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. The increase in bleeding associated with a risk factor will vary with: (1) severity of the risk factor (eg, location and extent of metastatic disease; platelet count); (2) temporal relationships (eg, interval from surgery or a previous bleeding episode197 ); and (3) how effectively a previous cause of bleeding was corrected (eg, upper GI bleeding). c Important for parenteral anticoagulation (eg, rst 10 d), but less important for long-term or extended anticoagulation. d Although there is evidence that risk of bleeding increases with the prevalence of risk factors,187,188,192,194,195,196,198,201,202,204,217,218 the categorization scheme suggested here has not been validated. Further- more, a single risk factor, when severe, will result in a high risk of bleeding (eg, major surgery within the past 2 d; severe thrombocytopenia). e Compared with low-risk patients, moderate-risk patients are assumed to have a twofold risk and high-risk patients are assumed to have an eightfold risk of major bleeding.79,185,187,189,195,196,198,204 f We estimate that anticoagulation is associated with a 2.6-fold increase in major bleeding based on comparison of extended anticoagulation with no extended anticoagulation (Table 6 in AT91 ). The relative risk of major bleeding during the rst 3 mo of therapy may be greater that during extended VKA therapy because: (1) the intensity of anticoagulation with initial parenteral therapy may be greater that with VKA therapy; (2) anticoagulant control will be less stable during the rst 3 mo; and (3) predispositions to anticoagulant-induced bleeding may be uncovered during the rst 3 mo of therapy.189,198,203 However, studies of patients with acute coronary syndromes do not suggest a higher than 2.6 relative risk of major bleeding with parenteral anticoagulation (eg, UFH, LMWH) compared with control.219,220 g 1.6% corresponds to the average of major bleeding with initial UFH or LMWH therapy followed by VKA therapy (Table 7 in AT91 ). We estimated baseline risk by assuming a 2.6 relative risk of major bleeding with anticoagulation (footnote f). h Consistent with frequency of major bleeding observed by Hull in high- i Our estimated baseline risk of major bleeding for low-risk patients (and adjusted up for moderate- and high-risk groups as per footnote e). j Consistent with frequency of major bleeding during prospective studies of extended anticoagulation for VTE (Table 6 in AT91 been treated for 6 or for 12 months. In the same study, all patients without residual DVT after 6 months of LMWH stopped therapy and had a low risk of recurrence during the next year (three episodes in 91 patients). This study s ndings have not changed our recommendations for treatment of VTE in patients with cancer. Evaluations of Extended Anticoagulant Therapy Since AT9: When AT9 was written, extended treatment of VTE with VKA therapy had been evaluated in six studies (mostly patients with unprovoked proximal DVT or PE46,61-64 or a second episode of VTE65 ), and with an NOAC (rivaroxaban vs placebo) in one study of Since AT9, no studies have compared extended VKA therapy with stopping anticoagulants, although the large reduction in recurrent VTE with 18 additional months of VKA therapy compared with placebo (ie, before study drug was stopped) in the PADIS study60 supports AT9 estimates for the ef cacy of extended VKA therapy. Since AT9, two additional studies have compared extended NOAC therapy (dabigatran,47 ) with stopping treatment (ie, placebo). These two studies, and the previous study that evaluated extended treatment with rivaroxaban, found that extended therapy with these three NOAC regimens reduced recurrent VTE by at least 80% and was associated with a modest risk of bleeding (Tables 8-10, e-Tables 10-12).49 These three studies, however, enrolled heterogeneous populations of patients (ie, not con ned to unprovoked VTE) and only followed patients for 6 to 12 months, which limits the implications of their ndings in relationship to extended therapy. When considering the risks and bene ts of extended anticoagulation in this update, the AT10 panel decided TABLE 12 ] Summary of Findings: 6, 12, or 24 mo vs 3 or 6 mo as Minimum Duration of Anticoagulation for VTEa,b Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with No Extended Use Risk Difference with E xtended Use (95% CI) Moderatec,d,e because of imprecision (from 4 fewer to 46 more) Recurrent VTE 2,466 Moderatec,d,e because of imprecision (from 40 fewer to 8 more) Major bleeding 2,466 Moderatec,d,e because of imprecision (from 1 fewer to 27 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). DACUS Warfarin Optimal Duration Italian Pulmonary Embolism; DOTAVK Dur e Optimale du Traitement AntiVitamines K; WODIT-DVT Warfarin Optimal Duration Italian Deep Vein Thrombosis; WODIT-PE Warfarin Optimal Duration Italian Pulmonary Embolism. See Table 1, 4, and 6 legends for expansion of other abbreviations and GRADE Working Group grades of evidence. a Studies vary in follow-up duration (10 mo-3 y) and in duration of time-limited VKA (3-6 mo). b VKA as NOACs are not included. c Timing of randomization relative to the start of treatment and length of treatment varied across studies: Pinede et al223 and Campbell et al222 randomized at diagnosis; and Agnelli et al,223 Eischer et al,227 and Couturaud et al60 randomized after the initial 3 mo (Agnelli et al224 ) or 6 mo (Eischer et al227 Couturaud et al60 ) of treatment to stop or continued treatment. The longer duration of treatment was 6 mo in Agnelli et al224 (provoked PE) and Pinede et al,223 , 12 mo in Agnelli et al224,225 (unprovoked DVT; unprovoked PE), 24 mo in Couturaud et al,60 and 30 mo in Eischer et al.227 Generally, study design was strong. No study stopped early for bene t; 3 stopped early because of slow recruitment (Campbell et al,222 Pinede et al,223 Eischer et al227 ) and 1 because of lack of bene t (Agnelli et al224 ). In 1 study (Campbell et al222 ), 20% of VTE outcomes were not objectively con rmed. Patients and caregivers were blinded in Couturaud et al,60 but none of the other studies was. Adjudicators of outcomes were blinded in all but 1 study (Campbell et al222 ). All studies used effective randomization concealment, intention-to-treat analysis, and a low unexplained dropout frequency. d Study populations varied across studies: Pinede et al223 enrolled provoked and unprovoked proximal DVT and PE; Campbell et al,222 enrolled provoked and unprovoked isolated distal DVT, proximal DVT, and PE; Agnelli et al224 had separate randomizations for provoked PE (3 vs 6 mo) and unprovoked (3 vs 12 mo); Agnelli et al225 enrolled unprovoked proximal DVT; Eischer et al227 enrolled unprovoked isolated DVT, proximal DVT, and PE with high levels of factor VIII; and Couturaud et al60 enrolled unprovoked PE. e CIs include both values suggesting no effect and values suggesting either bene t or harm. Bibliography: Campbell et al,222 Pinede et al223 (DOTAVK), Agnelli (WODIT-PE Provoked and Unprovoked), Agnelli et al225 (WODIT-DVT), Couturaud et al60 (PADIS-PE), Siragusa et al226 (DACUS), Eischer et al227 (AUREC-FVIII) 330 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] to use the same estimates for the reduction in recurrent VTE and the increase in bleeding with anticoagulation that we used in AT9, and that were based on VKA therapy. Our reasoning was: (1) VKA is still widely used for extended treatment of VTE; (2) we felt that there was not enough evidence of differences in ef cacy and bleeding during extended therapy to justify separate recommendations for NOACs, either as a group or as individual agents; and (3) our recommendations about whether or not to use extended therapy were not sensitive to assuming that there was a one-third reduction in bleeding with extended therapy compared with the estimated risk of bleeding with extended therapy that are shown in Table 11 and were used in AT9 (eg, with a NOAC compared with VKA)27,31,35,49 (the only recommendation to change would be a strong instead of a weak recommendation in favor of extended therapy in patients with a second unprovoked VTE who had a moderate risk of bleeding). Better Selection of Patients for Extended VTE Therapy: The most common and dif cult decision about whether to stop anticoagulants after a time- limited course or to use extended therapy is in patients with a rst unprovoked proximal DVT or PE without a high risk of bleeding. In this subgroup of patients, patient sex and D-dimer level measured about 1 month after stopping anticoagulant therapy can help to further stratify the risk of recurrent VTE.66-69 Men have about a 75% higher (1.75-fold) risk of recurrence compared with women, whereas patients with a positive D-dimer result have about double the risk of recurrence compared with those with a negative D-dimer, and the predictive value of these two factors appears to be additive. The risk of recurrence in women with a negative posttreatment D-dimer appears to be similar to the risk that we have estimated for patients with a proximal DVT or PE that was provoked by a minor transient risk factor (approximately 15% recurrence at 5 years); consequently, the argument for extended anticoagulation in these women is not strong, suggesting that D-dimer testing will often in uence a woman s decision. The risk of recurrence in men with a negative D-dimer is not much less than the overall risk of recurrence that we have estimated for patients with an unprovoked proximal DVT or PE (approximately 25% compared with approximately 30% recurrence at 5 years); consequently, the argument for extended anticoagulation in these men is still substantial, suggesting that D-dimer testing will often not in uence a male s decision. Because there is still uncertainty about how to use D-dimer testing and a patient s sex to make decisions about extended therapy in patients with a rst unprovoked VTE, we have not made recommendations based on these factors. Revised Recommendations: These are unchanged from AT9 with one minor exception. A qualifying remark has been added to the recommendation that suggests extended therapy over stopping treatment at 3 months in patients with a rst unprovoked proximal DVT or PE and a low or moderate risk of bleeding; this remark notes that patient sex and D-dimer level measured a month after stopping anticoagulant therapy may in uence this treatment decision. If it becomes clear that, during the extended phase of treatment, there are important differences in the risk of recurrence or bleeding with the different anticoagulant agents, agent-speci c recommendations for extended therapy may become justi ed. 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). 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 unpro- voked 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 sched- uled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recom- mend 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 anticoagulant therapy 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), and (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 Summary of the Evidence AT9 did not address if there was a role for aspirin, or antiplatelet therapy generally, in the treatment of VTE. Since then, two randomized trials have compared aspirin with placebo for the prevention of recurrent VTE in patients with a rst unprovoked proximal DVT or PE who have completed 3 to 18 months of anticoagulant These trials provide moderate-quality evidence that extended aspirin therapy reduces recurrent VTE by about one-third. In these trials, the bene ts of aspirin outweighed the increase in bleeding, which was not statistically signi cant (Table 13, e-Table 14). The two trials enrolled patients with a rst unprovoked VTE who did not have an increased risk of bleeding; patients for whom these guidelines have suggested extended anticoagulant therapy. Extended anticoagulant therapy is expected to reduce recurrent VTE by more than 80% and extended NOAC therapy may be associated with the same risk of bleeding as aspirin.49,50 If patients with a rst unprovoked VTE decline extended anticoagulant therapy because they have risk factors for bleeding or because they have a lower than average risk of recurrence, the net bene t of aspirin therapy is expected to be less than in the two trials that evaluated aspirin for extended treatment of VTE. Based on indirect comparisons, we expect the net bene t of extended anticoagulant therapy in patients with unprovoked VTE to be substantially greater than the bene ts of extended aspirin therapy.49 Consequently, 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 332 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] anticoagulants, prevention of recurrent VTE is one of the bene ts of aspirin (may also include reductions in arterial thrombosis and colon cancer) that needs to be balanced against aspirin s risk of bleeding and inconvenience. Use of aspirin should also be reevaluated when patients with VTE stop anticoagulant therapy because aspirin may have been stopped when anticoagulants were started (Table 13, e-Table 14). *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 Prescribe Anticoagulants to Patients With Isolated Distal DVT Summary of the Evidence AT9 discouraged routine whole-leg US examinations (ie, including the distal veins) in patients with suspected DVT, thereby reducing how often isolated distal DVT is The rationale for not routinely examining the distal veins in patients who have had proximal DVT excluded is that: (1) other assessment may already indicate that isolated distal DVT is either unlikely to be present or unlikely to cause complications if it is present (eg, low clinical probability of DVT, D-dimer is negative); (2) if these conditions are not met, a repeat US examination of the proximal veins can be done after a week to detect possible DVT extension and the need for treatment; and (3) false-positive ndings for DVT occur more often with US examinations of the distal compared with the proximal veins.1,73,74 If the calf veins are imaged (usually with US) and isolated distal DVT is diagnosed, there are two management options: (1) treat patients with anticoagulant therapy or (2) do not treat patients with anticoagulant therapy unless extension of their DVT is detected on a follow-up US examination (eg, after 1 and TABLE 13 ] Summary of Findings: Aspirin vs Placebo for Extended Treatment of VTE Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with Control Risk Difference with Aspirin (95% CI) All-cause mortality Up to 4 y Lowa,b because of imprecision Moderate-Risk Populationd (from 3 fewer to 3 more) Recurrent VTE 1,224 Up to 4 y Moderatea because of imprecision (from 24 fewer to 89 fewer) Major bleeding 1,224 Up to 4 y Moderatea,b because of imprecision (from 6 fewer to 29 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). ASPIRE Aspirin to Prevent Recurrent Venous Thromboembolism; HR hazard ratio; INSPIRE International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism; WARFASA Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin) study. See Table 1 legend for expansion of other abbreviations and GRADE Working Group grades of evidence. a The Brighton et al70 study was stopped early and included only one-third of the intended patients. b CI includes values suggesting no effect and values suggesting either bene t or harm. c Estimate based on Simes et al72 (INSPIRE) of synthesis of Brighton et al70 (ASPIRE) and Becattini et al71 (WARFASA). d Estimate taken from Douketis et al.228 Bibliography: Simes et al72 (INSPIRE) 2 weeks, or sooner if there is concern; there is no widely accepted protocol for surveillance US testing).75 Because about 15% of untreated isolated distal DVT are expected to subsequently extend into the popliteal vein and may cause PE, it is not acceptable to neither anticoagulate nor do surveillance to detect thrombus extension.1,76-79 In AT9, we judged that there was high-quality evidence that anticoagulant therapy was effective for the treatment of proximal DVT and PE, but uncertainty that the bene ts of anticoagulation outweigh its risks in patients with isolated distal DVT because of their lower risk of progressive or recurrent VTE. We suggest the following as risk factors for extension of distal DVT that would favor anticoagulation over surveillance: (1) D-dimer is positive (particularly when markedly so without an alternative reason); (2) thrombosis is extensive (eg, >5 cm in length, involves multiple veins, >7 mm in maximum diameter); (3) thrombosis is close to the proximal veins; (4) there is no reversible provoking factor for DVT; (5) active cancer; (6) history of VTE; and (7) inpatient status.1,75-77,80-84 We consider thrombosis that is con ned to the muscular veins of the calf (ie,, soleus, gastrocnemius) to have a lower risk of extension than thrombosis that involves the axial (ie, true deep; peroneal, tibial) veins.76,81,85 Severe symptoms favor anticoagulation, a high risk for bleeding (Table 11) favors surveillance, and the decision to use anticoagulation or surveillance is expected to be sensitive to patient preferences. We anticipate that isolated distal DVT that are detected using a selective approach to whole-leg US will often satisfy criteria for initial anticoagulation, whereas distal DVT detected by routine whole-leg US often will not. The updated literature search did not identify any new randomized trials that assessed management of patients with isolated distal DVT. Two new systematic and a narrative review83 addressed treatment of isolated distal DVT. In addition to summarizing available data, consistent with AT9, they emphasize the limitations of available evidence. In the absence of substantive new evidence, the panel endorsed the AT9 recommendations without revision. The evidence supporting these recommendations remains low quality because it is not based on direct comparisons of the two management strategies, and ability to predict extension of distal DVT is limited. 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), and (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). CDT for Acute DVT of the Leg Summary of the Evidence At the time of AT9, there was one small randomized comparing the effect of CDT vs anticoagulant alone on development of PTS, and another larger randomized trial (Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis [CAVENT] Study) assessing short-term (eg, venous patency and bleeding) but not long-term (eg, PTS) The CAVENT Study has since reported that CDT reduced PTS, did not alter quality of life, and appears to be cost-effective (Table 14, e-Table 15).89-92 A retrospective analysis found that CDT (3649 patients) was associated with an increase in transfusion (twofold), intracranial bleeding (threefold), PE (1.5-fold), and vena caval lter insertion (twofold); long-term outcomes and PTS were not reported.93 A single-center prospective registry found that US-assisted CDT in acute iliofemoral (87 patients) achieved high rates of venous patency, was rarely associated with bleeding, and that only 6% of patients had PTS at 1 year.94 This new evidence has not led to a change in our recommendation for the use of CDT in patients with 334 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] DVT. Although the quality of the evidence has improved, the overall quality is still low because of very serious imprecision. Unchanged from AT9, we propose that the patients who are most likely to bene t from CDT have iliofemoral DVT, symptoms for <14 days, good functional status, life expectancy of $1 year, and a low risk of bleeding (Tables 14 and 15, e-Table 15). Because the balance of risks and bene ts with CDT is TABLE 14 ] Summary of Findings: Catheter-Assisted Thrombus Removal vs Anticoagulation Alone for Acute Leg DVT Outcomes No. of Participants (Studies) Follow-up Quality of the Evidence (GRADE) Relative Effect Anticipated Absolute Effects Risk with Anticoagulation Alone Risk Difference with Catheter-Assisted Thrombus Removal (95% CI) All-cause mortality Lowa,b because of imprecision (from 43 fewer to 54 more) Recurrent VTE 189 Lowa,b because of imprecision Moderate-Risk Populatione (from 34 fewer to 12 more) Major bleeding 224 studies) Lowa,b because of imprecision Moderate-Risk Populatione,f (from 17 fewer to 1000 more) Moderatea because of imprecision Moderate-Risk Populationh (from 265 fewer to 0 more)i Moderateb because of imprecision (from 41 more to 386 more) Moderatek because of risk of bias The mean quality of life in the intervention groups was 0.2 higher (2.8 lower to 3 higher)l,m 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). CAVENT Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis; EQ-5D EuroQol 5 Dimensions; PTS postthrombotic syndrome; QoL quality of life. See Table 1 and 4 legends for expansion of other abbreviations and GRADE Working Group grades of evidence. a CI includes values suggesting both bene t and harm. b Low number of events. c Reported deaths from Enden et al90 (CAVENT). d Estimate taken from Watson et al.229 The 1 study included for this outcome was Enden et al90 (CAVENT). e Baseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.231 f Most of bleeding events occur during the rst 7 d. g This estimate is based on the Watson et al.229 The 1 study included for this outcome was Enden et al90 (CAVENT). For PTS at 6 mo, published data from Enden et al90 (CAVENT) provide an estimate RR of 0.93 (0.61-1.42) via Watson et al.229 h This estimate is based on the ndings of the VETO study.232 i For severe PTS, assuming the same RR of 0.46 and a baseline risk of 13.8%,232 the absolute reduction is 75 fewer severe PTS per 1,000 (from 29 fewer to 138 fewer) over 2 y. j Reported patency from Enden et al90 (CAVENT). k Open-label. l Disease-speci c QoL (VEINES-QOL) estimate used at 24 mo according to treatment allocation. m Generic QoL (EQ-5D) at 24 mo according to treatment allocation estimate is mean difference 0.04 (-0.01 to 0.17). Bibliography: Watson et al229 used for all outcomes except patency and QoL; Enden et al90 used for patency estimates; Enden et al230 used for QoL estimates. uncertain, we consider that anticoagulant therapy alone is an acceptable alternative to CDT in all patients with acute DVT who do not have impending venous gangrene. 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 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 IVC Filter in Addition to Anticoagulation for Acute DVT or PE Summary of the Evidence Our recommendation in AT9 was primarily based on ndings of the Prevention du Risque d Embolie Pulmonaire par Interruption Cave (PREPIC) randomized which showed that placement of a permanent IVC lter increased DVT, decreased PE, and did not in uence VTE(DVTand PEcombined)ormortality.Since then, several registries have suggested that IVC lters can reduce early mortality inpatients with acute VTE, although this evidence has been questioned.97-101 The recently published PREPIC 2 randomized trial found that placement of an IVC lter for 3 months did not reduce recurrent PE, including fatal PE, in anticoagulated patients with PE and DVT who had additional risk factors for This newevidence is consistent with our recommendations in AT9. However, because it is uncertain if there is bene t to placement of an IVC lter in anticoagulated patients with severe PE (eg, with hypotension), and this is done by some experts, our recommendation against insertion of an IVC lter in patients with acute PE who are anticoagulated may not apply to this select subgroup of patients. Although the PREPIC 2 study has improved the quality of evidence for this recommendation, overall quality is still moderate because of imprecision (Table 16, e-Table 16). The AT10 panel decided against combining the results of TABLE 15 ] Risk Factors for Bleeding With, and Contraindications to Use of, Thrombolytic Therapy (Both Systemic and Locally Administered) Major Contraindicationsa Structural intracranial disease Previous intracranial hemorrhage Ischemic stroke within 3 mo Active bleeding Recent brain or spinal surgery Recent head trauma with fracture or brain injury Bleeding diathesis Relative contraindicationsb Systolic BP >180 Diastolic BP >110 Recent bleeding (nonintracranial) Recent surgery Recent invasive procedure Ischemic stroke more than 3 mo previously Anticoagulated (eg, VKA therapy) Traumatic cardiopulmonary resuscitation Pericarditis or pericardial uid Diabetic retinopathy Pregnancy Age >75 y Low body weight (eg, <60 kg) Female Black race See Table 1 and 6 legends for expansion of abbreviations and GRADE Working Group grades of evidence. a The presence of major contraindications usually precludes use of thrombolytic therapy; consequently, these factors have not been well studied as risk factors for bleeding associated with thrombolytic therapy. Patients with 1 or more major contraindication are usually considered to be high risk for bleeding with thrombolytic therapy. The factors listed in this table are consistent with other recommendations for the use of thrombolytic therapy in patients with PE.138,233-235 b Risk factors for bleeding during anticoagulant therapy that are noted in Table 11 that are not included in this table are also likely to be relative contraindications to thrombolytic therapy. The increase in bleeding associ- atedwith a risk factor will vary with:(1) severity of the risk factor (eg, extent of trauma or recent surgery) and (2) temporal relationships (eg, interval from surgery or a previous bleeding episode; believed to decrease markedly after approximately 2 wk). Risk factorsfor bleeding at critical sites (eg, intracranial, intraocular) or noncompressible sites are stronger contraindications for thrombolytic therapy. Depending on the nature, severity, temporality, and numberofrelative contraindications,patientsmay beconsidered highriskof bleeding with thrombolytic therapy or non-high risk for thrombolytic therapy. Patients with no risk factors, 1-2 minor risk factors (eg, female and black race) are usually considered low risk of bleeding with thrombolytic therapy. Among 32,000 Medicare patients ($65 y) with myocardial infrac- tion who were treated with thrombolytic therapy, the following factors were independently associated with intracranial haemorrhage: age $75 y (OR, 1.6); black (OR, 1.6); female (OR, 1.4); previous stroke (OR, 1.5); systolic BP $160 mm Hg (OR, 1.8); women #65 kg or men # 80 kg (OR, 1.5); The rate of intracranial hemorrhage increased from 0.7% with 0 or 1 of these risk factors, to 4.1% with $5 risk factors. Among 32,000 patients with myocardial infraction who were treated with thrombolytic therapy in 5 clinical trials, the following factors were indepen- dently associated with moderate or severe bleeding: older age (OR, 1.04 per year); black (OR, 1.4); female (OR, 1.5); hypertension (OR, 1.2); lower weight We estimate that systemic thrombolytic therapy is associated with relative risk of major bleeding of 3.5 within 35 d (RR, approximately 7 for intracranial bleeding); about three-quarters of the excess of major bleeds with thrombolytic therapy occur in the rst 24 h.141 336 Evidence-Based Medicine [ 1 4 9 # 2 C H E S T F E B R U A R Y 2 0 1 6 ] the PREPIC and PREPIC 2 studies because of differences in the type of lter used, the duration of lter placement, and differences in the length of follow-up. 17. In patients with acute DVT or PE who are treated with anticoagulants, we recommend against the use of an IVC lter (Grade 1B). Compression Stocking to Prevent PTS Summary of the Evidence AT9 suggested routine use of graduated compression stockings for 2 years after DVT to reduce the risk of PTS. Thatrecommendationwasmainlybased on ndingsoftwo small, single-center, randomized trials in which patients and study personnel were not blinded to stocking use (no The quality of the evidence was moderate because of risk of bias resulting from a lack of blinding of an outcome (PTS) that has a large subjective component and because of serious imprecision of the combined ndings of the two trials (Table 17, e-Table 17). Since AT9, a much larger multicenter, placebo-controlled trial at low risk of bias found that routine use of graduated compression stockings did not reduce PTS or have other Based on this trial, we now suggest that graduated compression stockings not be used routinely to prevent PTS and consider the quality to the evidence to be moderate (Table 17, e-Table 17). The same study found that routine use of graduated compression stockings did not reduce leg pain during the 3 months after DVT diagnosis (Table 17, e-Tables 2 This nding, however, does not mean that graduated compression stockings will not reduce acute symptoms of DVT or chronic symptoms in those who have developed 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 Treat Subsegmental PE Summary of the Evidence Subsegmental PE refers to PE that is con ned to the subsegmental pulmonary arteries. Whether these patients should be treated, a question that was not addressed in AT9, has grown in importance because improvements in CT pulmonary angiography have increased how often subsegmental PE is diagnosed (ie, from approximately 5% to more than 10% of TABLE 16 ] Summary of Findings: Temporary IVC Filter vs No Temporary IVC Filter in Addition to Anticoagulation for Acute DVT or PEa,b Outcomes No. 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. 