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants. 9. In patients with a rst VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B). Remarks: Patient sex and D-dimer level measured a month after stopping anticoagulant therapy may in uence the decision to stop or extend anticoagulant therapy (see text). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). 10. In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulanttherapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B). Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). 11. In patients with DVT of the leg or PE and active cancer ( cancer-associated thrombosis ) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), or (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B). Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). Aspirin for Extended Treatment of VTE *12. In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B). Remarks: Because aspirin is expected to be much less effective at preventing recurrent VTE than anticoagulants, we do not consider aspirin a reasonable alternative to anticoagulant therapy in patients who want extended therapy. However, if a patient has decided to stop anticoagulants, prevention of recurrent VTE is one of the bene ts of aspirin that needs to be balanced against aspirin s risk of bleeding and inconvenience. Use of aspirin should also be reevaluated when patients stop anticoagulant therapy because aspirin may have been stopped when anticoagulants were started. Whether and How to Anticoagulate Isolated Distal DVT 13. In patients with acute isolated distal DVT of the leg and (i) without severe symptoms or risk factors for extension (see text), we suggest serial imaging of the deep veins for 2 weeks over anticoagulation (Grade 2C) or (ii) with severe symptoms or risk factors for extension (see text), we suggest anticoagulation over serial imaging of the deep veins (Grade 2C). Remarks: Patients at high risk for bleeding are more likely to bene t from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging. 14. In patients with acute isolated distal DVT of the leg who are managed with anticoagulation, we recommend using the same anticoagulation as for patients with acute proximal DVT (Grade 1B). 15. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we (i) recommend no anticoagulation if the thrombus does not extend (Grade 1B), (ii) suggest anticoagulation if the thrombus extends but remains con ned to the distal veins (Grade 2C), and (iii) recommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B). Catheter-Directed Thrombolysis for Acute DVT of the Leg 16. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C). Remarks: Patients who are most likely to bene t from CDT (see text), who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower value to the initial complexity, cost, and risk of bleeding with CDT, are likely to choose CDT over anticoagulation alone. Role of Inferior Vena Cava Filter in Addition to Anticoagulation for Acute DVT or PE 17. In patients with acute DVT or PE who are treated with anticoagulants, we recommend against the use of an inferior vena cava (IVC) lter (Grade 1B). Compression Stocking to Prevent PTS *18. In patients with acute DVT of the leg, we sug- gest not using compression stockings routinely to prevent PTS (Grade 2B). Remarks: This recommendation focuses on prevention of the chronic complication of PTS and not on the treatment of symptoms. For patients with acute or chronic symptoms, a trial of graduated compression stockings is often justi ed. Whether to Anticoagulate Subsegmental PE *19. In patients with subsegmental PE (no involve- ment of more proximal pulmonary arteries) and no proximal DVT in the legs who have a (i) low risk for recurrent VTE (see text), we suggest clinical surveillance over anticoagulation (Grade 2C) or (ii) high risk for recurrent VTE (see text), we suggest anticoagulation over clinical surveillance (Grade 2C). Remarks: Ultrasound (US) imaging of the deep veins of both legs should be done to exclude proximal DVT. Clinical surveillance can be supplemented by serial US imaging of the proximal deep veins of both legs to detect evolving DVT (see text). Patients and physicians are more likely to opt for clinical surveillance over anticoagulation if there is good cardiopulmonary reserve or a high risk of bleeding. Treatment of Acute PE Out of the Hospital *20. In patients with low-risk PE and whose home circumstances are adequate, we suggest treatment at home or early discharge over standard discharge (eg, after the rst 5 days of treatment) (Grade 2B). Systemic Thrombolytic Therapy for PE 21. In patients with acute PE associated with hypotension (eg, systolic BP <90 mm Hg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B). *22. In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1B). *23. In selected patients with acute PE who deteri- orate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C). Remarks: Patients with PE and without hypotension who have severe symptoms or marked cardiopulmonary impairment should be monitored closely for deterioration. Development of hypotension suggests that 318 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] thrombolytic therapy has become indicated. Cardiopulmonary deterioration (eg, symptoms, vital signs, tissue perfusion, gas exchange, cardiac biomarkers) that has not progressed to hypotension may also alter the risk-bene t assessment in favor of thrombolytic therapy in patients initially treated with anticoagulation alone. Catheter-Based Thrombus Removal for the Initial Treatment of PE *24. In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombo- lytic therapy using a peripheral vein over CDT (Grade 2C). Remarks: Patients who have a higher risk of bleeding with systemic thrombolytic therapy and who have access to the expertise and resources required to do CDT are likely to choose CDT over systemic thrombolytic therapy. *25. In patients with acute PE associated with hypotension and who have (i) a high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter- assisted thrombus removal over no such intervention (Grade 2C). Remarks: Catheter-assisted thrombus removal refers to mechanical interventions, with or without catheter directed thrombolysis. Pulmonary Thromboendarterectomy for the Treatment of Chronic Thromboembolic Pulmonary Hypertension *26. In selected patients with chronic thromboem- bolic pulmonary hypertension (CTEPH) who are identi ed by an experienced thromboendarter- ectomy team, we suggest pulmonary thromboen- darterectomy over no pulmonary thromboendarterectomy (Grade 2C). Remarks: Patients with CTEPH should be evaluated by a team with expertise in treatment of pulmonary hypertension. Pulmonary thromboendarterectomy is often lifesaving and life-transforming. Patients with CTEPH who are not candidates for pulmonary thromboendarterectomy may bene t from other mechanical and pharmacological interventions designed to lower pulmonary arterial pressure. Thrombolytic Therapy in Patients With Upper Extremity DVT 27. In patients with acute upper extremity DVT (UEDVT) that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis (Grade 2C). Remarks: Patients who (i) are most likely to bene t from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagulation alone. 28. In patients with UEDVT who undergo thrombolysis, we recommend the same intensity and duration of anticoagulant therapy as in patients with UEDVT who do not undergo thrombolysis (Grade 1B). Management of Recurrent VTE on Anticoagulant Therapy *29. In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), we suggest switching to treatment with LMWH at least temporarily (Grade 2C). Remarks: Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt the following assessments: (1) reevaluation of whether there truly was a recurrent VTE; (2) evaluation of compliance with anticoagulant therapy; and (3) consideration of an underlying malignancy. A temporary switch to LMWH will usually be for at least 1 month. *30. In patients who have recurrent VTE on long- term LMWH (and are believed to be compliant), we suggest increasing the dose of LMWH by about one-quarter to one-third (Grade 2C). Remarks: Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt the following assessments: (1) reevaluation of whether there truly was a recurrent VTE; (2) evaluation of compliance with anticoagulant therapy; and (3) consideration of an underlying malignancy. CHEST has been developing and publishing guidelines for the treatment of DVT and PE, collectively referred to as VTE, for more than 30 years. CHEST published the last (9th) edition of these guidelines in February 2012 Since then, a substantial amount of new evidence relating to the treatment of VTE has been published, particularly in relation the use of non-vitamin K oral anticoagulants (NOACs). Moreover, several VTE treatment questions that were not addressed in the last edition have been highlighted. This article focuses on new developments and ongoing controversies in the treatment of VTE, updating recommendations for 12 topics that were included in AT9, and providing recommendations for 3 new topics. The target users of this guideline are clinicians. Methods Composition and Selection of Topic Panel Members The Guidelines Oversight Committee (GOC) at CHEST appointed the editor for the guideline update. Then, the editor nominated the project executive committee, the chair, and the remaining panelists (see Acknowledgments section). The GOC approved all panelists after review of their quali cations and con ict of interest (COI) disclosures. The 15 panelists include general internists, thrombosis specialists, pulmonologists, hematologists, and methodologists. Throughout guideline development, panelists were required to disclose any potential nancial or intellectual con icts of interest by topic.2 Financial and intellectual con icts of interest were classi ed as primary (more serious) or secondary (less serious) (e-Table 1). Panelists with primary COIs were required to abstain from voting on related topic areas, but could participate in discussions provided they refrained from strong advocacy. Selection of Topics and Key Questions First, we listed all of the topic areas from AT9 and added potential new topics proposed by the panel members. Next, all panel members voted on whether each topic should be included in the update. Finally, the full panel reviewed the results of the vote and decided on the nal list. The panel selected a total of 15 topics: 12 update topics from AT9 and 3 new topics. For each topic, we developed standardized questions in the Population, Intervention, Comparator, Outcome format (e-Table 2). Systematic Search Systematic methods were used to search for evidence for each question. When available, the National Library of Medicine s medical subject headings keyword nomenclature was used. We searched MEDLINE via PubMed for original studies and the Cochrane Library for systematic reviews. For update topics, we searched the literature from January 2005 to July 2014. For new topics, we searched the literature from 1946 (Medline inception) to July 2014. All searches were limited to English-language publications. We augmented searches by checking reference lists of published articles and personal les, and with ongoing surveillance of the literature by panel members (e-Figures 1-4). When we identi ed systematic reviews, we assessed their quality according to the Assessment of Multiple Systematic Reviews tool.3 We used those that were of highest quality and up to date as the source of evidence. In the absence of a satisfactory systematic review, we did our own evidence synthesis using the primary studies identi ed in AT9 and in the updated search. If the panel judged that the identi ed randomized controlled trials (RCTs) were inadequate, we expanded the search to include prospective cohort studies. Study Selection, Data Abstraction, and Data Analysis The criteria for selecting the evidence were based on the Population, Intervention, Comparator, Outcome elements of the standardized questions and the study design (e-Table 2). We followed standard processes (duplicate independent work with agreement checking and disagreement resolution) for title and abstract screening, full text screening, data abstraction, and risk of bias assessment. We abstracted data on the characteristics of: study design, participants, intervention, control, outcomes, funding, and COI. We assessed risk of bias using the Cochrane Risk of Bias Tool in randomized trials4 and an adapted tool for observational studies5 (e-Table 3). When existing systematic reviews were not available or were inadequate, we performed meta-analyses when appropriate. For each outcome of interest, we calculated the risk ratios of individual studies then pooled them and assessed statistical heterogeneity using the I2 statistic. We used a xed-effects model when pooling data from two trials, or when one of the included trials was large relative to the others. Otherwise, we used a random-effects model. We used Review Manager software (version 5.2) to perform the meta-analyses and construct forest plots. We calculated absolute effects by applying pooled relative risks to baseline risks, ideally estimated from valid prognostic observational data or, in the absence of the latter, from control group risks. When credible data from prognostic observational studies were not available, we used risk estimates from control groups of RCTs included in the meta-analyses (e-Figures 5 and 6). Assessing Quality of Evidence Based on the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, quality of evidence (also known as certainty of evidence) is de ned as the extent to which our con dence in the effect estimate is adequate to support a recommendation.6,7 The quality of evidence is categorized as high (A level), moderate (B level), or low (includes very low) (C level).6,7 The rating of the quality of evidence re ects the strengths and limitations of the body of evidence and was based on the study design, risk of bias, imprecision, inconsistency, indirectness of results, and likelihood of publication bias, in addition to factors speci c to observational Using GRADEpro software (version 3.6), we generated tables to summarize the judgments of the quality of the evidence and the relative and absolute effects.13 The GRADE tables include Summary of Findings tables presented in the main text, and a more detailed version called Evidence Pro les presented in the online supplement. The evidence pro les also explicitly link recommendations to the supporting evidence. Drafting of Recommendations Following the GRADE approach, the strength of a recommendation is de ned as the extent to which we can be con dent that the desirable effects of an intervention outweigh its undesirable effects. The strength of recommendation was categorized as strong (grade 1) or 320 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] weak/conditional (grade 2). In determining the strength of the recommendation, the panel considered the balance of desirable and undesirable consequences (typically tradeoff between recurrent VTE and bleeding events), quality of evidence, resource implications, and patients average values and preferences for different outcomes and The chair drafted the recommendations after the entire panel had reviewed the evidence and discussed the recommendation. Recommendations were then revised over a series of conference calls and through e-mail exchanges with the entire panel. A major aim was to ensure recommendations were speci c and unambiguous. Methods for Achieving Consensus We used a modi ed Delphi technique17,18 to achieve consensus on each recommendation. This technique aims to minimize group interaction bias and to maintain anonymity among respondents. Using an online survey (www.surveymonkey.com), panelists without a primary COI voted their level of agreement with each recommendation (including quality of evidence and strength of recommendation) based on a 5-point scale derived from the GRADE grid (strongly agree, weakly agree, neutral, weakly disagree, strongly Each panelist could also provide open-ended feedback on each recommendation with suggested wording edits or general remarks. To achieve consensus and be included in the nal manuscript, each recommendation had to have at least 80% agreement (strong or weak) with a response rate of at least 75% of eligible panel members. All recommendations achieved consensus in the rst round. We then used an iterative approach that involved review by, and approval from, all panel members for the writing of this manuscript. Peer Review External reviewers who were not members of the expert panel reviewed the guideline before it was published. These reviewers included content experts, a methodological expert, and a practicing clinician. The nal manuscript was reviewed and approved by the CHEST GOC, the CHEST Board of Regents, and the CHEST journal. Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant Summary of the Evidence Phases of Anticoagulant Therapy for VTE: The need for anticoagulant therapy in patients with proximal DVT or PE is presented in AT9.1 The minimum duration of anticoagulant therapy for DVT or PE is usually 3 months; this period of treatment is referred to as long-term therapy. 1 A decision to treat patients for longer than 3 months, which we refer to as extended anticoagulant therapy, usually implies that anticoagulant therapy will be continued inde nitely.1 1. In patients with proximal DVT or pulmonary embolism (PE), we recommend long-term (3 months) anticoagulant therapy over no such therapy (Grade 1B). Choice of Anticoagulant for Acute and Long-Term (First 3 Months) Therapy AT9 recommendations on choice of anticoagulant therapy were based on comparisons of VKA with LMWH that were performed in the preceding two and with two of the NOACs (dabigatran,20 ) that had recently been published. Although we judged that there was no convincing evidence that the ef cacy of LMWH compared with VKA differed between VTE patients without and with cancer, there are, nevertheless, reasons to make different suggestions for the preferred anticoagulant in patients without and with cancer.1 We suggested VKA therapy over LMWH in patients without cancer for the following reasons: injections are burdensome; LMWH is expensive; there are low rates of recurrence with VKA in patients with VTE without cancer; and VKA may be as effective as LMWH in patients without cancer. We suggested LMWH over VKA in patients with cancer for the following reasons: there is moderate-quality evidence that LMWH was more effective than VKA in patients with cancer; there is a substantial rate of recurrent VTE in patients with VTE and cancer who are treated with VKA; it is often harder to keep patients with cancer who are on VKA in the therapeutic range; LMWH is reliable in patients who have dif culty with oral therapy (eg, vomiting); and LMWH is easier to withhold or adjust than VKA if invasive interventions are required or thrombocytopenia develops. One new randomized trial compared LMWH (tinzaparin) with warfarin for the rst 6 months of treatment in 900 cancer patients with VTE.22 The ndings of this study are consistent with evidence in AT9 that LMWH is more effective than VKA for long- term treatment of VTE, but that there is no difference in major bleeding or death (Table 1, e-Table 4). Consequently, we still suggest VKA over LMWH in patients without cancer, and LMWH over VKA in patients with cancer, and we have not changed our assessment of the quality of evidence for either of these recommendations (Table 1, e-Table 4). We suggested VKA therapy or LMWH over the NOACs in AT9 because only two randomized trials had compared a NOAC (dabigatran,20 ) with VKA therapy, and none had compared a NOAC with long-term LMWH. In addition, at that time, there was little experience using a NOAC for treatment of VTE and a scarcity of long-term follow-up data to support their ef cacy and safety. Since then, four new TABLE 1 ] Summary of Findings: LMWH vs VKA for Long-Term Treatment of VTEa Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with VKA Risk Difference with LMWH (95% CI) All-cause mortality Moderatec because of risk of bias Noncancerd (from 2 fewer to 2 more) Nonmetastatic Cancerd (from 5 fewer to 6 more) Metastatic Cancerd (from 28 fewer to 35 more) Recurrent VTE Moderatee because of risk of bias Lowf (from 5 fewer to 15 fewer) Moderatef (from 14 fewer to 39 fewer) Highf (from 34 fewer to 98 fewer) Major bleeding Moderateg,h because of imprecision Lowi (from 9 fewer to 6 more) Highi (from 35 fewer to 26 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CATCH Comparison of Acute Treatments in Cancer Haemostasis; GRADE Grades of Recommendations, Assessment, Development, and Evaluation; LITE Long-term Innovations in Treatment program; LMWH low-molecular-weight heparin; RIETE Registro Informatizado de Enfermedad Tromboembolica; RR risk ratio; UFH unfractionated heparin; VKA vitamin K antagonist. GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our con dence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our con dence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our con dence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. a The initial parenteral anticoagulation was similar in both arms for all except 1 study (Hull et al174 ) in which patients randomized to LMWH received initially the same LWMH, whereas patients randomized to VKA initially received UFH. b The relative effect (RR; 95% CI) of LMWH vs VKA was assessed, and compared, in the subgroup of trials that enrolled patients without (Hull et al174 [LITE], Lopez-Beret et al177 ) and with (Deitcher et al173 [ONCENOX], Hull et al174 [LITE], Lee et al170 [CLOT], Lee et al22 [CATCH], Lopez-Beret et al,177 Meyer et al178 ) cancer: Recurrent VTE: cancer RR 0.59 (0.44-0.78) vs no cancer RR 0.99 (0.46-2.13); P .21 for subgroup difference. Major bleeding: cancer RR 0.96 (0.65-1.42) vs no cancer RR 0.43 (0.17 -1.17); P .14 for subgroup difference. All-cause mortality: cancer RR 1.00 (0.88-1.33) vs no cancer RR 1.85 (0.59-5.77); P .29 for subgroup difference. c One study did not report deaths, which is unusual and could re ect selective reporting of outcomes. d Low corresponds to patients without cancer and patients with nonmetastatic cancer. High corresponds to patients with metastatic cancer. These control event rates were derived from the Computerized Registry of Patients with Venous Thromboembolism (RIETE) registry, an ongoing prospective registry of consecutive patients with acute VTE) (Prandoni et al180 ). e None of the studies was blinded, whereas the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for diagnosis of recurrent VTE in VKA- treated patients because switching the treatment of such patients to LMWH is widely practiced. At the same time, there is reluctance to diagnose recurrent VTE in patients who are already on LMWH because there is no attractive alternative treatment option. f Risk of recurrent VTE: Low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate to patients with local or recently resected cancer (appears to be consistent with Prandoni [particularly if low risk is increased to 4%]), and high to patients with locally advanced or distant metastatic cancer (Prandoni et al181 ). g CI includes both no effect and harm with LMWH. h 95% CIs for the risk ratio for major bleeding includes a potentially clinically important increase or decrease with LMWH, and may also vary with the dose of LMWH used during the extended phase of therapy i Risk of bleeding: Low corresponds to patients without risk factor for bleeding (ie, > 75 years, cancer, metastatic disease; chronic renal or hepatic failure; platelet count <80,0000; requires antiplatelet therapy; history of bleeding without a reversible cause) (Prandoni et al,180 Byeth et al182 ). Bibliography: Deitcher et al173 (ONCENOX), Hull et al174 (LITE), Hull et al175 (LITE Home), Lee et al170 (CLOT), Lopaciuk et al,176 Lopez-Beret et al,177 Meyer et al,178 Romera et al,179 Lee et al22 (CATCH) 322 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] randomized trials have compared a NOAC (with23,24 or initial heparin therapy) with VKA therapy (with initial heparin therapy) for the acute and long- term treatment of VTE.23-26 The ndings of these studies have been analyzed in a number of systematic including a network meta-analysis.35 In addition, there is now extensive clinical experience using NOACs in patients with VTE and atrial brillation. For the comparison of each of the NOACs with VKA in the initial and long-term treatment of VTE, current evidence for ef cacy is moderate or high quality, for safety (risk of bleeding) is moderate or high quality, and overall is moderate or high quality (Tables 2-5, e-Tables 5-8). In the 10th Edition of the Antithrombotic Guideline (AT10), the panel s overall assessment of the relative ef cacy and risk of bleeding with different anticoagulant agents is that: (1) the risk reduction for recurrent VTE with all of the NOACs appears to be similar to the risk reduction with VKA,35 including in patients with ; (2) in patients with VTE and cancer, the risk reduction for recurrent VTE appears to be greater with LMWH than with VKA therapy1,36,40 ; (3) the risk reduction for recurrent VTE with the NOACs compared to LMWH has not been assessed but, based on indirect comparisons, LMWH may be more effective that the NOACs in patients with VTE and cancer36 ; (4) the risk reduction for recurrent VTE with different NOACs has not been directly compared but, based on indirect comparisons, appears to be similar to all of the NOACs35 ; (5) the risk of bleeding with the NOACs, and particularly intracranial bleeding, is less with the NOACs than with ; (6) based on patients with atrial brillation, GI bleeding may be higher with dabigatran, rivaroxaban, and edoxaban than with VKA therapy, although this has not been seen in patients with ; (7) based on indirect comparisons, the risk of bleeding may be lower with apixaban than with the ; and (8) despite the lack of speci c reversal agents for the NOACs, the risk that a major bleed will be fatal appears to be no higher for the NOACs than for VKA therapy.33,34,45 Based on less bleeding with NOACs and greater convenience for patients and health- care providers, we now suggest that a NOAC is used in preference to VKA for the initial and long-term treatment of VTE in patients without cancer. Factors that may in uence which anticoagulant is chosen for initial and long-term treatment of VTE are summarized in Table 6. This decision is also expected to be sensitive to patient preferences. The order of our presentation of the NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) is based on the chronology of publication of the phase 3 trials in VTE treatment and should not be interpreted as the guideline panel s order of preference for the use of these agents. TABLE 2 ] Summary of Findings: Dabigatran vs VKA for Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with VKA Risk Difference with Dabigatran (95% CI) All-cause mortality Moderatec because of imprecision (from 6 fewer to 9 more) Recurrent VTE 5,107 Moderatec because of imprecision (from 5 fewer to 13 more) Major bleeding 5,107 Moderatec because of imprecision (from 10 fewer to 2 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). RE-COVER I Ef cacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II Phase III Study Testing Ef cacy & Safety of Oral Dabigatran Etexilate vs Warfarin for 6 m Treatment for Acute Symptomatic Venous Thromboembolism. See Table 1 legend for expansion of other abbreviations and GRADE Working Group grades of evidence. a Patients with acute VTE treated initially with LMWH or UFH. b Dabigatran 150 mg twice daily vs warfarin. c CI includes values suggesting no effect and values suggesting either bene t or harm. d Pooled analysis of Schulman et al20 (RE-COVER I) and Schulman et al24 (RE-COVER II) performed by Schulman et al.24 *2. In patients with DVT of the leg or PE and no cancer, as long-term ( rst 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apix- aban, or edoxaban over vitamin K antagonist (VKA) therapy (all Grade 2B). For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, we suggest VKA therapy over LMWH (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. In patients with VTE and cancer ( cancer-associated thrombosis ), as noted earlier in this section, we still suggest LMWH over VKA. In patients with VTE and cancer who are not treated with LMWH, we do not have TABLE 3 ] Summary of Findings: Rivaroxaban vs LMWH and VKA for Acute and Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated absolute effects Risk with LMWH and VKA Risk difference with Rivaroxaban (95% CI) All-cause mortality Moderatec because of imprecision (from 6 fewer to 6 more) Recurrent VTE 8,281 Moderatec because of imprecision (from 7 fewer to 5 more) Major bleeding 8,246 High (from 3 fewer to 11 fewer) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). EINSTEIN-DVT Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-PE Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism. See Table 1 legend for expansion of other abbreviations and GRADE Working Group grades of evidence. a Included patients had acute, symptomatic, objectively veri ed proximal DVT of the legs or PE (unprovoked, 73%; cancer, 5%; previous VTE, 19%). b Rivaroxaban 20 mg daily for 6 or 12 mo after initial long-term therapy. c CI includes values suggesting no effect and values suggesting either bene t or harm. d Pooled analysis of Bauersachs et al21 (EINSTEIN-DVT) and Buller et al26 (EINSTEIN-PE) performed by Prins et al.183 Bibliography: Prins et al183 TABLE 4 ] Summary of Findings: Apixaban vs LMWH and VKA for Acute and Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with LMWH and VKA Risk Difference with Apixaban (95% CI) All-cause mortality Moderatec because of imprecision (from 9 fewer to 4 more) Recurrent VTE 5,244 Moderatec because of imprecision (from 11 fewer to 5 more) Major bleeding 5,365 High (from 8 fewer to 15 fewer) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AMPLIFY Apixiban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; PE pulmonary embolism. See Table 1 legend for expansion of other abbreviations and GRADE Working Group grades of evidence. a Apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 mo. b Subcutaneous enoxaparin, followed by warfarin. c CI includes values suggesting no effect and values suggesting either bene t or harm. Bibliography: Agnelli et al25 (AMPLIFY) 324 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] a preference for either an NOAC or VKA. In the absence of direct comparisons between NOACs, and no convincing indirect evidence that one NOAC is superior to another, we do not have a preference for one NOAC over another NOAC. Factors that may in uence which anticoagulant is chosen for initial and long-term treatment of VTE are summarized in Table 6. This decision is also expected to be sensitive to patient preferences. *3. In patients with DVT of the leg or PE and cancer ( cancer-associated thrombosis ), as long-term ( rst 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2B), dabigatran (Grade or edoxaban (Grade 2C). Remarks: Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy. See text for factors that in uence choice of therapy. Choice of anticoagulant for extended therapy (after 3 months and no scheduled stop date) When AT9 was written, other than a comparison of low- and standard-intensity anticoagulant therapy,46 there were no comparisons of different types of extended therapy. Since AT9, dabigatran has been compared with VKA therapy for extended treatment of VTE and found to be similarly effective but associated with less bleeding Extended treatment with markedly reduces recurrent VTE without being associated with much bleeding (Tables 8-10, e-Tables 10-12).49,50 These studies provide moderate quality evidence that dabigatran is as effective and as safe as VKA for extended treatment of VTE (Table 7, e-Table 9) and provide moderate quality evidence that each of the NOACs are effective at preventing recurrent VTE without being associated with a high risk of bleeding (Tables 8-10, e-Tables 10-12). In AT9, we suggested that if a decision was made to use extended treatment of VTE, the same anticoagulant should be used as was used for the initial treatment period. Our intention then was to indicate that there was no obligation to switch from one anticoagulant to a different one after 3 or 6 months of treatment (eg, from LMWH to VKA in patients with VTE and cancer). We have revised the wording of this recommendation to make it clearer that we neither encourage nor discourage use of the same anticoagulant for initial and extended therapy. Although we anticipate that the anticoagulant that was used for initial treatment will often also be used for the extended therapy, if there are reasons to change the type of anticoagulant, this should be done. We also note that whereas apixaban 5 mg twice daily is used for long-term treatment, apixaban 2.5 mg twice daily is used for extended therapy.48 TABLE 5 ] Summary of Findings: Edoxaban vs VKA for Acute and Long-Term Treatment of VTEa,b Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with VKA Risk Difference with Edoxaban (95% CI) All-cause mortality Moderatec because of imprecision (from 6 fewer to 10 more) Recurrent VTE 8,240 Moderatec,d because of imprecision (from 15 fewer to 7 more) Major bleeding 8,240 Moderated because of imprecision (from 6 fewer to 3 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See Table 1 and 4 legends for expansion of abbreviations and GRADE Working Group grades of evidence. a Patients with acute VTE who had initially received heparin. b Edoxaban 60 mg once daily, or 30 mg once daily if patients with creatinine clearance of 30 to 50 mL/min or a body weight below 60 kg. c CI includes values suggesting no effect and values suggesting either bene t or harm. d Death, with PE not ruled out. Bibliography: Buller et al23 (Hokusai-VTE study) *4. In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the rst 3 months (Grade 2C). Remarks: It may be appropriate for the choice of anticoagulant to change in response to changes in the patient s circumstances or preferences during the long- term or extended phases of treatment. Duration of Anticoagulant Therapy Summary of the Evidence AT9 recommendations on how long VTE should be treated were based on comparisons of four durations of than 3 months but still a time-limited course of therapy (usually 6 or 12 months); or (4) extended (also termed inde nite ; no scheduled stopping date) therapy.1 These four options were assessed in four subgroups of VTE patients with different estimated risks of recurrence after stopping anticoagulant therapy: (1) VTE provoked by surgery (a major transient risk factor; 3% recurrence ; (2) VTE provoked by a nonsurgical transient risk factor (eg, estrogen therapy, pregnancy, leg injury, ight of >8 h; 15% recurrence at 5 years)51 ; (3) unprovoked (also termed idiopathic ) VTE; not meeting criteria for provoked by a transient risk factor or by cancer (30% recurrence at 5 years)52,53 ; and (4) VTE associated with cancer (also termed cancer- associated thrombosis ; 15% annualized risk of recurrence; recurrence at 5 years not estimated because of high mortality from cancer).54,55 Recurrence risk was further strati ed by estimating the risk of recurrence after: (1) an isolated distal DVT was half that after a proximal DVT or PE56,57 and (2) a second unprovoked TABLE 6 ] Factors That May In uence Which Anticoagulant Is Chosen for Initial and Long-Term Treatment of VTE Factor Preferred Anticoagulant Qualifying Remarks Cancer LMWH More so if: just diagnosed, extensive VTE, metastatic cancer, very symptomatic; vomiting; on cancer chemotherapy. Parenteral therapy to be avoided Rivaroxaban; apixaban VKA, dabigatran, and edoxaban require initial parenteral therapy. Once daily oral therapy preferred Rivaroxaban; edoxaban; VKA Liver disease and coagulopathy LMWH NOACs contraindicated if INR raised because of liver disease; VKA dif cult to control and INR may not re ect antithrombotic effect. Renal disease and creatinine clearance <30 mL/min VKA NOACs and LMWH contraindicated with severe renal impairment. Dosing of NOACs with levels of renal impairment differ with the NOAC and among jurisdictions. Coronary artery disease VKA, rivaroxaban, apixaban, edoxaban Coronary artery events appear to occur more often with dabigatran than with VKA. This has not been seen with the other NOACs, and they have demonstrated ef cacy for coronary artery disease. Antiplatelet therapy should be avoided if possible in patients on anticoagulants because of increased bleeding. Dyspepsia or history of GI bleeding VKA, apixaban Dabigatran increased dyspepsia. Dabigatran, rivaroxaban, and edoxaban may be associated with more GI bleeding than VKA. Poor compliance VKA INR monitoring can help to detect problems. However, some patients may be more compliant with a NOAC because it is less complex. Thrombolytic therapy use UFH infusion Greater experience with its use in patients treated with thrombolytic therapy Reversal agent needed VKA, UFH Pregnancy or pregnancy risk LMWH Potential for other agents to cross the placenta Cost, coverage, licensing Varies among regions and with individual circumstances INR International Normalized Ratio; NOAC non-vitamin K oral coagulant. See Table 1 legend for expansion of other abbreviations. 326 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] proximal DVT or PE was 50% higher (1.5-fold) than after a rst unprovoked event.57,58 For the decision about whether to stop treatment at 3 months or to treat inde nitely ( extended treatment ), we categorized a patient s risk of bleeding on anticoagulant therapy as low (no bleeding risk factors; 0.8% annualized risk of major bleeding), moderate (one bleeding risk factor; 1.6% annualized risk of major bleeding), or high (two or TABLE 7 ] Summary of Findings: Dabigatran vs VKA for Extended Treatment of VTEa,b,c,d Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with VKA Risk Difference with Dabigatran (95% CI) All-cause mortality 2,856 Moderatee,f because of imprecision (from 7 fewer to 9 more) Recurrent VTE 2,856 Moderatee,f,g because of imprecision (from 3 fewer to 20 more) Major bleeding 2,856 Moderatee,f because of imprecision (from 13 fewer to 0 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). REMEDY Secondary Prevention of Venous Thrombo Embolism. See Table 1 and 4 legends for expansion of other abbreviations and GRADE Working Group grades of evidence. a Included patients had acute, symptomatic, objectively veri ed proximal DVT of the legs or PE. b Dabigatran 150 mg twice daily taken orally for 6 mo after an initial treatment with LMWH or IV UFH. c Warfarin adjusted to achieve an INR of 2.0-3.0 for 6 mo after an initial treatment with LMWH or IV UFH. d Active-Control study outcomes used from Schulman et al47 (REMEDY). e Allocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Modi ed intention-to-treat analysis. 1.1% loss to follow-up. Not stopped early for bene t. f CI includes values suggesting no effect and values suggesting either bene t or harm. g Primary end point was composite of recurrent or fatal VTE or unexplained death. Bibliography: Schulman et al47 (REMEDY) TABLE 8 ] Summary of Findings: Dabigatran vs Placebo for Extended Treatment of VTEa,b,c Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with Placebo Risk Difference with Dabigatran (95% CI) All-cause mortality 1,343 Moderated because of imprecision Not estimablee Recurrent VTE 1,343 High (from 42 fewer to 55 fewer) Major bleeding 1,343 Moderated because of imprecision Not estimablef The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). RESONATE Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE. See Table 1 and 4 legends for expansion of other abbreviations and GRADE Working Group grades of evidence. a Patients with VTE who had completed at least 3 initial mo of therapy. b Dabigatran 150 mg twice daily. c Placebo-control study outcomes used from Schulman et al47 (RESONATE). d Event rate low in a large sample size. e Event rate with dabigatran was 0/681 (0%); event rate with placebo was 2/662 (0.3%); anticipated absolute effect risk difference with dabigatran is 3 fewer per 1,000 (from 11 fewer to 3 more). f Event rate with dabigatran was 2/681 (0.3%); event rate with placebo was 0/662 (0%); anticipated absolute effect risk difference with dabigatran is 3 more per 1,000 (from 3 fewer to 11 more). Bibliography: Schulman et al47 (RESONATE) more bleeding risk factors; $6.5% annualized risk of major bleeding) (Table 11). A VKA targeted to an International Normalized Ratio (INR) of about 2.5 was the anticoagulant in all studies that compared different time-limited durations of therapy. We, therefore, assumed that VKA therapy was the anticoagulant when we were making our AT9 recommendations, including for the comparison of extended therapy with stopping treatment at 3 months. Comparison of Different Time-Limited Durations of Anticoagulation Since AT9: Two additional studies have compared two time-limited durations of In patients with a rst unprovoked PE who had completed 6 months of VKA therapy (target INR 2.5), the Extended Duration of Oral Anticoagulant Therapy After a First Episode of Idiopathic Pulmonary Embolism: a Randomized Controlled Trial (PADIS) study randomized patients to TABLE 9 ] Summary of Findings: Rivaroxaban vs Placebo for Extended Treatment of VTEa,b Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with Placebo Risk Difference with Rivaroxaban (95% CI) All-cause mortality Moderatec because of imprecision (from 3 fewer to 15 more) Recurrent VTE High (from 42 fewer to 64 fewer) Major bleeding Moderate because of risk of bias Not estimabled The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See Table 1 and 4 legends for expansion of other abbreviations and GRADE Working Group grades of evidence. a Patients who had completed 6 to 12 mo of treatment for VTE. b Rivaroxaban 20 mg daily or placebo, speci c to the continued treatment study. c CI includes values suggesting no effect and values suggesting either bene t or harm. d Event rate with rivaroxaban was 4/598 (0.67%); event rate with placebo was 0/590 (0%); anticipated absolute effect risk difference with rivaroxaban is 4 more per 1,000 (from 1 less to 17 more). Bibliography: Bauersachs et al21 (EINSTEIN-Extension) TABLE 10 ] Summary of Findings: Apixaban vs Placebo for Extended Treatment of VTEa,b Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with Placebo Risk Difference with Apixaban (95% CI) All-cause mortality 1,669 Moderatec,d because of imprecision (from 14 fewer to 4 more) Recurrent VTE 1,669 High (from 59 fewer to 78 fewer) Major bleeding 1,669 Moderatec,d because of imprecision (from 4 fewer to 8 more) The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). See Table 1 and 4 legends for expansion of abbreviations and GRADE Working Group grades of evidence. a Patients with VTE who had completed 6 to 12 mo of anticoagulation therapy. b Apixaban 2.5 mg twice-daily dose vs placebo. c Signi cantly wide CIs, including appreciable bene t /harm and no effect line. d Low number of events. Bibliography: Agnelli et al48 (AMPLIFY-EXT) 328 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] another 18 months of treatment or to placebo, and then followed both groups of patients for an additional 24 months after study drug was stopped (Table 12, The study s ndings were consistent with our recommendations in AT9; the additional 18 months of VKA was very effective at preventing recurrent VTE but, once anticoagulation was stopped, the risk of recurrent VTE was the same in those who had been treated for 6 or for 24 months. This new information has not increased the quality of evidence for comparison of a longer vs a shorter, time-limited course of anticoagulation in patients without cancer. In patients with a rst proximal DVT or PE and active cancer who had residual DVT on US imaging after completing 6 months of LMWH therapy, the Cancer- Duration of Anticoagulation based on Compression Ultrasonography (DACUS) study randomized patients to another 6 months of LMWH or to stop therapy and followed patients for 12 months after they stopped The additional 6 months of LMWH reduced recurrent VTE but, once anticoagulation was stopped, the risk of recurrent VTE was the same in those who had TABLE 11 ] Risk Factors for Bleeding with Anticoagulant Therapy and Estimated Risk of Major Bleeding in Low-, Moderate-, and High-Risk categoriesa Risk Factorsb Poor anticoagulant control189,196,203 Comorbidity and reduced functional capacity191,196,204 Nonsteroidal anti-in ammatory drug210 Categorization of Risk of Bleedingd Estimated Absolute Risk of Major Bleeding Low Riske Factors) Moderate Riske Factor) High Riske Factors) Anticoagulation Increased risk (%) Total risk (%) 1.6g Anticoagulation after rst 3 mof Baseline risk (%/y) 0.3i Increased risk (%/y) Total risk (%/y) 0.8j AT9 9th Edition of the Antithrombotic Guideline. a From AT9. Since AT9, references for bleeding with individual factors have ; nonsteroidal anti-in ammatory drug has been added as a risk factor; a systematic review has described the risk in VTE trial patients who were randomized to no antithrombotic therapy211 ; and several recent publications have compared clinical prediction rules for bleeding in various populations.193,212-216 b Most studies assessed risk factors for bleeding in patients who were on VKA therapy. The risk of bleeding with different anticoagulants is not addressed in this table. 