Invited Commentary <\/p>\n\n\n\n
Pulmonary Medicine<\/p>\n\n\n\n
January 3, 2025<\/p>\n\n\n\n
Systemic anticoagulation is the foundation of treatment for most patients with pulmonary embolism (PE). Guidelines recommend that most patients hospitalized for acute PE who are treated with parenteral anticoagulation should receive low-molecular-weight heparin (LMWH) rather than unfractionated heparin (UFH) because LMWH achieves therapeutic anticoagulation more quickly and is associated with fewer bleeding complications.1<\/a><\/sup>-3<\/a><\/sup><\/a><\/p>\n\n\n\n Despite this recommendation, the proportion of US patients with acute PE initially treated with UFH increased from 41.9% to 56.3% between 2011 and 2020, whereas less than 10% of similar patients in Europe were treated with UFH.4<\/a><\/sup> Faced with such contradictory data, Stubblefield and colleagues5<\/a><\/sup> conducted a robust qualitative study of 46 emergency physicians, hospitalists, and interventionalists in the US to understand the factors associated with anticoagulation decisions for PE. Among the authors\u2019 conclusions were that emergency and hospitalist physicians share misconceptions regarding anticoagulation and thrombolytic therapies for PE.5<\/a><\/sup> Here, we address several of these crucial misunderstandings and the imperative to update these practices.<\/a><\/p>\n\n\n\n Heparin revolutionized the care of thromboembolic disease when it was first introduced to clinical care in the late 1930s, yet it is far from perfect. The action of UFH is affected by extensive binding to plasma proteins and vascular endothelial cells; minor UFH dose changes can produce dramatic swings in the intensity of anticoagulation due to its nonlinear and dose-dependent elimination. As a result, UFH infusions require frequent monitoring and dose adjustments. In contrast, LMWH and direct oral anticoagulants (DOACs) experience less protein binding, more predictable pharmacokinetics, and a more consistent anticoagulation effect.6<\/a><\/sup><\/a><\/p>\n\n\n\n In their study, Stubblefield et al5<\/a><\/sup> found several major themes behind the selection of UFH as an initial anticoagulant for acute PE. Three common misconceptions regarding pharmacology and contraindications to anticoagulation therapy represent opportunities for intervention to improve the safety of PE care.<\/a><\/p>\n\n\n\n First, there was a misconception about speed of anticoagulation. Study participants often characterized UFH as \u201cstronger\u201d or \u201cquicker\u201d than other anticoagulants because it is administered intravenously (IV).5<\/a><\/sup> Intravenous UFH starts working as soon as it is injected, but anticoagulation is not an all-or-nothing phenomenon. To achieve therapeutic anticoagulation for PE, the patient must reach a target activated partial thromboplastin time (APTT) or anti\u2013factor Xa level. The belief that UFH leads to immediate therapeutic anticoagulation is contrary to published evidence. One study demonstrated that more than 75% of patients receiving UFH do not have a single therapeutic APTT within 12 hours of starting treatment, and more than 40% do not have a therapeutic level within 48 hours.7<\/a><\/sup> In contrast, LMWH typically reaches therapeutic levels 3 to 4 hours after administration.6<\/a><\/sup><\/a><\/p>\n\n\n\n Participants who referred to the rapid onset of UFH often later acknowledged potential delays in achieving therapeutic levels.5<\/a><\/sup> This pattern suggests that physicians\u2019 initial anticoagulant choice may be based on heuristics (eg, mental shortcuts) rather than purposeful consideration of risks and benefits. Acute care physicians are accustomed to using IV infusions for many of the sickest patients: vasopressors for septic shock, propofol for sedation, and epinephrine for anaphylaxis or life-threatening asthma, for example. We rely on these medications to deliver rapid results in life-threatening situations. A heuristic favoring IV administration over other routes may lead some physicians to assume that UFH is a superior approach to anticoagulation in PE; yet for most patients, this assumption is not true.3<\/a><\/sup><\/a><\/p>\n\n\n\n Second, there was a fear of precluding procedural intervention. Participants expressed a preference for UFH because it can be turned off or reversed if patients needed a procedural intervention.5<\/a><\/sup> This belief reflects the misconception that anticoagulation is a contraindication to advanced therapies, such as catheter-directed interventions or systemic thrombolysis. Guidelines recommend continuing anticoagulation during catheter-directed interventions,8<\/a><\/sup> although there remains heterogeneity in clinical practice regarding choice of anticoagulant and monitoring during catheter-directed thrombolytic infusion.8<\/a><\/sup>,9<\/a><\/sup> Parenteral anticoagulation with either UFH or LMWH is not a contraindication to systemic thrombolysis.1<\/a><\/sup>,8<\/a><\/sup>,10<\/a><\/sup><\/a><\/p>\n\n\n\n Third, preferences for UFH also centered on risks of bleeding and the ability to address bleeding complications if they occurred.5<\/a><\/sup> This rationale is unfounded as UFH is associated with a higher risk of bleeding than LMWHs and DOACs. In a systematic review of 21 trials for treatment of venous thromboembolism, LMWHs were associated with a lower risk of major hemorrhage (odds ratio [OR], 0.62; 95% CI, 0.43-0.90; P<\/em>\u2009=\u2009.01) and overall mortality (OR, 0.77; 95% CI, 0.63-0.93; P<\/em>\u2009=\u2009.008) compared with UFH.3<\/a><\/sup> Participants also cited the ability to reverse UFH (eg, with protamine sulfate).5<\/a><\/sup> Another important misconception is that no steps can be taken to reverse LMWH. Protamine achieves partial (approximately 60%) reversal of LMWH, and guidelines recommend protamine for management of life-threatening bleeding associated with either UFH or LMWH.2<\/a><\/sup> DOACs may be reversed with prothrombin complex concentrates or specific reversal agents (eg, idarucizumab for dabigatran; andexanet alfa for apixaban and rivaroxaban).<\/a><\/p>\n\n\n\n While LMWH and DOACs are the recommended choice for most patients with acute PE, there are circumstances in which UFH may be considered appropriate. First, patients with advanced kidney disease (creatinine clearance below 30 mL\/min) should either receive UFH or a renally adjusted dose of LMWH, since LMWH relies on renal clearance to a greater degree than UFH.1<\/a><\/sup>,2<\/a><\/sup> Second, UFH may be considered in hemodynamically unstable patients with acute PE. Variability in published guidelines reflects the lack of robust comparative data on this topic. Some guidelines suggest that UFH may be preferred in patients who are hemodynamically unstable.1<\/a><\/sup> Other guidelines state that the priority is to start parenteral anticoagulation quickly, even if other interventions are being considered, and that both UFH and LMWH may be considered based on institutional practices.10<\/a><\/sup> Numerous guidelines recommend starting anticoagulation for patients with high pretest probability of PE, even before a PE diagnosis is confirmed, and LMWH is generally recommended in this context.1<\/a><\/sup>,10<\/a><\/sup><\/a><\/p>\n\n\n\n