Successful strategies used to improve medication adherence in other chronic disease states have included (1) ensuring access to providers across the continuum of care and implementing team- based care (see recommendation 11); (2) educating and empower- ing patients to understand the treatment regimen and its benefits (see recommendation 12); (3) reducing barriers to obtaining medication, including cost reduction and efforts to retain or reengage patients in care; and (4) use of health information technology tools to improve decision-making and communication during and after office visits (see recommendations 3 and 4).165 The panel identified the following additional research priority: develop- ment and testing of adherence interventions that are acceptable, feasible, and affordable, especially for patients on DOAC or on VKA and not considered eligible for PST or PSM, and determining the impact of those interventions on clinical outcomes and cost-effectiveness. For patients receiving anticoagulation therapy for treatment of VTE, the ASH guideline panel suggests against using elec- tronic reminders (daily alarm via an electronic medication monitoring system) to improve medication adherence (condi- tional recommendation based on very low certainty in the evi- dence about effects ). Remark: This recommendation applies specifically to a sophisticated alert system used in the study evaluated by the panel. Summary of the evidence. One RCT reported the effect of an electronic medication monitoring system with a daily alarm to remind patients to take their anticoagulant medication as sched- The main outcome was anticoagulation control, as measured by out-of-range INRs, and secondary outcomes included mortality, bleeding, and thromboembolic events. The EtD framework is shown online at https://dbep.gradepro.org/profile/92492887-D3C0-CAC2- BEEE-D88978A91C30. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. The percentage time out-of-INR range was lower in the electronic reminder group than in controls (adjusted OR for likelihood of being out of INR range, 0.64 [95% CI, 0.45-0.93]; very low certainty). There was no difference in median days with incorrect adherence between the electronic reminder and control groups (difference in the fully adjusted model for percentage incorrect adherence, 22.0% [95% CI, 28.2 to 4.2]; very low certainty). Harms and burden. There was no effect of electronic reminders on mortality and PE/DVT because these outcomes did not occur in any study patient. There was no difference in major bleeding between the electronic reminders group and controls (RR, 45 fewer to 178 more per 1000]; very low certainty). Other EtD criteria and considerations. Resource require- ments for the electronic reminder system would be large. Furthermore, the panel determined that given the requirement for specialized equipment, the intervention is probably not feasible to implement in most settings. Conclusions and research needs for this recommendation. Given the large uncertainty regarding net health benefit/harm from using electronic reminders to improve adherence to anticoagula- tion therapy for patients receiving treatment of VTE, the high costs, and the probable lack of feasibility, the panel suggests against using electronic reminders. See recommendation 13a for additional comments regarding adherence interventions in general and research needs pertaining to this recommendation. For patients receiving anticoagulation therapy for treatment of VTE, the ASH guideline panel recommends against using a daily lottery (see recommendation 13a) plus electronic re- minders (see recommendation 13b) to improve medication adherence (strong recommendation based on very low cer- tainty in the evidence about effects ). Remark: This recommendation applies specifically to a sophisticated alert system used in the study evaluated by the panel. Summary of the evidence. One RCT reported the effect of a daily lottery-based incentive intervention combined with an electronic medication monitoring system with a daily alarm to remind patients to take their anticoagulant medication as scheduled.162 The main outcome was anticoagulation control as measured by out-of-range INRs, and secondary outcomes included mortality, bleeding, and thromboem- bolic events. The EtD framework is shown online at https://dbep. gradepro.org/profile/06290825-AF53-134F-9191-7E26113C0FDA. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. The percentage time outside of the INR range was lower in the group with the daily lottery plus electronic reminder than in controls, but the CI was wide and included no effect (adjusted OR for likelihood of being out of INR range, 0.77 [95% CI, 0.54-1.09]; very low certainty). There was no difference in median days with incorrect adherence between the group with the daily lottery plus electronic reminder and the control group (difference in the fully adjusted model for percentage incorrect adherence, 24.6% [95% CI, 211.1 to 1.9]; very low certainty). Harms and burden. There was no effect of a daily lottery plus electronic reminders on mortality and PE/DVT because these outcomes did not occur in any study patient. There was no difference in major bleeding between the daily lottery plus electronic reminder group and control (RR, 1.23 [95% CI, 0.35-4.38]; ARR, 14 more episodes per 1000 [95% CI, 40 fewer to 208 more per 1000]; very low certainty). Other EtD criteria and considerations. Resource require- ments for the daily lottery would be large because the use of an electronic medication monitoring system would be required for each patient, and cost for monetary prizes averaged $3 per patient per day. Furthermore, key stakeholders would probably not find a daily lottery acceptable, and given the requirement for specialized equipment, the intervention is probably not feasible to implement in most settings. Conclusions and research needs for this recommendation. The panel decided on a strong recommendation against the intervention based on very low quality evidence pointing toward harm for all critical outcomes and on the intervention having high costs and probably not being acceptable or feasible. The GRADE approach includes situations in which strong recommendations are warranted despite very low certainty in evidence about the effects, including situations where the panel determined there is high certainty that cost of the intervention outweighs any potential benefits.166 See recommen- dation 13a for additional comments regarding adherence interventions in general and research needs pertaining to this recommendation. For patients receiving anticoagulation therapy for treatment of VTE, the ASH guideline panel suggests against using visual medication schedules (provided to patients at each visit, along with brief counseling) to improve medication adherence (con- ditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. One RCT reported the effect of a visual medication schedule provided to patients at each visit, along with brief counseling.164 The main outcome was the time elapsed before achieving target anticoagulant control. Secondary outcomes included TTR during the 90-day study period, mortal- ity, and hospitalizations. The EtD framework is shown online at 1ECEC061E826. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Compared with controls, a visual medication schedule modestly increased TTR, but the CI included no effect (MD, 2.6% higher [95% CI, 7.6% lower to 12.9% higher]; very low certainty). There was no effect of a visual medication schedule on PE/DVT because these outcomes did not occur in any study patient. Harms and burden. The estimate of the intervention on mortality was unreliable as only 1 death occurred in the study (ARR, 14 more per 1000; very low certainty). Hospitalization was increased in those using the visual medication schedule (RR, 1000 [95% CI, 3 more to 568 more per 1000]; very low certainty). 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3275 Other EtD criteria and considerations. The intervention was feasible to implement, as it is currently being used in some settings. Although costs have not been formally assessed, they are likely moderate. Conclusions and research needs for this recommendation. Given that the net health benefit/harm from using a visual medication schedule to improve adherence to anticoagulation therapy for patients receiving treatment of VTE remains very uncertain and the costs are moderate, the panel suggests against using visual medication schedules as defined in the included study. See recommendation 13a for additional comments regarding adherence interventions in general and research needs pertaining to this recommendation. Invasive procedure management Question: For patients at low to moderate risk of recurrent VTE who require interruption of VKA therapy for invasive procedures, should periprocedural bridging with LMWH or UHF vs interruption of VKA therapy alone be used? For patients at low to moderate risk of recurrent VTE (see Table 4) who require interruption of VKA therapy for invasive procedures, the ASH guideline panel recommends against periprocedural bridging with LMWH or UHF in favor of in- terruption of VKA alone (strong recommendation based on moderate certainty in the evidence about effects ). Summary of the evidence. We found 1 systematic review that addressed this question,167 but we did not use any studies in the evidence for this question because (1) they evaluated patients receiving anticoagulation therapy for mixed indications, and iso- lating the minority of patients with low to moderate risk of recurrent VTE was not possible, or (2) the studies included only patients with indications for anticoagulation therapy other than VTE. We identified 2 additional relevant studies.168,169 Mortality, recurrent VTE, and clinically relevant bleeding outcomes were derived from an observational study that included patients receiving warfarin therapy for treatment of VTE who required anticoagulation interruption for The other study was an RCT evaluating uninterrupted vs interrupted anticoagulation during pacemaker or defibrillator surgery and reported patient satisfaction (a surrogate measure of quality-of-life impairment) and delay of intervention as Although only 5% of patients in this study had VTE as the indication for anticoagulation therapy, the evidence for these outcomes was considered relevant for our population of interest. The EtD framework is shown online at https://dbep.gradepro.org/ profile/510d8142-f0d4-47f4-8998-e153cec6018f. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. There was no effect of bridging therapy on mortality risk because no deaths occurred during the 30-day follow-up period in either group (low certainty evidence). Bridging with LMWH may reduce the risk for any recurrent VTE, but the effect, if present, is probably very small, and the relative effect CI includes both important benefit and important harm. Because very few events occur for patients at low to moderate risk for recurrent VTE, the magnitude of the absolute effect, whatever the true relative effect, will be very small, and the certainty in evidence for recurrent VTE was upgraded (RR, 0.34 [95% CI, 0.02-6.58]; ARR, 2 fewer DVTs certainty). Harms and burden. The risk of clinically relevant bleeding was increased among those receiving bridging with LMWH compared with those who interrupted warfarin therapy alone (RR, per 1000 [95% CI, 3 more to 196 more per 1000]; very low certainty). Bridging with LMWH was associated with lower patient satisfaction (MD, 0.5 lower [95% CI, 0.25 lower to 0.75 lower]; low certainty) and increased the risk of delay in intervention, as measured by a composite of prolonged hospitalization and hematoma requiring interruption of anticoagulation or evacuation (RR, 4.57 [95% CI, 2.49-8.38]; ARR, 125 more delayed interventions per 1000 [95% CI, 52 more to 258 more]; low certainty). Other EtD criteria and considerations. The resource requirements associated with LMWH bridging are likely to be large, driven by the LMWH cost, complexity of teaching patients the intervention, and management of bleeding events. Conclusions and research needs for this recommendation. When the evidence for this question was weighed, a much higher value was placed on the risk for bleeding, which has been consistently associated with LMWH bridging in available studies, than on the possible reduction in the risk of recurrent VTE, which in this patient population is very small. The panel was confident that that the desirable effects of LMWH bridging are outweighed by the undesirable effects and that a strong recommendation against LMWH bridging was warranted. This recommendation does not apply to patients requiring VKA therapy for indications in addition to VTE (eg, mechanical heart valves). The panel identified the following additional research priority: sufficiently powered RCTs comparing LMWH/UFH bridging vs VKA interruption alone in VTE patients at high recurrent VTE risk undergoing an invasive procedure. Question: For patients interrupting DOAC therapy for scheduled invasive procedures, should performing laboratory testing for DOAC anticoagulant effect be used vs interrupting DOAC therapy alone? For patients interrupting DOAC therapy for scheduled invasive procedures, the ASH guideline panel suggests against per- forming laboratory testing for DOAC anticoagulant effect prior to procedures (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. We found no systematic reviews but did identify 5 individual studies that included patients receiving DOAC therapy, mostly for atrial fibrillation, who required temporary interruption of anticoagulation for an invasive No studies directly compared outcomes for patients interrupting DOAC therapy for invasive procedures in which laboratory testing to assess DOAC anticoagulant effect was and was not performed prior to the procedure; thus, intervention and control studies represent different populations. Event rates for the intervention groups171,172,174 came from different studies than the event rate for the control groups.170,173 Three studies reported mortality outcomes,170,171,174 and 5 studies reported development of any thromboembolism and major bleeding.170-174 No studies reported quality of life or delays in procedure outcomes. The EtD framework is shown online at https://dbep.gradepro.org/ profile/ee27563e-0db8-464d-ae48-0e72bec3da3b. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Indirect comparison of the available evidence from separate studies showed that laboratory testing to assess DOAC effect prior to invasive procedures may or may not reduce mortality (RR, 0.47 fewer to 8 more]; very low certainty) and VTE (RR, 0.37 [95% CI, more]; very low certainty). Harms and burden. Indirect comparison of the available evidence from separate studies showed that laboratory testing to assess DOAC effect prior to invasive procedures had no effect on the risk of major bleeding compared with interrupting DOAC alone [95% CI, 10 fewer to 15 more per 1000]; very low certainty). Other EtD criteria and considerations. There is very little evidence bearing on other EtD criteria. Conclusions and research needs for this recommendation. The net health benefit/harm from laboratory testing to assess DOAC effect prior to scheduled invasive procedures compared with interrupting DOAC therapy remains very uncertain. Further- more, the clinical use of DOAC tests is not well established, and there is no evidence to support a beneficial effect. Therefore, the panel made a conditional suggestion against confirming the absence of DOAC effect prior to proceeding with scheduled invasive procedures. Confirming the absence of DOAC affect may be advisable in scenarios where anticoagulant effect may be prolonged (eg, patients with renal dysfunction and/or on interacting drugs), when DOAC interruption cannot be reliably confirmed by the patient/caregiver (eg, urgent or emergent invasive procedures), or for patients undergoing a procedure that entails a very high risk of bleeding. It is advisable not to rely on any single (either pharmacokinetic or laboratory) strategy in isolation to assess DOAC effect prior to procedures but instead to use a comprehen- sive approach to assessing, confirming, and communicating DOAC cessation of therapy among the patient and all providers involved. The panel identified the following additional research priorities: (1) developing validated specific DOAC effect tests, particularly those that can be performed rapidly and, ideally, at the point of care; (2) testing the effect on clinical outcomes of using a validated specific DOAC test with prespecified thresholds at which patients on DOACs can safely proceed to surgery or invasive diagnostic procedures; (3) assessing the cost-effectiveness, acceptability, and feasibility of implementing a validated specific DOAC test. Excessive anticoagulation and bleeding management. Question: For patients receiving VKA for treatment of VTE with INRs of .4.5 but ,10 and without clinically relevant bleeding, should temporary cessation of VKA plus administration of vitamin K vs temporary cessation of VKA alone be used? For patients receiving VKA for treatment of VTE with INRs of .4.5 but ,10 and without clinically relevant bleeding, the ASH guideline panel suggests using temporary cessation of VKA alone without the addition of vitamin K (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. We included eligible studies from the most recent systematic review in nonbleeding patients who did and did not receive oral vitamin K for an INR of .4.5 but ,10 (or the upper limit of the laboratory INR readout).175 The search was updated from 2006 onward, yielding a total of 5 RCTs.176-180 Three studies reported the effect of vitamin K administration on 2 studies reported on development of any thromboembolism and major bleeding,176,179 1 study reported the outcome of DVT,176 and 5 studies reported the proportion of patients who reached various INR goal ranges.176-180 No studies reported the outcomes of emergency department visits, hospitalization, or quality- of-life impairment. The EtD framework is shown online at https://dbep. gradepro.org/profile/a457eb13-cb1d-40a8-a081-5e0c535d2a49. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Administration of oral vitamin K in addition to withholding VKA did not reduce the risk of all-cause mortality compared with withholding VKA alone (RR, 1.24 [95% CI, 0.62- per 1000]; moderate certainty) or affect the proportion of patients who achieved the target INR (RR, 1.95 [95% CI, 0.88-4.33]; ARR, 165 more per 1000 [95% CI, 21 fewer to 579 more per 1000]; very low certainty), but the CI for both mortality and INR goal attainment includes appreciable reduction and increase in events. The risk of major bleeding was higher among those receiving oral vitamin K than those receiving placebo, but the CI includes the possibility of a very small bleeding reduction (RR, 2.43 [95% CI, 0.81-7.27]; ARR, 14 more major bleeds per 1000 [95% CI, 2 fewer to 61 more per 1000]; moderate certainty). Harms and burden. Administration of oral vitamin K in addition to withholding VKA did not increase the risk of any thromboembolism compared with withholding VKA alone (RR, 1.29 [95% CI, 0.35-4.78]; more per 1000]; moderate certainty). The estimate of oral vitamin K administration on the risk for DVT is imprecise, and the CI includes the possibility of no effect (RR, 0.32 [95% CI, 0.01-8.04]; ARR, 15 fewer DVTs per 1000 [95% CI, 23 fewer to 160 more per 1000]; moderate certainty). Other EtD criteria and considerations. The panel agreed that resource requirements associated with administering oral vitamin K are likely to be moderate owing to the high cost of pharmaceutical-grade phytonadione (vitamin K) in the United States. The feasibility of using over-the-counter (OTC) sources of vitamin K may be constrained by the variable quality and actual 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3277 active-ingredient content of available OTC vitamin K formulations (available OTC tablet strengths would require the administration of many tablets to achieve recommended doses, and there have been reports that some OTC brands contain less or more actual vitamin K than advertised on the product label).181 Conclusions and research needs for this recommendation. Based on the low quality of the available evidence, the guideline panel remained uncertain regarding the net benefit associated with administration of oral vitamin K in addition to withholding VKA doses for patients presenting with INRs between 4.5 and 10.0 (or the upper limit of the laboratory readout). Given the high cost of prescription oral vitamin K tablets in the United States and the variable vitamin K content of available OTC products, the panel conditionally recom- mends against administering oral vitamin K. Administration of oral vitamin K might be considered for patients at high risk of developing bleeding complications (eg, those who have undergone recent surgical procedures) or in situations where the INR is expected to be prolonged for a longer period of time (eg, intentional overdose, presence of interacting drugs, or very low weekly VKA dose requirement). Data for VKAs other than warfarin are limited, reducing confidence in this recommendation for patients treated with phenprocoumon, which has a longer half-life than warfarin. The panel identified the following additional research questions. (1) Is withholding VKA alone a safe and effective option for patients presenting with INRs of .10.0 in the absence of bleeding? (2) What is the minimum amount of oral vitamin K required to reverse the hypoprothrombinemic effect of VKA? (3) Can dietary sources of vitamin K (eg, broccoli, spinach, etc) be used to manage excessive VKA anticoagulation in nonbleeding patients? Question: For patients with life-threatening bleeding during VKA treatment of VTE, should 4-factor PCC vs FFP be used, in addition to cessation of VKA and IV vitamin K? For patients with life-threatening bleeding during VKA treatment of VTE who have an elevated INR, the ASH guideline panel suggests using 4-factor PCC rather than FFP, in addition to cessation of VKA and IV vitamin K (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. We included eligible studies from the most recent systematic review for patients presenting with VKA-associated bleeding who received PCC vs FFP in addition to vitamin K and temporary cessation of VKA.182 The search was updated from 2016 onward, yielding 3 eligible RCTs.183-185 Additional studies included in the systematic review proved ineligible because patients needed VKA reversal for urgent or semiurgent surgery and not because of bleeding. Three studies reported the effect of PCC vs FFP on mortality,183-185 2 studies reported on development of any thromboembolism and 1 study reported the outcomes of PE and 2 studies reported on volume overload (this outcome was not originally prioritized but was felt by the panel to be an important outcome for consideration),183,184 and 2 studies reported on the proportion of patients who reached the INR goal of ,1.3185 or (follow-up ranged from 0.5 to 3 hours). The EtD framework is shown online at https://dbep.gradepro.org/profile/e58f8d6b- 8fd6-4164-b9da-2c62605e845c. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Studies assessing mortality reported no difference between those receiving 4-factor PCC and FFP (RR, 0.92 [95% CI, 0.37- more per 1000]; very low certainty). Four-factor PCC reduced the incidence of volume overload (RR, 0.34 [95% CI, 0.13-0.85]; ARR, 107 fewer episodes per 1000 [95% CI, 24 fewer to 141 fewer per 1000]; low certainty) and increased the proportion of patients who reached an INR of #1.2 to 1.3 within 0.5 to 3 hours (RR, 6.66 [95% CI, 3.82-11.61]; moderate certainty). Harms and burden. The risk of major bleeding during 45 to 90 days of follow-up, as assessed with hematoma expansion or recurrent intracranial hemorrhage (ICH), was higher following 4- factor PCC administration than following FFP administration, but the CI includes appreciable risk increases and decreases (RR, 1.34 20 fewer to 117 more per 1000]; low certainty). Administration of 4- factor PCC possibly increased the risk of PE (ARR, 148 more PE per 1000 [95% CI was not estimable]; low certainty) and DVT (ARR, 37 more DVT per 1000 [95% CI was not estimable]; low certainty), but these estimates were unreliable due to few events in the intervention group and no events in the control group. Similarly, 4-factor PCC was possibly associated with increased risk of any thromboembolism (eg, myocardial infarction, stroke, PE, or DVT), but again, the CI included appreciable risk reduction and increase [95% CI, 20 fewer to 179 more per 1000]; low certainty). Other EtD criteria and considerations. In the United States, the upfront cost of PCC is approximately threefold higher than that of FFP; in Europe, however, FFP upfront costs are higher than those of PCC. Reduction of potentially severe transfusion- associated circulatory overload reactions reduces the cost and should be factored into the resource use equation.186 In addition, FFP requires additional staff time to prepare and administer. A cost- effectiveness analysis based on a systematic review and UK National Health Service perspective estimated that the cost per quality-adjusted life-year gained with PCC vs FFP was 3000 or less, depending on hemorrhage type.187 Conclusions and research needs for this recommendation. The guideline panel s assessment was that the benefits and harms with 4-factor PCC vs FFP were balanced based on very low Table 4. VTE recurrence risk stratification High risk Moderate risk Low risk VTE within past 3 mo VTE within past 3-12 mo VTE . 12 mo previously No other risk factors Deficiency of protein C, protein S, or antithrombin Heterozygous factor V Leiden Antiphospholipid antibody syndrome mutation Multiple thrombophilic abnormalities Recurrent VTE Active cancer certainty evidence. Nevertheless, the panel favored 4-factor PCC over FFP because of ease of administration, the increased probability of achieving a near-normalized INR, and the lower risk of volume overload. The panel determined that this recommendation most directly applies to intracranial bleeding, where speed of reversal is likely to be a particularly important consideration. The panel identified the following additional research questions. (1) What is the cost-effectiveness of 4-factor PCC vs FFP from the payer perspective in various health care systems? (2) What is the true magnitude of increased thromboembolic risk associated with 4-factor PCC administration compared with the same risk for patients treated with FFP? Question: For patients with life-threatening bleeding during oral direct Xa inhibitor treatment of VTE, should cessation of direct Xa inhibitor plus reversal of the direct Xa inhibitor anticoagulant effect vs cessation of direct Xa inhibitor alone be used? This question aimed to evaluate management options for life- threatening bleeding related to administration of an oral direct Xa inhibitor. Two approaches have emerged for this situation, administra- tion of 4-factor PCC and administration of coagulation factor Xa (recombinant), inactivated-zhzo (formerly known as andexanet alpha). These approaches have not been directly compared, and the panel was unable to provide a judgment regarding which is preferred and therefore made independent recommendations regarding each intervention. For patients with life-threatening bleeding during oral direct Xa inhibitor treatment of VTE, the ASH guideline panel suggests using either 4-factor PCC administration as an addition to cessation of oral direct Xa inhibitor or cessation of oral direct Xa inhibitor alone (conditional recommendation based on very low certainty in the evidence about effects ). Remark: This recommendation does not apply to non life-threatening bleeding. No data are available comparing the efficacy of 4-factor PCC and coagulation factor Xa (recombinant), inactivated-zhzo. The guideline panel of- fers no recommendation for 1 approach over the other. Summary of the evidence. We found no systematic reviews that addressed this question, but we identified 8 individual Eligible studies included patients receiv- ing direct Xa inhibitors who were experiencing major bleeding and reported the effect of 4-factor PCC on mortality, ineffective bleeding management, and thromboembolic complications.106,110,113,188-192 The EtD framework is shown online at https://dbep.gradepro.org/ profile/2ec6099d-9b00-4bac-bc31-34653ee10737. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Because a suitable comparator group was not available, the panel was unable to make a judgment on the benefits of 4-factor PCC on outcomes associated with life-threatening bleeding during oral direct Xa inhibitor therapy for VTE. Harms and burden. Because a suitable comparator group was not available, the panel was unable to make a judgment on the harms and burdens of 4-factor PCC on outcomes associated with life-threatening bleeding during oral direct Xa inhibitor therapy. Studies did report that bleeding either worsened or did not improve in 32% of patients receiving 4-factor PCC. Other EtD criteria and considerations. There was very limited evidence to inform other considerations. Conclusions and research needs for this recommendation. Lack of evidence left the net health benefit/harm from using 4-factor PCC as an addition to cessation of direct Xa inhibitors very uncertain. The ASH guideline panel therefore suggests that either 4-factor PCC administration as an addition to temporary cessation of oral direct Xa inhibitor or cessation of oral direct Xa inhibitor alone be used for patients with life-threatening bleeding during treatment of VTE (conditional recommendation based on very low certainty in the evidence). In a life-threatening situation, the experience and judgment of the prescriber weighing individual risks and benefits would likely be the deciding factors. This recommendation does not apply to non life-threatening bleeding because cost likely outweighs potential benefit and there is likely a small but quantifiable increased risk of thromboembolism associated with administration of PCC.193 The panel identified the following additional research questions. (1) What clinical parameters define the need for intervention with 4-factor PCC over withholding oral direct Xa inhibitor alone? (2) What is the comparative effectiveness of 4-factor PCC in real-world patients presenting with potentially life-threatening oral direct Xa inhibitor- associated bleeding vs withholding direct Xa inhibitor alone?. For patients with life-threatening bleeding during oral direct Xa inhibitor treatment of VTE, the ASH guideline panel suggests using coagulation factor Xa (recombinant), inactivated-zhzo in addition to cessation of oral direct Xa inhibitor rather than no coagulation factor Xa (recombinant), inactivated-zhzo (condi- tional recommendation based on very low certainty in the evi- dence about effects ). Remark: This recommendation does not apply to non life-threatening bleeding. No data are available comparing the efficacy of 4-factor PCC and coagulation factor Xa (recombinant), inactivated-zhzo. The guideline panel offers no recommendation for 1 approach over the other. Summary of the evidence. We found no systematic reviews that addressed this question but identified a single study that measured relevant outcomes for patients receiving direct Xa inhibitors who were experiencing major bleeding.194 The eligible study reported the effect of administration of coagulation factor Xa (recombinant), inactivated-zhzo on mortality, ineffective bleeding management, and thromboembolic The EtD framework is shown online at https://dbep. gradepro.org/profile/8FD0D118-359D-B5A1-A933-FB225270E86A. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Because a suitable comparator group was not available, the panel was unable to judge the benefits of administration of coagulation factor Xa (recombinant), inactivated-zhzo on outcomes associated with life-threatening bleeding during direct Xa inhibitor therapy. Harms and burden. Because a suitable comparator group was not available, the panel was unable to judge the harms and burdens of administration of coagulation factor Xa (recombinant), 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3279 inactivated-zhzo on outcomes associated with life-threatening bleeding during direct Xa inhibitor therapy. Other EtD criteria and considerations. Costs of coagula- tion factor Xa (recombinant), inactivated-zhzo are extremely high (estimated at $27 500 to $50 000 for the bolus dose in the United States). Access to coagulation factor Xa (recombinant), inactivated-zhzo is also uncertain, due to issues pertaining to the manufacturing process. Administration of coagulation factor Xa (recombinant), inactivated-zhzo in the setting of life-threatening bleeding is likely to be somewhat complicated but is probably feasible in the hospital setting. Conclusions and research needs for this recommendation. Based on the absence of data for the comparator, very low certainty evidence from 1 observational study, and the extremely high cost of the intervention, the panel could not come to a unanimous decision. Voting resulted in a conditional recommendation for administration of coagulation factor Xa (recombinant), inactivated-zhzo, primarily based on the evidence for direct Xa inhibitor reversal and biological plausibility of preventing worsening of bleeding for widely used anticoagulants, the direct Xa inhibitors, using a specific reversal agent. Whether coagulation factor Xa (recombinant), inactivated- zhzo is associated with excess thromboembolism is unknown. This recommendation does not apply to non life-threatening bleeding, because the cost likely outweighs potential benefit. The panel identified the following additional research questions. (1) What is the comparative effectiveness of administration of co- agulation factor Xa (recombinant), inactivated-zhzo in the setting of direct Xa inhibitor-associated life-threatening bleeding compared with cessation of direct Xa inhibitor alone? (2) What is the cost- effectiveness of administration of coagulation factor Xa (recombi- nant), inactivated-zhzo using pharmacoeconomic modeling based on comparative data and the actual costs of the intervention? (3) What is the relative benefit of coagulation factor Xa (recombinant), inactivated-zhzo compared with alternate interventions such as nonspecific procoagulants (antifibrinolytics and/or PCCs)? (4) Would a rapidly available test for anti-Xa effect prevent administra- tion of coagulation factor Xa (recombinant), inactivated-zhzo to patients who do not have significant Xa inhibitor concentrations? Question: For patients with life-threatening bleeding during dabiga- tran treatment of VTE, should cessation of dabigatran plus idarucizu- mab administration vs cessation of dabigatran alone be used? For patients with life-threatening bleeding during dabigatran treatment of VTE, the ASH guideline panel suggests using idar- ucizumab in addition to cessation of dabigatran rather than no idarucizumab (conditional recommendation based on very low certainty in the evidence about effects ). Remark: This recommendation does not apply to non life-threatening bleeding. Summary of the evidence. We found no systematic reviews addressing this question but identified 3 relevant observa- tional studies. Two studies included an intervention arm only and 1 study included a control arm only (none of the patients received idarucizumab).109 We combined the number of events and the total number of patients from the 3 studies to calculate a relative effect. All studies included patients receiving dabigatran presenting with life-threatening bleeding; 1 included some patients who were not bleeding but required urgent dabigatran reversal for invasive procedures. All studies reported the outcomes of life-threatening bleeding associ- ated with dabigatran therapy, including death, worsening and/or recurrence of bleeding, and thromboembolic complications. The EtD framework is shown online at https://dbep.gradepro.org/ profile/b1deb68f-2ed2-4734-bb86-0a66117969cd. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Idarucizumab administration may or may not reduce the mortality risk (RR, 0.47 [95% CI, 0.14-1.58]; ARR, 151 fewer deaths per 1000 [95% CI, 246 fewer to 166 more per 1000]; very low certainty) and worsening and/or recurrence of bleeding associated with life-threatening bleeding during dabigatran therapy (RR, 0.12 [95% CI, 0.03-0.43]; ARR, 251 fewer bleeding episodes per 1000 [95% CI, 163 fewer to 277 fewer per 1000]; very low certainty); the CIs are very wide and include large risk reductions and increases. Harms and burden. There were 5 VTE events (3 DVTs and 2 PEs) reported following idarucizumab administration in 1 study.195 Estimating the relative and absolute risk estimates was not possible, as there were no VTEs in the comparison group. The certainty in these estimated effects is very low. Other EtD criteria and considerations. The acquisition cost of idarucizumab is considerable, although no formal economic analyses are available. Conclusions and research needs for this recommendation. There is very low certainty evidence for a net health benefit from using idarucizumab to manage life-threatening bleeding for patients re- ceiving dabigatran therapy for VTE, mandating a conditional recommendation. Some panel members were concerned about the possibility of VTE following idarucizumab administration. Furthermore, this recommendation does not apply to patients with non life- threatening bleeding, as the cost likely outweighs the potential benefit. The panel identified the following additional research questions. (1) What variables define the need for intervention with idarucizumab over withholding dabigatran alone? (2) What is the comparative effective- ness of idarucizumab in real-world patients presenting with potentially life-threatening dabigatran-associated bleeding compared with dabi- gatran cessation alone? (3) Would the use of a rapidly available test for a dabigatran effect prevent administration of idarucizumab to patients who do not have significant dabigatran concentrations? Question: For patients with life-threatening bleeding during LMWH or UFH treatment of VTE, should cessation of LMWH or UFH plus protamine vs cessation of LMWH or UFH alone be used? For patients with life-threatening bleeding during LMWH or UFH treatment of VTE, the ASH guideline panel suggests using prot- amine in addition to cessation of LMWH or UFH rather than no protamine (conditional recommendation based on very low cer- tainty in the evidence about effects ). Remark: This rec- ommendation does not apply to non life-threatening bleeding. Summary of the evidence. We updated evidence from 2 systematic reviews that addressed this question,198,199 and 13 observational studies that measured relevant outcomes for patients receiving protamine for LMWH/UFH reversal when undergoing invasive procedures, not for major bleeding during VTE treatment.203-215 Most studies did not specify whether heparin included UFH or LMWH; therefore, we could not analyze according to heparin subgroup. Given that only 74 patients receiving protamine were included in the RCTs, the panel elected to consider only the evidence from the observa- tional studies. Six studies reported the effect of protamine administration on 10 studies reported development of 10 studies assessed the risk of and 6 studies reported the risk of myocardial infarction.205-207,212-214 No studies reported the risk of PE or DVT. The EtD framework is shown online at https://dbep. gradepro.org/profile/770de24b-7077-4e3d-a7b9-cd7f401d31b4. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Studies assessing mortality reported no difference between those receiving protamine and control groups (RR, 0.98 [95% CI, 0.66-1.45]; ARR, 0 fewer deaths per 1000 [95% CI, 6 fewer to 9 more per 1000]; very low certainty). Protamine administration reduced the risk of de- veloping major bleeding (RR, 0.61 [95% CI, 0.39-0.96]; ARR, fewer per 1000]; very low certainty). Harms and burden. The risk of stroke (RR, 0.87 [95% CI, more per 1000]; very low certainty) and myocardial infarction (RR, fewer to 4 more per 1000]; very low certainty) did not differ among those receiving protamine and controls. Other EtD criteria and considerations. Compared with planned use of protamine at the conclusion of an invasive procedure, the panel considered that in a life-threatening bleeding situation, ordering protamine and having it prepared and infused may prove more difficult. Therefore, the feasibility of this intervention might vary according to whether centers perform invasive cardiac procedures where routine use of protamine is common. Conclusions and research needs for this recommendation. The guideline panel determined that though there is very low certainty evidence for a net health benefit associated with administering protamine to patients receiving heparin (LMWH or UFH) who develop life-threatening bleeding in addition to heparin therapy cessation, the possibility of benefit warranted a conditional recommendation in favor of protamine administra- tion. The recommendation does not, however, apply to patients with less serious bleeding when cessation of LMWH/UFH alone is likely to be sufficient. Although most studies did not specify whether heparin included UFH or LMWH, protamine should primarily be used for patients on UFH due to complete rather than partial reversal of the anticoagulant effect, as is seen with administration to patients who have been treated with The panel identified the following additional research question. What is the comparative effectiveness of protamine administration for management of life-threatening bleeding in VTE or other patients on UFH/LMWH compared with UFH/LMWH cessation alone? Anticoagulant resumption following bleeding Question: For patients receiving anticoagulant treatment of VTE who survive an episode of major bleeding, should resumption of oral anticoagulation therapy vs discontinuation of oral anticoagu- lation therapy be used? For patients receiving anticoagulation therapy for VTE who survive an episode of major bleeding, the ASH guideline panel suggests resumption of oral anticoagulation therapy within 90 days rather than discontinuation of oral anti- coagulation therapy (conditional recommendation based on very low certainty in the evidence about effects ). Remark: This recommendation specifically applies to pa- tients who require long-term or indefinite anticoagulation (ie, are at moderate to high risk for recurrent VTE, are not at high risk for recurrent bleeding, and are willing to continue anti- coagulation therapy). Summary of the evidence. We included eligible studies from the most recent systematic review for patients who did and did not resume anticoagulation therapy after surviving an episode of gastrointestinal tract bleeding (GIB).216 The search was updated from 2014 onward and expanded to include ICH, yielding a total of Most studies compared outcomes for patients who did and did not resume anticoagulation therapy following a GIB or ICH episode. Follow-up periods varied between studies (range, 3 months to 10 years). Six studies reported the effect of anticoagulation therapy resumption on all-cause mortality,218,219,222,229,230,233 6 studies reported devel- opment of PE,218,223,225,227,229,230 7 studies reported development 9 studies reported the occurrence of VTE (PE, DVT, or both),218-220,222,223,225,227,229,230 reported development of thromboembolism (including events other and 14 studies reported worsening or new bleeding.217-220,222,223,225,227-233 The EtD frame- work is shown online at https://dbep.gradepro.org/profile/098f8dae- 062b-41b2-a51e-f7cc74379f3a. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Resuming anticoagulation following GIB or ICH was associated with reduced risk of all-cause mortality (RR, 0.62 247 fewer to 48 fewer per 1000]; very low certainty) and reduced risk of thromboembolism (RR, 0.45 [95% CI, 0.25-0.83]; ARR, 58 fewer per 1000 [95% CI, 80 fewer to 18 fewer per 1000]; low certainty). Resuming anticoagulation following GIB or ICH possibly reduces the risk for PE (RR, 0.35 [95% CI, 0.11-1.11]; ARR, 17 fewer episodes per 1000 [95% CI, 23 fewer to 3 more per 1000]; very low certainty) and VTE (RR, 0.58 [95% CI, 0.26-1.28]; ARR, 16 fewer episodes per 1000 [95% CI, 23 fewer to 11 more per 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3281 1000]; very low certainty), but the estimates are imprecise, and CIs include no effect. Studies assessing DVT found no difference between those resuming anticoagulation therapy and control groups who did not resume therapy (RR, 0.81 [95% CI, 0.31- 2.16]; very low certainty). Harms and burden. Resuming anticoagulation following GIB or ICH was associated with increased risk of major bleeding (RR, 1.57 [95% CI, 1.12-2.21; ARR, 43 more bleeding events per 1000 [95% CI, 9 more to 92 more per 1000]; very low certainty). Other EtD criteria and considerations. There was very little evidence bearing on the other considerations. Whether the intervention is acceptable to key stakeholders likely varies: patient representatives on the panel were comfortable resuming anti- coagulation therapy following bleeding, but providers were concerned about causing harm. The severity of the bleeding, presence of ongoing bleeding risk factors, and elapsed time since the bleeding episode were also felt to influence the acceptability of the intervention. Conclusions and research needs for this recommendation. The guideline panel determined that there is uncertainty regarding the net health benefit from resuming anticoagulation therapy after surviving a major bleeding episode. Although only very low certainty evidence is available, some panel members felt that the potential to avoid mortality was more important than increasing the risk of recurrent bleeding. This recommendation specifically applies to patients who require long-term or indefinite anticoagulation (ie, are at moderate to high risk for recurrent VTE, are not at high risk for recurrent bleeding, and are willing to continue anticoagulation therapy). The available evidence was insufficient to allow the panel to state with certainty the optimal timing of anticoagulation therapy resumption. However, the panel determined that waiting at least 2 weeks but not more than 90 days after the bleeding event is reasonable based on the intervals for restarting anticoagulation therapy examined in clinical studies and depending on the patient-specific risk factors for thrombosis and bleeding (eg, indication for anticoagulation therapy and type of bleeding event). Earlier resumption may be appropriate if the source of bleeding is identified and corrected. The panel identified the following additional research questions. (1) What is the optimal timing of and what patient-specific factors should influence anticoagulation therapy resumption? (2) For patients who developed major bleeding during oral anticoagulant therapy, how does transition to an alternative anticoagulant influence the risk of bleeding recurrence? (3) What is the impact on mortality, recurrent VTE risk, and recurrent bleeding risk associated with resumption of anticoagulation therapy following extracranial bleeding from sites other than the gastrointestinal tract? (4) Is resuming anticoagulation therapy following major bleeding a cost-effective strategy? Good practice statements: renal function monitoring For patients with creatinine clearance of $50 mL/min receiving DOAC therapy for treatment of VTE, the ASH guideline panel agrees that good practice includes renal function monitoring every 6 to 12 months (ungraded good practice statement). For patients with creatinine clearance of ,50 mL/min receiving DOAC therapy for treatment of VTE, the ASH guideline panel agrees that good practice includes renal function monitoring approximately every 3 months (ungraded good practice statement). What are others saying and what is new in these ASH guidelines? One other recent set of guidelines on the optimal management of anticoagulation therapy is available, issued by the 2012 American College of Chest Physicians (ACCP).234 Major differences between the ASH guidelines and the ACCP guidelines include the consistent use of systematic reviews and EtD frameworks, which increase transparency, and the use of marker states to estimate the relative importance to patients of key outcomes of treatment. Both ASH and ACCP guidelines suggest using longer INR recall intervals for patients receiving VKA therapy during periods of stable INR control. The ASH guidelines make a graded recommendation in favor of using AMS, whereas ACCP provided an ungraded best practice statement suggesting that health care providers who manage oral anticoagulation therapy should do so in a systematic and coordinated fashion, incorporating patient education, system- atic INR testing, tracking, follow-up, and good patient communica- tion of results and dosing decisions. Both ASH and ACCP guidelines favor PSM over other methods of INR monitoring; however, the ASH guidelines makes a strong recommendation for PSM, whereas the ACCP guidelines make a weak (or conditional) recommendation favoring PSM. For patients with renal insufficiency (creatinine clearance of ,30 mL/min), ACCP recommends using reduced LMWH doses over standard doses, whereas the ASH guidelines suggest against using anti factor Xa monitoring to adjust LMWH doses in this patient population. These recom- mendations are complementary, suggesting that for patients with renal insufficiency, clinicians should use reduced LMWH doses without anti factor Xa monitoring. Both ASH and ACCP guidelines suggest against administering vitamin K to patients presenting with INRs between 4.5 and 10.0 and no evidence of bleeding. Both guidelines suggest the administration of 4-factor PCC over FFP for patients with VKA-associated life-threatening bleeding. The ASH guidelines include recommendations for optimal man- agement of DOAC therapy, whereas the ACCP guidelines do not, as DOAC agents were introduced during the time when the ACCP guidelines were being prepared. Although both guidelines evalu- ated evidence pertaining to supplemental patient anticoagulant therapy education, only the ASH guidelines make a graded suggestion in favor of this intervention. Limitations of these guidelines The limitations of these guidelines are inherent in the low or very low certainty in the evidence we identified for many of the questions. In addition, clinicians may encounter clinical questions that were not included among those prioritized by the panel. Revision or adaptation of the guidelines Plans for updating these guidelines After publication of these guidelines, ASH will maintain them through surveillance for new evidence, ongoing review by experts, and regular revisions. Updating or adapting recommendations locally Adaptation of these guidelines will be necessary in many circum- stances. These adaptations should be based on the associated EtD Acknowledgments The authors acknowledge Ann Wittkowski for her participation on the guideline panel. The authors acknowledge Miney Paquette, Gian Paolo Morgano, Sara Balduzzi, Meng Zhu, Samantha Craigie, Angela Barbara, Maja Ludwikowska, Piotr Stankowicz, Anna Starok, Siavash Piran, Reza Mirza, Itziar Etxeandia, Rachel Couban, Laura Fullerton, and Laura Charry for supporting the systematic reviews and Robby Nieuwlaat, Wojtek Wiercioch, and Holger Schu nemann for cocoordi- nation of the systematic review team. Holger Schu nemann prepared a template of these guidelines for all panels that was critically reviewed by Adam Cuker, Rob Kunkle, the Guideline Oversight Subcommittee, the Methods Group supporting the guidelines, and Blood Advances editors. Authorship Contribution: D.M.W. prepared the first draft of this manuscript and revised the manuscript based on authors suggestions; G.G. and R.N. contributed to drafting and critical revisions of the manuscript and contributed to further drafts; Guideline Panel members (J.A., N.P.C., M.A.C., F.D., A.H., J.M., T.M., N.S., J.S.) critically reviewed the manuscript and provided suggestions for improvement; members of the Knowledge Synthesis Team (A.A., M.B., R.K., J.J.R., Y.Z.) contributed evi- dence summaries to the guidelines; R.N. cocoordinated the systematic review team; D.M.W. and G.G. were the chair and vice chair of the panel and led the panel meeting; and all au- thors approved the content. Conflict-of-interest disclosure: All authors were members of the guideline panel or members of the systematic review team or both. As such, they completed a disclosure of interest form, which was reviewed by ASH and is available as supplements 2 and 3. 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