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Treatment of Deep Vein Thrombosis and Pulmonary Embolism

This section examines treatment of VTE, including thrombolytic therapy, anticoagulant therapy, combination therapy and the single-drug approach, and guideline recommendations

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From EINSTEIN to real-world evidence
The EINSTEIN clinical trial programme assessed the safety and efficacy of rivaroxaban compared with VKAs in patients with VTE
© 2017, Bayer AG. All rights reserved. | Approval number PP-XAR-ALL-0092-1

The most effective and economical approach for decreasing the burden of VTE is preventing the development of DVT and PE in patients at high risk. Nevertheless, DVT and PE do occur in these patients and also sometimes develop spontaneously. 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 VTE treatment are:

  • Prevention of thrombus growth
  • Symptomatic relief
  • Prevention of recurrence

 

Haemodynamically unstable patients with PE associated with cardiogenic shock or hypotension (high-risk PE) have a high risk of in-hospital or 30-day mortality. Thrombolytic therapy (also known as fibrinolytic or reperfusion therapy), the use of ‘clot-busting’ drugs that break up or dissolve blood clots more quickly than anticoagulants, is recommended for these patients.1-3

 

Thrombolysis is:

  • Commonly performed using tPA
  • Administered by regional catheter-directed infusion or systemically
  • Associated with a high risk of major bleeding (5–10% of patients) and, therefore, generally reserved for high-risk patients

 

The European Society of Cardiology (ESC) guidelines also recommend rescue thrombolytic therapy for patients with intermediate-high risk PE whose haemodynamic condition deteriorates2

  • The results of the randomized PEITHO study suggested avoiding thrombolysis in stable patients with intermediate-risk PE because of the bleeding risk,4 although the MOPETT study indicated that low-dose thrombolysis may provide a better efficacy/safety balance5
  • Nevertheless, patients with stable intermediate-risk PE and those with low-risk PE are recommended to receive anticoagulant therapy2

 

Patients with DVT and/or haemodynamically stable non-high-risk PE will usually be treated with anticoagulants. Combination therapy – heparin or other parenteral anticoagulation followed by an oral VKA – is a traditional approach. More recently, the NOACs have provided an alternative to VKAs and also offer the option of a single oral drug from the start of therapy. Apixaban, edoxaban, rivaroxaban and dabigatran are approved in Europe6-9 North America10-13 and elsewhere for the treatment of DVT and haemodynamically stable PE, and prevention of recurrent VTE, in adult patients.

 

The NOACs have been tested against conventional therapy in large, randomized phase III studies for the treatment of VTE: EINSTEIN DVT and EINSTEIN PE for rivaroxaban,14-16 RE-COVER and RE-COVER II for dabigatran,17,18 AMPLIFY for apixaban19 and Hokusai-VTE for edoxaban.2020 Compared with conventional treatment (LMWH/VKA), the NOACs:

  • Were at least as effective as VKAs for preventing recurrent VTE and VTE-related death for all studies (primary efficacy endpoints)
  • Had a similar or reduced incidence of major and/or major plus non-major clinically relevant bleeding (principal safety endpoints)

 

These studies are difficult to compare directly owing to variations in study design; therefore, in the absence of head-to-head comparisons, there is no direct evidence to support the use of one NOAC over another.

 

Traditionally, VTE treatment is initiated with a fast-acting parenteral anticoagulant (UFH or more usually LMWH or fondaparinux) overlapping with and followed by VKA therapy (e.g. warfarin) for long-term and extended prevention of VTE recurrence1,2,21

  • VKAs have a delayed onset of action, so a fast-acting parenteral agent must be infused/injected for a minimum of 5 days and until the INR is ≥2.0 for at least 24 hours
  • Self-injection is an option for LMWH and fondaparinux, but this may be unsuitable for some patients (e.g. those with poor dexterity or needle phobia)
  • Frequent coagulation monitoring and dose adjustments are required throughout VKA treatment to maintain therapy within a narrow therapeutic range (INR 2.0–3.0)

 

As an alternative to VKAs, dabigatran and edoxaban can be administered as part of a dual-drug approach, following acute-phase parenteral anticoagulation for at least 5 days. Unlike with VKAs, there is no overlap period and no requirement for routine coagulation monitoring.

 

Parenteral anticoagulants are associated with particular adverse events:

  • HIT can occur with UFH, and to a lesser extent with LMWH; patients with a history of HIT should receive an alternative anticoagulant (e.g. argatroban, lepirudin, danaparoid or [with limited evidence] fondaparinux22)
  • Osteoporosis can also occur when heparin is administered for longer than 1 month2

 

Rivaroxaban and apixaban can be administered from the start of treatment in a ‘single-drug approach’, thus overcoming the complications of overlapping a parenteral anticoagulant with a VKA. There is a period of intensive dosing in the acute phase of therapy – when the risk of recurrent VTE is highest23,24 – followed by a dose change for medium or longer-term secondary prevention.

 

Evidence is accumulating to show that the efficacy and safety of the single-drug approach demonstrated in clinical trial settings translates to real-world situations, for example the Dresden NOAC Registry and the phase IV XALIA study of rivaroxaban.25,26

 

Since 2014, the ESC guidelines have recommended NOACs as alternatives to parenteral/VKA anticoagulation for acute-phase treatment of low/intermediate-risk PE and secondary prevention of VTE. Rivaroxaban, dabigatran and apixaban are also recommended as alternatives to conventional therapy for patients requiring extended anticoagulation (>3 months).2,27

ESC guidelines for the acute treatment of PE
  ESC recommendationa Class of recommendationb/level of evidencec
Acute treatment
Parental anticoagulation/VKA LMWH or fondaparinux (for most patients) I A
VKA targeting an INR of 2.5 (range 2.0–3.0) in parallel to parental anticoagulation I B
NOACs are recommended as alternatives to parenteral anticoagulation/VKAa Rivaroxaban (15 mg bid for 3 weeks, followed by 20 mg od) I B
Apixaban (10 mg bid for 7 days, followed by 5 mg bid) 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
Edoxaban (60 mg od, or 30 mg od for patients with ≥1 of the following: CrCl 15–50 ml/min; body weight ≤60 kg; concomitant use of ciclosporin, dronedarone, erythromycin or ketoconazole)d following acute-phase parenteral anticoagulation for ≥5 days I B
Thrombolytic therapy (for patients who do not have high risk of bleeding) I B
Extended anticoagulation (≥3 months)
NOACs 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

Adapted from Konstantinides et al.2,27
aRivaroxaban, apixaban, dabigatran and edoxaban are not recommended in patients with cardiogenic 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 was under EU regulatory review for VTE treatment when the ESC guidelines were published; the dose reduction recommended is based on the European Summary of Product Characteristics9
bid, twice daily; od, once daily

 

The 2016 American College of Chest Physicians (ACCP) update of its guidelines on VTE treatment recommend:1,21

  • Patients with DVT/PE but without cancer should receive a NOAC in preference to a VKA for the first 3 months of treatment
  • Patients with DVT/PE and cancer should receive LMWH rather than a VKA or NOAC for the first 3 months
  • Patients requiring extended treatment beyond 3 months can continue with their initial therapy choice

 

Anticoagulants are effective in treating DVT and PE but can be associated with increased risks of bleeding and, in some cases, other adverse events. The balance between benefit and risk often drives the decision on the duration of anticoagulation treatment. Because longer-term anticoagulation may increase the risk of bleeding, it should generally be used for patients at high risk of VTE recurrence or for specific patient subgroups. The ACCP and ESC guidelines recommend that the benefit–risk ratio of continuing anticoagulation treatment should be reassessed at regular intervals.1,2,21

 

The ACCP 2016 guidelines make recommendations for therapy duration based on whether the VTE is provoked or unprovoked:21

  • Provoked VTE: 3 months is advised
  • Unprovoked VTE:
    • Low-moderate bleeding risk: extended therapy
    • High bleeding risk: stop treatment at 3 months
    • Patients with cancer: extended therapy regardless of bleeding risk

 

Elastic compression stockings have traditionally been recommended as an important adjunct to pharmacological treatment in patients with DVT, particularly for the prevention of PTS. However, the latest ACCP guidelines do not support their routine use.21 A randomized, placebo-controlled study suggested that stockings did not help prevent PTS,28 although this conclusion is controversial.

 

Other VTE treatments may include:1,2,21

  • Surgery,
  • Vena cava filters
  • Catheter-guided thrombectomy or thrombolytic therapy (for patients with a DVT that threatens the viability of a limb or PE associated with cardiogenic shock or hypotension)

 

Previous studies have demonstrated a therapeutic benefit of aspirin compared with placebo for extended secondary prevention of VTE when given to patients after anticoagulant therapy.29,30 However, results from the more recent EINSTEIN CHOICE trial has shown the NOAC rivaroxaban, to be more effective than aspirin for the prevention of recurrent VTE among patients who were in equipoise for continued anticoagulation. The lower risk of VTE recurrence with rivaroxaban was also associated with a rate of bleeding similar to that with aspirin.31 Learn more about long-term prevention of VTE recurrence in the next section.

 

Next section: Extended Treatment

References

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