CLINICAL GUIDELINES American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy Daniel M. Witt,1 Nathan P. Clark,3 Mark A. Crowther,11 John J. Riva,2,14 and Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT; 2 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada; 3 Clinical Pharmacy Anticoagulation and Anemia Service, Kaiser Permanente Colorado, Aurora, CO; 4 School of Medicine, Hofstra Northwell, Hempstead, NY; 5 Division of Clinical Pharmacology and Toxicology, Department of Medicine, McMaster University, Hamilton, ON, Canada; 6 Unit for Health Promotion Research, Department of Public Health, University of Southern Denmark, Esbjerg, Denmark; 7 Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, GA; 8 Aurora Medical Center Summit, Summit, WI; 9 Cambridge, ON, Canada; 10 Department of Medicine and Surgery, Insubria University, Varese, Italy; 11 Department of Medicine, McMaster University, Hamilton, ON, Canada; 12 Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL; and 14 Department of Family Medicine, McMaster University, Hamilton, ON, Canada Background: Clinicians confront numerous practical issues in optimizing the use of anticoagulants to treat venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the use of anticoagulants in the management of VTE. These guidelines assume the choice of anticoagulant has already been made. Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 25 recommendations and 2 good practice statements to optimize management of patients receiving anticoagulants. Conclusions: Strong recommendations included using patient self-management of international normalized ratio (INR) with home point-of-care INR monitoring for vitamin K antagonist therapy and against using periprocedural low-molecular-weight heparin (LMWH) bridging therapy. Conditional recommendations included basing treatment dosing of LMWH on actual body weight, not using anti factor Xa monitoring to guide LMWH dosing, using specialized anticoagulation management services, and resuming anticoagulation after episodes of life-threatening bleeding. Summary of recommendations Anticoagulant therapy is complex and associated with both substantial benefits (reduced risk for thrombus extension and fatal pulmonary embolism [PE] in the setting of acute illness and recurrent venous thromboembolism [VTE] thereafter) and risks (life-threatening bleeding complications).1 Recognizing and mitigating risk for harm from anticoagulants requires an evidence-based approach to anticoagulant management and patient education. These guidelines focus on the optimal management of anticoagulant drugs for the prevention and treatment of VTE following the choice of an anticoagulant. Key management strategies for optimal use of anticoagulants include initial anticoagulant dose selection bloodadvances.2018024893. Resources for implementing these guidelines, including apps, patient decision aids, and teaching slide sets, may be accessed at the ASH web page hematology.org/vte. The full-text version of this article contains a data supplement. (recommendation 1), drug-interaction management (recommen- dation 2), point-of-care international normalized ratio (INR) testing (recommendations 3 and 4), INR recall interval selection (recommen- dations 5 and 6), laboratory monitoring of the anticoagulant response (recommendations 7-9), transitions between anticoagulants (recom- mendation 10), the use of specialized anticoagulation-management services (AMSs) (recommendation 11), structured patient education (recommendation 12), efforts to improve adherence to anticoagulant- medication regimens (recommendations 13a-d), invasive procedure management (recommendations 14 and 15), excessive anticoagulation and bleeding management (recommendations 16, 17, 18a and b, 19, and 20), anticoagulant resumption following bleeding (recommendation 21), and renal function monitoring (good practice statements). These guidelines are based on updated and original systematic reviews of evidence developed under the direction of the McMaster University GRADE Centre. The panel followed best practice for guideline development recommended by the Institute of Medicine and the Guidelines International Network.2-5 The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach6-12 to assess certainty in evidence and formulate recommendations. Interpretation of strong and conditional recommendations The strength of a recommendation is expressed as either strong ( the guideline panel recommends ), or conditional ( the guideline panel suggests ) and has the following interpretations. Strong recommendation c For patients: Most individuals in this situation would want the recommended course of action, and only a small proportion would not. c For clinicians: Most individuals should follow the recommended course of action. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences. c For policy makers: The recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. c For researchers: The recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. On occasion, a strong recommendation is based on low or very low certainty in the evidence. In such instances, further research may provide important information that alters the recommendations. Conditional recommendation c For patients: The majority of individuals in this situation would want the suggested course of action, but many would not. Decision aids may be useful in helping patients to make decisions consistent with their individual risks, values, and preferences. c For clinicians: Different choices will be appropriate for individual patients, and clinicians must help each patient arrive at a management decision consistent with the patient s values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences. c For policy makers: Policy-making will require substantial debate and involvement of various stakeholders. Performance measures should assess whether decision-making is duly documented. c For researchers: This recommendation is likely to be strength- ened (for future updates or adaptation) by additional research. An evaluation of the conditions and criteria (and the related judgments, research evidence, and additional considerations) that determined the conditional (rather than strong) recom- mendation will help identify possible research gaps. Recommendations Initial anticoagulant dose selection Recommendation 1. In obese patients receiving low-molecular- weight heparin (LMWH) therapy for treatment of acute VTE, the American Society of Hematology (ASH) guideline panel suggests initial LMWH dose selection according to actual body weight rather than dose selection based on a fixed maximum daily dose (ie, capped dose) (conditional recommendation based on very low certainty in the evidence about effects ). Drug-interaction management Recommendation 2. For patients requiring administration of inhibitors or inducers of P-glycoprotein (P-gp) or strong inhibitors or inducers of cytochrome P450 (CYP) enzymes, the ASH guideline panel suggests using an alternative anticoagulant (such as vitamin K antagonist [VKA] or LMWH) rather than a direct oral anticoagulant (DOAC) for the treatment of VTE (conditional recommendation based on very low certainty in the evidence about effects ). Point-of-care INR testing Recommendation 3. For patients receiving maintenance VKA therapy for treatment of VTE, the ASH guideline panel suggests using home point-of-care INR testing (patient self-testing [PST]) over any other INR testing approach except patient self- management (PSM) (see recommendation 4) in suitable patients (those who have demonstrated competency to perform PST and who can afford this option) (conditional recommendation based on low certainty in the evidence about effects ). Recommendation 4. For patients receiving maintenance VKA therapy for treatment of VTE, the ASH guideline panel recom- mends using point-of-care INR testing by the patient at home and self-adjustment of VKA dose (PSM) over any other management approach, including PST in suitable patients (those who have demonstrated competency to perform PSM and who can afford this option) (strong recommendation based on low certainty in the evidence about effects ). Selecting the timing between INR measurements (INR recall interval) Recommendation 5. For patients receiving VKA therapy for treatment of VTE, the ASH guideline panel suggests using an INR recall interval of 4 weeks or fewer rather than intervals longer than 4 weeks following VKA dose adjustment due to an out-of-target- range INR (conditional recommendation based on very low certainty in the evidence about effects ). Recommendation 6. For patients receiving maintenance VKA therapy for treatment of VTE, the ASH guideline panel suggests using a longer (6-12 weeks) INR recall interval rather than a shorter (4 weeks) INR recall interval during periods of stable INR control (conditional recommendation based on very low certainty in the evidence about effects ). Laboratory monitoring of the anticoagulant response Recommendation 7. For patients with renal dysfunction (creatinine clearance, ,30 mL/min) receiving LMWH therapy for treatment of VTE, the ASH guideline panel suggests against using anti factor Xa concentration monitoring to guide LMWH dose adjustment (conditional recommendation based on very low certainty in the evidence about effects ). Remark: Instead of monitoring anti factor Xa concentrations, providers should con- sider using doses adjusted for renal function as recommended in product labeling (eg, enoxaparin) or switching to an alternative anticoagulant with lower renal clearance, such as unfractionated heparin (UFH) or a different LMWH. Recommendation 8. For patients with obesity receiving LMWH therapy for treatment of VTE, the ASH guideline panel suggests against using anti factor Xa concentration monitoring to guide LMWH dose adjustment (conditional recommendation based on very low certainty in the evidence about effects ). Remark: Providers should consider LMWH using doses based on actual body weight (see recommendation 1) and not monitoring anti factor Xa concentrations, similar to the approach used in nonobese patients. Recommendation 9. For patients receiving DOAC therapy for the treatment of VTE, the ASH guideline panel suggests against measuring the DOAC anticoagulant effect during management of bleeding (conditional recommendation based on very low certainty in the evidence about effects ). Transitions between anticoagulants Recommendation 10. For patients transitioning from DOAC to VKA, the ASH guideline panel suggests overlapping DOAC and VKA therapy until the INR is within the therapeutic range over using LMWH or UFH bridging therapy (conditional recommen- dation based on very low certainty in the evidence about effects ). Use of specialized AMSs Recommendation 11. For patients receiving anticoagulation therapy for treatment of VTE, the ASH guideline panel suggests using specialized AMS care rather than care provided by the patient s usual health care provider (conditional recommendation based on very low certainty in the evidence about effects ). Structured patient education Recommendation 12. For patients receiving oral anticoagula- tion therapy for VTE treatment, the ASH guideline panel suggests using supplementary patient education in addition to basic education (conditional recommendation based on very low certainty in the evidence about effects ). Efforts to improve anticoagulant-medication adherence Recommendation 13a. For patients receiving anticoagula- tion therapy for treatment of VTE, the ASH guideline panel suggests against using a daily lottery (between a 1-in-5 and 1-in- 100 chance of a monetary reward each day if a pill compartment on a sophisticated electronic-medication-monitoring system is accessed) to improve medication adherence (conditional rec- ommendation based on very low certainty in the evidence about effects ). Recommendation 13b. For patients receiving anticoagulation therapy for treatment of VTE, the ASH guideline panel suggests against using electronic reminders (daily alarm via an electronic- medication-monitoring system) to improve medication adherence (conditional recommendation based on very low certainty in the evidence about effects ). Remark: This recommendation applies specifically to a sophisticated alert system used in the study evaluated by the panel. Recommendation 13c. For patients receiving anticoagula- tion therapy for treatment of VTE, the ASH guideline panel recommends against using a daily lottery (see recommendation 13a) plus electronic reminders (see recommendation 13b) to improve medication adherence (strong recommendation based on very low certainty in the evidence about effects ). Remark: This recommendation applies specifically to a sophisticated alert system used in the study evaluated by the panel. Recommendation 13d. For patients receiving anticoagula- tion therapy for treatment of VTE, the ASH guideline panel suggests against using visual medication schedules (pro- vided to patients at each visit, along with brief counseling) to improve medication adherence (conditional recommendation based on very low certainty in the evidence about effects ). Invasive procedure management Recommendation 14. For patients at low to moderate risk of recurrent VTE who require interruption of VKA therapy for invasive procedures, the ASH guideline panel recommends against periprocedural bridging with LMWH or UHF in favor of interruption of VKA alone (strong recommendation based on moderate certainty in the evidence about effects ). Recommendation 15. For patients interrupting DOAC therapy for scheduled invasive procedures, the ASH guideline panel suggests against performing laboratory testing for DOAC anticoagulant effect prior to procedures (conditional recom- mendation based on very low certainty in the evidence about effects ). Excessive anticoagulation and bleeding management Recommendation 16. 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 ). 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3259 Recommendation 17. For patients with life-threatening bleed- ing during VKA treatment of VTE who have an elevated INR, the ASH guideline panel suggests using 4-factor prothrombin complex concentrates (PCCs) rather than fresh-frozen plasma (FFP) as an addition to cessation of VKA and IV vitamin K (conditional recommendation based on very low certainty in the evidence about effects ). Recommendation 18a. For patients with life-threatening bleed- ing 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 offers no recommendation for 1 approach over the other. Recommendation 18b. For patients with life-threatening bleed- ing during oral direct Xa inhibitor treatment of VTE, the ASH guideline panel suggests using coagulation factor Xa (recombi- nant), inactivated-zhzo in addition to cessation of oral direct Xa inhibitor rather than no coagulation factor Xa (recombinant), inactivated-zhzo (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 guide- line panel offers no recommendation for 1 approach over the other. Recommendation 19. For patients with life-threatening bleed- ing during dabigatran treatment of VTE, the ASH guideline panel suggests using idarucizumab 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. Recommendation 20. For patients with life-threatening bleed- ing during LMWH or UFH treatment of VTE, the ASH guideline panel suggests using protamine in addition to cessation of LMWH or UFH rather than no protamine (conditional recommendation based on very low certainty in the evidence about effects ). Remark: This recommendation does not apply to non life- threatening bleeding. Anticoagulant resumption following bleeding Recommendation 21. For patients receiving anticoagulation therapy for VTE who survive an episode of major bleeding, the ASH guideline panel suggests resumption of oral anticoagula- tion therapy within 90 days rather than discontinuation of oral anticoagulation therapy (conditional recommendation based on very low certainty in the evidence about effects ). Remark: 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). Values and preferences In general, these recommendations place greater value on outcomes related to prevention of mortality, PE, deep vein thrombosis (DVT), major bleeding, quality of life, and emergency department and/or hospital visits. The impact of recommendations on measures of anticoagulation control, medication adherence, and inconvenience of therapy was also considered in relation to their importance for patients. Explanations and other considerations These recommendations take into consideration cost and cost- effectiveness, impact on equity, acceptability, and feasibility. 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 monitor- ing approximately every 3 months (ungraded good practice statement). Introduction Aim(s) of these guidelines and specific objectives The purpose of these guidelines is to provide evidence-based recommendations addressing the optimal use of anticoagulant therapy in the management of VTE assuming the choice of which anticoagulant to use has already been made. Other aspects of VTE treatment (such as choice and duration of anticoagulant treatment, inpatient or outpatient management, treatment of cancer-associated VTE, indications for advanced therapies, and treatment of superficial vein thrombosis, calf vein thrombosis, and subsegmental PE) are addressed in other guidelines. Recom- mendations focus on commonly used anticoagulant medications, including UFH, LMWH, fondaparinux, VKA, and the DOACs apixaban, dabigatran, edoxaban, and rivaroxaban (betrixaban was not available during panel deliberations and is not currently approved for treatment of VTE; thus, it was not considered in any of the evidence). The specific objectives of the recommendations are to improve patient-important outcomes, including overall mortality, recurrent VTE, major bleeding, and quality of life. For specific recommendations, the panel considered time in the therapeutic INR range (TTR) as a surrogate for bleeding and thrombosis. For all recommendations, the panel considered resource use, cost-effectiveness, potential impact on health care equity, acceptability, and feasibility when such information was available. The target audience for these recommendations includes patients, physicians, other clinicians, and decision-makers. Policy makers interested in these guidelines include those involved in developing local, national, or international plans aimed at reducing the incidence and improving the management of VTE and evaluat- ing direct and indirect harms and costs related to VTE and associated treatments. This document may also serve as the basis for adaptation by local, regional, or national guideline panels. Description of the health problem(s) Optimal use of anticoagulant drugs for treatment of VTE requires a comprehensive approach to patient management.13 Bleeding and therapeutic failure are common and serious complications of administering anticoagulant drugs.14-16 Methods The guideline panel developed and graded the recommenda- tions and assessed the certainty in the supporting evidence following the GRADE approach.6-12 The overall guideline devel- opment process, including funding of the work, panel forma- tion, management of conflicts of interest, internal and external review, and organizational approval, was guided by ASH policies and procedures derived from the Guidelines International Network McMaster Guideline Development Checklist (http:// cebgrade.mcmaster.ca/guidecheck.html) and was intended to meet recommendations for trustworthy guidelines by the In- stitute of Medicine and the Guidelines International Network.2-5 An article detailing the methods used to develop these guidelines is forthcoming. Organization, panel composition, planning, and coordination The work of this panel was coordinated with that of 9 other guideline panels (addressing other aspects of VTE) by ASH and the McMaster GRADE Centre (funded by ASH under a paid agreement). Project oversight was provided initially by a coordination panel, which reported to the ASH Committee on Quality, and then by the coordination panel chair (Adam Cuker) and vice chair (Holger J. Schu nemann). ASH vetted and appointed individuals to the guideline panel. The McMaster GRADE Centre vetted and retained researchers to conduct systematic reviews of evidence and coordinate the guideline development pro- cess, including the use of the GRADE approach. The member- ship of the panel and the GRADE center team is described in supplement 1. The panel included hematologists, internists, a clinical pharmacol- ogist, other physicians, and pharmacists with clinical and research expertise in the use of anticoagulants; physicians and other scientists from other disciplines with similar expertise; methodolo- gists with expertise in evidence appraisal and guideline develop- ment; and 2 patient representatives. The panel chair was a practicing anticoagulation pharmacist and content expert. The vice chair was a practicing internist and methodologist with experience in guideline development processes. In addition to synthesizing evidence systematically, the McMaster GRADE Centre supported the guideline develop- ment process, including determining methods, preparing agendas and meeting materials, and facilitating panel discus- sions. The panel s work was done using web-based tools (www.surveymonkey.com and www.gradepro.org) and face-to-face and online meetings. Guideline funding and management of conflicts of interest Development of these guidelines was wholly funded by ASH, a nonprofit medical specialty society that represents hematologists. Most members of the guideline panel were members of ASH. ASH staff supported panel appointments and coordinated meetings but had no role in choosing the guideline questions or determining the recommendations. Members of the guideline panel received travel reimbursement for attendance at in-person meetings, and the patient representa- tives were offered an honorarium of US $200 each (1 individual accepted the honorarium, and 1 declined it). The panelists received no other payments. Through the McMaster GRADE Centre, some researchers who contributed to the systematic evidence reviews received salary or grant support. Other researchers participated to fulfill requirements of an academic degree or program. Conflicts of interest of all participants were managed according to ASH policies based on recommendations of the Institute of and the Guidelines International Network.5 At the time of appointment, a majority of the guideline panel, including the chair and the vice chair, had no conflicts of interest as defined and judged by ASH, that is, no current material interest in any commercial entity with a product that could be affected by the guidelines. Some panelists disclosed new interests or relation- ships during the development process, but the balance of the majority was maintained. Before appointment to the panel, individuals disclosed both financial and nonfinancial interests. Members of the VTE Guideline Coordination Panel reviewed the disclosures and judged which interests were conflicts and should be managed. Supplement 2 provides the complete Disclosure of Interests forms of all panel members. In part A of the forms, individuals disclosed material interests for 2 years prior to appointment. In part B, they disclosed interests that were not mainly financial. Part C summarizes ASH decisions about which interests were judged to be conflicts. Part D describes new interests disclosed by individuals after appointment. Recusal was also used to manage conflicts of interest. During all deliberations, panel members with a current, direct financial interest in a commercial entity with any product that could be affected by the guidelines were recused from making judgments about relevant recommendations.5,18-20 The Evidence-to-Decision (EtD) framework for each recommendation describes which individuals were recused from making judgments about each recommendation. None of the McMaster-affiliated researchers who supported the guideline development process had any current, material interest in a commercial entity with any product that could be affected by the guidelines. On a recommendation-by-recommendation basis, none of the researchers who contributed to the systematic evidence reviews informing a recommendation had any current, material interest in a commercial entity with any product that could be affected by the recommendation. Supplement 3 provides the 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3261 complete disclosure of interest forms of researchers who contrib- uted to these guidelines. Formulating specific clinical questions and determining outcomes of interest The panel used the GRADEpro Guideline Development Tool (www. and SurveyMonkey (www.surveymonkey.com) to brainstorm and then prioritize the questions described in Table 1. The panel selected outcomes of interest for each question a priori, following the approach described in detail elsewhere.22 In brief, the panel brainstormed all possible outcomes and then rated their relative importance for decision-making following the GRADE During this rating process, the panel used definitions of the outcomes ( marker states ) developed for these guidelines. Rating outcomes by their relative importance helps focus attention on those outcomes that are most important and helps resolve or clarify potential disagreements. The panel rated the following outcomes as critical for decision-making across questions: mortality, PE, DVT in the upper leg, DVT in the upper arm, and major bleeding. For specific questions, other outcomes were included to inform decision-making, including TTR as a surrogate for bleeding and thrombosis, impairment of quality of life, critical INR as a surrogate for bleeding and thrombosis, increased duration of hospitalization, medication adherence as a surrogate for bleeding and thrombosis, and delay of intervention. Some studies reported outcomes differently from what the panel determined to be critical or important for decision-making. Typically, outcomes are reported as any VTE, any PE, any DVT, any proximal DVT, or any distal DVT, sometimes preceded by asymptomatic or symptomatic. Table 1. Prioritized questions for optimal management of anticoagulation therapy Prioritized questions 1. In obese patients receiving LMWH therapy for treatment of acute VTE, should initial LMWH dose selection according to actual body weight vs dose selection based on a fixed maximum daily dose (i.e., capped dose) be used? 2. For patients requiring administration of inhibitors or inducers of P-gp or strong inhibitors or inducers of CYP enzymes, should a DOAC or an alternative anticoagulant be used for treatment of VTE? 3. For patients receiving maintenance VKA therapy for treatment of VTE, should point-of-care INR testing by the patient at home (PST) vs any other INR testing approach be used? 4. For patients receiving maintenance VKA therapy for treatment of VTE, should point-of-care INR testing by the patient at home and self-adjustment of VKA dose (PSM) vs any other management approach be used? 5. For patients receiving VKA therapy for treatment of VTE, should a shorter INR recall interval vs a longer INR recall interval be used following VKA dose adjustment due to an out-of-target-range INR? 6. For patients receiving maintenance VKA therapy for treatment of VTE, should a longer (eg, 6-12 wk) INR recall interval vs a shorter (eg, 4 wk) INR recall interval be used during periods of stable INR control? 7. For patients with renal dysfunction (creatinine clearance of ,30 mL/min) receiving LMWH therapy for treatment of VTE, should clinicians monitor anti factor Xa concentration to guide LMWH dose adjustment vs no such monitoring? 8. For patients with obesity receiving LMWH therapy for treatment of VTE, should clinicians monitor anti factor Xa concentration to guide LMWH dose adjustment vs no such monitoring? 9. For patients receiving DOAC therapy for the treatment of VTE, should measurement of the DOAC anticoagulant effect vs no measurement of DOAC anticoagulant effect be used during management of bleeding? 10. For patients transitioning from DOAC to VKA, should LMWH or UFH bridging therapy vs overlapping DOAC therapy be used until the INR is within the therapeutic range? 11. For patients receiving anticoagulation therapy for treatment of VTE, should specialized AMS care vs care provided by the patient s regular health care provider be used for anticoagulation management? 12. For patients receiving oral anticoagulation therapy for VTE treatment, should supplementary patient education be offered vs no supplementary patient education? 13. For patients receiving anticoagulation therapy for VTE, should interventions to improve adherence (eg, refill reminders, INR reminders) vs usual care be used? 14. 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? 15. For patients interrupting DOAC therapy for scheduled invasive procedures, should performing laboratory testing for DOAC anticoagulant effect be used vs interrupting DOAC therapy alone? 16. For patients receiving VKA for treatment of VTE with INR 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? 17. 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? 18. 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? 19. For patients with life-threatening bleeding during dabigatran treatment of VTE, should cessation of dabigatran plus idarucizumab administration vs cessation of dabigatran alone be used? 20. 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? 21. For patients receiving treatment of VTE who survive an episode of anticoagulation therapy-related major bleeding, should resumption of oral anticoagulation therapy vs discontinuation of oral anticoagulation therapy be used? 22. For patients with creatinine clearance of $50 mL/min receiving DOAC therapy for treatment of VTE, should renal function be monitored every 6 to 12 mo vs no such monitoring? 23. For patients with creatinine clearance of ,50 mL/min receiving DOAC therapy for treatment of VTE, should renal function be monitored more frequently (every 3 mo) vs no such monitoring? Reporting of outcomes was inconsistent across studies. Some studies assessed thromboembolic and bleeding outcomes for indications other than VTE; in these cases, those results were extrapolated to PE and DVT outcomes and used to estimate the relative effects on prioritized outcomes. In such instances, the panel rated down certainty for indirectness. Evidence review and development of recommendations For each guideline question, the McMaster GRADE Centre prepared a GRADE EtD table, using the GRADEpro Guideline Development Tool The EtD table summarized the results of systematic reviews of the literature that were updated or performed specifically for these guidelines. The EtD table addressed desirable and undesirable effects of interventions, certainty in the evidence, values and preferences (relative importance of outcomes), resource use, health equity, acceptability, and feasibility. The guideline panel reviewed draft EtD tables before, during, or after the guideline panel meeting and made suggestions for improvement. To ensure that recent studies were not missed, searches (presented in supplement 4) were updated during February and March 2017, and panel members remained alert for new eligible studies and could bring these to the panel for potential inclusion. Under the direction of the McMaster GRADE Centre, researchers followed the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (handbook.cochrane.org) for conducting updated or new systematic reviews of intervention effects. When existing reviews were used, judgments of the original authors regarding risk of bias were accepted and checked for accuracy or conducted de novo. For new reviews, risk of bias was assessed at the outcome level using the Cochrane Collaboration s risk-of-bias tools for randomized trials or nonrandomized studies. In addition to conducting systematic reviews of intervention effects, the researchers searched for evidence related to baseline risks, values and preferences, and costs and summarized findings within the EtD frameworks.6,7,12 Subsequently, the certainty in the body of evidence (also known as quality of the evidence or confidence in the estimated effects) was assessed for each of the effects estimate of the outcomes of interest, test accuracy, and the importance of outcomes following the GRADE approach based on the following domains: risk of bias, precision, consistency and magnitude of the estimates of effects, directness of the evidence, risk of publication bias, presence of a dose-effect relationship, and an assessment of the effect of residual, opposing confounding. The certainty was categorized into 4 levels from very low to high.8-10 During a 2-day in-person meeting preceded and followed by online discussion, the panel developed clinical recommendations based on the evidence summarized in the EtD tables. For each recommendation, the panel took a population perspective and agreed on the following: the certainty in the evidence, the balance of benefits and harms of the compared management options, and inferences regarding the values and preferences associated with the decision. The guideline panel explicitly considered the extent of resource use associated with alternative management options. The guideline panel agreed on the recommendations (including direction and strength), remarks, and qualifications on the basis of consensus or, in rare instances, by voting, based on the balance of all desirable and undesirable consequences. All panel members reviewed and approved the final recommendations. Interpretation of strong and conditional recommendations The recommendations are labeled as either strong or condi- tional according to the GRADE approach. The words the guideline panel recommends are used for strong recommendations and the guideline panel suggests for conditional recommenda- tions. Table 2 provides the suggested interpretation of strong and conditional recommendations by patients, clinicians, and health care policy makers. Document review Draft recommendations were reviewed by all members of the panel, revised, and then made available online on 5 December 2017 for external review by stakeholders, including allied organizations, other medical professionals, patients, and the public. Ten individuals or organizations submitted comments. The document was revised to address pertinent comments. On 30 June 2018, the ASH Guideline Oversight Subcommittee and the ASH Committee on Quality approved that the defined guideline development process was followed, and on 3 August 2018, the officers of the ASH Executive Committee approved submission of the guidelines for publication under the imprimatur of ASH. The guidelines were then subjected to peer review by Blood Advances. How to use these guidelines ASH guidelines are primarily intended to help clinicians make decisions about diagnostic and treatment alternatives. Other purposes are to inform policy, education, and advocacy and to state future research needs. They may also be used by patients. These guidelines are not intended to serve or be construed as a standard of care. Clinicians must make decisions on the basis of the clinical presentation of each individual patient, ideally through a shared process that considers the patient s values and preferences with respect to the anticipated outcomes of the chosen option. Decisions may be constrained by the realities of a specific clinical setting and local resources, including but not limited to institutional policies, time limitations, and availability of treatments. These guidelines may not include all appropriate methods of care for the clinical scenarios described. As science advances and new evidence becomes available, recommendations may become outdated. Following these guidelines cannot guaran- tee successful outcomes. ASH does not warrant or guarantee any products described in these guidelines. Statements about the underlying values and preferences as well as qualifying remarks accompanying each recommendation are its integral parts and serve to facilitate more accurate interpretation. They should never be omitted when recommendations from these guidelines are quoted or translated. Implementation of the guidelines will be facilitated by the related interactive forthcoming decision aids. The use of these guidelines is also facilitated by the links to the EtD frameworks and interactive summary-of-findings tables in each section. Recommendations Initial anticoagulant dose selection Question: In obese patients receiving LMWH therapy for treatment of acute VTE, should initial LMWH dose selection according to 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3263 actual body weight vs dose selection based on a fixed maximum daily dose (ie, capped dose) be used? In obese patients receiving LMWH therapy for treatment of acute VTE, the ASH guideline panel suggests initial LMWH dose selection according to actual body weight rather than dose selection based on a fixed maximum daily dose (ie, cap- ped dose) (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 relevant individual studies.23-27 No study evaluated a direct comparison between LMWH doses based on actual body weight and capped doses for patients with obesity; thus, intervention and control studies represent different populations. Two studies included mortality as an outcome,23,24 5 studies reported development of and 5 studies reported major bleeding outcomes.23-27 The EtD framework is shown online at https://dbep.gradepro.org/profile/ 18c9f7b9-df8a-45ec-a63a-4f517a3a23d6. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. After indirectly comparing the available evidence from separate studies, we found no difference in VTE between those receiving LMWH dosed according to actual body weight and capped LMWH doses, but confidence intervals (CIs) included the possibility of appreciable benefit and harm (relative risk [RR], 0.76 [95% CI, 0.11- 5.45]; absolute RR [ARR], 5 fewer events per 1000 [95% CI, 19 fewer to 95 more per 1000]; very low certainty). There was no effect of the intervention on mortality, as no deaths were reported in the included studies. Harms and burden. Indirect comparison of the available evidence from separate studies showed that there were no major bleeding episodes reported for patients in the capped-LMWH-dose group compared with 0.5% of those in the actual-body-weight-dose group. There is very low certainty in the available evidence. Other EtD criteria and considerations. LMWH dosing based on actual body weight is somewhat more expensive than using capped dosing and may lead to extra injections, but it is clearly feasible to implement. Conclusions and research needs for this recommendation. Because of the very low quality evidence, the net health benefit/harm associated with using initial LMWH doses based on actual body weight compared with capped dosing is very uncertain, though it is acceptable and feasible. Because of concerns for potentially underdosing very large patients, the potentially serious conse- quences of therapeutic failure, and the lack of correlation between supratherapeutic anti factor Xa concentrations and bleeding, the panel chose to make a conditional recommendation in favor of LMWH doses based on actual body weight over capped dosing. The panel identified the following additional research priority: comparative evidence for different LMWH initiation dosing strate- gies in obese VTE patients. Drug-interaction management Question: For patients requiring administration of inhibitors or inducers of P-gp or strong inhibitors or inducers of CYP enzymes, should a DOAC or an alternative anticoagulant be used for treatment of VTE? For patients requiring administration of inhibitors or inducers of P-gp or strong inhibitors or inducers of CYP enzymes, the ASH guideline panel suggests using an alternative anticoagulant (such as VKA or LMWH) rather than a DOAC for the treatment of VTE (conditional recommendation based on very low cer- tainty in the evidence about effects ). Summary of the evidence. DOAC absorption is mediated by P-gp proteins, and, therefore, P-gp inhibitors potentially increase DOAC absorption and effect, whereas P-gp inducers potentially decrease DOAC absorption and effect. Furthermore, CYP3A4 Table 2. Interpretation of strong and conditional recommendations Implications for Strong recommendation Conditional recommendation Patients Most individuals in this situation would want the recommended course of action, and only a small proportion would not. The majority of individuals in this situation would want the suggested course of action, but many would not. Decision aids may be useful in helping patients to make decisions consistent with their individual risks, values, and preferences. Clinicians Most individuals should follow the recommended course of action. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences. Different choices will be appropriate for individual patients; clinicians must help each patient arrive at a management decision consistent with the patient s values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences. Policy makers The recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Policy-making will require substantial debate and involvement of various stakeholders. Performance measures should assess whether decision-making is appropriate. Researchers The recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. On occasion, a strong recommendation is based on low or very low certainty in the evidence. In such instances, further research may provide important information that alters the recommendations. The recommendation is likely to be strengthened (for future updates or adaptation) by additional research. An evaluation of the conditions and criteria (and the related judgments, research evidence, and additional considerations) that determined the conditional (rather than strong) recommendation will help identify possible research gaps. enzymes are involved in the metabolism of oral direct Xa inhibitors, but not dabigatran, and strong inhibitors of CYP3A4 enzymes potentially decrease the metabolism and increase direct Xa inhibitor effect, whereas inducers of CYP3A4 enzymes potentially increase the metabolism and decrease direct Xa inhibitor effect. It is uncertain whether patients who require coadministration of potentially interact- ing drugs (see Table 3) and DOACs would have better outcomes if instead of a DOAC they received another anticoagulant. We found no systematic reviews that addressed this question. There were no randomized trials that addressed the outcomes prioritized for this question. Available evidence was very limited and consisted of pharmacokinetic studies with small sample sizes, subgroup analysis of clinical trials,28 information from product labeling, and drug- interaction reference texts. The EtD framework is shown online at 03ff16ff4bbb. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Theoretically, the concurrent use of P-gp or CYP3A4 inducers could decrease DOAC benefits, but the panel was unable to estimate the magnitude of decrease, if any. Harms and burden. Theoretically, the concurrent use of P- gp or CYP3A4 inhibitors could increase risk for bleeding for patients being treated with DOACs, but the panel was unable to estimate the magnitude of increase, if any. Use of P-gp/CYP inhibitors was associated with an increased risk of major bleeding and intracranial hemorrhage but not a significant change in the safety or efficacy of rivaroxaban compared with warfarin.28 Other EtD criteria and considerations. The panel de- termined that the acceptability of using DOACs for patients requiring P-gp or CYP3A4 inhibitors or inducers varies depending on factors such as the specific DOAC, whether the interacting medication was a strong inhibitor or inducer, the underlying bleeding or thromboembolic risk of the patient, comorbid disease states such as renal dysfunction, and patient preferences. The panel was unable to identify any evidence regarding other considerations. Conclusions and research needs for this recommendation. The guideline panel was unable to determine whether using DOACs concomitantly with P-gp or CYP3A4 inhibitors or inducers would result in a net health benefit or harm. Given the lack of evidence, we suggest that clinicians consider using an alternative anticoagulant (such as VKA or LMWH) rather than DOACs for patients requiring administration of P-gp inhibitors or inducers or strong inhibitors or inducers of CYP enzymes (conditional recommendation based on very low certainty in the evidence about effects). The recommen- dation places a high value on avoiding the uncertainty in DOAC anticoagulant response associated with coadministration of the interacting drug and a low value on avoiding the burden of warfarin or LMWH therapy. Patients strongly adverse to INR monitoring or daily injections are likely to remain on DOACs, whereas avoiding DOACs in favor of VKA may be favored in the very elderly, those with compromised renal function, and situations where multiple drugs affecting P-gp and/or CYP enzymes are coprescribed. The panel identified the following additional research question. What are the patient-important outcomes associated with concomitant administration of DOACs with P-gp/CYP3A4 inhibitors/inducers compared with DOACs alone or compared with other anticoagulants coadministered with strong P-gp or Point-of-care INR testing Question: For patients receiving maintenance VKA therapy for treatment of VTE, should point-of-care INR testing by the patient at home (PST) vs any other INR testing approach be used? For patients receiving maintenance VKA therapy for treatment of VTE, the ASH guideline panel suggests using home point-of- care INR testing (PST) over any other INR testing approach except for PSM (see recommendation 4) in suitable patients (those who have demonstrated competency to perform PST and who can afford this option) (conditional recommendation based on low certainty in the evidence about effects ). Summary of the evidence. We found 1 systematic review that addressed this question,29 but this review included studies using both PST and PSM. For this specific question, we were interested only in PST and performed meta-analysis on this subset of studies. We included 11 studies measuring outcomes relevant to this question for patients performing PST.30-40 Studies included patients requiring VKA therapy for various indications, mainly for indications other than VTE treatment. Three studies reported the effect of PST on mortality.31,33,36,41,42 Recurrent PE and DVT rates were estimated by extrapolat- ing pooled thromboembolic event rates from 9 studies (8 published and 1 unpublished [Scott Kaatz, data presented at the 6th National Conference of the Anticoagulation Forum, May to baseline recurrent VTE rates from the LMWH/VKA arms of recent randomized, controlled trials (RCTs). Nine studies (8 published and 1 unpublished [Scott Kaatz, data presented at the 6th National Conference of the Anticoagulation Forum, May 2001])30,31,33,34,36,38-42 assessed major bleeding risk; reported information on TTR; and 1 study reported quality of life.36 The EtD framework is shown online 0cc000c55993. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Studies assessing mortality found no difference between those receiving PST and control groups (RR, 0.94 fewer to 5 more deaths per 1000]; high certainty). The effect of PST on recurrent PE and DVT was estimated by applying the RR estimate for thromboembolic events to baseline recurrence rates of PE and DVT. PST possibly reduces the risk for recurrent PE 10 fewer to 1 more per 1000]; low certainty) and DVT (RR, 0.73 more per 1000]; low certainty), but the estimate is imprecise and the CI includes no effect. At 2 years (the minimum duration of follow-up), patient satisfaction with anticoagulation, as measured by the Duke Anticoagulation Satisfaction Scale (in which scores range from 25 to 225, with lower scores indicating better satisfaction), was greater in 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3265 the PST group than in the control group (difference, 22.4 points [95% CI, 23.9 to 21.0]; low certainty), and a cumulative gain in health utilities according to the Health Utilities Index Mark 319 was noted in the self-testing group compared with the control group (difference, 0.155 points [95% CI, 0.111-0.198]; low certainty). In studies assessing INR control, TTR was modestly higher in the PST group (mean difference [MD], 5.37% [95% CI, 3.17%-7.56% higher]; low certainty). Harms and burden. The risk of major bleeding was possibly lower for patients when PST was used than when other INR monitoring methods were used, but the estimate is imprecise and the CI includes no effect (RR, 0.73 [95% CI, 0.46-1.15]; ARR, 5 fewer per 1000 [95% CI, 9 fewer to 3 more per 1000] for a population at average bleeding risk. Other EtD criteria and considerations. The guideline panel considered that moderate costs were associated with PST resource requirements, owing mainly to the costs of the point-of- care monitors and testing supplies and more frequent INR testing generally used with PST. The likelihood of PST being cost- effective varied, with 1 review, 1 RCT, and 1 modeling study indicating that PST is likely to be cost-effective compared with whereas 2 other reviews concluded that PST is unlikely to be cost-effective within accepted standards46,47 and that PST implementation would probably result in reduced health equity for patients in lower socioeconomic classes and those with cognitive problems and poor manual dexterity. Because some patients are unwilling to perform PST, the panel determined that the acceptability of PST to major stakeholders varies, but the intervention is probably feasible to implement, though a substantial investment in patient training and testing equipment is necessary. Conclusions and research needs for this recommendation. The guideline panel determined that there is low certainty evidence for a net health benefit from using point-of-care INR monitoring at home by the patient over other INR testing approaches (except for PSM, see recommendation 4) for patients receiving VKA mainte- nance therapy for treatment of VTE. This benefit is conditional upon patients and health care systems being able to afford and manage the self-testing equipment. In settings in which resources are limited or when patients are not willing or able to perform PST, deviation from this suggestion is appropriate. Furthermore, systems using PST should be able to perform regular external quality assessment of the testing equipment and patient s ability to obtain accurate INR results. The panel calls upon payers, including the Centers for Medicare and Medicaid Services, to carefully evaluate current reimbursement regulations and make changes as necessary to ensure that unnecessary testing is not incentivized, that providers and patients are aware of this testing option, and that funding is available for those who would like to use PST. The panel identified the following additional research ques- tions. (1) What is the effectiveness of PST compared with DOAC therapy? (2) What is the effectiveness of PST compared with other INR-testing strategies specifically for patients with VTE? Question: For patients receiving maintenance VKA therapy for treatment of VTE, should point-of-care INR testing by the patient at home and self-adjustment of VKA dose (PSM) vs any other management approach be used? For patients receiving maintenance VKA therapy for treatment of VTE we recommend using point-of-care INR testing by the patient at home and self-adjustment of VKA dose (PSM) over any other management approach, including PST, in suitable patients (those with demonstrated competency to perform PSM and who can afford this option) (strong recommendation based on low certainty in the evidence about effects ). Summary of the evidence. Building on the systematic review that addressed PST and PSM,29 we performed a meta- analysis on 16 studies measuring outcomes for patients performing Table 3. Examples of drugs known to inhibit or induce P-gp and/or Inhibitors Strong inhibitors Antihypertensive/heart rate control Anti-infectives Verapamil Clarithromycin Dronedarone Telithromycin Anti-infectives Itraconazole Itraconazole Ketoconazole Ketoconazole Antidepressants Voriconazole Nefazodone Posaconazole Protease inhibitors Clarithromycin Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Inducers Strong inducers Anti-infectives Anti-infectives Rifampin Rifampin Anticonvulsants Anticonvulsants Carbamazepine Carbamazepine Phenytoin Phenytoin Barbiturates Barbiturates Natural products Natural products St. John s wort St. John s wort Not an inclusive list. Available evidence reported the effects of various drugs that inhibit or induce P-gp or CYP3A4 on DOAC pharmacokinetic parameters, such as area under the plasma concentration time curve, maximal plasma DOAC concentration, and DOAC half- life. In general, these parameters are increased by P-gp or CYP3A4 inhibitors and decreased by inducers. No studies have reported different rates of bleeding, thromboembo- lism, or mortality between DOACs and a comparator (eg, VKA). Reference texts on tertiary drug interaction generally suggested observing patients for symptoms of bleeding or thromboembolism and to consider adjusting DOAC doses. Depending on the specific DOAC, product labeling in some cases suggested modification of DOAC dosing (eg, apixaban) or recommended avoiding the use of DOACs when interacting drugs were coprescribed (eg, rivaroxaban). Studies included patients requiring VKA therapy for various indications, mainly for indications other than VTE treatment. Eleven studies reported the effect of PSM on recurrent PE and DVT rates were estimated by extrapolating pooled relative thromboembolic to baseline recurrent VTE rates from the LMWH/VKA arms of recent RCTs. assessed major bleeding risk, and 9 reported information on TTR. Two studies evaluated the effect of PSM on quality of life.52,59 The EtD framework is shown online at https://dbep.gradepro.org/ profile/323c2cad-e2ab-4fd6-b35f-be34eee8219a. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Studies assessing mortality found a benefit favoring those performing PSM (RR, 0.58 [95% CI, 0.38-0.89]; ARR, 16 fewer deaths per 1000 [95% CI, 4 fewer to 24 fewer deaths per 1000]; high certainty). PSM reduced the risk for recurrent PE (RR, 0.48 14 fewer per 1000]; moderate certainty) and DVT (RR, 0.48 [95% fewer per 1000]; moderate certainty). In studies assessing INR control, TTR was modestly higher in the PSM group, but the estimate is imprecise and the CI includes no effect (MD, 4.41% [95% CI, 0.09% lower to 8.92% higher]; very low certainty). General treatment satisfaction and daily hassles scores improved with PSM and remained unchanged in the control group.59 Self- efficacy and distress scores improved in both groups but improved significantly more with PSM. PSM had no significant effect on the strained social network scores.59 After 4 months, treatment satisfaction significantly improved and daily hassles, psychological distress, and a strained social network all significantly decreased with PSM compared with the control group.52 Harms and burden. PSM vs other INR monitoring methods probably has no influence on the risk of major bleeding (RR, 1.09 more per 1000] for an average bleeding risk population. Other EtD criteria and considerations. The guideline panel considered that moderate costs were associated with PSM resource requirements, owing mainly to the costs of the point-of-care monitors and testing supplies and the more frequent INR testing that is generally used with PSM. The likelihood of PSM being cost-effective varied, with 1 modeling study indicating that PSM is likely to be cost- effective compared with usual care,74 whereas 1 RCT concluded that PSM is unlikely to be cost-effective.75 Most panel members also believed that PSM implementation would result in reduced health equity for patients in lower socioeconomic classes and those with cognitive problems and poor manual dexterity. The acceptability of PSM to major stakeholders varies but is probably feasible to implement. However, a substantial investment in patient training (even more so than with PST) and testing equipment is necessary. Conclusions and research needs for this recommendation. The guideline panel determined that there is low certainty evidence for a net health benefit from using point-of-care INR monitoring and VKA dose adjustment by patients at home over other INR testing approaches (including PST) for patients receiving VKA maintenance therapy for treatment of VTE. This benefit is conditional upon patients and health care systems being able to afford and manage the self-testing equipment and patients being able to make independent decisions about VKA dosing based on INR results. The panel determined that PSM was superior to PST, as it has shown reduction in mortality. Although the panel agreed that a strong recommendation in favor of PSM was warranted based on the available evidence, in settings where resources are limited or when patients are not willing or able to perform PSM, system decision- makers or individual patients may choose against PSM. Furthermore, systems using PSM should be able to perform regular external quality assessment of the testing equipment and patients ability to obtain accurate INR results and make rational VKA dosing decisions using instructions from their health care providers. The panel calls upon payers, including the Centers for Medicare and Medicaid Services, to carefully evaluate current reimbursement regulations and make changes as necessary to ensure that unnecessary testing is not incentivized, that providers and patients are aware of this testing option, and that funding is available for those who wish to use PSM. The panel identified the following additional research questions. (1) What is the effectiveness of PSM of VKA compared with DOAC therapy? (2) What is the effectiveness of PSM compared with other INR management strategies, specifically for patients with VTE? (3) What minimum competencies are required to engage in PSM and what is the most effective way to train patients to perform PSM? Selecting the timing between INR measurements (INR recall interval) Question: For patients receiving VKA therapy for treatment of VTE, should a shorter INR recall interval vs a longer INR recall interval be used following VKA dose adjustment due to an out-of-target-range INR? For patients receiving VKA therapy for treatment of VTE, the ASH guideline panel suggests using an INR recall interval of 4 weeks or fewer rather than intervals longer than 4 weeks fol- lowing VKA dose adjustment due to an out-of-target-range INR (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. We found no systematic reviews or randomized trials that addressed this question. Three observational studies have evaluated the impact of INR recall interval on surrogate outcomes such as site-level TTR performance and TTR below No studies reported the risks of mortality, recurrent VTE, or bleeding. The EtD framework is shown online at https://dbep. gradepro.org/profile/768b8b3c-7ac2-48ff-a5d6-e13b7b0044cf. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. The panel was unable to estimate the magnitude of benefit for clinically important outcomes such as mortality, recurrent VTE, and bleeding. One study reported a decrease in site-level TTR of 1.12% (95% CI, 0.8%-1.43%) following each additional INR recall Another study reported that for patients measuring their own INRs at home and self-adjusting VKA doses, long intervals between INR measurements (.14 days) were associated with poor anticoagulation control (defined as percentage of in-range INRs 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3267 In this study, the temporal relationship between INR test interval and the outcome was unclear, and the outcome itself (poor anticoagulation control) would have an impact on the determination of the test interval. The study population was different from patients receiving INR monitoring and VKA dose adjustments from their anticoagulation providers. Another study evaluated the association between center next-visit INR interval ratio (the mean number of days after a visit with an INR outside the therapeutic range, divided by the number of days after a visit with an INR within the therapeutic range) and site-level TTR.78 The results suggested that site-level TTR increased with shorter INR recall intervals. Harms and burden. No studies reported adverse effects, and the panel assumed no harms but greater burden associated with more frequent INR testing after an out-of-range INR. Other EtD criteria and considerations. There was little evidence bearing on other criteria, which, as a result, had little impact on the recommendation. Conclusions and research needs for this recommendation. The guideline panel determined that there is very low certainty evidence for net health benefit/harm associated with the INR recall interval following an out-of-range INR. Based on the limited body of available evidence, the panel was able only to suggest INR recall intervals of 4 weeks or less vs longer intervals. Most patients are adverse to frequent INR monitoring yet will return for INRs as directed by their anticoagulation provider. How much the INR is out of range should guide the choice for the INR recall interval, as well as the etiology of the out-of-range INR. For example, a recall interval between 2 and 4 weeks might be reasonable following a VKA dose adjustment for an INR of 3.3 in a patient with generally stable INR control, whereas a recall interval not exceeding a few days might be needed after temporary interruption of VKA following an INR of 8.2 in a patient who recently started taking antibiotics. The panel identified the following additional research questions. (1) Does a strategy of using 1-week recall intervals for INRs that are farther out of range (eg, .4.0 or ,1.5) and 2- to 3-week recall intervals following INRs that are only slightly out of range (eg, 3.1-4.0 or 1.5-1.9) reduce the risk of mortality, recurrent VTE, and bleeding? (2) Could pharmacogenomic testing inform INR recall intervals by helping to predict the time required for a given patient to reach a new steady state following VKA dose adjustments? Question: For patients receiving maintenance VKA therapy for treatment of VTE should a longer (eg, 6-12 weeks) INR recall interval vs a shorter (eg, 4 weeks) INR recall interval be used during periods of stable INR control? For patients receiving maintenance VKA therapy for treatment of VTE, the ASH guideline panel suggests using a longer (6-12 weeks) INR recall interval rather than a shorter (4 weeks) INR recall interval during periods of stable INR control (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. We found no systematic reviews that addressed this question. All studies included patients receiving VKA anticoagulation therapy but were not limited to patients being treated for VTE. 