Essence of this Article
Prompt diagnosis and treatment of deep vein thrombosis (DVT) is essential to decrease both the risk of recurrence and a potentially fatal pulmonary embolism (PE). Traditionally, treatment of DVT and PE begins with a parenteral anticoagulant, overlapping with and transitioning to longer-term treatment with a vitamin K antagonist (VKA). Novel oral anticoagulants (OACs) provide an alternative option for the treatment of DVT and PE, and overcome many of the practical limitations associated with VKAs. The updated 2014 European Society of Cardiology (ESC) guidelines now recommend the novel OACs rivaroxaban, dabigatran, apixaban and edoxaban as alternatives to traditional therapy for the treatment of PE in patients with a low/intermediate risk for early mortality. The use of compression stockings is an important adjunct to pharmacological treatment in patients with DVT. Other venous thromboembolism (VTE) treatment approaches may include surgery catheter-guided thrombectomy or thrombolytic therapy.
Venous thromboembolism is a serious public health concern
The most effective and economical approach to decreasing the burden of VTE is to prevent the development of DVT and PE in patients at high risk.
DVT and PE continue to be a common problem in hospitalized patients, and in some cases this may be attributable to underutilization of thromboprophylaxis. DVT and PE also develop spontaneously in nonhospitalized patients. Prompt diagnosis and treatment of DVT are essential to decrease the risk of recurrence, potentially fatal PE and other long-term complications.
The goals of DVT and PE treatment are:
- Prevention of thrombus growth
- Symptomatic relief
- Prevention of DVT and PE recurrence
Treatment of DVT and PE with anticoagulants
Traditionally, DVT and PE treatment is initiated with a fast-acting parenteral anticoagulant overlapping with VKA therapy (such as warfarin) for long-term and extended use. Because VKAs have a delayed onset of action, the transition requires close monitoring of the international normalized ratio (INR), with parenteral anticoagulation continued for a minimum of 5 days and until the INR is 2.0 or above for at least 24 hours.565 Frequent coagulation monitoring and dose adjustment is continued throughout VKA treatment in order to maintain a narrow therapeutic range (INR 2.0–3.0).566
Low molecular weight heparin (LMWH) is the parenteral treatment of choice for most patients, although fondaparinux and unfractionated heparin (UFH) are also options.149, 565 Although effective, heparins and fondaparinux require administration by injection, and UFH can also be administered intravenously. Self-injection is an option with LMWH and fondaparinux but may be unsuitable for patients who lack dexterity, such as the elderly, or for those with self-injection anxiety. Heparin-induced thrombocytopenia (HIT) is an adverse event that should be considered when using UFH, and to a lesser extent LMWH and fondaparinux. Patients with a history of HIT should receive an alternative anticoagulant, such as argatroban, lepirudin or danaparoid. Limited evidence suggests that fondaparinux may be another alternative treatment for patients with a history of HIT.567 Osteoporosis is another potential adverse effect when heparin is administered for longer than 1 month.146
The novel OACs apixaban, edoxaban, rivaroxaban, (direct Factor Xa inhibitors) and dabigatran (direct thrombin inhibitor), are approved in Europe568-571 and North America572-575 for the treatment of DVT, PE and prevention of recurrent DVT and PE in adult patients. As with VKAs, dabigatran and edoxaban are administered as part of a dual-drug approach, following acute-phase parenteral anticoagulation. Rivaroxaban and apixaban can be administered from the start of treatment in a ‘single-drug approach’, thus overcoming the complications of overlapping parenteral anticoagulant with VKA.
Recently, the updated ESC guidelines have recommended rivaroxaban, dabigatran, apixaban and edoxaban as alternatives to parenteral/VKA anticoagulation for acute-phase treatment and secondary prevention of patients at an intermediate or low risk of early mortality from PE (Class I, Level B). Rivaroxaban, dabigatran and apixaban are also recommended as alternatives to conventional therapy for patients who require extended anticoagulation (>3 months) (Class IIa, Level B).149
The novel OACs have been tested against conventional therapy in large phase III studies for the treatment of VTE: EINSTEIN DVT and EINSTEIN PE for rivaroxaban, RE-COVER and RE-COVER II for dabigatran, AMPLIFY for apixaban and Hokusai-VTE for edoxaban.576-581 Across these studies, novel OACs (administered following initial heparin therapy in the case of dabigatran and edoxaban) were shown to be at least as effective as VKAs for preventing recurrent VTE and VTE-related death for all studies (primary efficacy endpoint events), and demonstrated a similar or reduced incidence of the major and/or major plus non-major clinically relevant bleeding (principal safety outcome events), compared with conventional treatment. The efficacy and safety of novel OAC use for the extended secondary prevention of VTE following an initial DVT/PE in patients who have received 6–12 months anticoagulation therapy has been evaluated in placebo-controlled studies: EINSTEIN EXT for rivaroxaban, RE-SONATE for dabigatran and AMPLIFY-EXT for apixaban.576, 582, 583 All three novel OACs demonstrated superior efficacy compared with placebo for preventing recurrent VTE and VTE-related death, with small but non-significant differences in the incidence of major bleeding. Dabigatran was also compared with warfarin for extended VTE treatment in the RE-MEDY study,582 and was associated with non-inferior efficacy and similar rates of major bleeding. These studies are difficult to compare directly owing to variations in study design; therefore, in the absence of head-to-head comparison trials, there is no direct evidence to support the use of one novel OAC over another.
2012 American College of Chest Physicians (ACCP) guidelines for the treatment of DVT and PE with anticoagulants565
|ACCP recommendation||Grade of recommendation|
|Acute DVT or PE||Parenteral anticoagulation (overlapping with a VKA) or rivaroxaban||1Ba|
|LMWH or fondaparinux suggested over:|
|PE with hypotension||Thrombolytic therapy (for patients who do not have high risk of bleeding)||2C|
|DVT or PE without cancer||VKA suggested over LMWH||2C|
|LMWH suggested over dabigatran or rivaroxaban||2Ca|
|DVT or PE with cancer||LMWH suggested over VKA||2B|
|VKA suggested over dabigatran or rivaroxaban||2Ba|
|Duration of anticoagulant therapy|
|Proximal DVT or PE||3 months recommended over shorter duration||1B|
|First proximal DVT or PE provoked by surgery or a non-surgical transient risk factor||3 months||1B (2B if provoked by a nonsurgical risk factor and a low/moderate risk of bleeding)|
|Unprovoked DVT or PE||Extended therapy if risk of bleeding is low/moderate||2B|
|3 months if risk of bleeding is high||1B|
|DVT or PE associated with active cancer||Extended therapy recommended over 3 months therapy||1B (2B if risk of bleeding is high)|
|aNo Grade of recommendation available for rivaroxaban or dabigatran.
DVT, deep vein thrombosis; i.v., intravenous; LMWH, low molecular weight heparin; PE, pulmonary embolism; s.c., subcutaneous; UFH, unfractionated heparin; VKA, vitamin K antagonist.
2014 updated European Society of Cardiology (ESC) guideline recommendations for novel OACs for low- to intermediate-risk PE patientsa149
|ESC recommendation||Class of recommendationb/level of evidencec|
|Novel OACs are recommended as alternatives to VKA/parenteral anticoagulation||Rivaroxaban (15 mg bid for 3 weeks, followed by 20 mg od)||I B|
|Dabigatran (150 mg bid, or 110 mg bid for patients ≥80 years of age or those under concomitant verapamil treatment) following acute-phase parenteral anticoagulation||I B|
|Edoxaband following acute-phase parenteral anticoagulation||I B|
|Thrombolytic therapy (for patients who do not have high risk of bleeding)||I B|
|Extended anticoagulation (≥3 months)|
|Novel OACs should be considered as alternatives to VKA anticoagulation if extended anticoagulation treatment is necessary||Rivaroxaban: 20 mg od||IIa B|
|Dabigatran: 150 mg bid (or 110 mg bid for patients >80 years old /those taking verapamil)||IIa B|
|Apixaban: 2.5 mg bid||IIa B|
|aRivaroxaban, apixaban, dabigatran and edoxaban are not recommended in patients with shock or hypotension, or in patients with severe renal impairment (CrCl <30 ml/min for rivaroxaban, dabigatran and edoxaban, and CrCl <25 ml/min for apixaban). bClass of recommendation: I, is recommended/is indicated; IIa, should be considered. cLevel of evidence: B, data derived from a single randomized clinical trial or large non-randomized studies. dEdoxaban is in European Union regulatory review for venous thromboembolism treatment.
bid, twice-daily; CrCl, creatinine clearance; OAC, oral anticoagulant; od, once-daily; PE, pulmonary embolism; VKA, vitamin K antagonist.
Approved anticoagulants for treatment of DVT and PE
|UFH||Factor Xa and thrombin (indirect via AT)||Weight-adjusted s.c. bolus dose followed by i.v. infusion; overlapping with a VKA for at least 5 days and until INR >2.0 for 2 consecutive days|
|LMWH||Factor Xa and thrombin (indirect via AT)||Weight-adjusted s.c. regimen; overlapping with a VKA for at least 5 days and until INR >2.0 for 2 consecutive days||COLUMBUS584|
|Fondaparinux||Factor Xa (indirect via AT)||Weight-adjusted s.c. regimen (standard dose 7.5 mg) od; overlapping with a VKA for at least 5 days and until INR >2.0 for 2 consecutive days585||MATISSE DVT585
|VKA||Vitamin K (inhibits synthesis of Factors II, VII, IX and X)||Oral, commenced in parallel with initial parenteral agent, continued for a minimum of 5 days and until the INR is 2.0 or above for at least 24 hours565
For warfarin, typical induction 5 mg (for older, frailer patients) or 10 mg (for younger, healthier patients) od for 2 days, followed by adjusted-doses to maintain a target INR of 2.5 (range, 2.0–3.0)
Treatment continues for 3–12 months depending on risk factors, or longer if risk factors for recurrence persist
|Cochrane Database Systematic Review587|
|Novel OACs: treatment of patients with DVT and/or haemodynamically stable PE, and prevention of recurrent VTE*|
|Rivaroxaban||Factor Xa (direct)||Oral 15 mg bid for 3 weeks then 20 mg od, including patients with moderate (CrCl 30–49 ml/min) or severe (CrCl 15–29 ml/min) renal impairment568
A reduction of the dose from 20 mg od to 15 mg od should be considered if the patient’s assessed risk of bleeding outweighs the risk of recurrent DVT and PE
|Apixaban||Factor Xa (direct)||Oral 10 mg bid for 7 days than 5 mg bid (day 8 to month 6), followed by 2.5 mg bid (>6 months)571||AMPLIFY580
|Dabigatran||Thrombin (direct)||Oral 150 mg bid following initial parenteral therapy (≥5 days)570
A reduction of the dose from 150 mg od to 110 mg od for patients ≥80 years old or patients who receive concomitant verapamil
|Edoxaban||Factor Xa (direct)||Oral 60 mg od following initial parenteral therapy (5–10 days)573
A reduction of the dose from 60 mg od to 30 mg od for patients with CrCl 15–50 ml/min or body weight ≤60 kg or who use certain P-gp inhibitors
|AT, antithrombin; bid, twice daily; CI, confidence interval; CrCl, creatinine clearance; DVT, deep vein thrombosis; INR, international normalized ratio; i.v., intravenous; LMWH, low molecular weight heparin; od, once daily; PE, pulmonary embolism; s.c., subcutaneous; UFH, unfractionated heparin; VKA, vitamin K antagonist.|
Other treatment approaches for DVT and PE
The use of compression stockings is an important adjunct to pharmacological treatment in patients with DVT, particularly for the prevention of post-thrombotic syndrome. Other VTE treatment approaches may include surgery, vena cava filters, catheter-guided thrombectomy or thrombolytic therapy.565
Thrombolytic agents are given by regional catheter-directed infusion or systemically, and they dissolve fresh thrombi and restore venous flow more rapidly than anticoagulants.588 However, thrombolytic therapy is associated with an increased risk of bleeding (major bleeding occurs in 5–10% of patients).589 For this reason, it is generally reserved for patients with a DVT that threatens the viability of a limb,565 or for PE associated with cardiogenic shock or hypotension.149
Acetylsalicylic acid (ASA) is not suitable for acute treatment for DVT and PE, but there is evidence to support its use for the extended secondary prevention of VTE after completion of an initial period of anticoagulation therapy. In the WARFASA study, ASA was associated with a significant reduction in the risk of recurrence compared with placebo, without an increase in the risk of major bleeding in patients with unprovoked VTE who had discontinued anticoagulant treatment.590 In another similar study, ASA significantly reduced the rate of major vascular events but not recurrent VTE alone compared with placebo.591 The updated 2014 ESC guidelines recommend that ASA may be considered for extended secondary VTE prophylaxis in patients who refuse to take or are unable to tolerate any form of OAC.149