Update on Pharmacologic Therapy for Pulmonary Embolism

Abstract

Warfarin, unfractionated heparin (UFH), and low-molecular-weight heparins are anticoagulants that have been used for treatment of pulmonary embolism. Currently approved drugs for treatment of venous thromboembolism include UFH, enoxaparin, dalteparin, fondaparinux, warfarin, and rivaroxaban. The advent of newer oral anticoagulants such as rivaroxaban, dabigatran, and apixaban has provided us with alternative therapeutic options for long-term anticoagulation. This article will give an overview of the various anticoagulant drugs, use in various clinical scenarios, data supporting their clinical use, and recommendations regarding duration of anticoagulant therapy.

Keywords

pulmonary embolism warfarin dabigatran rivaroxaban apixaban

Introduction

The estimated incidence of venous thromboembolism (VTE) in the United States ranges from 1 to 2 per 1000 persons per year to as high as 1 in 100 persons per year in those more than 80 years of age.¹ About 60 000 to 100 000 Americans die of VTE each year.¹ Of these patients, 10% to 30% die within a month of diagnosis. The initial symptom is sudden death in 25% of the patients with pulmonary embolism (PE).¹ A recurrence of PE within 10 years occurs in about one-third of the patients.¹

Management of PE

The degree of hemodynamic compromise is the most powerful predictor of in-hospital death in patients with massive PE with an early mortality rate of 15%.² Initial measures should be directed to treat hypoxia and failure of circulation, especially in patients with massive PE. Hypoxia is initially treated with supplemental oxygen. If hypoxia becomes refractory to supplemental oxygen or if failure of ventilation occurs, then the patient needs to be placed on noninvasive mechanical ventilation or invasive positive pressure mechanical ventilation after intubation. Hypotension in the setting of massive PE is due to severe pulmonary arterial hypertension and right ventricular (RV) failure. This is treated by optimization of intravascular volume, enhancement of RV inotropy, and reduction in RV afterload.³ Hypotension due to PE is initially managed with an intravenous normal saline bolus of 500 to 1000 mL. This fluid therapy is more successful in patients with a lower RV end-diastolic volume. However, fluids should be used judiciously. Excess fluid administration in the presence of RV dysfunction increases its wall stress, exacerbates RV ischemia, and leads to more interventricular septal shift toward the left ventricle. This reduces left ventricular compliance and filling, leading to decreased cardiac output. If the initial fluid therapy fails, there should be a low threshold to start inotropes to improve RV function and vasopressors to improve hypotension.⁴ Both cardiac output and systemic vascular resistance are increased by norepinephrine and may be useful as initial therapy. The first-line inotropes for the treatment of PE-related shock are dobutamine and dopamine. These drugs augment cardiac output with lesser increase in pulmonary artery pressure, thus reducing pulmonary vascular resistance. Dobutamine may be used in combination with norepinephrine to increase myocardial contractility, blunting vasodilation, and hypotension.⁴ Epinephrine, milrinone, and phenylephrine can also be added if other agents fail. The RV afterload can be decreased by definitive therapy for the PE and by using medications to decrease the pulmonary arterial hypertension.

Antithrombotic Therapy

All patients with a diagnosis of acute PE should be started on initial treatment with parenteral anticoagulation. Various anticoagulants that are used in management of VTE are mentioned in Table 1. While awaiting diagnosis, antithrombotic treatment requires balancing of the benefits of avoiding thrombotic complications versus the risk of bleeding complications with anticoagulation. Patients with a high clinical suspicion of acute PE should also be treated with parenteral anticoagulants while awaiting the final diagnosis. In patients with an intermediate clinical suspicion of acute PE, treatment with parenteral anticoagulants is recommended if diagnosis is expected to be delayed for longer than 4 hours. Patients with a low-clinical suspicion of acute PE should not be treated with parenteral anticoagulants while awaiting the diagnosis, if the results are expected within 24 hours.⁵

Table 1.

Anticoagulants Used in the Management of Venous Thromboembolism.

Parenteral Anticoagulants
Low-molecular-weight heparins (enoxaparin, tinzaparin, nadroparin, ardeparin, and reviparin)
Unfractionated heparin
Direct thrombin inhibitors (argatroban)
Factor Xa inhibitors (pentasaccharide—fondaparinux)
Oral anticoagulants
Vitamin K antagonists—warfarin
Factor Xa inhibitors—rivaroxaban, apixaban, edoxaban
Direct thrombin inhibitor—dabigatran

Low-Molecular-Weight Heparins

Low-molecular-weight heparins (LMWHs) are polysulfated glycosaminoglycans synthesized from unfractionated heparin (UFH) by chemical or enzymatic depolymerization. Their molecular weight is about one-third that of UFH. Low-molecular-weight fragments derived from depolymerization of heparin cause reduced binding to plasma proteins and thus has different pharmacokinetic and biological properties.⁶ The LMWHs have a more predictable dose–response relationship and longer plasma half-life than UFH.^6,7 Subcutaneous (SC) bioavailability of LMWH approaches 100% at low doses. After SC injection, the half-life of LMWHs is longer (3-6 hours) and not dose dependent compared to UFH.^7

–11 As the molecular size of LMWH fractions is low, they have a progressively lower effect on activated partial thromboplastin time (aPTT) with similar inhibition of activated factor X (Xa).^12
–14 Peak activity of antifactor Xa occurs 3 to 5 hours after SC injection.¹⁵ The antifactor Xa–antifactor IIa ratio of heparin is 1:1 compared to LMWHs that have ratios between 2:1 and 4:1, depending on molecular size distribution.⁶ The LMWHs are different in their anticoagulant profiles and pharmacokinetic properties and should not be clinically interchanged.¹⁶ The various LMWHs available for treatment of PE include enoxaparin, tinzaparin, nadroparin, ardeparin, and reviparin. The LMWHs should be given in fixed thromboprophylactic doses or in doses adjusted to total body weight (TBW).

The LMWH or fondaparinux is preferred in patients with acute PE over intravenous (IV) or SC UFH.⁵ In a Cochrane analysis of 17 studies, LMWH was associated with decreased mortality (relative risk [RR] 0.79, confidence interval [CI] 0.66-0.95), lower recurrence of VTE (RR 0.72, CI 0.58-0.89), and decreased incidence of major bleeding (RR 0.67, CI 0.45-1.00) compared with IV UFH.¹⁷ Studies show no significant difference in all-cause mortality, recurrent VTE, and bleeding risk in patients treated with SC LMWH or SC UFH.^18

–21 The SC LMWH is preferred over SC UFH because of less frequent dosing and less frequent complications like heparin-induced thrombocytopenia and osteoporosis.^22,23 A trial that compared monitored and unmonitored treatment of VTE with dalteparin showed that routine monitoring of antifactor Xa levels was not beneficial.²⁴ However, in patients with severe obesity, renal dysfunction, and in pregnancy, monitoring should be considered.^25,26 After SC injection of LMWHs, peak antifactor Xa activity occurs at approximately 4 hours, and monitoring assays should be obtained at this time.^27,28 The therapeutic range for peak antifactor Xa effect with enoxaparin or nadroparin administered twice daily for VTE is 0.6 to 1.0 IU/mL. Levels greater than 1.0 IU/mL should be avoided to prevent bleeding. In patients treated with enoxaparin administered once daily, the target range for peak antifactor Xa effect is greater than 1.0 IU/mL. For treatment of VTE, the target mean antifactor Xa level for tinzaparin, nadroparin, and dalteparin are 0.85 IU/mL, 1.3 IU/mL, and 1.05 IU/mL, respectively. In patients with a TBW greater than 150 kg and a BMI of greater than 50 kg/m², antifactor Xa monitoring should be performed.¹⁶ A lower dose should be given if the antifactor Xa activity is increased. There are no clear guidelines on the safety of use of standard doses of LMWH to patients with severe chronic kidney disease. If LMWH is used in such patients, antifactor Xa activity monitoring should be performed. A safe cutoff value in terms of creatinine clearance for use of different LMWHs is greater than 30 mL/min/1.73 m².¹⁶

There is no antidote for LMWH. In clinical situations that necessitate the reversal of the antithrombotic effect of LMWH, the following approach should be used.²⁹ If LMWH was given within 8 hours, protamine may be administered in a dose of 1 mg per 100 antifactor Xa units of LMWH. A second dose of 0.5 mg protamine per 100 antifactor Xa units may be given if there is continued bleeding. Smaller doses are indicated if LMWH was administered more than 8 hours prior to the event requiring neutralization.

Dosing of LMWH

The recommended enoxaparin dose is 1 mg/kg SC given every 12 hours or 1.5 mg/kg SC administered once daily for at least 5 days until the patient has adequate anticoagulation with warfarin. In patients with severe chronic kidney disease, the dose is 1 mg/kg SC once daily.²⁹ The recommended tinzaparin dose for treatment of VTE is 175 anti-Xa IU/kg, given SC once daily for at least 6 days and until the patient has adequate anticoagulation with warfarin.³⁰ Dalteparin is indicated for extended treatment of VTE in patients with cancer. However, it is not indicated for treatment of acute PE. The recommended dose is 200 IU/kg SC administered once daily for the first month followed by 150 IU/kg SC once daily from the second to sixth month.³¹

Unfractionated Heparin

Unfractionated heparin binds with antithrombin (AT), and the heparin–AT complex exerts its anticoagulation action by inactivating factors IIa, Xa, IXa, XIa, and XIIa. The UFH is preferred to LMWH in the initial management of patients with acute PE with severe renal impairment, morbid obesity, and severe edema where SC absorption of LMWH may be erratic. The UFH is also preferred in patients with increased bleeding risk because of its short half-life compared to LMWH. For management of PE, UFH is given IV with a bolus dose of 80 U/kg and then with an infusion of 18 U/kg/h.³² Heparin’s anticoagulant effect is monitored by measuring aPTT 6 hourly when therapeutic doses are administered, and the infusion rate titrated to goal aPTT. The therapeutic aPTT range varies between institutions according to reagents that are used. When the SC route of UFH is used to treat PE, there are 2 alternatives: (1) an IV bolus of 5000 units followed by 250 units/kg SC twice daily or (2) an SC dose of 333 units/kg followed by 250 units/kg SC twice daily thereafter. This SC regimen need not be monitored by aPTT. A study in patients with VTE showed that use of weight-adjusted, unmonitored SC UFH administered twice daily in high doses was as efficacious and safe as weight-adjusted, unmonitored LMWH.³³ Heparin resistance is a situation where patients require an unusually large dose of heparin to achieve therapeutic aPTT levels. A randomized study has shown that in such patients total heparin dose can be reduced with efficacy remaining the same if the dose is titrated to achieve goal antifactor Xa activity (target range between 0.35 and 0.7 units/mL) than targeting therapeutic aPTT.³⁴ Protamine is administered IV in a dose of 1 to 1.5 mg per 100 units of heparin to reverse the anticoagulation in case of heparin-induced bleeding.

Fondaparinux

Fondaparinux is a synthetic pentasaccharide analogous to LMWHs. A study compared the use of IV UFH with fondaparinux for acute management of PE in 2213 patients who were followed for 3 months.³⁴ In this study, fondaparinux was found to have a similar frequency of mortality (RR 1.20, 95% CI 0.82-1.74), recurrent VTE (RR 0.75, 95% CI 0.51-1.12), and major bleeding as IV UFH (RR 0.85, 95% CI 0.49-1.49).³⁴ No trial has compared SC fondaparinux with SC LMWH in treatment of PE. However, a study of 2205 patients with deep vein thrombosis (DVT) followed for 3 months showed no significant differences in mortality, DVT recurrence, or bleeding risk between fondaparinux and LMWH.³⁵ Also, the adverse drug effect profile of fondaparinux is better than UFH. So fondaparinux is preferred for initial management of acute PE compared to SC or IV UFH and is considered equally efficacious as LMWH. The dose of SC fondaparinux for treatment of PE is 5 mg for patients less than 50 kg, 7.5 mg for patients between 50 and 100 kg, and 10 mg for patients >100 kg. The dose of fondaparinux should be reduced by 50% for a creatinine clearance between 30 and 50 mL/min/1.73 m² and is contraindicated in patients with severe chronic kidney disease. Routine measurement of anti-Xa activity is not needed.

Vitamin K Antagonists

Warfarin is the most commonly administered vitamin K antagonist (VKA). Warfarin exerts its anticoagulation action by inhibiting vitamin K epoxide reductase, an enzyme that replenishes reduced form of vitamin K1 which is required for the γ-carboxylation and production of vitamin K-dependent clotting factors II, VII, IX, and X. In patients with newly diagnosed PE, early administration of warfarin is recommended.⁵ The duration of treatment with heparin and the duration of hospitalization were significantly reduced when VKAs were started early than late.^36
–38 Parenteral anticoagulation with LMWH, UFH, or fondaparinux has to be continued for at least 5 days and until the international normalized ratio (INR) is 2.0 or higher for longer than 24 hours. This is because the INR may become therapeutic even before the anticoagulation action gets started because of the rapid depletion of factor VII. The therapeutic target INR is 2 to 3. Attempts to decrease bleeding risk by reducing intensity of warfarin treatment have caused reduced efficacy with similar bleeding. In the Prevention of Recurrent Venous Thromboembolism (PREVENT) study, warfarin treatment with an INR of 1.5 to 2.0 was compared with placebo in patients with idiopathic VTE who had received warfarin treatment with an INR of 2.0 to 3.0 for 6.5 months. The trial was terminated early as warfarin treatment with an INR of 1.5 to 2.0 was associated with a 48% decrease in end point of recurrent VTE, major bleeding, or mortality.³⁹ In the Extended Low-Intensity Anticoagulation for Thrombo-Embolism (ELATE) study, 738 patients with unprovoked VTE who had been treated for 3 or more months with warfarin were randomized to receive warfarin treatment with a target INR of 2.0 to 3.0 or to a target INR of 1.5 to 1.9. The risk of recurrent VTE was higher among patients randomized to low-intensity warfarin treatment (1.9 episodes per 100 person-years versus 0.7 episode per 100 person-years). No significant differences were observed in major hemorrhage or overall bleeding.⁴⁰ Target INRs above 3.0 result in higher bleeding risk without reducing recurrent VTE.⁴¹

For outpatients, VKA therapy should be initiated with warfarin 10 mg daily for 2 days followed by subsequent doses based on INR measurements. In patients with previously stable therapeutic INRs that present with a single measurement of subtherapeutic INR, bridging with heparin is not necessary. Paper nomograms or computerized dosing programs should be considered for dosing decisions during management of warfarin therapy. Concomitant treatment of VKAs and nonsteroidal anti-inflammatory drugs should be avoided. Patients taking VKAs should not be started on concomitant antiplatelet drugs unless benefit outweighs bleeding risk in patients with mechanical valves, acute coronary syndrome, or recent coronary revascularization. For patients with INRs between 4.5 and 10 and no evidence of bleeding, routine use of vitamin K is not recommended. Oral vitamin K should be administered to patients with INRs greater than 10.0 and no bleeding. For patients with major hemorrhage caused by warfarin, anticoagulation should be rapidly reversed with prothrombin complex concentrate (PCC). In addition, vitamin K 5 to 10 mg should be given by slow IV injection.

Newer Oral Anticoagulants

Table 2 lists the pharmacokinetic profile of newer agents that have been studied for VTE treatment.

Table 2.

Pharmacokinetic and Pharmacodynamic Properties of Anticoagulants Used to Treat Venous Thromboembolism.

Characteristic	Warfarin	Rivaroxaban	Apixaban	Dabigatran
Prodrug	No	No	No	Yes
Mechanism of action	Interferes with γ-carboxylation of vitamin K dependent clotting factors by inhibition of epoxide reductase enzyme	Direct inhibitor of factor Xa	Direct inhibitor of factor Xa	Direct inhibitor of thrombin
Half-life, hours	20-60	5-9	12	12-17
Bioavailability	100%	Depends on the dosage and food intake. 10 mg—80%-100% (with or without food) 20 mg—66% (without food)	50%	6%
Renal clearance	>90%	Excreted via tubular secretion 36% as unchanged drug and 33% as inactive metabolites	25%	None
Cytochrome p450 metabolism	>90%	30% (mainly by CYP3A4 and CYP2J2)	15% (mainly by CYP3A4)	No
Interaction with food and diet modifications	Increase dietary vitamin K intake	Food increases absorption	No interaction	No interaction
Dosage	Variable	Fixed once or twice daily dosing Dosage reduction required in renal dysfunction	Fixed twice daily dosing Dosage reduction in 2 of the following 3 conditions: age ≥ 80 years; weight ≤ 60 kg; serum creatinine ≥ 1.5 mg/dL	Fixed twice daily dosing Dosage reduction required in renal dysfunction
Monitoring	INR	None	None	None
Reversal agent	Vitamin K, fresh frozen plasma, factor VIIa, prothrombin complex concentrate	Prothrombin complex concentrate^a	Prothrombin complex concentrate^a	Prothrombin complex concentrate^a

Abbreviations: CYP3A4, cytochrome P450 3A4 isozyme; CYP2J2, cytochrome P450 2J2 isozyme; INR, international normalized ratio.

^a Not a specific antidote.

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. The Regulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE trial (RECORD) studied use of rivaroxaban for the VTE prevention after knee and hip replacement surgery. These studies showed a better efficacy of rivaroxaban 10 mg once daily as compared with SC enoxaparin for VTE prophylaxis without higher bleeding risk.^42,43 The EINSTEIN-DVT study compared oral rivaroxaban alone with SC enoxaparin followed by a VKA for 3, 6, or 12 months in 3449 patients with acute, symptomatic DVT.⁴⁴ Rivaroxaban was noninferior for recurrent VTE (2.1% with rivaroxaban vs 3.0% with enoxaparin; hazard ratio [HR] 0.68; 95% CI 0.44-1.04; P < .001 for noninferiority). The primary safety outcome of major hemorrhage or clinically relevant nonmajor hemorrhage occurred in 8.1% of both the groups.⁴⁴ The recommended dose of rivaroxaban for the initial management of acute PE is 15 mg taken twice daily with food for the first 21 days followed by 20 mg once daily with food. The Continued Treatment Study (EINSTEIN-Extension) included patients with confirmed symptomatic VTE treated for 6 or 12 months with warfarin or rivaroxaban who were randomized to continued treatment with rivaroxaban (20 mg once daily) or placebo.⁴⁴ This study included 602 patients managed with rivaroxaban and 594 patients managed with placebo, with rivaroxaban showing better efficacy (1.3% vs 7.1%; HR 0.18; 95% CI 0.09-0.39; P < .001). There was no significant difference in nonfatal major bleeding. The EINSTEIN-PE study included 4832 patients with acute symptomatic PE with or without DVT.⁴⁵ These patients were followed for 3, 6, or 12 months. The primary end point of symptomatic recurrent VTE was 2.1% in rivaroxaban-treated patients versus 1.8% events in standard-therapy patients (P = .003 for noninferiority). Major hemorrhage was reduced in rivaroxaban-treated patients (HR 0.49; 95% CI 0.31-0.79; P = .003).⁴⁵ In November 2012, the Food and Drug Administration (FDA) expanded the approval of rivaroxaban for management of DVT or PE and to lower the risk of recurrent VTE following initial therapy. Rivaroxaban has already been approved by the FDA for VTE thromboprophylaxis after knee or hip replacement surgery (July, 2011) and to lower the risk of stroke in patients with nonvalvular atrial fibrillation (November, 2011). The American College of Chest Physicians recommends VKAs or LMWH over rivaroxaban for long-term anticoagulation treatment in patients with PE. However, this recommendation does not reflect additional evidence supporting the use of rivaroxaban from the EINSTEIN studies.

Apixaban

Apixaban is a factor Xa inhibitor approved to decrease stroke and systemic embolism risk in patients with nonvalvular atrial fibrillation. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study compared apixaban with warfarin (INR 2.0-3.0) in 18 201 patients with nonvalvular atrial fibrillation with >1 additional risk factor for stroke. At 5 mg twice daily, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less hemorrhage, and caused lower mortality.⁴⁶ A dose of 2.5 mg twice daily was used in patients with any 2 of the following: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL. At a dose of 2.5 mg twice daily, it has been found to be efficacious for thromboprophylaxis after hip and knee surgery.⁴⁷ In the Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial, a study of 6528 medically ill patients extended thromboprophylaxis with apixaban (2.5 mg orally twice daily) for 30 days was compared with enoxaparin (40 mg SC once daily) for 6 to 14 days. The primary end point at 30 days of death related to VTE, PE, symptomatic DVT, or asymptomatic proximal-leg DVT was observed in 2.71% of the apixaban-treated patients versus 3.06% of enoxaparin-treated patients (P not significant). Major hemorrhage occurred in 0.47% of apixaban-treated patients versus 0.19% of enoxaparin-treated patients (RR, 2.58; 95% CI, 1.02-7.24; P = .04).⁴⁸ This was followed by 2 large trials that studied the efficacy of apixaban for acute and extended treatment of VTE. The Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial was a randomized study of 5395 patients with acute VTE that compared initial treatment with apixaban (10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) to treatment with SC enoxaparin, followed by warfarin. The primary end point of recurrent symptomatic VTE or death related to VTE occurred in 2.3% of apixaban-treated patients versus 2.7% in the other group (P < .001 for noninferiority). Major hemorrhage occurred in 0.6% of apixaban-treated patients versus 1.8% in the other group (RR, 0.31; 95% CI, 0.17-0.55; P < .001). The composite outcome of major hemorrhage and clinically relevant nonmajor hemorrhage occurred in 4.3% of apixaban-treated patients versus 9.7% in the other group (RR, 0.44; 95% CI, 0.36-0.55; P < .001).⁴⁹ In the Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) study, the efficacy and safety of 2 apixaban doses (2.5 mg and 5 mg, twice daily) were compared with placebo in 2486 patients with VTE who completed 6 to 12 months of anticoagulation and for whom treating physicians were uncertain about continuing therapy.⁵⁰ The study drugs were given for 1 year. Symptomatic recurrent VTE or VTE-related death occurred in 8.8% of placebo-treated patients compared with 1.7% in the 2 apixaban-treated groups (P < .001). The rates of major hemorrhage were 0.5% in placebo-treated patients, 0.2% in the 2.5 mg apixaban-treated patients, and 0.1% in the 5 mg apixaban-treated patients. All-cause mortality was 1.7% in the placebo-treated patients compared with 0.8% for 2.5 mg of apixaban and 0.5% for 5 mg of apixaban. The authors concluded that treatment with apixaban for 12 months at either a 5-mg dose or a 2.5-mg dose decreased the risk of recurrent VTE or death from recurrent VTE without increasing major hemorrhage. However, apixaban has not been approved by the FDA for treatment of PE.

Dabigatran

Dabigatran is a direct thrombin inhibitor which has been approved to lower the risk of stroke and systemic embolism in nonvalvular atrial fibrillation. The dose of dabigatran is 150 mg orally, twice daily. For patients with severe chronic kidney disease (creatinine clearance 15-30 mL/min/1.73 m²), the dose of dabigatran is 75 mg twice daily. Although the clinical efficacy of dabigatran was not studied in patients with a creatinine clearance lower than 30 mL/min/1.73 m², this dosing regimen (75 mg twice daily) was derived by studies using pharmacokinetic modeling and simulation.⁵¹ The drug is contraindicated in patients with a creatinine clearance lower than 15 mL/min/1.73 m² or on dialysis. Dabigatran is also being studied for use in the management of acute VTE. In a trial of 2539 patients with acute VTE (31% had symptomatic PE), parenteral anticoagulation was administered for 9 days, dabigatran 150 mg twice daily was compared with warfarin (INR 2.0-3.0). At 6-months follow-up, there was no significant difference in safety and efficacy between dabigatran and warfarin.⁵² In 2 double-blind, randomized trials, Schulman et al⁵³ compared dabigatran with warfarin or placebo in patients with VTE who received at least 3 months of therapy. Dabigatran was found to be efficacious in the treatment of VTE and had a lower risk of bleeding than warfarin but a higher risk than placebo. Dabigatran has not yet been approved by the FDA for treatment of PE.

Edoxaban

Edoxaban is a novel, oral, direct, specific, and reversible factor Xa inhibitor. Edoxaban given orally once daily is effective for preventing VTE in patients having hip or knee replacement surgery. The Hokusai-VTE study⁵⁴ evaluated the effectiveness and safety of initial LMWH followed by edoxaban (60 mg once daily) versus LMWH followed by warfarin for management of patients with acute symptomatic VTE. Treatment with edoxaban is to be continued for at least 3 months in all patients and for up to a maximum of 1 year after randomization. The primary end point is symptomatic recurrent VTE during the study period. The principal safety end point is clinically relevant bleeding occurring during or within 3 days of stopping study treatment. The study has been completed by April 2013, and the results are expected to be available soon.

In a meta-analysis of 4 trials that included 7877 patients, newer oral anticoagulants were found to significantly lower the risk of recurrent VTE or VTE-related death compared to placebo or warfarin (odds ratio [OR] 0.25, 95% CI 0.07-0.86; number needed to treat = 30).⁵⁵ All-cause mortality was significantly lower in the newer oral anticoagulants group compared to placebo (OR 0.38, 95% CI 0.18-0.80). No significant difference in major bleeding was observed with newer oral anticoagulants compared to placebo or warfarin. Newer oral anticoagulants caused a higher rate of major or clinically relevant bleeding compared to placebo (OR 2.69, 95% CI 1.25-5.77). The study also showed that apixaban, rivaroxaban, and dabigatran individually significantly reduced recurrent VTE or VTE-related death compared to placebo. Major or clinically relevant bleeding was higher with dabigatran and rivaroxaban but not with apixaban.

As bleeding is the significant adverse effect of these newer oral anticoagulants, various agents are being evaluated for reversing their anticoagulant effect. The PCC and recombinant activated factor VII (rFVIIa) are being evaluated as anticoagulation reversing agents. Laboratory and human studies suggest that PCC might reverse the anticoagulation effects of rivaroxaban better than dabigatran.⁵⁶ Clinical efficacy of these reversing agents has not been studied yet. Available data suggest that PCC might be the best way to reverse the anticoagulant effect of newer agents. Data for efficacy of rFVIIa are less convincing.

Duration of Antithrombotic Therapy

Numerous trials have addressed the issue of optimal duration of anticoagulation in patients with VTE. For recurrent VTE, anticoagulation for an indefinite period is clearly indicated. In a study of 227 patients who had a second episode of VTE, 6 months of anticoagulation was compared with indefinite anticoagulation.⁵⁷ At 4-year follow-up, recurrent VTE occurred in 20.7% in the 6-month group versus 2.6% in the infinite-treatment group (P < .001). Major hemorrhage and all-cause mortality were not significantly different between the 2 groups. For patients presenting with a first episode of VTE, evidence regarding optimal duration of anticoagulation has evolved. After a first episode of VTE, anticoagulation for 6 weeks only was associated with a higher recurrence rate than 6 months of treatment.⁵⁸ In a study of 162 patients with a first episode of VTE who had completed 3 months of anticoagulation, 83 were randomized to continued treatment group and 79 to placebo for 24 months.⁵⁹ Recurrent VTE was observed in 27.4% per patient-year in placebo-treated patients versus 1.3% per patient-year in the continued treatment group (P < 0.001). A trend toward higher nonfatal major hemorrhage was observed in the continued treatment group. The authors concluded that a first episode of idiopathic VTE should be managed with anticoagulants for longer than 3 months. In a subsequent trial, patients with a first episode of idiopathic proximal DVT who were treated with 3 months of anticoagulation were randomized to discontinuation of oral anticoagulants versus continued anticoagulation for 9 more months.⁶⁰ During the initial 9 months after randomization, the recurrence of VTE was 0.7% for the continued therapy group versus 8.3% for the discontinuation group (P = .003). However, this clinical benefit was not maintained after the therapy was discontinued. Based on the above-mentioned data, American College of Chest Physicians recommended the following: in patients with unprovoked PE or in patients with PE and active cancer, anticoagulation is recommended for at least 3 months followed by consideration of extended treatment. Patients with a low to moderate bleeding risk should be considered for extended duration of anticoagulation. Patients at high risk of bleeding may not need anticoagulation after 3 months. In all patients who receive an extended duration of anticoagulation, this treatment should be reassessed periodically. In patients with VTE and cancer, LMWH is the preferred agent for long-term anticoagulation.

Assessing Risk of Recurrent VTE

Patients with acute unprovoked VTE have an increased risk of a recurrent event compared to patients with secondary thrombosis. The incidence of recurrent VTE in 1626 consecutive patients who had discontinued anticoagulation after a first episode of clinically symptomatic VTE was 11.0% after 1 year, 19.6% after 3 years, 29.1% after 5 years, and 39.9% after 10 years.⁶¹ Risk factors for recurrent VTE after cessation of oral anticoagulant therapy for unprovoked VTE include elevated d-dimer levels, elevated factor VIII levels, residual venous obstruction on Doppler ultrasonography, postthrombotic syndrome, male gender, and older age.^62

–65 Patients with an elevated d-dimer level measured 1 month after cessation of anticoagulation have a higher incidence of recurrent VTE.⁶² Repeated d-dimer testing 3 months or later after cessation of anticoagulation could also help further tailor the duration of treatment as patients with persistently elevated d-dimer levels have an increased higher risk of recurrent VTE than those with normal levels.⁶³ In 7 studies totaling 1888 patients with a first unprovoked VTE who had at least 3 months of anticoagulant therapy, a negative d-dimer result had a 3.5% annual risk of recurrent VTE versus 8.9% for those with a positive d-dimer result.⁶⁴ This may help the patients and health care providers assess the risk and benefit of extended duration anticoagulation. Residual vein obstruction diagnosed by compression ultrasonography after a few months of anticoagulation has also been proposed to predict recurrent VTE. In a review of 9 prospective cohort studies and 5 randomized controlled trials, the presence of residual vein obstruction was not found to be a predictor of recurrent VTE after cessation of anticoagulation in patients with unprovoked DVT. However, residual vein obstruction was a significant predictor of recurrent VTE in patients with unprovoked or provoked DVT (OR 1.5, 95% CI 1.1-2.0).⁶⁵

Antithrombotic Therapy in Pregnancy

For pregnant patients, initial treatment of VTE should be with LMWH instead of UFH. For acute VTE in pregnant women, anticoagulant therapy should be continued for at least 6 weeks postpartum with 3 months minimum duration of therapy. For women on anticoagulant for management of VTE who become pregnant, LMWH is recommended over warfarin. Women needing long-term warfarin therapy who want to become pregnant and are candidates for LMWH should get frequent pregnancy tests as indicated. The LMWH can be substituted for warfarin when pregnancy occurs. Pregnant women should avoid using oral direct thrombin and anti-Xa inhibitors. Lactating women on warfarin or UFH who breast feed can continue warfarin or UFH. For pregnant women receiving a LMWH, this therapy should be discontinued at least 24 hours prior to induction of labor or cesarean section. For pregnant women with prior VTE, postpartum prophylaxis for 6 weeks is recommended with LMWH or warfarin (INR 2-3). For pregnant women at low risk of recurrent VTE, antepartum clinical vigilance is recommended.

Aspirin for Prevention of Recurrent VTE

Aspirin is effective for prevention of arterial thrombosis.⁶⁶ However, aspirin is not as effective as anticoagulants in the venous vasculature. The Warfarin and Aspirin (WARFASA) study⁶⁷ and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study⁶⁸ investigated aspirin 100 mg daily versus placebo in patients with VTE who had received a minimum of 6 weeks of anticoagulation. The WARFASA study showed a 42% decrease in recurrent VTE with aspirin compared to placebo (6.6% vs 11.2% per year; P = .02). Major vascular events were not significantly different between both the groups.⁶⁷ However, the ASPIRE trial demonstrated no significant reduction in recurrent VTE with aspirin compared with placebo. Aspirin-treated patients had a significant decrease in major vascular events (HR, 0.66; 95% CI, 0.48- 0.92; P = .01).⁶⁸ Combining data from these 2 trials showed a 32% decrease in recurrent VTE (HR, 0.68; 95% CI 0.51-0.90; P = .007) and a 34% decrease in major vascular events (HR, 0.66; 95% CI 0.51-0.86; P = .002).⁶⁹

Thrombolytics

Thrombolytic agents activate plasminogen and convert it to plasmin that degrades fibrin. Tissue-type plasminogen activator (tPA), recombinant tPA (rt-PA or alteplase), streptokinase, recombinant human urokinase, tenecteplase, and reteplase are the various thrombolytic agents. Systemic administration of thrombolytic therapy is recommended in patients with massive PE who do not have a high-bleeding risk.⁵ Patients with imminent or actual cardiac arrest should receive a bolus infusion of thrombolytic therapy. Thrombolysis is not recommended in patients with acute PE who do not have hypotension. However, in these patients who have a low-bleeding risk and a clinical course suggesting a high risk of developing hypotension, thrombolytic therapy can be considered. Prolonged use of thrombolytics (about 12 hours) results in increased bleeding, and 2-hour infusions are associated with faster clot lysis than 12- or 24-hour infusions.⁷⁰ There is no significant difference in efficacy or safety of rt-PA versus streptokinase when a 2-hour infusion is given.⁷¹ Direct administration of rt-PA into a pulmonary artery does not accelerate thrombolysis but increases bleeding at the catheter insertion site.⁷² The recommended route of administration of thrombolytics is through a peripheral vein. In patients with acute PE, a 2-hour infusion time of thrombolytics is preferred to a 24-hour infusion. A rt-PA dose of 100 mg for 2 hours is the most widely used thrombolytic therapy. An IV rt-PA bolus (50 mg in about 15 minutes) is as efficacious and safe as a 2-hour infusion of 100 mg of rt-PA.⁷³ Also, low-dose rt-PA regimen (50 mg for 2 hours) shows similar efficacy and possibly better safety than the conventional 100 mg regimen.⁷⁴ In a study of 256 patients with acute PE and pulmonary hypertension or RV dysfunction without hypotension or shock, patients were randomized to receive heparin plus 100 mg of alteplase versus heparin plus placebo for 2 hours. The primary end point of in-hospital mortality or clinical deterioration needing intensification of therapy was significantly higher in the heparin-plus-placebo group than in the heparin-plus-alteplase group (24.6% vs 11%; P = .006). The difference in mortality was not significantly different.⁷⁵ The Pulmonary Embolism Thrombolysis (PEITHO) study evaluated fibrinolysis compared with placebo among patients with acute intermediate-risk PE without hypotension or shock.⁷⁶ Patients were randomized to fibrinolysis with tenecteplase (n = 506) versus placebo (n = 500). Both the study groups received UFH on day 1 followed by warfarin therapy. The primary outcome of all-cause mortality or hemodynamic collapse at 7 days occurred in 2.6% of fibrinolysis-treated patients versus 5.6% of placebo-treated patients (P = .015). There was significantly higher nonintracranial major bleeding (6.3% vs 1.5%; P < .001) and total strokes (2.4% vs 0.2%; P = .003) in the tenecteplase-treated patients. Benefit was observed among patients <75 years (HR 0.33, 95% CI 0.12-0.85) and possible harm among patients ≥75 years (HR 0.63, 95% CI 0.23-1.66).⁷⁶ Catheter-directed thrombolysis with or without ultrasonography assistance can potentially shorten lysis time and lower the dose of thrombolytics.^77,78 This results in reduced clot burden and improved RV function and hemodynamics. The IV UFH is the only anticoagulant recommended in patients who may require thrombolysis. A full therapeutic dose of IV UFH should be continued before and after thrombolysis. The IV UFH should be suspended during the 2 hours of infusion of thrombolytic agent. The major contraindications to thrombolytics include structural intracranial disease, prior intracranial bleeding, ischemic stroke within 3 months, active bleeding, recent brain or spinal surgery, recent head trauma with fracture or brain injury, and bleeding diathesis.⁵ Relative contraindications include a systolic blood pressure more than 180 mm Hg, a diastolic blood pressure more than 110 mm Hg, recent bleeding, recent surgery, recent invasive procedure, an ischemic stroke more than 3 months ago, anticoagulation (eg, warfarin therapy), traumatic cardiopulmonary resuscitation, pericarditis or pericardial effusion, diabetic retinopathy, pregnancy, and age more than 75 years.⁵ Based on the available data, patients aged >75 years should be treated with thrombolytics only if the benefits clearly outweigh the risk of intracranial hemorrhage, especially in the presence of hypotension and shock.

Emerging Therapies

Statins have been demonstrated to reduce the levels of some clotting factors and activate protein C pathway, which can have a beneficial effect in patients with PE on anticoagulation. Statins decrease inflammatory cytokines and increase nitric oxide bioavailability which can have a favorable effect in PE. Biere-Rafi et al⁷⁷ reported that among 3093 patients hospitalized for PE and who received a prescription for a VKA, the adjusted risk of symptomatic recurrent PE was lower by 50% among those taking statins (HR 0.50, 95% CI 0.36-0.70). Analysis of a secondary end point of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial found that rosuvastatin reduced the risk of VTE in study patients.⁸⁰ A meta-analysis of 10 studies also showed that statin use was associated with a decrease in VTE (adjusted OR 0.68, 95% CI 0.54-0.86).⁸¹ However, pending further evidence from randomized trials, statins should not be substituted for proven prophylaxis or treatment of VTE at this point. Matrix metalloproteinase 9 (MMP-9) has been shown to modulate vascular contractility and is considered to be one of the causes for PE-induced pulmonary hypertension.⁸² Animal studies have shown that inhibitors of MMP-9 including statins and doxycycline improve hemodynamics in acute PE.^83,84

Conclusions

Despite increasing awareness among health care providers, PE is a major cause of mortality in hospitalized patients. Early diagnosis, timely initiation of anticoagulant therapy, and optimization of hemodynamics can lead to improved outcomes. The drugs currently approved by the FDA for treatment of VTE include UFH, enoxaparin, dalteparin, fondaparinux, warfarin, and rivaroxaban. The advent of newer anticoagulants has heralded a new era in long-term management of these patients. Future therapeutic targets such as the role of matrix metalloproteinase inhibitors are currently under clinical investigation.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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