**4. Vitamin K antagonist (VKA)**

VKA such as warfarin is a vitamin K receptor antagonist that continues to play a role in PE treatment, particularly in patients with severe renal insufficiency, antiphospholipid syndrome, and financial constraints who are unable to afford DOACs [23]. International normalized ratio (INR) monitoring is recommended for warfarin monitoring [24]. Due to the drug's long half-life, slow depletion of factor II, and rapid depletion of anticoagulant protein C, patients are bridged with UFH, LMWH, or fondaparinux for at least 5 days and until the INR reaches the therapeutic range of 2 to 3 [25].

Frequent monitoring may be a barrier to initiating this agent. Furthermore, several food and drug interactions may also limit the desire to initiate warfarin for long-term therapy. Food that is high in vitamin K content such as oils, fats, liver, nuts, and green vegetables may decrease the efficacy of warfarin. Medications that are inducers and inhibitors of CYP2C9, 2C19, 1A2, and 3A4 must require dose adjustments and/or more frequent monitoring of their INR. For these reasons, patients are educated about maintaining consistency with their vitamin K intake and encouraged to discuss any dietary or medication changes with their healthcare provider [26].

Vitamin K is recommended for warfarin reversal if the INR is >10 without significant bleeding and with repeated vitamin K doses every 6–24 h as needed [27]. Vitamin K can be administered by IV or the oral route, with a preference for oral administration; there is an associated risk of anaphylactoid reactions in 3 out of 10,000 patients when IV formulations were administered [28]. Subcutaneous injection is not recommended due to a delayed and unpredictable effect [27]. The availability of 4F-PCC (KCentra®) during the last decade has resulted in its use over FFP as a reversal agent for warfarin-associated bleeding complications. This agent has been employed especially for life-threatening bleeding, where 4F-PCC has demonstrated 25 times more potency in replacing vitamin K-dependent clotting factors than FFP [29]. The limitations of FFP in comparison with 4F-PCC include its slower onset, risks of allergic reaction and infection transmission, blood group compatibility, longer preparation time, and higher volume [29]. A major advantage of 4F-PCCs is their ability to be stored at room temperature as a lyophilized powder and the fact that they can quickly be reconstituted and administered [29]. With life-threatening bleeding, the addition of vitamin K 5 to 10 mg by slow IV infusion is suggested [30].

### **5. Factor Xa inhibitor injectable**

Fondaparinux (Arixtra®) is a synthetic pentasaccharide anticoagulant selectively inhibiting factor Xa *via* antithrombin-dependent actions with no inhibition of thrombin (factor IIa) [31]. Unlike LMWH and UFH, fondaparinux inhibits a targeted step in the coagulation cascade that leads to its anticoagulant effect [31]. Fondaparinux is currently approved in the United States for the treatment of PE in conjunction with warfarin [31]. Dosing and special considerations for fondaparinux are discussed in **Table 1**.

The most common adverse reaction associated with the use of fondaparinux is bleeding complications. While most other agents used for PE management do have a reversal agent, this medication does not. Fondaparinux does not require laboratory monitoring. However, periodic complete blood count, serum creatinine level, stool occult tests, and anti-Xa level can be monitored on an individual basis [31].

For fondaparinux, recombinant activated factor VII and aPCC have some data in human and animal studies, respectively, as reversal agents. Both andexanet alfa (a recombinant factor Xa) and aripazine have been shown to bind to Xa inhibitors but lack any human data with fondaparinux [32].

### **6. Direct oral anticoagulant (DOACs)**

### **6.1 Apixaban**

Apixaban is an oral direct factor Xa inhibitor approved for the treatment and prevention of DVT and PE [11]. Dosing and special considerations for apixaban use for PE treatment are discussed in **Table 1**. The oral bioavailability is approximately 50%, with most of the drug absorption occurring in the small intestine [33]. Drug elimination occurring *via* the metabolism through the CYP3A4 systems in the intestine and liver and the P-glycoprotein system can be enhanced through drug–drug interactions [23, 26, 31, 33–35]. Once absorbed, the terminal half-life ranges between 8 and 12 h, with a steady state achieved within 3 days [23, 26, 31, 33–35]. The premature discontinuation of any anticoagulant, including apixaban, increases the risk of thrombotic events and is listed as a black box warning [11]. Epidural or spinal hematomas may occur in patients treated with apixaban in neuraxial anesthesia or spinal puncture. These hematomas have long-term consequences, such as permanent paralysis. Such risks should be taken into account when patients on apixaban therapy are scheduled for spinal procedures [11].

Andexanet alfa (Andexxa®) can be used to reverse apixaban (off-label) in lifethreatening or uncontrollable bleeding. The dosing is based on the specific factor Xa agent-inhibitor to be reversed, dose, and the time since the last dose was administered [36]. Andexanet alfa 400 mg intravenous bolus is administered at a rate of 30 mg/min, followed by 4 mg/min *via* continuous infusion for up to 120 min, to reverse apixaban (5 mg or less) or rivaroxaban (10 mg or less), administered within 8 h or if the time is unknown [36]. High-dose andexanet alfa is also indicated for apixaban doses of greater than 5 mg, or, if unknown, administered within 8 h or an unknown time. The high-dose andexanet alfa regimen is 800 mg intravenous bolus at a target rate of 30 mg/min, followed by 8 mg/min continuous infusion for up to 120 min [36]. The safety and efficacy of administering more than one dose of any of these regimens have not been established [36]. In the absence of either idarucizumab or andexanet alfa for DOAC reversal, administering prothrombin complex concentrate (PCC) or activated prothrombin complex concentrate (aPCC) is alternative to consider. This is based on the limited available human and animal *in vitro* studies [29]. Activated charcoal for the known recent ingestion of DOACs may also be effective when DOAC ingestion occurs within the last 2–4 h [29].

### **6.2 Rivaroxaban**

Rivaroxaban is an oral direct factor Xa inhibitor approved for the prevention and treatment of DVT and PE. Dosing and special considerations for rivaroxaban use for PE treatment are discussed in **Table 1**. The oral bioavailability ranges from approximately 80 to 100% for a 10 mg dose and up to 66% for a 20 mg [37–39]. Bioavailability of doses ≥15 mg is improved with food [37–39]. Renal elimination accounts for approximately 36% of unchanged drug, its use in patients with a

CrCL <30 mL/min is not advised, and <15 mL/min employment is contraindicated [37–39]. Rivaroxaban is not dialyzable [37–39]. Rivaroxaban follows a similar elimination pattern to that of apixaban, with metabolism through the CYP3A4 systems accounting for 57% elimination [37–39]. P-glycoprotein system inhibitors may lead to elevated rivaroxaban serum levels [33, 35, 40]. Rivaroxaban's terminal half-life ranges between 5 and 9 h, with a prolonged half-life of 11–13 h seen in elderly patients [37–39]. The steady-state concentrations for this agent tend to occur within 3 days. The premature discontinuation of any anticoagulant, including rivaroxaban, increases the risk of thrombotic events and is listed as a black box warning [12]. To minimize this risk, an alternate coverage should be considered, should rivaroxaban be discontinued for a reason apart from pathological bleeding or therapy completion [12]. Epidural or spinal hematomas have been observed in patients managed with rivaroxaban undergoing neuraxial anesthesia or spinal puncture. Such hematomas are known to result in long-term or permanent paralysis [12].

Andexanet alfa (Andexxa®) can also be used to reverse rivaroxaban (off-label) in life-threatening or uncontrollable bleeding. Rivaroxaban doses of greater than 10 mg, or if an unknown amount is administered within 8 h or at an unknown time, are managed with the high-dose andexanet alfa regimen [36].

### **6.3 Dabigatran**

Dabigatran (Pradaxa®) is a direct thrombin (IIa) inhibitor approved for the prevention and treatment of DVT and PE. Dosing and special considerations for dabigatran use for PE treatment are discussed in **Table 1**. Dabigatran should be initiated 0–2 h before the next dose of parenteral anticoagulant would have been due, or at the time of discontinuation of UFH continuous infusion [16]. The medication has low oral bioavailability and undergoes hepatic metabolism. P-glycoprotein (P-gp) inducers, such as phenobarbital, rifampin, and fosphenytoin, reduce exposure to dabigatran and should be avoided [16]. In contrast, P-glycoprotein (P-gp) inhibitors increase exposure to dabigatran, and recommendations vary based on the P-gp inhibitor and the indication for dabigatran use [16]. Renal impairment and P-gp inhibition are the major independent risk factors for increased dabigatran exposure and increased risk of bleeding. Hence, renal function assessment at baseline and periodically thereafter is recommended. Dose adjustments for dabigatran doses in patients with severe renal impairment (CrCl 30 mL/min or less) are recommended. Caution must be used in the elderly, as the risk of stroke and bleeding increases with age, as seen in an analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial [41]. Dabigatran is contraindicated for use in patients with mechanical heart valves. The RE-ALIGN (Randomized, Phase II Study to Evaluate the sAfety and Pharmacokinetics of oraL dabIGatran Etexilate in Patients after Heart Valve replacement) trial was terminated early due to thromboembolic events (valve thrombosis, stroke, and myocardial infarction), and major bleeding was observed in the dabigatran group compared to the warfarin group in heart valve patients [42].

Besides major and minor bleeding, gastrointestinal adverse effects have been reported in studies at an incidence rate ranging from 24.7 to 35% [16]. The gastrointestinal adverse effects reported include but are not limited to dyspepsia, gastritis, abdominal pain or discomfort, and epigastric discomfort [16]. Due to the prevalence of these adverse effects, it is necessary to educate the patient about the potential side effects and advise them not to abruptly discontinue the medication before notifying their healthcare provider [16].

One distinguishing feature of dabigatran is the increase in bioavailability by 75% that occurs if the capsule is broken, chewed, or emptied out of the capsule shell [16]. This leads to an increased risk of toxicity, such as major bleeds [16]. Since the capsule cannot be manipulated due to the stated reason, the medication should not be administered *via* a feeding tube of any type [16]. The medication must be kept in its original container. It must be discarded after 4 months from the date the package was opened due to the lack of stability with light or humidity exposure that may lead to product breakdown and potency loss [16].

There is a specific reversal agent approved for dabigatran. The agent named idarucizumab (Praxbind®) is a monoclonal antibody with 350 times more affinity for dabigatran than thrombin [10, 43]. Diuresis may also help with the excretion of dabigatran as well [16].

### **6.4 Edoxaban**

Edoxaban is an oral direct factor-X inhibitor approved in the United States for the treatment of PE. Approval was based primarily on the Hokusai VTE study, which evaluated 3319 patients with PE. The trial showed that edoxaban was not inferior to warfarin but had a lower bleeding risk [44]. Dosing and special considerations for edoxaban use for PE treatment are discussed in **Table 1**. The oral bioavailability is approximately 60%, and renal elimination accounts for approximately 50% of unchanged drug. Edoxaban's terminal half-life ranges between 10 and 14 h. Interestingly, edoxaban blood levels are lower in patients with better renal function averaging about 40% less in patients with CrCL >95 mL/min when compared to those with CrCl >50 to ≤80 mL/min [45]. Bleeding complications such as hemorrhage (major or minor) appear to be the most common adverse effects associated with edoxaban use [45, 46]. Lastly, andexanet alfa (Andexxa®) can also be used to reverse edoxaban (off-label) in life-threatening or uncontrollable bleeding [36].

### **7. Thrombolytic therapy**

Thrombolytic therapy for PE may be administered systemically or directed by a catheter into the pulmonary arteries to accelerate the resolution of acute PE. Thrombolytic therapy can lower pulmonary artery pressure and increase arterial oxygenation [23]. Studies limiting thrombotic therapy in acute PE have shown the best outcomes by restricting it to patients presenting with a massive (high-risk) PE [23, 47]. Patients presenting with hemodynamic instability, right ventricular dysfunction, and without significant risk of bleeding are considered potential candidates for emergency thrombolytic therapy [4, 48]. The results from timely administration of thrombolytic therapy may be seen within 36 h [49]. Mortality rates occur in up to 30% of patients categorized as high risk and make the timing of therapeutic intervention critical [50–52]. Adverse events, especially the high incidence of bleeding and hemorrhagic stroke, require careful consideration prior to starting thrombolytic therapy [53, 54]. Systemic alteplase (Activase®) is the only FDA-approved thrombolytic for the management of acute massive (high risk) hemodynamically unstable PE [55]. All anticoagulants must be stopped prior to the initiation of alteplase and 100 mg IV infused over 2 h is the most common regimen. Alternative weight-based regimens for patients weighing <65 kg may be considered [56]. A weight-based regimen with a 15 mg bolus followed by 0.75 mg/kg over 30 min (max 50 mg) and then 0.5 mg/kg over the next 30 min (max 35 mg) have shown efficacy without increased bleeding [56]. Intra-catheter-directed alteplase 0.5–2 mg/h for 2–15 h for a total dose of 4–24 mg has been used successfully in facilities by experienced physicians and well-designed protocols, but this route of administration is not FDA approved [57]. Tenecteplase (TNKase®) and reteplase

(Retavase®) have been used for acute massive (high risk) PE, but are not FDA approved for use in patients with PE [58, 59].
