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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
Overview of evidence for rivaroxaban in 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 PE whose haemodynamic condition deteriorates while on anticoagulation treatment4
  • The results of the randomized PEITHO study suggested avoiding thrombolysis in stable patients with intermediate-risk PE because of the bleeding risk,5 although the MOPETT study indicated that low-dose thrombolysis may provide a better efficacy/safety balance6
  • 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 Europe7-10 North America11-14 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,15-17 RE-COVER and RE-COVER II for dabigatran,18,19 AMPLIFY for apixaban20 and Hokusai-VTE for edoxaban.21 Additionally, the EINSTEIN JUNIOR and DIVERSITY studies have tested NOACs in paediatric patients with VTE. See here for further information on the use of anticoagulation in this population. 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 recurrence.1,2,22

  • 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 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 highest24,25 – 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.26,27

 

The 2019 ESC guidelines provide a class IA recommendation for NOACs over VKAs in eligible patients. Continuation of oral anticoagulant therapy beyond 3 months is recommended for patients with recurrent VTE not related to a major transient or reversible risk factor. When oral anticoagulation is continued beyond 6 months, then reduced doses of apixaban (2.5 mg bid) and rivaroxaban (10 mg od) should be considered.4 Anticoagulation beyond 6 months is discussed in more detail in the Extended Treatment section here: https://www.thrombosisadviser.com/patients-at-risk-of-VTE-recurrence/

ESC guidelines for the acute-phase treatment of PE
ESC recommendation Class of recommendation/level of evidence
Acute treatment
High-risk PE
It is recommended that anticoagulation with UFH, including a weight-adjusted bolus injection, be initiated without delay I C
Systemic thrombolytic therapy is recommended I B
Intermediate- or low-risk PE
Initiation of anticoagulation is recommended without delay in patients with high or intermediate clinical probability of PE, while diagnostic workup is in progress I C
If anticoagulation is initiated parenterally, LMWH or fondaparinux is recommended (over UFH) for most patients I A
When oral anticoagulation is started in a patient with PE who is eligible for a NOAC (apixaban, dabigatran, edoxaban or rivaroxaban), a NOAC is recommended in preference to a VKA I A
When patients are treated with a VKA, overlapping with parenteral anticoagulation is recommended until an INR of 2.5 (range 2.0–3.0) is reached I A
NOACs are not recommended in patients with severe renal impairment,a during pregnancy and lactation, and in patients with antiphospholipid antibody syndrome III C

aDabigatran is not recommended in patients with CrCl <30 ml/min. Edoxaban should be given at a dose of 30 mg once daily in patients with CrCl of 15–50 ml/min and is not recommended in patients with CrCl <15 ml/min. Rivaroxaban and apixaban are to be used with caution in patients with CrCl 15–29 ml/min, and their use is not recommended in patients with CrCl <15 ml/min

 

CrCl, creatinine clearance; INR, international normalized ratio; NOAC, non-vitamin K antagonist oral anticoagulant; LMWH, low molecular weight heparin; PE, pulmonary embolism; UFH, unfractionated heparin; VKA, vitamin K antagonist

 

The 2016 American College of Chest Physicians (ACCP) update of its guidelines on VTE treatment recommend:1,22

  • 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.1,4,22

 

The ACCP 2016 guidelines make recommendations for therapy duration based on whether the VTE is provoked or unprovoked:22

  • 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.22 A randomized, placebo-controlled study suggested that stockings did not help prevent PTS,28 although this conclusion is controversial.

 

Other VTE treatments may include:1,2,22

  • 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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