The treatment of patients with pulmonary embolism (PE) has evolved substantially over the past few decades. Many patients with PE can be discharged directly from the emergency department (ED). Advanced therapies such as catheter-directed treatments (CDT) are now available in many centers, and anticoagulants such as low-molecular–weight heparins (LMWH) and direct oral anticoagulants (DOACs) have been developed, which obviate the need for frequent laboratory monitoring and dose titration in many patients. Anticoagulant selection may seem much less important and exciting than the decision to administer thrombolytics or send a patient for thrombectomy; however, it is the cornerstone of PE treatment—and we are getting it wrong in a fair number of patients.

Although intravenous unfractionated heparin (UFH) was the first anticoagulant developed and routinely used in venous thromboembolism (VTE), the pharmacokinetics are wild. UFH has a variable half-life, extensive protein binding, and two-phased elimination requiring patients to undergo frequent bloodwork to ensure levels fall within a narrow therapeutic range. Despite nursing or pharmacy-driven protocols to adjusted doses based on activated partial thromboplastin (aPTT) or anti-factor Xa levels, a minority of patients anticoagulated with UFH for PE sustain therapeutic values across timepoints in the first couple of days.¹ Further, a Cochrane review found that LMWH is associated with improved outcomes compared with UFH including reduced incidence of major hemorrhage (odds ratio [OR]=0.69; 95 percent CI, 0.50-0.95) and recurrent VTE during initial treatment up to 15 days (OR=0.69; 95 percent CI, 0.49-0.98). As a result, professional society guidelines have recommended alternatives to UFH such as LMWH or DOACs for most patients with PE for more than a decade.^2-4

A study in Annals of Emergency Medicine of almost 300,000 patients hospitalized with acute PE between 2011-2020 found that the use of UFH increased from 41.9 percent to 56.3 percent despite guideline recommendations. During the same period, there was no sign that patients were sicker (i.e., no increase in vasopressor use, mechanical ventilation, admission to an intensive care unit, in-hospital mortality).⁵ The opposite trend in UFH use exists in countries outside the United States, where UFH use steadily decreased to less than 10 percent of patients.⁶ The question is: Why? What is driving this gap?

Anticoagulant Misconceptions

Misconceptions regarding anticoagulant pharmacology and contraindications are common. First, UFH is often perceived as “stronger” than alternatives, partially owing to the intravenous route of administration.⁷ Although UFH begins working immediately, studies demonstrate it takes a median of six to 15 hours to achieve therapeutic aPTT or anti-Xa levels.^1,8 In contrast, the peak effect for LMWH and DOACs such as rivaroxaban and apixaban are much quicker (three to four hours and one to four hours, respectively). The pervasive maxim “quick on, quick off” for UFH doesn’t hold up as well as touted.

Second, a nearly ubiquitous belief exists that anticoagulation is withheld or reversed for CDT.⁷ In fact, anticoagulation is continued during CDT and can include LMWH.^9,10 Similarly, use of LMWH does not preclude salvage thrombolytic use. The TOPCOAT trial, evaluating tenecteplase for intermediate-risk PE, protocolized the use of LMWH prior to thrombolysis, switching patients started on UFH to a LMWH.¹¹ Most patients hospitalized with PE undergo neither CDT nor thrombolysis and, even if they do, administration of LMWH is not a contraindication. Although we may worry about the potential for decompensation and don’t want to preclude advanced therapies, this fear should not motivate us to choose UFH over a LMWH for most patients.

In addition, a circular pattern of deference of anticoagulant choice exists within the hospital spectrum of care. In the qualitative study, emergency physicians revealed choosing UFH over LMWH not only because this is how they were trained and the inertia of their practice pattern, but also to allow more flexibility to the inpatient team. Hospital medicine clinicians revealed that even if they preferred an alternative to UFH, they were unlikely to change the anticoagulant until preparation for discharge. Hospitalists cited not wanting to “second guess” the emergency physician and the hassle of multiple changes in anticoagulation regimens as reasons they continued UFH use in these cases.⁷

Unfractionated heparin has a role in a select minority of patients with acute PE, largely in patients on vasopressors who may have impaired subcutaneous absorption of LMWH, those who are actively bleeding or are imminently undergoing invasive surgical procedures, and those with severe renal dysfunction in whom renally dosed LMWH or DOACs are contraindicated. However, these exceptions account for a minority of patients hospitalized with PE. It’s time to dispel the myths associated with UFH and embrace alternatives as the default, reserving UFH for a much narrower subset of patients with PE.

Dr. Westafer (@Lwestafer) is an attending physician and research fellow at Baystate Medical Center, clinical instructor at the University of Massachusetts Medical School in Worcester, and co-host of FOAMcast.

References

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