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. The 2 RCTs directly compared outcomes between 4-week INR recall intervals and 6-week79 recall intervals for patients meeting predefined criteria for stable VKA anticoagulation. No studies reported the impact of INR recall interval on quality of life. The EtD framework is shown online at https://dbep.gradepro. org/profile/87B38659-8876-FBC5-97CC-195E03A1F1FE. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Mortality was lower in the groups randomized to 6- to 12- week INR recall intervals, but the estimate is very imprecise, and CIs include both large increases and decreases in mortality (RR, 0.73 fewer to 140 more per 1000]; very low certainty). The 12-week INR recall interval was associated with a reduced risk for PE and DVT, but the estimates were based on only 1 event, and the CIs therefore include both important benefit and harm. The thromboembolic event rate from the other study was not used as it only included patients receiving anticoagulants for mechanical heart valves. There were also no differences between those using 6- to 12-week INR recall intervals and 4-week recall intervals for surrogate outcomes, including TTR and the number of extreme low/high INRs. Fewer patients using 6- to 12-week INR recall intervals had at least 1 dosing change during follow-up than those using 4-week recall [95% CI, 272 fewer to 67 fewer per 1000]; very low certainty). Harms and burden. Studies assessing major bleeding found no difference between those using 6- to 12-week INR recall intervals and those using 4-week recall intervals (RR, 1.05 [95% CI, per 1000] for average-bleeding-risk patients; low certainty). Other EtD criteria and considerations. The guideline panel agreed that 6- to 12-week INR recall intervals would probably result in moderate resources savings. The panel determined that longer INR recall intervals would increase health equity, would be acceptable to key stakeholders, and are feasible. Conclusions and research needs for this recommendation. Given that less frequent INR monitoring reduces the burden on patients, lessens workload on anticoagulation providers, is acceptable to key stakeholders, and is feasible to implement and likely reduces cost without incurring convincing adverse conse- quences, the panel made a conditional recommendation in favor of longer INR recall intervals. The panel did not specify a definition of stable INR control and agreed that this should be defined according to local standards. The panel also determined that this recommendation should not be used for patients engaging in PST or PSM, as these patients were not included in the RCTs for longer INR recall intervals and are usually monitored more frequently than the 4-week INR recall interval comparator used for this recommendation. Patients with psychiatric disorders and/ or history of poor adherence were also excluded from these studies and are poor candidates for extended INR recall intervals. Patients should be instructed to have their INR tested any time their health status changes, their current medications change, or there is a significant change in their dietary intake of vitamin K containing foods. The panel identified the following additional research questions. (1) What is the comparative effectiveness of 6- to 12-week INR recall intervals compared with a 4-week recall interval in real- world patients during periods of stable INR control? Given the low risk of adverse events in stable patients, a very large patient sample will likely be required to answer this question. (2) What is the cost-effectiveness of 6- to 12-week INR recall intervals compared with a 4-week recall interval from the societal perspective? Laboratory monitoring of the anticoagulant response Question: 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? For patients with renal dysfunction (creatinine clearance of ,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 monitor- ing anti factor Xa concentrations, providers should consider 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 UFH or a different LMWH. Summary of the evidence. We included eligible studies from the most recent systematic review of LMWH for patients with renal The search was updated from 2006 onward, yielding a No studies directly compared anti-Xa monitoring to no such monitoring. Most included studies were single-arm cohort studies in which patients receiving LMWH with renal dysfunction had anti- Xa concentrations monitored. For the no-monitoring comparator group, we used a study that reported no anti-Xa monitoring or dose adjustments (enoxaparin, 1 mg/kg body weight, was administered subcutaneously twice a day) to determine the risk of major bleeding.96 We found no studies that reported the risk of VTE or mortality associated with no anti- Xa monitoring. Included studies grouped patients with varying indications for LMWH, most commonly patients with acute VTE, atrial fibrillation, and acute coronary syndrome. The panel agreed that studies with grouped indications would be used for the outcome of major bleeding and the evidence rated down for indirectness. Studies with grouped indications were also combined for the outcome of percentage of anti-Xa concentrations in the therapeutic range. Studies with grouped indications were not used for the outcome of PE, DVT, or mortality. Combined studies administered different LMWHs (enoxaparin and tinzaparin) and used different dosing regimens (once daily and twice daily). The EtD framework is shown in online at https://dbep.gradepro.org/profile/ 44981d40-71aa-4205-bda3-a8471c085c8b. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. After indirect comparison of the available evidence from separate studies, it appears that adjusting the LMWH dose based on monitoring anti factor Xa concentrations for patients with renal dysfunction was associated with reduced risk of developing major bleeding (RR, 0.12 [95% CI, 0.03-0.44]; ARR, 95 fewer episodes per 1000 [95% CI, 60 fewer to 104 fewer episodes per 1000]; very low certainty). In an analysis of observational studies not included in the measured peak enoxaparin anti factor Xa concentrations were found to be within the defined therapeutic range.86,88,90,93-95 In 100.0%]) measured tinzaparin anti factor Xa concentrations fell within the defined therapeutic range.91 It was difficult to put these results into perspective given the lack of a control group where LMWH doses were not adjusted based on anti factor Xa concentrations. Harms and burden. Given the limited information regarding potential undesirable effects associated with adjusting LMWH doses based on the results of anti factor Xa monitoring that was available, the panel determined that the balance between desirable and undesirable effects of this intervention is very uncertain. Other EtD criteria and considerations. The panel agreed that there would likely be moderate costs associated with measuring anti factor Xa concentrations; cost-effectiveness remains unclear. Many payers would not consider this in- tervention acceptable without convincing evidence of benefit, and this evidence is lacking. The feasibility of implementing this intervention may also be affected by the following barriers reported by observational studies: (1) anti factor Xa tests are not widely available97 ; (2) anti factor Xa tests are poorly standardized between laboratories, making proper LMWH dose adjustments impossible in some cases97 ; and (3) anti factor Xa test reproducibility is poor.98-100 Conclusions and research needs for this recommendation. The guideline panel considered the net benefit associated with adjusting LMWH doses based on the results of anti factor Xa monitoring very uncertain. Because of concerns relating to anti factor Xa test standardization and reproducibility and weak correlation between bleeding events and anti factor Xa concentrations,101 the panel suggests against adjusting LMWH doses based on anti factor Xa concentration monitoring. Seven panel members preferred making a strong recommendation against the intervention, but this majority was not sufficiently large to satisfy the criterion for a strong recommendation (80% of the panel). The panel identified the following additional research questions. (1) What are the anti factor Xa concentration cutoffs (determined in a manner that ensures accuracy and reproducibility) that correlate with risk of recurrent VTE and bleeding events? (2) What percentage change in LMWH dose in response to an out-of- range anti factor Xa concentration is optimal to return the concentration to the therapeutic range? (3) What is the compar- ative effectiveness of adjusting LMWH doses based on the results of anti factor Xa concentrations (performed in a manner that ensures accuracy and reproducibility) vs no such monitoring for patients with estimated creatinine clearance values of ,30 mL/min requiring treatment of VTE? Question: For patients with obesity receiving LMWH therapy for treatment of VTE, should clinicians monitor anti factor Xa 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3269 concentration to guide LMWH dose adjustment vs no such monitoring? 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 recommen- dation 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. Summary of the evidence. We included eligible studies from the most recent systematic review for patients with obesity receiving LMWH for VTE treatment.101 The search was updated from 2014 onward, yielding a total of 7 studies.27,86,93,102-105 No studies directly compared anti factor Xa monitoring to no such monitoring. Included studies were single-arm cohort studies in which patients with obesity receiving LMWH had anti factor Xa concentrations monitored. For the no-monitoring arm, we used a study that reported no anti factor Xa monitoring to determine the risk of major bleeding and VTE events.23 Included studies grouped patients with varying indications for LMWH most commonly patients with acute VTE, atrial fibrillation, and acute coronary syndrome. We used studies with grouped indications for the outcome of major bleeding and rated down the evidence for indirectness. Studies with grouped indications were also combined for the outcome of percentage of anti factor Xa concentrations in the therapeutic range. Studies with grouped indications were not used for PE or DVT. No studies reported the outcome of mortality. When multiple studies reported the prioritized outcomes, the number of events was added across all studies and reported over the total sample. The EtD framework is shown online at 4dec32706a8b. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. In an analysis of observational studies not included in the measured peak enoxaparin anti factor Xa concentrations were found to be within the therapeutic range defined by the individual studies following a therapeutic enoxaparin dose (1.5 mg/kg once daily or 1 mg/kg twice daily).86,93,102,103 In another observational dalteparin anti factor Xa concentrations fell within the defined therapeutic range (between 0.5 and 1.0 units per milliliter for twice-daily dosing and between 1.0 and 2.0 units per milliliter for once-daily dosing) following a therapeutic dalteparin dose (200 units per kilogram per day) (assessed with peak anti factor Xa concentration).105 It was difficult to put these results into perspective given the lack of a control group where LMWH doses were not adjusted based on anti factor Xa concentrations. Harms and burden. After indirect comparison of the available evidence from separate studies, it appears that adjusting LMWH doses based on monitoring anti factor Xa concentrations for patients with obesity may increase the risk of recurrent PE (RR, [95% CI, 4 fewer to 245 more episodes per 1000]; very low certainty) and DVT (RR, 1.53 [95% CI, 0.14-16.61]; ARR, 5 more episodes per 1000 [95% CI, 9 fewer to 162 more episodes per 1000]; very low certainty), but the estimates are imprecise, and CIs include large reductions and very large increases in events. Results also suggested the possibility of increased risk of major bleeding, but again, the CI includes no difference and a very large increase in bleeding (RR, 3.91 [95% CI, 0.67-22.95]; ARR, 30 more episodes per 1000 [95% CI, 3 fewer to 227 more episodes per 1000]; very low confidence). Other EtD criteria and considerations. The panel de- termined that there would likely be moderate costs associated with measuring anti factor Xa concentrations, but the actual cost- effectiveness of this intervention could not be estimated due to the lack of comparative studies. Some payers would not consider this intervention acceptable without convincing evidence of benefit, and this evidence is currently lacking. The feasibility of implementing this intervention may also be affected by the following barriers reported by observational studies. (1) Anti factor Xa tests are not widely (2) Anti factor Xa tests are poorly standardized between laboratories, making proper LMWH dose adjustments impossible in some cases.97 (3) Anti factor Xa test reproducibility Thus, whereas it is feasible to order and obtain the results of anti factor Xa tests for patients with obesity during LMWH therapy in some settings, the panel determined that poor anti factor Xa test standardization and reproducibility were significant issues arguing against adjusting LMWH doses based on results of these tests. Conclusions and research needs for this recommendation. The guideline panel determined that there is very low certainty evidence for net harm from adjusting LMWH doses based on anti factor Xa concentration monitoring over no such monitor- ing for patients with obesity on LMWH therapy for treatment of VTE. In addition, there were concerns relating to anti factor Xa test standardization and reproducibility, weak correlation be- tween bleeding events and anti factor Xa concentrations,101 and no evidence that anti factor Xa testing is needed for patients with obesity. The panel identified the following additional research ques- tions. (1) What are the anti factor Xa concentration cutoffs (determined in a manner that ensures accuracy and reproduc- ibility) that correlate with risk of recurrent VTE and bleeding events? (2) What percentage change in LMWH dose in response to an out-of-range anti factor Xa concentration is optimal to return the concentration to the therapeutic range? (3) What is the comparative effectiveness of adjusting LMWH doses based on the results of anti factor Xa concentrations (performed in a manner that ensures accuracy and reproduc- ibility) vs no such monitoring for patients with obesity requiring treatment of VTE? Question: 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? 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 ). Summary of the evidence. We found no relevant systematic reviews but did identify 8 studies106-113 that included patients on DOACs receiving treatment of bleeding, some of whom had measurements of the DOAC anticoagulant effect using a variety of tests (eg, activated partial thromboplastin time, anti factor Xa concentrations, and thrombin time), but none had a primary objective of evaluating the impact of measuring DOAC anticoagulant effect or reported a direct comparison of outcomes for patients who did and did not receive DOAC anticoagulant effect measurement. Eight studies reported mortality as an outcome,106-113 reported development of thromboembolism,106,111 and 1 study assessed the occurrence of major bleeding during the 30 days following the index bleeding event.107 The EtD framework is shown online at https://dbep.gradepro.org/profile/9e7da133-8251-461a- 9a11-7b08b197a77e. 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 mortality between patients in whom the DOAC anticoagulant effect was measured and those in whom it was not measured, but CIs included appreciable mortality increases and decreases (RR, 1.28 [95% CI, 0.80-2.05]; ARR, 44 more deaths per 1000 [95% CI, 32 fewer to 166 more]; very low certainty). Harms and burden. Estimating the relative and absolute risk estimates was not possible, as there were no thromboembolic events in the intervention group and no bleeding events reported in the comparison group, leaving very low certainty evidence. Other EtD criteria and considerations. Very little evi- dence was available regarding other EtD criteria. Conclusions and research needs for this recommendation. Considering that only very low quality evidence is available regarding the net health benefit/harm from measuring the DOAC anticoagulant effect during management of bleeding, clinical use of DOAC tests is not well established, and no evidence supports a beneficial effect, the panel judged that it is better not to delay intervention for bleeding while waiting for a DOAC test result. It is advisable not to rely on any single (either pharmacokinetic or laboratory) strategy in isolation to assess DOAC effect during bleeding management but instead to use a comprehensive approach to assessing, confirming, and communicat- ing when the last DOAC dose was administered 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 for patients with bleeding; and (3) assessing the cost-effectiveness, acceptability, and feasibility of implementing a validated specific DOAC test during bleeding management. Transitions between anticoagulants Question: 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? 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 recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. We found no systematic reviews but did identify 3 studies114-116 that included patients with atrial fibrillation, not VTE, transitioning from DOAC therapy to VKA therapy at the conclusion of RCTs. Three studies reported mortality outcomes, but only in the group overlapping DOAC during the transition ; 1 study reported development of thromboembolic ; and 1 study reported development of hemorrhagic stroke.115 No studies reported outcomes related to quality-of-life impairment. The EtD framework is shown online at https://dbep.gradepro.org/ profile/b1889d83-5875-453f-b047-fb742c25e43e. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. The effect of LMWH-bridging therapy on mortality risk during the transition from DOAC to VKA could not be estimated because data on deaths during the 30-day follow-up period were not available for the intervention group, leaving very low certainty regarding the impact of the alternative management strategies. Harms and burden. LMWH-bridging therapy during the transition from DOAC to VKA may increase the risk for VTE compared with overlapping DOAC therapy (RR, 5.58 [95% CI, more per 1000]; very low certainty). In the eligible studies, the LMWH- bridging strategy was implemented only when the patient was at high thromboembolic risk; thus, intervention and control groups had important differences. The intervention was associated with a lower major bleeding risk (ARR, 1 fewer event per 1000), but no reliable RR and 95% CI could be estimated because very few bleeding events were observed and none occurred in the LMWH-bridging group, leaving very low certainty evidence regarding the risk of adverse effects. Other EtD criteria and considerations. LMWH-bridging therapy is more expensive than overlapping DOAC therapy, potentially disadvantaging patients in lower socioeconomic strata. Patients may prefer DOAC overlap, as they would avoid the inconvenience and expense of LMWH injections. Careful INR monitoring during transitions to VKA is always required, regardless of bridging strategy. Conclusions and research needs for this recommendation. The net health benefit/harm associated with using LMWH-bridging therapy during transitions from DOAC to VKA compared with 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3271 overlapping DOAC with VKA alone remains very uncertain, but use of LMWH is certain to increase burden and cost. In an anonymous vote of 9 eligible panel members, 6 voted for a conditional recommendation against LMWH-bridging therapy, and 3 voted for a conditional recommendation for either LMWH-bridging therapy or overlapping DOAC. To minimize DOAC interference with the INR, the panel suggests measuring the INR just before the next DOAC dose if overlapping DOAC therapy is used. However, providers will need to be aware of the varying potential among DOACs to influence INR results. Ultimately, the strategy for transitioning from DOAC to VKA should be based on patient preference and willingness to use and ability to afford injections. The panel identified the following research priority: sufficiently powered pragmatic clinical trials comparing thromboembolic and bleeding outcomes for DOAC overlap vs LMWH-bridging therapy for patients transitioning from DOAC to VKA. Use of specialized AMSs Question: 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 anti- coagulation management? 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 regular health care provider (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. We found evidence from both RCTs and observational studies and systematic reviews addressing this question. There was considerable discussion among panel members regarding the type of evidence that best represented the outcomes of contemporary anticoagulant therapy. Evidence sum- maries prepared for RCTs and observational studies revealed that evidence certainty was very low regardless of study type. After careful review of the included studies, the panel decided to use evidence summarized from observational studies, as these best reflected real-world anticoagulation therapy management practices. Although not required under ASH policy, 4 panelists, including the chair (N.P.C., Ann Wittkowski, J.S., and D.M.W.), recused themselves from making judgments about the evidence or deciding the recommendation thereafter, because they viewed their roles as directors of large anticoagulation clinics to be a professional and/or intellectual conflict of interest. R.N. led the panel discussion assessing both RCT and observational evidence instead of D.M.W. We included eligible studies from a systematic review comparing the effectiveness of pharmacist-managed AMS with other mod- The search was updated from 2015 onward and also to include studies evaluating AMS models other than those staffed by pharmacists, yielding a total of 29 observational studies.118-146 All studies included outcomes for patients on anticoagulants (mostly VKA) who received AMS care compared with those who received management coordinated by their regular health care provider. Five studies reported the effect of AMS care on ; 18 studies reported develop- ment of thromboembolic complications, including DVT and ; 19 studies assessed the risk of major bleeding118,120,122,123,129-132,134-138,140-143,145,146 ; and 19 studies measured TTR.118,122,124-129,132,133,135-138,140,141,145,146 One RCT reported on quality-of-life impairment during 30 days of follow- up using the EuroQoL instrument, whereas no observational studies reported on this outcome.147 Two observational studies assessed medication adherence for patients taking DOACs.130,139 The EtD framework is shown online at https://dbep.gradepro.org/profile/ B936B888-511A-8A14-A111-9B7DAF184C41. 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 AMS care and the care provided by their regular health care provider (RR, 0.97 [95% CI, 0.51-1.85]; ARR, 1 fewer deaths per 1000 [95% CI, 19 fewer to 33 more per 1000]; very low certainty). Compared with the usual care provided to patients by their regular health care provider, enrollment in an AMS reduced the risk of developing PE (RR, 0.45 [95% CI, 0.26-0.78]; ARR, 11 fewer episodes per 1000 [95% CI, 4 fewer to 15 fewer per 1000]; very low certainty) and DVT (RR, 0.45 [95% CI, 0.26-0.78]; ARR, 14 fewer episodes per 1000 [95% CI, 6 fewer to 19 fewer per 1000]; very low certainty). Quality of life as measured by the EuroQoL change score from baseline to follow-up was the same in groups receiving care from AMSs and those receiving care from their regular health care Patients enrolled in AMS had higher TTR than patients cared for by their regular health care provider (MD, 3.51% higher [95% CI, 2.74% higher to 4.28% higher]; very low certainty). Harms and burden. AMS care possibly reduced the risk for major bleeding in patients that were at average risk for bleeding, but the estimate is imprecise, and the CI includes no effect (RR, 0.66 fewer to 1 more episodes per 1000]; very low certainty). Other EtD criteria and considerations. The panel esti- mated moderate resource requirements associated with AMS care, mainly secondary to personnel costs. Several studies indicated that AMS care is cost-effective compared with care provided by the patient s regular health care provider; however, these studies were of very low quality and generally did not take into account startup costs associated with establishing an AMS.122,143,148-151 The option to refer patients to an AMS might help practitioners feel more confident prescribing anticoagulation therapy. On the other hand, if the AMS is situated in a hospital, rural patients out-of-pocket costs for visits might be higher. Given these competing impacts, the panel was not able to determine the effect of AMS care on health equity. The panel agreed that in general, AMS care seems acceptable to patients and providers, but the willingness of health system administrators to dedicate funds to setting up and running an AMS was less certain, especially considering that DOAC manage- ment based on AMS has been less well studied. Conclusions and research needs for this recommendation. The guideline panel determined that there is very low certainty evidence for a net health benefit from using AMS care over the care usually provided by a patient s regular health care provider for VTE treatment. Based on the body of available evidence, it is likely that AMS care reduces the risk of developing recurrent VTE and possibly also major bleeding, as well as improving TTR. There is very low certainty that AMS care has an effect on mortality. The panel agreed that this recommendation mainly applies to patients using VKA, as all but 2 of the studies focused on VKA treatment. Furthermore, AMS is most likely to be beneficial when implemented in a population with inadequate TTR managed by nonspecialized providers. Decision-makers should consider the upfront costs of setting up the AMS as well as costs to maintain the service. The panel also noted that AMS can provide specialized consulting and education for health care providers in the region, thereby potentially enhancing anticoagulation management beyond the service s direct patient management. AMS providers should keep track of the service s TTR as well as anticoagulation-related clinical outcomes for their patients. Health care providers referring patients to an AMS should keep track of whether they attended the AMS. With regard to research priorities, the panel determined that RCT evidence needs to be strengthened to be considered superior to the reported observational evidence. Cluster RCTs are needed that are appropriately randomized, enroll patients before unblinding of allocation, are sufficiently powered to detect a difference in clinical outcomes using blinded outcome assessment (including the follow- up time after dropping out of AMS care), use a consistent definition or elements of AMS, and address the impact of AMS for patients receiving DOAC therapy. Structured patient education Question: For patients receiving oral anticoagulation therapy for VTE treatment, should supplementary patient education be offered vs no supplementary patient education? For patients receiving oral anticoagulation therapy for VTE treatment, the ASH guideline panel suggests using supple- mentary patient education in addition to basic education for patients receiving oral anticoagulation for VTE treatment (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. This question specifically evaluated whether educational interventions over and above what most patients receive from health care providers (eg, the prescriber and/or dispensing pharmacist) in the usual course of anticoagulant prescribing improves anticoagulation therapy outcomes. We found 1 systematic review evaluating the impact of supplemental patient education on outcomes that concluded that there was not sufficient evidence to support supplemental patient education to improve outcomes for patients with VTE.152 The quality of evidence included in this review was deemed to have very low certainty; therefore, we sought additional studies that might provide more information. We included 8 RCTs evaluating patients receiving anticoagulation therapy that tested various educational interventions.33,153-159 One study reported the effect of supplemental education interven- tions on mortality154 ; 3 studies each reported thromboembolic154,155,158 outcomes. Three studies assessed the impact of supplemental education interventions on TTR for patients receiving VKA Five studies reported change in various knowledge assessment scores following the educational intervention.153,156-159 The EtD framework is shown online at https://dbep.gradepro.org/profile/ 17f7766f-74b7-462f-9041-f509df9c7d6a. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Although supplemental education might reduce mortality (RR, to 305 more]; low certainty), PE (RR, 0.57 [95% CI, 0.17-1.95]; ARR, 9 fewer per 1000 [95% CI, 17 fewer to 19 more]; low certainty), and recurrent DVT (RR, 0.57 [95% CI, 0.17-1.95]; ARR, 11 fewer per 1000 [95% CI, 22 fewer to 25 more]; low certainty), the effect estimates are extremely imprecise, and CIs include both large benefits and great harm. Studies reporting TTR as an outcome for patients receiving VKA therapy found no difference between those receiving supplemental education and control groups (MD, 2.40% higher [95% CI, 2.79% lower to 7.58% higher]; low certainty). Supplemental education was effective in improving patient perfor- mance on various knowledge assessments (standardized MD, 0.77 higher [95% CI, 0.43-1.11 higher]; low certainty). Harms and burden. Although supplemental education might reduce the risk of bleeding in patients that were at average risk for bleeding compared with control patients (RR, 0.54 [95% CI, 0.06 to 4.76]; ARR, 8 fewer per 1000 [95% CI, 16 fewer to 64 more]; very low certainty), the effect estimate is very imprecise, and CIs include large benefit and great harm. Other EtD criteria and considerations. The guideline panel determined that the uncertainty about resources required to implement this intervention is large, depending on the nature of the intervention itself. Some interventions consisted of a 5-minute whereas others involved 20 to 30 minutes of one-on-one The cost-effectiveness of supplemental education could not be determined, as there were no available studies. The panel agreed that individual patients will have different experiences when supplemental education is delivered, in part due to differ- ences in the manner in which health care providers deliver the intervention. There may also be differences between patients receiving DOACs and those receiving VKA, given that patients on DOACs may not receive the same level of follow-up or may be less likely to receive care in specialized AMSs. According to some panel members, supplemental education might increase health care equity if it is uniformly administered in a consistent way; others thought that equitable delivery is unlikely. The panel agreed that this intervention is probably acceptable to key stakeholders, including patients, health care providers, and payers (although payers may be less accepting due to lack of clear benefit), and is also feasible to implement for most patients, although less so for patients with low health literacy or those whose primary language differs from that of the educational material. Conclusions and research needs for this recommendation. The guideline panel determined that there is a very low certainty in evidence for a net health benefit from using supplemental educational interventions. Not surprisingly, supplemental education increased performance on knowledge assessments; however, the panel viewed the importance of this outcome as uncertain relative to actual clinical outcomes. This recommendation places a high value on a very uncertain benefit of the education intervention and a low value on avoiding the burden and cost associated with the intervention. 27 NOVEMBER 2018 x VOLUME 2, NUMBER 22 ASH 2018 VTE GUIDELINES: ANTICOAGULATION MANAGEMENT 3273 The panel identified the following additional research priorities: (1) identifying a standardized definition of what constitutes a patient education intervention and (2) acquiring more information regarding DOAC educational interventions. Efforts to improve anticoagulant- medication adherence Question: For patients receiving anticoagulation therapy for VTE, should interventions to improve adherence (eg, refill reminders and INR reminders) vs usual care be used? In general, adherence to prescribed medication regimens is associated with improved clinical outcomes for patients with chronic conditions, and nonadherence is associated with higher rates of hospital admissions, suboptimal health outcomes, in- creased morbidity and mortality, and increased health care Initially, we searched for any evidence regarding specific interventions to improve anticoagulation therapy adherence (eg, refill reminders and INR reminders). We searched only for RCTs and identified 3 RCTs addressing specific interventions designed to improve adherence, and we prepared separate EtD frameworks for each adherence intervention (recommendations For patients receiving anticoagulation 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 elec- tronic medication monitoring system is accessed) to improve medication adherence (conditional recommendation based on very low certainty in the evidence about effects ). Summary of the evidence. Two RCTs reported the effect of a daily lottery-based incentive intervention for patients using In the lottery arm, participants had between a 1-in-5 and a 1-in-100 chance of a monetary reward each day if they opened the pill compartment on a sophisticated electronic medication monitoring system and confirmed that they took their warfarin as prescribed that day. 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/ e5b45031-b8d4-4f50-8472-6617781ff3e3. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. There was no difference in the percentage time out of INR range (adjusted odds ratios [ORs] for likelihood of being out of INR ; very low certainty) or days with incorrect adherence (fully adjusted OR for likelihood of nonadherence, 0.84 [95% CI, 0.55- between those receiving the daily lottery intervention and control groups. Harms and burden. Mortality (ARR, 8 more per 1000; very low certainty), PE/DVT (ARR, 26 more per 1000; very low certainty), and major bleeding (RR, 1.63 [95% CI, 0.33-8.09]; ARR 22 more per 1000 [95% CI, 24 fewer to 249 more]; very low certainty) were all higher in the daily lottery intervention group than in controls, but the CIs were extremely wide, including both appreciable benefit and great harm. 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 the cost for monetary prizes averaged $3 per patient per day. Furthermore, the panel determined that health equity would probably be reduced by the intervention, key stakeholders would probably not find a daily lottery acceptable, and given the requirement for specialized equipment, the in- tervention is probably not feasible to implement in most settings. Conclusions and research needs for this recommendation. Given that no evidence supports the benefit of the lottery approach, the likely high costs, and the probable lack of acceptability and feasibility, the panel suggests against using the lottery. This recommendation should not be interpreted to mean that interventions aimed at improving anticoagulant adherence are not important. 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. 