Clots, Catheters, and Clinical Pearls: Pulmonary Embolism Updates for Practicing Pharmacists

Background

Venous thromboembolism (VTE) affects approximately 900,000 individuals in the United States annually and consists of deep vein thrombosis (DVT) and pulmonary embolism (PE).¹ A pulmonary embolism is a clot formed in the venous vasculature that travels through circulation until trapped in smaller pulmonary vessels, occluding blood flow.^2-4 Common symptoms include chest pain, dyspnea, and tachycardia, although more severe symptoms such as syncope, shock, and hemoptysis may occur.^5-7 Because PEs typically develop from DVTs, risk factors are similar and include hypercoagulable states (eg, cancer, thrombophilia, pregnancy), venous stasis (eg, prolonged bed rest), and endothelial injury (eg, surgery).² The risk of mortality from an untreated PE can reach up to 30%, thus requiring prompt diagnosis and treatment.⁸

The American Heart Association (AHA) and American College of Cardiology (ACC) released guidelines in February 2026 to aid in the diagnosis and treatment of adult patients with acute PE.⁵ This article highlights recommendations from the guidelines most applicable to pharmacists on the interdisciplinary team managing acute PE.

Staging

The 2026 AHA/ACC acute pulmonary embolism guideline provides a new framework for PE staging.⁵ Once diagnosed, patients are stratified into PE categories based on severity and symptoms. The categories are labeled A through E, with category A being the lowest severity and E the highest.⁵ Category A is subclinical and asymptomatic. It includes PE found incidentally. Category B is symptomatic with a low clinical severity score (pulmonary embolism severity index [PESI] ≤85, simplified pulmonary embolism severity index [sPESI]=0, or Bova ≤4) and contains subcategories based on PE location: B1 (subsegmental) and B2 (more proximal). Category C is symptomatic with an elevated clinical severity score (PESI >85, sPESI ≥1, or Bova >4) and has subcategories distinguished by right ventricular size or function, and the presence or absence of cardiac biomarkers: troponin I or T, or brain-type natriuretic peptide. Category D is incipient cardiopulmonary failure and contains 2 subcategories, D1 (transient hypotension) and D2 (normotensive shock). Category E is cardiopulmonary failure and includes category E1 (recurrent or persistent hypotension with cardiogenic shock) and E2 (refractory cardiogenic shock or cardiac arrest).

Treatment

Anticoagulation remains the cornerstone of therapy for acute PE in the absence of absolute contraindications. Treatment options depend on the PE category.⁵ Severe hemodynamic compromise may require additional therapies beyond the scope of this article, including vasopressors, inotropes, or extracorporeal membrane oxygenation.

Direct Oral Anticoagulants

Outpatient oral anticoagulation is the preferred treatment modality for PE categories A and B with a low risk of 90-day adverse outcomes.⁵ Direct oral anticoagulants (DOACs), such as apixaban (Eliquis; Bristol Myers Squibb), dabigatran (Pradaxa; Boehringer Ingelheim Pharmaceuticals), edoxaban (Savaysa; Daiichi Sankyo), or rivaroxaban (Xarelto; Janssen Pharmaceuticals), are recommended over vitamin K antagonists (VKAs) to prevent VTE recurrence for the majority of patients.⁵ Apixaban, edoxaban, and rivaroxaban inhibit factor Xa in the coagulation cascade, preventing the formation of thrombin and a fibrin clot downstream while dabigatran directly inhibits thrombin.^9-12 Dosing and additional considerations for DOAC use in VTE are listed in Table 1.

DOACs are partially excreted via the urine, raising concerns for patients with renal impairment.^9-17 DOACs have not been extensively studied in patients with severe renal impairment. The guidelines (Table 2) recommend DOACs over VKAs in patients with acute PE and mild to moderate (stage 2 or 3) chronic kidney disease (CKD) to reduce major bleeding. The preferred treatment option is not as apparent in patients with severe CKD (stage 4 or 5).⁵

Severe liver impairment is also concerning, as DOACs are hepatically eliminated to varying extents and are highly protein bound.^9-14 DOAC trials in VTE excluded patients with significantly elevated liver function tests (LFTs).^15,18-20 Subsequent trials in liver impairment have often been retrospective and limited by small sample sizes.^21-23 A meta-analysis found less major bleeding with DOACs compared with low–molecular weight heparin (LMWH) and VKAs in patients with cirrhosis (OR, 0.63; 95% CI, 0.45-0.89), but most included studies were retrospective.²⁴ For acute PE, it may be reasonable to use DOACs over warfarin for patients with mild to moderate liver dysfunction (Child-Pugh class A or B), but DOACs should be avoided in patients with severe liver dysfunction (Child-Pugh class C) due to bleeding risk.⁵

DOACs have volumes of distribution ranging from 21 L to 107 L, so obesity may impact pharmacokinetics.^9-13 The PE guidelines state that it is reasonable to use DOACs rather than VKAs in patients with obesity.⁵ The International Society ON Thrombosis and Hemostasis (ISTH) recommends using either apixaban or rivaroxaban in patients with body mass index (BMI) over 40 kg/m² or weight over 120 kg when a DOAC is indicated; data supporting the use of alternative DOACs in this patient population have not been established.²⁵

DOACs should be avoided in patients who are pregnant or breastfeeding due to the risk of fetal abnormalities during pregnancy and the paucity of data on breastfeeding.^5,9-12

In March 2026, Castellucci et al published a prospective, randomized, open-label, blinded end point trial comparing the bleeding risk for patients treated with apixaban vs rivaroxaban for VTE.²⁶ Eligible patients had either a symptomatic, acute proximal lower-limb DVT, segmental PE, or more proximal PE. Patients treated with apixaban were less likely to experience the primary outcome—a composite of major bleeding or clinically relevant nonmajor bleeding as defined by ISTH—compared with those on rivaroxaban at 3 months (3.3% vs 7.1%; 95% CI, 0.33-0.65). This trial was published after the ACC/AHA Acute PE guideline but may encourage prescribers to choose apixaban over rivaroxaban, given its lower bleeding risk.

Vitamin K antagonist

The vitamin K antagonist warfarin inhibits vitamin K epoxide reductase, preventing the formation of new vitamin K-dependent clotting factors—II, VII, IX, and X—and proteins C and S.²⁷ For PE, it is recommended to bridge warfarin with heparin until a stable, therapeutic international normalized ratio (INR) of 2 to 3. Warfarin dosing is affected by various patient-specific factors, including vitamin K intake, genetic polymorphisms in CYP2C9 or vitamin K epoxide reductase, age, renal or liver impairment, heart failure, drug interactions, and obesity.^27-31 Reduced risk of major bleeds, elimination of routine INR monitoring, and standardized dosing have made DOACs preferable over warfarin; however, warfarin remains the drug of choice in patients with thrombotic antiphospholipid antibody syndrome or who are breastfeeding.⁵ Warfarin can cross the placenta and cause fetal abnormalities.²⁷ It is contraindicated in pregnancy except in select patients with mechanical heart valves at a high risk for VTE.⁵

Heparins

Patients with PE category C or greater should be admitted to the hospital and treated with parenteral anticoagulation. The guidelines recommend LMWH over unfractionated heparin (UFH) for patients with acute PE in categories C1 to E1.⁵

The pharmacokinetics of LMWH are more predictable than those of UFH, and therapeutic levels typically occur 3 to 4 hours post dose.³² UFH has a quick onset but requires monitoring to ensure a therapeutic level is achieved. Multiple studies have shown that patients receiving UFH for acute PE remain out of therapeutic range at 48 hours of treatment, creating concern for the reliability of treatment.^33,34 Compared with UFH, LMWH has been shown to decrease the rates of recurrent VTE with fewer major bleeding events.⁵

When catheter-directed thrombolysis (CDT) is indicated for acute PE, therapeutic anticoagulation (LMWH or UFH) or subtherapeutic anticoagulation (UFH) is recommended over no anticoagulation.⁵ Given the concerns for UFH and unreliable therapeutic anticoagulation, LMWH is recommended over UFH in patients who have received thrombolytic therapy or an endovascular procedure to decrease the risk of recurrent VTE.⁵

Routine monitoring for LMWH is not indicated in most patients.⁵ However, obtaining an anti-Xa in patients with severe CKD (creatinine clearance <30 mL/min) is reasonable.⁵ Anti-Xa levels should be obtained during steady state (>3 doses) and 3 to 5 hours post dose.⁵ The benefit of anti-Xa monitoring in patients with a BMI of >40 kg/m² or >150 kg receiving LMWH for acute PE is inconclusive.⁵ It may be reasonable to reduce the LMWH dose for acute PE in patients with class III obesity (BMI >40 kg/m²) to decrease bleeding risk.⁵ However, the guidelines leave the dosing strategy to clinical judgment.

A randomized control trial (RCT) compared reduced-dose LMWH (0.8 mg/kg) to standard dosing (1 mg/kg) in 62 patients with BMIs ≥ 40 kg/m^2,35 The reduced-dose group had a higher percentage of patients with therapeutic anti-Xa levels, while the standard dosing group required more dose adjustments due to supratherapeutic levels. Although this RCT was small, the results mimic what is seen in clinical practice. In patients with a BMI of 40 kg/m² or greater or weighing over 150 kg, pharmacists should consider a reduced dosing strategy of 0.7 to 0.8 mg/kg (typically rounded to the nearest available syringe size for ease of administration) and obtain an anti-Xa level around 4 hours after the third or fourth dose.

Both LMWH and UFH are recommended in patients with an active PE who are pregnant or breastfeeding.⁵

Lytics, CDT

The guidelines recommend considering thrombolytic medications in patients with incipient or active cardiopulmonary failure (categories D1-E2).⁵ Alteplase (Activase; Genentech) and tenecteplase (TNKase; Genentech) are the most studied thrombolytic agents in recent literature, and both promote fibrinolysis by binding to fibrin and converting plasminogen to plasmin.^36,37 For acute PE, thrombolytic therapy can be administered via systemic thrombolysis or CDT.⁵ Systemic thrombolysis is administered intravenously at higher therapeutic doses, whereas CDT delivers a much lower dose of thrombolytic via catheter directly to the thrombus.⁵

Catheter-Directed Thrombolysis

CDT, in combination with anticoagulation, may be considered for PE categories D1 and D2 to prevent further clinical deterioration, and in category E1 to prevent further clinical deterioration and early mortality.⁵ While the benefit of short- and long-term outcomes between CDT vs systemic thrombolysis remains uncertain, CDT is often favored in patients with a high bleeding risk.

Several studies have demonstrated that CDT reduces right ventricular (RV) strain compared with anticoagulation alone in patients with intermediate-risk PE (defined as hemodynamically stable with evidence of RV strain).^38,39 Sadeghipour et al evaluated 94 patients with intermediate-risk PE and found that the median RV/left ventricular (LV) ratio at 3 months was significantly lower in the CDT group compared with those treated with anticoagulation alone (0.7 vs 0.8; P = .01).³⁸ Similarly, Kucher et al studied 59 patients with intermediate-risk PE and reported a greater reduction in RV/LV ratios among patients who received CDT compared with anticoagulation alone (0.30 vs 0.03; P < .001).³⁹ Notably, the number of bleeding complications reported in these studies was small, which is expected given the relatively limited sample sizes of the trials.

More recently, Gupta et al conducted a retrospective study evaluating long-term outcomes of CDT vs systemic anticoagulation in 1357 patients with intermediate-risk PE.⁴⁰ All-cause mortality and overall cardiac complications were lower in the CDT group compared with patients treated with anticoagulation alone (30% vs 50%, resistive reserve ratio [RRR] 40%; and 23.3% vs 33.3%, RRR 15%, respectively). However, intensive care unit and overall hospital length of stay were longer among patients treated with CDT.

Systemic Thrombolysis

Systemic thrombolysis, in combination with anticoagulation, is recommended for patients with acute PE in categories D1 and D2 to prevent further clinical deterioration. It is also recommended for use in categories E1 and E2 to reduce mortality and recurrent PE.⁵ Systemic thrombolysis should be used only in patients with an acceptable bleeding risk.

Several studies evaluated the safety and efficacy of systemic thrombolysis for acute PE. A meta-analysis by Chatterjee et al included patients consistent with categories C3 to D2. The study demonstrated that use of systemic thrombolytics was associated with a reduction in all-cause mortality compared with anticoagulation alone (2.17% vs 3.89%; 95% CI, 0.32-0.88) but also found an increased risk of major bleeding (9.24% vs 3.42%; 95% CI, 1.91-3.91).⁴¹ Another meta-analysis by Marti et al included a small percentage of patients that would fit into categories E1 and E2 and suggested a trend toward reduction of early mortality in patients who received systemic thrombolysis, although it was not statistically significant in this high-risk patient population.⁴² Further details are in Table 3.

The guidelines do not provide a specific recommendation regarding a preferred systemic thrombolytic for PE.⁵ Murphy et al retrospectively evaluated alteplase vs tenecteplase in 283 hemodynamically unstable patients with PE.⁴³ Mortality rates were similar in the tenecteplase and the alteplase groups (19.4% vs 19.8%, 95% CI, 0.704-1.371). The investigators, however, noted that bleeding events occurred too infrequently to allow a meaningful comparison between groups. Johnson et al retrospectively evaluated the safety and efficacy of alteplase and tenecteplase in 319 patients with intermediate and high-risk PE.⁴⁴ While no significant differences were observed in efficacy outcomes, the incidence of major bleeding within 72 hours was significantly higher in the tenecteplase group compared with the alteplase group (31.1% vs 10.9%; P = .004). Although tenecteplase is an attractive alternative to alteplase due to its ease of administration, additional high-quality studies are needed to better evaluate its comparative safety and efficacy for the treatment of PE.

CDT vs Systemic Thrombolysis

Planer et al conducted a meta-analysis that compared outcomes of CDT vs systemic thrombolysis in patients with intermediate- or high-risk PE.⁴⁵ In this study, CDT was associated with improved efficacy outcomes including a lower risk of death (OR, 0.4; 95% CI, 0.32-0.57) and safety outcomes including a decreased risk of intracerebral hemorrhage (OR, 0.44; 95% CI, 0.29-0.64), major bleeding (OR, 0.61; 95% CI, 0.53-0.70) and blood transfusion (OR, 0.46; 95% CI, 0.28-0.77); however, this meta-analysis was largely based on small, observational studies and included a relatively low number of patients with high-risk PE, limiting the strength and generalizability of the conclusions. The guidelines recommend that systemic thrombolysis should be reserved for patients with the highest risk of mortality and the lowest risk of bleeding, in whom the potential net clinical benefit is the greatest.⁵

Bleeding complications associated with systemic thrombolysis are often difficult to quantify in the available literature due to variability of study design, dosing strategies, and agents used. The risk of major bleeding from systemic thrombolysis ranges from 0% to 20% in most studies.⁴⁶ Although the PE guidelines do not provide a formal definition of an acceptable bleeding risk, clinicians should carefully evaluate each patient’s individual risk profile when considering thrombolytics. Risk factors associated with an increased risk of major bleeding include, but are not limited to, recent bleeding or major surgery, venous access, severe hypertension, advanced age, low BMI, underlying coagulopathy, and elevated LFTs or bilirubin.⁴⁶

Pharmacist’s Role

Pharmacists play an essential role in ensuring safe and effective medication therapy as notable members of the interdisciplinary PE response team. They are uniquely qualified to assist with the appropriate selection and timely monitoring of anticoagulation and/or thrombolytic therapy for patients presenting with acute PE. Understanding the 2026 ACC/AHA acute pulmonary embolism guideline recommendations and their nuances would be useful for hospital pharmacists managing these patients.

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