The EtD framework is shown at https://dbep.gradepro.org/profile/783DCF1B-50FC-72D0-A1E1-3C31011E9471. Should LMWH vs UFH be used for VTE prophylaxis in critically ill patients? UHL Guideline for Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in adults, with Direct Oral Anti-Coagulants Trust Ref B11/2018 1.Introduction and Who Guideline applies to The introduction of the Direct Oral Anti-Coagulants (DOACs) represents a major change in … We excluded studies that addressed this question in critically ill patients who underwent surgery or had trauma. American Society of Hematology 2018 guidelines for management of venous thromboembolism: ... (DVT), and major bleeding as critical for decision making and placed a high value on these outcomes and avoiding them with the interventions that were evaluated. Eleven reports91,104-113  compared the cost-effectiveness of LMWH with UFH in hospitalized patients; 1 was a trial-based analysis that the panel considered most informative.106  All reports concluded that LMWH was cost-effective for thromboprophylaxis compared with UFH, with 4 reports suggesting that LMWH was more effective and provided net savings compared with UFH.91,104,105,111  The panel recognized that cost may change or differ widely across settings. and one third will have a recurrent DVT or PE within 10 years. Thirty-three individuals or organizations submitted comments. About 90% of patients in this study40  were low risk for bleeding (score < 7). The guideline panel determined that there is low certainty in the evidence for a net health benefit from using LMWH over UFH in acutely ill medical patients. 0000019023 00000 n For PE, the ARR was 11 fewer per 1 000 000 (95% CI, 9-12 fewer per 1 000 000), for proximal DVT, the ARR was 540 fewer per 1 000 000 (95% CI, 450-576 fewer per 1 000 000), and for distal DVT, the ARR was 2112 fewer per 1 000 000 (95% CI, 1760-2253 fewer per 1 000 000). For policy makers: policy making will require substantial debate and involvement of various stakeholders. Question: If pharmacologic prophylaxis is used, should fondaparinux vs LMWH or UFH be used? Several VTE risk factors (eg, cancer, plaster casts, hormone replacement therapy, oral contraceptives, and pregnancy) multiplicatively increase the risk of air travel–related VTE.162  For example, pregnant women who traveled by air had an odds ratio (OR) for VTE of 14.3 (95% CI, 1.7-121.0) compared with an OR of 4.3 (95%, 0.9-19.8) associated with pregnancy alone.164  Women who traveled by air while using oral contraceptives had an 8.2-fold (95% CI, 2.3-28.7) elevated risk for VTE compared with nontravelers who were not on contraceptives, whereas the risk with oral contraceptives alone was increased 2.5-fold (95% CI, 0.9-7.0).162. Interpretation of strong and conditional recommendations. Remark: These 3 recommendations also apply to anticoagulant choices when VTE prophylaxis is considered for patients with stroke. Initial treatment may be with medication intravenously or injected under the skin, with eventual transition to a medi-cation taken by mouth. The panel assumed that avoidance of PE, DVT, and bleeding events was critical or important for decision making to patients. The panel assumed that avoidance of death, PE, and DVT was critical or important for decision making to patients. 0000020861 00000 n Compare combined mechanical and pharmacological prophylaxis with mechanical prophylaxis alone utilizing comparative effectiveness research studies. The mortality RR was 0.89 (95% CI, 0.78-1.02), and ARR was 32 fewer per 1000 (95% CI, from 64 fewer to 6 more per 1000). Mechanical combined with pharmacological vs pharmacological alone, 10. The guideline panel rated mortality, pulmonary embolism (PE), moderate to severe deep venous thrombosis (DVT), and major bleeding as critical for decision making and placed a high value on these outcomes and avoiding them with the interventions that were evaluated. This is similar to the ASH guidelines, although the recommendations were not specifically keyed to bleeding risk but to persons at risk who are not receiving pharmacological prophylaxis. Typically, outcomes were reported as “any VTE,” “any PE,” “any DVT,” “any proximal DVT,” or “any distal DVT,” sometimes preceded by “asymptomatic” or “symptomatic,” but reporting was inconsistent across studies. Question. With regard to future research, the panel suggests: Studies of risk assessment tools for guidance on defining high-risk status for VTE and bleeding at discharge; Trials of pharmacological or nonpharmacological interventions in selected high-risk medical patients for VTE at discharge143 ; and. 0000033190 00000 n They should never be omitted when recommendations from these guidelines are quoted or translated. Search for other works by this author on: American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee, Heart disease and stroke statistics-2018 update: a report from the American Heart Association [published correction appears in Circulation. Patient populations and interventions for the prevention of VTE and the corresponding recommendations. For researchers: this recommendation is likely to be strengthened (for future updates or adaptation) by additional research. As science advances and new evidence becomes available, recommendations may become outdated. Pharmacological prophylaxis vs no prophylaxis. The panel considered risk of falls, ischemia, and limb ulceration with mechanical prophylaxis as important outcomes (as discussed for recommendation 7). Supplement 2 provides the complete “Disclosure of Interests” forms of all panel members. Among these anticoagulants, the panel suggests using LMWH (low certainty in the evidence of effects ⊕⊕◯◯) or fondaparinux (very low certainty in the evidence of effects ⊕⊕◯◯) rather than UFH (conditional recommendation). The panel assumed that avoidance of PE, DVT, and bleeding events was critical or important for decision making to patients. In 2014, in response to long-standing member interest, ASH initiated an effort to develop evidence-based clinical practice guidelines for hematology that meet the highest standards of development, rigor and trustworthiness. No existing systematic review addressed this question, and our systematic search for RCTs identified 1 study providing direct evidence for this question.88  This trial reported any confirmed VTE as an outcome. This document may also serve as the basis for adaptation by local, regional, or national guideline panels. Although the panel assumed no impact on health equity for aspirin, it felt that equity would be reduced if LMWH were recommended, given challenges with access. We identified 1 systematic review that provided evidence to address this question.145  Our update of the systematic review identified 1 additional study.42  All studies included acutely and critically ill medical patients. Seven studies reported the effect of mechanical prophylaxis vs pharmacological prophylaxis on risk of mortality.122,124-129  Seven studies reported the effect of mechanical prophylaxis vs pharmacological prophylaxis on development of symptomatic PE.121,122,124-127,129  Three studies reported the effect of mechanical prophylaxis vs pharmacological prophylaxis on development of symptomatic DVT.121,126,127  Seven studies reported the effect of mechanical prophylaxis vs pharmacological prophylaxis on risk of major bleeding.121,124-128,130  The EtD framework is shown at https://dbep.gradepro.org/profile/95794127-BD67-D33B-BCDA-3FF49A76A6F2. In DVT a blood clot forms in the lower extremities that may break off and travel to the lungs causing a pulmonary embolism. Differences from the ASH guidelines include: No prophylaxis generally for patients with acute coronary syndrome; Consider prophylaxis in those on long-term anticoagulation if this is interrupted; Use intermittent pneumatic compression in acute stroke patients for 30 days or until the patient is mobile or discharged; Use pharmacological prophylaxis in acutely ill medical patients for 7 days minimally, with LMWH preferentially; Use LMWH or UFH, with lower doses of each if desired, for medical patients with renal impairment; Use prophylaxis with LMWH in those receiving palliative care if desired, but not in the last days of life; Use mechanical prophylaxis in critically ill patients if pharmacological prophylaxis is contraindicated; Use daily, or more frequent, VTE and bleeding risk assessments in critically ill patients; For acute psychiatric patients, perform VTE risk assessment, and if prophylaxis is used, use fondaparinux or LMWH; and. All studies included acutely ill medical patients, with 5 studies in stroke patients.93-97  The EtD framework is shown at https://dbep.gradepro.org/profile/FA048403-345D-A41B-8147-6657D26C1399. 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 to identify possible research gaps. Diagnostic strategies were evaluated for pulmonary embolism (PE), deep vein thrombosis (DVT) of the lower and upper extremity, and recurrent VTE. Patients with peripheral vascular disease may experience higher rates of adverse events, including leg ulceration, ischemia, and amputations. The ASH guidelines define the treatment period of acute DVT/PE as “initial management” (first 5-21 days), “primary treatment” (first 3-6 months), and “secondary prevention” (beyond the first 3-6 months). Mechanical prophylaxis, including pneumatic compression devices, appeared to be cost-effective. Research questions are listed in under recommendation 13. Agency for Healthcare Research and Quality. In particular, can lower or higher doses be used in different settings (perhaps dependent on baseline risk), and should dosing be adjusted in obese patients, underweight patients, and patients with renal disease? Extended-duration DOACs vs shorter-duration non-DOAC prophylaxis, 15. For example, patients given mechanical prophylaxis must be observed to reduce the risk of falls and other complications. The panel assumed that avoidance of death, PE, and DVT was critical or important to patients for decision making. Most patients with catheter-related DVT are treated for a period of 3 months, unless the cath-eter is to remain in place long-term. In Part A of the forms, individuals disclosed material interests for 2 years prior to appointment. 0000012853 00000 n Members of the guideline panel received travel reimbursement for attendance at in-person meetings, and the patient representative was offered, but declined, an honorarium of $200. 0000070774 00000 n Although this trial adds important information to the body of evidence for this recommendation, the guideline panel agreed that the trial results should not change the recommendation. The membership of the panel and the GRADE Centre team is described in Supplement 1. Overall, the certainty in these estimated effects is very low owing to very serious indirectness and serious risk of bias for the estimates (see evidence profile in the online EtD framework). The panel included hematologists, internists, other physicians, and a pharmacist who all had clinical and research expertise on the guideline topic; methodologists with expertise in evidence appraisal and guideline development; and 1 patient representative. We made decisions a priori regarding search methods, eligibility criteria, data collection, and data analysis. Given that this recommendation was based on indirect data and extrapolation, further research is required. PDF | The review article ... 10th edition of the ACCP guidelines for diagnosis and treatment of venous thromboembolism. We did not identify any systematic review that addressed this question, but our comprehensive search for RCTs identified 2 studies121,122  in acutely or critically ill medical patients that provided limited evidence for this question. Evidence for outpatients with cancer is addressed in a separate ASH guideline. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences. 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. A template of the guidelines for all panels (prepared by H.J.S.) The guideline panel determined that, although the health effects may suggest net benefit for the use of graduated compression stockings, cost would be moderate, and use of stockings would not be cost-effective. For PE, the RR was 1.54 (95% CI, 0.48-4.93), and the ARI was 1 more per 1000 (95% CI, from 1 fewer to 4 more per 1000), for a baseline risk of 0.1%. In addition to conducting systematic reviews of intervention effects, the researchers searched for evidence related to baseline risks, values, preferences and costs, and summarized findings within the EtD frameworks.12,13,18  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 effect estimate of the outcomes of interest following the GRADE approach based on the following domains: risk for bias, precision, consistency and magnitude of the estimates of effects, directness of the evidence, risk for publication bias, presence of large effects, dose–response relationship, and an assessment of the effect of plausible residual and opposing confounding. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. The absolute risk reduction in VTE may be higher in high-risk VTE patients, and the benefits may outweigh the harms among patients at increased risk of bleeding. Medical Patients with Enoxaparin, Economic evaluation of enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients, Economic evaluation of enoxaparin vs. placebo for the prevention of venous thromboembolism in acutely ill medical patients, Prophylaxis of thrombotic and embolic events in acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial, A multicentre, double-blind, randomized study to compare the safety and efficacy of once-daily ORG 10172 and twice-daily low-dose heparin in preventing deep-vein thrombosis in patients with acute ischaemic stroke, Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study, The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison, A low-molecular-weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. The EtD framework is shown at https://dbep.gradepro.org/profile/0F91C482-0EC7-18AC-8738-817C23635ED2. Performance measures should assess whether decision making is appropriate. The panel considered that the EtDs were formulated using RCTs that tested 3 DOACs, but there was no heterogeneity observed in the systematic review, and the drugs have the same mechanism of action. The EtD framework is shown online at https://dbep.gradepro.org/profile/54B577E9-7F80-3A78-B3EA-3850E9A1D432. 0000027983 00000 n 0000097383 00000 n 0000071057 00000 n These guidelines are not intended to serve or be construed as a standard of care. We did not identify trials that directly addressed this question. During a 2-day in-person meeting, followed by online communication and conference calls, the panel developed clinical recommendations based on the evidence summarized in the EtD tables. The study did not report on major bleeding. These guidelines are intended to support patients, clinicians, and health care professionals in VTE diagnosis. In absolute and relative terms, LMWH appeared to have a moderate impact on mortality and no impact on VTE, but these effects were considered very uncertain. Overall, the certainty in these estimated effects is very low owing to very serious imprecision and serious indirectness of the estimates (see evidence profile and online EtD framework). Medical inpatients, long-term care residents, persons with minor injuries, and long-distance travelers are at increased risk. In absolute terms, extended use of DOACs appeared to have no impact on mortality (RR, 1.01; 95% CI, 0.89-1.14), with an ARR of 0 fewer per 1000 treated (95% CI, 5 fewer to 7 more per 1000). Other EtD criteria were generally in favor of using LMWH so that the desirable consequences were greater than the undesirable consequences. 0000036783 00000 n 0000050562 00000 n ASH does not warrant or guarantee any products described in these guidelines. Recommendation for education of patients/caregivers on VTE and VTE prevention at admission and discharge. The same RR was used for distal DVT, resulting in an ARR of 0 fewer per 1000 (95% CI, 1 fewer to 20 more per 1000) for a low-risk population and 0 fewer per 1000 (95% CI, 4 fewer to 61 more per 1000) for a high-risk population. They recommended against the use of aspirin or anticoagulants. 0000007538 00000 n Two RCTs reported an increase in gastrointestinal bleeding (RR, 2.61; 95% CI, 0.36-18.86; ARR, 50 more per 1000; 95% CI, from 20 fewer to 558 more per 1000), and 3 reported little impact on thrombocytopenia (RR, 0.95; 95% CI, 0.47-1.92; ARR, 0 per 1000; 95% CI, from 1 fewer to 2 more per 1000), with 1 of the studies specifically reporting no HIT in either group. Bleeding did not occur with LMWH or aspirin in the 1 available RCT. DEEP VEIN THROMBOSIS (DVT): TREATMENT . 0000002896 00000 n The panel made a conditional recommendation for using pharmacological prophylaxis over mechanical prophylaxis and determined that the recommendation would not apply to groups in whom the risk of VTE would be too small to justify the downsides or burden of any prophylaxis. The panel selected outcomes of interest for each question a priori, following the approach described in detail elsewhere.50  In brief, the panel brainstormed all possible outcomes before rating their relative importance for decision making following the GRADE approach.50  During this rating process, the panel used definitions of the outcomes (“marker states”) that were developed for these guidelines. Question: Should graduated compression stockings, LMWH, or aspirin vs no VTE prophylaxis be used by long-distance (>4 hours) travelers? Studies that evaluate dose adjustments or lower doses of anticoagulants that might maximize benefit while minimizing harm when used for extended treatment to prevent VTE after hospital discharge. As such, they completed a disclosure of interest form, which was reviewed by ASH and is available as Supplements 2 and 3. This study compared intermittent pneumatic compression with graduated compression stockings. treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B). For PE, the RR was 0.73 (95% CI, 0.51-1.04), translating to an ARR of 0 fewer per 1000 (95% CI, from 0 fewer to 0 fewer per 1000) using a baseline risk of 0.1% per admission for PE; for proximal or distal DVT, the RR was 0.82 (95% CI, 0.61-1.10), translating to an ARR of 0 fewer per 1000 (95% CI, 0-1 fewer per 1000) using a baseline risk of 0.2%. 0000005268 00000 n Other purposes are to inform policy, education, and advocacy and to state future research needs. OBJECTIVE: To provide an evidence-based approach to treatment of patients presenting with deep vein thrombosis (DVT). Before appointment to the panel, individuals disclosed financial and nonfinancial interests. Catheter-related DVT. Development of these guidelines was wholly funded by ASH, a nonprofit medical specialty society that represents hematologists. These patients may be referred to the KPWA Anticoagulation/Anemia Management Service (AMS). The majority of individuals in this situation would want the suggested course of action, but many would not. On 30 April 2018, the ASH Guideline Oversight Subcommittee and the ASH Committee on Quality approved that the defined guideline-development process was followed; on 4 May 2018, the officers of the ASH Executive Committee approved submission of the guidelines for publication under the imprimatur of ASH. Part D describes new interests disclosed by individuals after appointment. doi: https://doi.org/10.1182/bloodadvances.2018022954. 1,2. On occasion, a strong recommendation is based on low or very low certainty in the evidence. For example, 1 study134  comparing pneumatic compression devices with no devices for immobile stroke patients suggested an additional cost of US $2171 to prevent 1 DVT of any type. The panel made a strong recommendation for using pharmacological prophylaxis, although the exact magnitude of the mortality benefit is still in question. For patients: the majority of individuals in this situation would want the suggested course of action, but many would not. In addition, the panel expressed caution about existing cost-effectiveness analyses that differed in their assumptions and input parameters from that used by the panel in the EtD. Based on enhanced understanding of these issues, a paradigm shift in VTE risk assessment and prevention is underway that prompts clinicians to strive for individualized prophylaxis based on VTE and bleeding risk. Correspondence: Holger J. Schünemann, Department of Health Research Methods, Evidence and Impact, McMaster University, HSC-2C16, 1280 Main St West; Hamilton, ON L8N 3Z5, Canada; e-mail: schuneh@mcmaster.ca. Other EtD criteria generally favored LMWH use in hospital only because the undesirable effects of DOACs were greater than the desirable consequences. Fondaparinux vs low molecular weight heparin or unfractionated heparin, 6. The panel also suggested that pneumatic compression devices might reduce mobility and cause falls in patients who ambulate, although the panel did not review specific evidence for these outcomes, and some evidence suggests no increased risk of falls with pneumatic compression devices.139. None of the studies reported whether the symptomatic DVTs were proximal or distal; therefore, we estimated the absolute effect on proximal and distal DVT by applying results to a representative baseline risk. We found 8 systematic reviews51,52,54,58,59,63,65,67  that addressed this question and included 11 RCTs.93-103  We identified 1 additional study99  published after the search for the systematic reviews was completed. ASH guidelines are primarily intended to help clinicians make decisions about diagnostic and treatment alternatives. Risk factors for hospital-acquired VTE include acute medical illness, surgery, cancer and cancer therapy, trauma, immobilization, central venous catheters, previous history of VTE, older age, and obesity.19  Almost all hospitalized patients have ≥1 risk factor for VTE, and ∼40% have ≥3 risk factors.20  In a United States population-based study, hospital-acquired DVT and PE occurred in 1.3% and 0.4% of hospital admissions, respectively.21  The increased risk of VTE persists for 45 to 60 days after hospital discharge.22  Other medical populations that may be at increased risk for VTE include long-term care residents, frail persons, those with minor injuries, and long-distance travelers, particularly those with preexisting VTE risk factors.2-7. In the 3 trials, extended use of a DOAC led to an increased risk for major bleeding (RR, 1.99; 95% CI, 1.08-3.65). Question: Should mechanical combined with pharmacological vs mechanical VTE prophylaxis alone be used in acutely or critically ill medical patients? Medical inpatients are a heterogeneous population in terms of VTE risk, but these patients have conventionally been subject to universal, or group-based, VTE-prevention strategies.20,23-25  We defined acutely ill medical patients as patients hospitalized for a medical illness. Mechanical vs pharmacological prophylaxis, 8. Two studies115,117  assessed the risk of major bleeding, and 1 study assessed the risk of thrombocytopenia.115  No studies reported the outcome of HIT specifically. Two studies117,118  reported on the development of any PE, and 1 of these studies118  reported on development of symptomatic PE specifically, which was used to extrapolate data for the outcome of PE representing the moderate marker state. 0000003520 00000 n Question: Should extended-duration (ie, up to 30 or 40 days) vs in-hospital–only UFH or LMWH be used for the thromboprophylaxis of VTE in critically ill hospitalized medical patients? The guideline panel used indirect evidence from acutely ill medical patients that evaluated extended outpatient prophylaxis and determined that there is low certainty in the evidence for net health harm from that evidence in medical outpatients with minor provoking factors for VTE. In the 3 included trials, use of a DOAC compared with LMWH led to an increased risk for major bleeding (RR, 1.70; 95% CI, 1.02-2.82; ARI, 2 or 8 more hemorrhages per 1000 for 2 representative baseline risks of bleeding [low and high]). Although no studies reported on HIT, 1 study reported an increased risk for thrombocytopenia with heparin use, with an RR of 1.49 (95% CI, 0.59-3.78) and an ARI of 30 more per 1000 (95% CI, 25 fewer to 171 more per 1000). 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. In acutely or critically ill medical patients, the ASH guideline panel suggests pharmacological or mechanical VTE prophylaxis alone over mechanical combined with pharmacological VTE prophylaxis (conditional recommendation, very low certainty in the evidence of effects ⊕◯◯◯). Accurate diagnosis of VTE is important due to the morbidity and mortality associated with missed diagnoses and the potential side effects, patient inconvenience, and resource implications of anticoagulant treatment given for VTE. Parenteral anticoagulant vs no parenteral anticoagulant, 3. 0000017198 00000 n 0000042209 00000 n Our update of the review identified 11 additional relevant studies.152-162  We did not consider studies addressing biomarkers as predictors of travel-related VTE. h�b```b`�. For researchers: the recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. We evaluated outcomes in 2 phases: first, we focused on outcomes at the end of the standard-course inpatient treatment with enoxaparin or oral DOAC (ie, enoxaparin and DOAC for the same period of time), and then we evaluated outcomes separately at the end of the prophylaxis period (ie, standard inpatient duration for enoxaparin vs extended-duration DOAC).