Update on the management of venous thromboembolism

Direct oral anticoagulants. The DOACs, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) and the direct thrombin inhibitor dabigatran (Pradaxa), been studied extensively and shown to be noninferior to VKAs for treatment of VTE.⁷ DOACs are currently recommended by the ACCP for long-term treatment of VTE, and several have extended treatment recommendations for VTE over the VKAs.³

The advantages of DOACs include no need for PT/INR monitoring, a fixed dosage, shorter half-life, rapid onset of action (for monotherapy), and in most cases, no need for bridging for interventional or surgical procedures. Additional advantages may include a decreased burden of care for the physician and improved quality of life for the patient. DOACs are also the agents of choice for patients who prefer oral therapy (avoiding parenteral therapy), have limited access to an anticoagulation clinic (home bound or geographic inaccessibility for PT/INR monitoring), or have food or drug-drug interactions. Patients at risk of gastrointestinal bleeding or dyspepsia should avoid dabigatran, while apixaban may be preferred if there is a history of gastrointestinal bleeding.⁸

Rivaroxaban or apixaban can be used as monotherapy for the initial treatment of VTE, while a 5-day course of heparin, LMWH, or fondaparinux is necessary with dabigatran or edoxaban. Rivaroxaban has been approved by the FDA for use in the prevention and treatment of VTE.^9,10 For VTE prophylaxis, rivaroxaban is given orally at 10 mg once daily for 35 days for patients undergoing total hip replacement surgery and for 12 days for patients undergoing knee replacement surgery. For the treatment of VTE, rivaroxaban is given orally at 15 mg twice a day for the initial 21 days of treatment, followed by once daily at 20 mg per day for long-term treatment. It is also approved for extended-duration therapy in both 10-mg and 20-mg doses. In a recently published randomized double-blind trial of rivaroxaban compared with aspirin, the risk of a recurrent event was lower with either dose of rivaroxaban compared with aspirin without an increase in bleeding.¹¹ Rivaroxaban is contraindicated in patients with renal insufficiency (CrCL < 30 mL/min). Both the 15-mg and 20-mg tablets must be taken with food.

Apixaban is also approved for monotherapy of VTE and was found to be noninferior to standard therapy of LMWH and warfarin with less bleeding.¹² Apixaban is used for VTE prophylaxis in patients undergoing hip or knee replacement surgery, given at 2.5 mg twice daily beginning 12 to 24 hours postoperatively for 35 days (hip) or 12 days (knee). The acute-phase dosage is 10 mg twice daily for 7 days followed by 5 mg twice daily for long-term treatment of VTE. The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater. Apixaban is also approved for extended treatment of VTE. In a randomized, double-blind study of 2 doses (2.5 mg and 5 mg, twice daily) of apixaban compared with placebo, apixaban reduced the risk of recurrent VTE without increasing the risk of bleeding.¹³

Both dabigatran and edoxaban require an initial 5-day overlap with a parenteral anticoagulant.^14,15  Dabigatran is given at 150 mg orally twice daily if the CrCL is greater than 30 mL/min for the long-term treatment of VTE. Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors. Dabigatran has been evaluated in 2 double-blind, randomized controlled trials comparing the extended use of dabigatran with warfarin or placebo in patients with VTE.¹⁶ Dabigatran carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. Dabigatran was noninferior to warfarin but significantly reduced the rate of recurrence in the placebo group.¹⁶

The major side effect observed with all DOACs is bleeding, but they have been proven safer particularly in the terms of major bleeding compared with the standard heparin-LMWH-VKA regimen for treatment of VTE.^17–19 The risk of major bleeding, and in particular intracranial bleeding, has been shown to be less with DOACs compared with VKAs in 2 meta-analysis trials.^17,18 Of the 4 new DOACs, only dabigatran currently has an anticoagulant-reversing agent (idarucizumab), although an antidote for the other 3 agents is awaiting FDA approval.²⁰

Subsegmental pulmonary embolism

There is debate as to the need for treatment of patients with subsegmental PE. The most recent guidelines advise clinical surveillance over anticoagulation for patients with a low risk for recurrent VTE and no evidence for a proximal DVT.³ However, individuals who are hospitalized, have reduced mobility, have active cancer or are being treated with chemotherapy, or have a low cardiopulmonary reserve should be considered for anticoagulation unless they have a high bleeding risk.

Thrombolytic therapy

Thrombolytic therapy may be beneficial in select patients with VTE and can be delivered systemically or locally per catheter-directed therapy (CDT). Both routes carry an increased risk of hemorrhage compared with standard anticoagulation. The Catheter-Directed-Venous Thrombolysis (CaVenT) trial and Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial compared CDT with standard therapy.^21,22 In CaVEnT, CDT resulted in increased clinical benefit during the 5-year follow-up but did not result in improved quality of life.²¹ In the TORPEDO trial, patients with proximal DVT receiving percutaneous endovenous intervention and anticoagulation compared with anticoagulation alone demonstrated superiority in the reduction of PTS at greater than 2 years.²² Early results of the Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial show that most patients with DVT did not have a long-term benefit from CDT, buy they did have reduced leg pain and swelling and some had reduced risk of moderate-to-severe PTS.²³

The 2012 and 2016 ACCP guidelines advise anticoagulant therapy over CDT for patients with acute DVT of the leg but suggest patients who may benefit are those with iliofemoral DVT with symptoms for less than 14 days, good functional status, a life expectancy greater than 1 year, and a low risk of bleeding.^3,4 This is in contrast to the 2008 CHEST guidelines that recommended patients who have extensive proximal DVT, who have a high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status be given CDT if the expertise and resources are available.²⁴ It has been suggested that CDT promotes early recanalization and minimizes the incidence of PTS.

Thrombolytic therapy for acute PE remains controversial because there is no clearly established short-term mortality benefit. In the Pulmonary Embolism Thrombolysis (PEITHO) trial, thrombolysis prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.²⁵ A lower dose (50 mg) of thrombolytic therapy was studied in the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET) trial and was found to be safe and effective in the treatment of moderate PE.²⁶

CDT has also been shown to be effective in the treatment of PE. The Ultrasound Acceleration Thrombolysis of Pulmonary Embolism (ULTIMA) trial demonstrated that catheter-directed thrombolysis with ultrasonographic guidance in patients with acute intermediate-risk PE was superior in reversing right ventricular dilatation without an increase in bleeding complications compared with UFH.²⁷ The Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) study found that this approach decreased right ventricular dilation, decreased pulmonary hypertension, decreased anatomic burden, and minimized the risk of intracranial hemorrhage in patients with massive and submassive PE.²⁸

Alteplase (Activase) is a recombinant tissue-type plasminogen activator approved by the FDA for treatment of acute PE. Alteplase is administered as a 100-mg infusion over 2 hours. Because of favorable outcomes with prompt recognition and anticoagulation for PE, the ACCP guidelines recommend systemic thrombolysis for hemodynamically unstable patients (systolic blood pressure < 90 mm Hg) with acute PE and a low risk of bleeding using a peripheral vein.³ These guidelines also recommend thrombolysis for the patient whose condition deteriorates after starting anticoagulant therapy but who have yet to develop hypotension.

If the appropriate expertise is available, CDT is suggested for patients with acute PE if they have hypotension and a high bleeding risk, have failed systemic thrombolysis, or are in shock that is likely to cause death before systemic thrombolysis can take effect.³ An area of ongoing debate is whether there is a benefit for thrombolytic therapy in patients with submassive PE who are hemodynamically stable but have evidence of right ventricular dysfunction on echocardiography or computed tomographic angiography. Bleeding remains the most serious complication of thrombolytic therapy.⁴