of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk With No Temporary IVC Filter in Addition to Anticoagulation Risk Difference with Temporary IVC Filter (95% CI) All-cause mortality Moderatec,d because of imprecision (from 24 fewer to 96 more) Recurrent PE 399 Moderatec,d because of imprecision (from 7 fewer to 104 more) Major bleeding 399 Moderatec,d because of imprecision (from 34 fewer to 49 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). IVC inferior vena cava. See Table 1 and 4 legends for expansion of other abbreviations and GRADE Working Group grades of evidence. a All patients received full-dose anticoagulant therapy according to guidelines for at least 6 mo. b Filter removal was attempted in 164 patients and successful for 153 (93.3%). c CI includes values suggesting no effect and values suggesting either bene t or harm. d Small number of events. Bibliography: Mismetti et al237 There is uncertainty whether these patients should be anticoagulated for two reasons. First, because the abnormalities are small, a diagnosis of subsegmental PE is more likely to be a false-positive nding than a diagnosis of PE in the segmental or more proximal Second, because a true subsegmental PE is likely to have arisen from a small DVT, the risk of progressive or recurrent VTE without anticoagulation is expected to be lower than in patients with a larger PE.110,111,117,118 Our literature search did not identify any randomized trials in patients with subsegmental PE. There is, however, high-quality evidence for the ef cacy and safety of anticoagulant therapy in patients with larger PE, and this is expected to apply similarly to patients with subsegmental PE.1 Whether the risk of progressive or recurrent VTE is high enough to justify anticoagulation in patients with subsegmental PE is There were no episodes of recurrent VTE in retrospective reports that included about 60 TABLE 17 ] Summary of Findings: Elastic Compression Stockings vs No Elastic Compression Stockings to Prevent PTS of the Leg Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with No Elastic Compression Stockings Risk Difference with Elastic Compression Stockings (95% CI) PTS Villalta Scorea Moderateb because of imprecision Moderate-Risk Populationd (from 67 fewer to 86 more) Recurrent VTE Moderateb,e because of imprecision Moderate-Risk Populationg (from 97 fewer to 65 more) Acute Leg Pain Moderatee,h because of imprecision The mean acute leg pain in the control groups was 1.13 leg pain severity assessed on an 11-point numerical pain rating scalei The mean acute leg pain in the intervention groups lower to 0.55 higher)i High The mean QoL in the intervention groups was 0.12 lower (1.11 lower to 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). ECS elastic compression stockings; SF- 36 Short Form 36. See Table 1 and 14 legends for expansion of other abbreviations and GRADE Working Group grades of evidence. a For included studies, number of PTS events as assessed by Villalta s criteria b Low number of events. c There were 3 studies originally included for this outcome (Brandjes et al,103 Prandoni et al,104 and Kahn et al106 [SOX]). There was very high heterogeneity among the 3 studies, I2 92% (P < .01). The pooled effect of the 3 studies was RR, 0.63 (0.35-1.13). Yet, because of the high risk of bias associated with Brandjes et al103 and Prandoni et al,104 it was decided to focus on the estimate of the low-risk trial, Kahn et al106 (SOX), which is used here. d This estimate is based on the ndings of the VETO study.232 e CI includes values suggesting no effect and values suggesting either bene t or harm. f There were 3 studies originally included for this outcome (Brandjes et al,103 Prandoni et al,104 and Kahn et al106 [SOX]). The pooled effect of the 3 studies was RR, 0.91 (0.65-1.27). Yet, because of the high risk of bias associated with Brandjes et al103 and Prandoni et al,104 it was decided to focus on the estimate of the low-risk trial, Kahn et al106 (SOX), which is used here. g This estimate is the mean of 2 estimates derived from 2 studies: 12.4% probable/de nite VTE170 h Wide CI that includes no effect. i Estimate derived from Kahn et al.107 j Estimate based on VEINES-QOL score improvement of 5.8 points (SD, 7.5) for active ECS vs 5.9 (SD, 7.1) for placebo ECS. k SF-36 physical component score improved by 8.4 points (SD, 13.6) for active ECS vs 9.9 (SD, 13.2) for placebo ECS (difference between groups of -1.53 points, 95% CI, -3.44 to 0.39; P .12). Bibliography: Kahn et al106 (SOX) for PTS and recurrent VTE; Kahn et al107 for acute leg pain 338 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] patients with subsegmental PE and no proximal DVT and who were not anticoagulated.110,111 However, in another retrospective analysis, patients with subsegmental PE appeared to have a similar risk of recurrent VTE during 3 months of anticoagulant therapy as patients with larger PE, and a higher risk than in patients who were suspected of having PE but had PE The AT10 panel endorsed that, if no anticoagulant therapy is an option, patients with subsegmental PE should have bilateral US examinations to exclude proximal DVT of the legs.110,114 DVT should also be excluded in other high-risk locations, such as in upper extremities with central venous catheters. If DVT is detected, patients require anticoagulation. If DVT is not detected, there is uncertainty whether patients should be anticoagulated. If a decision is made not to anticoagulate, there is the option of doing one or more follow-up US examinations of the legs to detect (and then treat) evolving proximal DVT.110,114 Serial testing for proximal DVT has been shown to be a safe management strategy in patients with suspected PE who have nondiagnostic ventilation-perfusion scans, many of whom are expected to have subsegmental PE.110,111,120 We suggest that a diagnosis of subsegmental PE is more likely to be correct (ie, a true positive) if: (1) the CT pulmonary angiogram is of high quality with good opaci cation of the distal pulmonary arteries; (2) there are multiple intraluminal defects; (3) defects involve more proximal subsegmental arteries (ie, are larger); (4) defects are seen on more than one image; (5) defects are surrounded by contrast rather than appearing to be adherent to the pulmonary artery walls; (6) defects are seen on more than one projection; (7) patients are symptomatic, as opposed to PE being an incidental nding; (8) there is a high clinical pretest probability for PE; and (9) D-dimer level is elevated, particularly if the increase is marked and otherwise unexplained. In addition to whether or not patients truly have subsegmental PE, we consider the following to be risk factors for recurrent or progressive VTE if patients are not anticoagulated patients who: are hospitalized or have reduced mobility for another reason; have active cancer (particularly if metastatic or being treated with chemotherapy); or have no reversible risk factor for VTE such as recent surgery. Furthermore, a low cardiopulmonary reserve or marked symptoms that cannot be attributed to another condition favor anticoagulant therapy, whereas a high risk of bleeding favors no anticoagulant therapy. The decision to anticoagulate or not is also expected to be sensitive to patient preferences. Patients who are not anticoagulated should be told to return for reevaluation if symptoms persist or worsen. The evidence supporting our recommendations is low quality because of indirectness and because there is limited ability to predict which patients will have VTE complications without anticoagulation. *19. In patients with subsegmental PE (no involvement 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), and (ii) high risk for recurrent VTE (see text), we suggest anticoagulation over clinical surveillance (Grade 2C). Remarks: 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 Summary of the Evidence Our recommendation in AT9 was based on: (1) two trials that randomized patients with acute PE to receive LMWH for only 3 days in the hospital121 or entirely at compared with being treated with LMWH in the hospital for a longer period; (2) 15 observational studies, 9 of which were prospective, that evaluated treatment of acute PE out of the hospital1 ; and (3) longstanding experience treating DVT without admission to a hospital. Since AT9, no further randomized trials have evaluated out-of-hospital treatment of acute PE. Several additional prospective and retrospective observational studies have reported ndings consistent with earlier reports, and the ndings of all of these studies have been included in recent meta- analyses that have addressed treatment of acute PE out of the hospital.123-125 Studies that evaluated NOACs for the acute treatment of PE did not report the proportion of patients who were treated entirely out of hospital, but it is probable that this was uncommon. Treatment of acute PE with a NOAC that does not require initial heparin therapy (eg, rivaroxaban, apixaban) facilitates treatment without hospital admission. Consistent with AT9, we suggest that patients who satisfy all of the following criteria are suitable for treatment of acute PE out of the hospital: (1) clinically stable with good cardiopulmonary reserve; (2) no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia ); (3) expected to be compliant with treatment; and (4) the patient feels well enough to be treated at home. Clinical decision rules such as the Pulmonary Embolism Severity Index (PESI), either the original form with score <85 or the simpli ed form with score of 0, can help to identify low-risk patients who are suitable for treatment at home.126-131 However, we consider clinical prediction rules as aids to decision- making and do not require patients to have a prede ned score (eg, low-risk PESI score) to be considered for treatment at home. Similarly, although we do not suggest the need for routine assessment in patients with acute PE, we agree that the presence of right ventricular dysfunction or increased cardiac biomarker levels should discourage treatment out of the hospital.130,132-138 The quality of the evidence for treatment of acute PE at home remains moderate because of marked imprecision. The updated recommendation has been modi ed to state that appropriately selected patients may be treated entirely at home, rather than just be discharged early. *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 Summary of the Evidence It has long been established that systemic thrombolytic therapy accelerates resolution of PE as evidenced by more rapid lowering of pulmonary artery pressure, increases in arterial oxygenation, and resolution of perfusion scan defects, and that this therapy increases The net mortality bene t of thrombolytic therapy in patients with acute PE, however, has been uncertain and depends on an individual patient s baseline (ie, without thrombolytic therapy) risk of dying from acute PE and risk of bleeding. Patients with the highest risk of dying from PE and the lowest risk of bleeding obtain the greatest net bene t from thrombolytic therapy. Patients with the lowest risk of dying from PE and the highest risk of bleeding obtain the least net bene t from thrombolytic therapy and are likely to be harmed. Evidence for the Use of Thrombolytic Therapy in Patients With Acute PE: AT9 recommendations for the use of thrombolytic therapy in acute PE were based on At that time, only about 800 patients with acute PE had been randomized to receive thrombolytic therapy or anticoagulant therapy alone and, consequently, estimates of ef cacy, safety, and overall mortality were very imprecise. In addition, the trials that enrolled these 800 patients had a high risk of bias and there was a strong suspicion that there was selective reporting of studies that favored thrombolytic therapy (ie, publication bias). Randomized trials have clearly established that thrombolytic therapy increases bleeding in patients with acute myocardial infarction,140 but that evidence was indirect when applied to patients with PE. Since AT9, two additional small, randomized trials141,142 and a much larger trial143 have evaluated systemic thrombolytic therapy in about 1,200 patients with acute PE. The ndings of these new studies have been combined with those of earlier studies in a number of These new data, by reducing imprecision for estimates of ef cacy and safety and the overall risk of bias, have increased the quality of the evidence from low to moderate for recommendations about the use of systemic thrombolytic therapy in acute PE (Table 18, e-Table 18). Most of the new evidence comes from the Pulmonary Embolism Thrombolysis trial, which randomized 1,006 patients with PE and right ventricular dysfunction to tenecteplase and heparin or to heparin therapy alone The most notable ndings of this study were that thrombolytic therapy prevented cardiovascular collapse but increased major (including intracranial) bleeding; these bene ts and harms were nely balanced, with no convincing net bene t from thrombolytic therapy. An additional nding was that rescue thrombolytic therapy appeared to be of bene t in patients who developed cardiovascular collapse after initially being treated with anticoagulant therapy alone. Management Implication of the Updated Evidence: The improved quality of evidence has not resulted in substantial changes to our recommendations because: (1) the new data support that the bene ts of systemic thrombolytic therapy in patients without hypotension, including those with right ventricular dysfunction or an increase in cardiac biomarkers ( intermediate-risk PE ), 340 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] are largely offset by the increase in bleeding; and (2) among patients without hypotension, it is still not possible to con dently identify those who will derive net bene t from this therapy. PE With Hypotension: Consistent with AT9, we suggest that patients with acute PE with hypotension (ie, systolic BP <90 mm Hg for 15 min) and without high bleeding risk (Table 15) are treated with thrombolytic therapy. The more severe and persistent the hypotension, and the more marked the associated features of shock and myocardial dysfunction or damage, the more compelling the indication for systemic thrombolytic therapy. Conversely, if hypotension is transient or less marked, not associated with features of shock or myocardial dysfunction, and if there are risk factors for bleeding, physicians and patients are likely to initially choose anticoagulant therapy without thrombolytic therapy. If thrombolytic therapy is not used and hypotension persists or becomes more marked, or clinical features of shock or myocardial damage develop or worsen, thrombolytic therapy may then be used. PE Without Hypotension: Consistent with AT9, we recommend that most patients with acute PE who do not have hypotension are not treated with thrombolytic therapy. However, patients with PE without hypotension include a broad spectrum of presentations. At the mild end of the spectrum are those who have minimal symptoms and minimal cardiopulmonary impairment. As noted in the section Setting for initial anticoagulation for PE, many of these patients can be treated entirely at home or can be discharged after a brief admission. At the severe end of the spectrum are those with severe symptoms and more marked cardiopulmonary impairment (even though systolic BP is >90 mm Hg). In addition to clinical features of cardiopulmonary impairment (eg, heart rate, BP, respiratory rate, jugular venous pressure, tissue hypoperfusion, pulse oximetry), they may have evidence of right ventricular dysfunction on their CT pulmonary angiogram or on echocardiography, or evidence of myocardial damage as re ected by increases in cardiac biomarkers (eg, troponins, brain natriuretic peptide). TABLE 18 ] Summary of Findings: Systemic Thrombolytic Therapy vs Anticoagulation Alone for Acute PE Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with Anticoagulation Alone Risk Difference with Systemic Thrombolytic Therapy (95% CI) All-cause mortality Moderatea because of imprecision (from 5 fewer to 26 fewer) Recurrent PE 2,043 Moderatea because of imprecision (from 8 fewer to 24 fewer) Major bleeding 2,115 High (from 29 more to 87 more) Intracranial hemorrhage Moderatea because of imprecision (from 2 more to 21 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 Low number of events. b Estimate from Chatterjee et al.147 Other estimates from meta-analyses on this topic include Dong et al:238 (intermediate-risk PE only): OR, 0.46 (intermediate-risk PE only): OR, 0.42 (0.17-1.03). c Majority (83%) of participants in Chatterjee et al147 were moderate risk. d Estimate from Chatterjee et al.147 Other estimates from meta-analyses on this topic include Dong et al:238 RR, 0.60 (0.21-1.69). e Estimate from Chatterjee et al.147 Other estimates from meta-analyses on this topic include Dong et al:238 : RR, 1.16 RR, 2.07 (0.58-7.35). f Estimate from Chatterjee et al.147 Bibliography: Chatterjee et al147 We suggest that patients without hypotension who are at the severe end of the spectrum be treated with aggressive anticoagulation and other supportive measures, and not with thrombolytic therapy. These patients need to be closely monitored to ensure that deteriorations are detected. Development of hypotension suggests that thrombolytic therapy has become indicated. Deterioration that has not resulted in hypotension may also prompt the use of thrombolytic therapy. For example, there may be a progressive increase in heart rate, a decrease in systolic BP (which remains >90 mm Hg), an increase in jugular venous pressure, worsening gas exchange, signs of shock (eg, cold sweaty skin, reduced urine output, confusion), progressive right heart dysfunction on echocardiography, or an increase in cardiac biomarkers. We do not propose that echocardiography or cardiac biomarkers are measured routinely in all patients with PE, or in all patients with a non low-risk PESI This is because, when measured routinely, the results of these assessments do not have clear therapeutic implications. For example, we do not recommend thrombolytic therapy routinely for patients without hypotension who have right ventricular dysfunction and an increase in cardiac biomarkers. However, we encourage assessment of right ventricular function by echocardiography and/or measurement of cardiac biomarkers if, following clinical assessment, there is uncertainty about whether patients require more intensive monitoring or should receive thrombolytic therapy. 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 systemi- cally administered thrombolytic therapy (Grade 1B). *23. In selected patients with acute PE who deteriorate 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 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 Summary of the Evidence Interventional catheter-based treatments for acute PE include delivery of CDT if there is not a high risk of bleeding, or catheter-based treatment without thrombolytic therapy if there is a high risk of bleeding. CDT: The most important limitation of systemic thrombolytic therapy is that it increases bleeding, including intracranial bleeding. CDT, because it uses a lower dose of thrombolytic drug (eg, about one-third), is expected to cause less bleeding at remote sites (eg, intracranial, GI).138,150-153 CDT, however, may be as or more effective than systemic thrombolytic therapy for two reasons: (1) it achieves a high local concentration of thrombolytic drug by infusing drug directly into the PE and (2) thrombus fragmentation resulting from placement of the infusion catheter in the thrombus or additional maneuvers, or an increase in thrombus permeability from US delivered via the catheter, may enhance endogenous or pharmacologic thrombolysis. Thrombolytic therapy is usually infused over many hours or overnight. In emergent situations, systemic thrombolytic therapy can be given while CDT is being arranged, and active thrombus fragmentation and aspiration (see below) can be combined with CDT. A single randomized trial of 59 patients found that, compared with anticoagulation alone, US-assisted CDT improved right ventricular function at 24 h.154 Observational studies also suggest that CDT is effective at removing thrombus, lowering pulmonary arterial pressure, and improving right ventricular function without being associated with a high risk of Most of these studies are small (fewer than 30 patients) and retrospective, although a recent prospective registry of 101 patients and a prospective cohort study of 150 patients also support the ef cacy of Whereas there was no major bleeding in the registry, there were 15 episodes in the cohort study 342 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] (10%; no intracranial or fatal bleeds). An older randomized trial of 34 patients with massive PE found that infusion of recombinant tissue plasminogen activator into a pulmonary artery as opposed to a peripheral vein did not accelerate thrombolysis, but caused more frequent bleeding at the catheter insertion No randomized trials or observational studies have compared contemporary CDT with systemic thrombolytic therapy. For patients who require thrombolytic therapy and do not have a high risk of bleeding, the AT10 panel favored systemic thrombolytic therapy over CDT because, compared with anticoagulation alone, there is a higher quality of evidence in support of systemic thrombolytic therapy than for CDT. Catheter-Based Thrombus Removal Without Thrombolytic Therapy: Catheter-based mechanical techniques for thrombus removal involve thrombus fragmentation using various types of catheters, some of which are designed speci cally for this purpose.150-153 Fragmentation results in distal displacement of thrombus, with or without suctioning and removal of some thrombus through the catheter. Mechanical methods alone are used when thrombus removal is indicated but there is a high risk of bleeding that precludes thrombolytic therapy. No randomized trial or prospective cohort studies have evaluated catheter-based thrombus removal of PE without thrombolytic therapy. Evidence for the use of CDT compared with anticoagulation alone, CDT compared with systemic thrombolytic therapy, and catheter-based treatment without thrombolytic therapy is of low quality and our recommendations are weak. *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 hy- potension 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 in for the Treatment of Chronic Thromboembolic Pulmonary Hypertension Summary of the Evidence The AT9 recommendation was based on case series that have shown marked improvements in cardiopulmonary status after thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension Although additional case series have been reported, the quality of the evidence for thromboendarterectomy in patients with CTEPH has The AT10 panel decided, however, that our previous recommendation for thromboendarterectomy in selected patients with CTEPH was too restrictive and could contribute to suboptimal evaluation and treatment of patients with CTEPH. For example, because of improvements in surgical technique, it is now often possible to remove organized thrombi from peripheral pulmonary arteries. In patients with inoperable CTEPH or persistent pulmonary hypertension after pulmonary thromboendarterectomy, there is new evidence from a randomized trial that pulmonary vasodilator therapy may be of bene t.163 For these reasons, we no longer identify central disease as a selection factor for thromboendarterectomy in patients with CTEPH, and we emphasize that patients with CTEPH should be assessed by a team with expertise in the evaluation and management of pulmonary hypertension.153,159,164-166 *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 Summary of the Evidence The AT9 recommendation was based on: (1) mostly retrospective observational studies suggesting that thrombolysis could improve short- and long-term venous patency, but a lack of data about whether thrombolysis reduced PTS of the arm; (2) occasional reports of bleeding in patients with UEDVT who were treated with thrombolysis, and clear evidence that thrombolysis increases bleeding in other settings; and (3) recognition that, compared to anticoagulation alone, thrombolytic therapy is complex and costly.1,167,168 We suggest that thrombolysis is most likely to be of bene t in patients who meet the following criteria: severe symptoms; thrombus involving most of the subclavian vein and the axillary vein; symptoms for <14 days; good functional status; life expectancy of $1 year; and low risk for bleeding. We also suggested CDT over systemic thrombolysis to reduce the dose of thrombolytic drug and the risk of bleeding. There is new moderate quality evidence that CDT can reduce PTS of the leg90 (Table 14, e-Table 15) and that systemic thrombolysis increases bleeding in patients with acute PE,143,147 and low-quality evidence that CDT can accelerate breakdown of acute PE.154 This evidence has indirect bearing on thrombolysis in patients with UEDVT, but it has not changed the overall quality of the evidence or our recommendations for use of thrombolysis in these patients. 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 Summary of Evidence There are no randomized trials or prospective cohort studies that have evaluated management of patients with recurrent VTE on anticoagulant therapy. Consequently, management is based on low-quality evidence and an assessment of the probable reason for the recurrence. Risk factors for recurrent VTE while on anticoagulant therapy can be divided into two broad categories: (1) treatment factors and (2) the patient s intrinsic risk of recurrence. How a new event should be treated will depend on the reason(s) for recurrence. Treatment Factors: The risk of recurrent VTE decreases rapidly after starting anticoagulant therapy, with a much higher risk during the rst week (or month) compared with the second week (or month).169,170 A recurrence soon after starting therapy can generally be managed by a time-limited (eg, 1 month) period of more aggressive anticoagulant intensity (eg, switching from an oral agent back to LMWH, an increase in LMWH dose). Other treatment factors that are associated with recurrent VTE and will suggest speci c approaches to management include: (1) was LMWH being used; (2) was the patient adherent; (3) was VKA subtherapeutic; (4) was anticoagulant therapy prescribed correctly; (5) was the patient taking an NOAC and a drug that reduced anticoagulant effect; and (6) had anticoagulant dose been reduced (drugs other than VKA)? There is moderate-quality evidence that LMWH is more effective than VKA therapy in patients with VTE and cancer. A switch to full-dose LMWH, therefore, is often made if there has been an unexplained recurrent VTE on VKA therapy or an NOAC. If the recurrence happened on LMWH, the dose of LMWH can be increased. If the dose of LMWH was previously reduced (eg, by 25% after 1 month of treatment), it is usually increased to the previous level. If the patient was receiving full-dose LMWH, the dose may be increased by about 25%. In practice, the increase in dose is often in uenced by the LMWH pre lled syringe dose options that are available. Once-daily LMWH may also be switched to a twice- daily regimen, particularly if two injections are required to deliver the increase in LMWH dose. Treatment adherence, including compliance, can be dif cult to assess; for example, symptoms of a recurrent DVT may 344 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] encourage medication adherence and a return of coagulation results to the therapeutic range. Patient Factors: The most important intrinsic risk factor for recurrent VTE while on anticoagulant therapy is active cancer, with an unexplained recurrence often pointing to yet-to-be-diagnosed disease. Antiphospholipid syndrome is also associated with recurrent VTE, either because of associated hypercoagulability or because a lupus anticoagulant has led to underdosing of VKA because of spurious increases in INR results. Anticoagulated patients may be taking medications that increase the risk of thrombosis such as estrogens or cancer chemotherapy, in which case these treatments may be withdrawn. A retrospective observational study found an acceptable risk of recurrence (8.6%) and major bleeding (1.4%) during 3 months of follow-up in 70 cancer patients with recurrent VTE while on anticoagulant therapy who either switched from VKA therapy to LMWH (23 patients) or had their LMWH dose increased by If there is no reversible reason for recurrent VTE while on anticoagulant therapy, and anticoagulant intensity cannot be increased because of risk of bleeding, a vena caval lter can be inserted to prevent PE.172 However, it is not known if insertion of a lter in these circumstances is worthwhile, and the AT10 panel consider this an option of last resort. *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. Conclusion There is substantial new evidence since AT9 about how to treat VTE. This evidence led the panel to change many of the AT9 recommendations that are included in this update, and has strengthened the evidence quality that underlies others that are unchanged. We now suggest the use of NOACs over VKA for the treatment of VTE in patients without cancer. Although we still suggest LMWH as the preferred long-term treatment for VTE and cancer, we no longer suggest VKA over NOACs in these patients. Although we note factors in individual patients that may favor selection of one NOAC over another in patients without or with cancer, or may favor selection of either a NOAC or VKA in patients with cancer, we have not expressed an overall preference for one NOAC over another, or for either a NOAC or VKA in patients with cancer, because: (1) there are no direct comparisons of different NOACs; (2) NOACs have not been compared with VKA in a broad spectrum of patients with VTE and cancer; and (3) indirect comparisons have not shown convincingly different outcomes with different NOACs. Another notable change in AT10 is that, based on a new low risk of bias study, we now suggest that graduated compression stocking are not routinely used to prevent PTS. Recommendations that are unchanged but are now supported by better evidence include: (1) discouragement of IVC lter use in anticoagulated patients; (2) encouragement of inde nite anticoagulant therapy after a rst unprovoked PE; and (3) discouragement of thrombolytic therapy in PE patients who are not hypotensive and are not deteriorating on anticoagulation. Of the 54 recommendations that are included in the 30 statements in this update, 20 (38%) are strong recommendations (Grade 1) and none is based on high- quality (Grade A) evidence. The absence of high-quality evidence highlights the need for further research to guide VTE treatment decisions. As new evidence becomes available, these guidelines will need to be updated. Goals of our group and CHEST include transition to continually updated living guidelines. The modular format of this update is designed to facilitate this development, with individual topics and questions being addressed as new evidence becomes available. We will also facilitate implementation of our recommendations into practice by developing new and convenient ways to disseminate our recommendations. This will enable achievement of another of our goals reduction in the burden of VTE in individual patients and in the general population. Acknowledgments Author contributions: C. K. was the chair of the panel. C. K., E. A., A. B., J. O., D. J., and L .M. were executive committee members of the panel. C. K. and N. S. were the topic editors for Treatment of Acute Pulmonary Embolism Out of Hospital . C. K. and D. J. were the topic editors for Pulmonary Thromboendarterectomy in the Treatment of Chronic Thromboembolic Pulmonary Hypertension . E. K. and A. B. were the topic editors for Compression Stocking to Prevent Post- Thrombotic Syndrome . E. K. and A. B. were the topic editors for Thrombolytic Therapy in Patients with Upper Extremity Deep Vein Thrombosis . D. J. and C. S. K. were the topic editors for Management of Recurrent Venous Thromboembolism on Anticoagulant Therapy . H. B. and N. S. were the topic editors for Whether and How to Anticoagulate Patients with Isolated Distal Deep Vein Thrombosis . M. H. and H. B. were the topic editors for Catheter-Directed Thrombolysis for Acute Deep Vein Thrombosis of the Leg . M. H. and J. V. were the topic editors for Duration of Anticoagulant Therapy . L. M. and C. S. K. were the topic editors for Whether to Anticoagulate Subsegmental Pulmonary Embolism . S. S., T. M. and P. W. were the topic editors for Catheter-Based Thrombus Removal for the Initial Treatment of Pulmonary Embolism . S.W. and T. M. were the topic editors for Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant . S. S., S. W. and J. V. were the topic editors for Systemic Thrombolytic Therapy for Pulmonary Embolism . L. M. and P. W. were the topic editors for Aspirin for Extended Treatment of Venous Thromboembolism . L. M. and C. S. K. were the topic editors for Role of Inferior Vena Caval Filter in Addition to Anticoagulation in Patients with Acute Deep Vein Thrombosis or Pulmonary Embolism . E. A. and J. O. were methodologists for the panel. A. B. was the GOC liaison to the panel. L. M. was an overall guideline editor. Financial/non nancial disclosures: The authors have reported to CHEST the following: In the past 3 years, E. A. A. was an author on a number of systematic reviews on anticoagulation in patients with cancer. H. B. has received compensation for participation on advisory committees with speaking engagements sponsored by Sano -Aventis, Bayer Healthcare, and Daiichi-Sankyo. His institution has received grant funding (no salary support) from Daiichi-Sankyo for studying VTE treatment. He has also served as a coauthor of original studies using rivaroxaban (EINSTEIN, EINSTEIN Pulmonary Embolism [PE]) and edoxaban (Hokusai-VTE study). M. H. has received grant funding and has delivered talks related to long-term and extended anticoagulation and treatment of subsegmental PE. He has also authored several papers related to long-term and extended anticoagulation, treatment of subsegmental PE, and compression stocking in preventing postthrombotic syndrome. D. J. s institution has received grant funding (no salary support) from Instituto de salud Carlos III, Sociedad Espa ola de Neumolog a y Cirug a Tor cica, and NeumoMadrid for studying PE. He was a member of Steering Committee of the Pulmonary Embolism Thrombosis Study (PEITHO), a principal investigator of an original study related to the role of the inferior vena cava lter in addition to anticoagulation in patients with acute DVT or PE and has participated in the derivation of scores for identi cation of low-risk PE. He has delivered talks related to treatment of acute PE. C. K. has been compensated for speaking engagements sponsored by Boehringer Ingelheim and Bayer Healthcare related to VTE therapy. His institution has received grant funding (no salary support) from the National Institutes of Health related to the topic of catheter-assisted thrombus removal in patients with leg DVT. He has also published many studies related to long- term anticoagulation and compression stockings in preventing postthrombotic syndrome. L. M. has frequently lectured on the duration of long-term anticoagulation and is a coauthor on several risk-strati cation papers. She has received honoraria from CHEST Enterprises for VTE talks. T. M. and C. S. K. have received honoraria from Chest Enterprises for VTE Prep Courses. T. M. s institution has received grant funding (no salary support) from Portola Pharmaceuticals for the Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study (APEX) related to extended prophylaxis against VTE with betrixaban. T. M. s institution received grant support from Bayer Pharmaceuticals for a research project concerning the etiology of chronic thromboembolic pulmonary hypertension. He has also authored textbook chapters related to thrombolytic interventions in patients with acute PE and pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension. S. M. S. s and S. C. W. s institution has received grant funding (no salary support) from the Canadian Institutes of Health for the D-dimer Optimal Duration Study Phase II (DODS- Extension), from Washington University via the National Institutes of Health (Genetic Informatics Trial), Bayer related to VTE (EINSTEIN studies), and from Bristol-Myers Squibb related to apixaban for the Secondary Prevention of Thromboembolism (Apixaban for the Secondary prevention of Thromboembolism: A prospective Randomized Outcome pilot study among patients with the AntiphosPholipid Syndrome). J. R. E. V. s institution has received grant funding (no salary support) from Bristol-Myers Squibb for evaluating the role of apixaban for long-term treatment of VTE. P. W. is a coinvestigator on a grant regarding the treatment of subsegmental PE. He has authored several studies and grants related to the long- term and extended anticoagulation (using vitamin K antagonists and the direct oral anticoagulants). P. 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