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September Issue - Recent developments in the management of pulmonary embolism: risk stratification, novel oral anticoagulants and follow-up

Luke Howard, DPhil, FRCP

Dr Luke Howard is a consultant respiratory physician at Hammersmith Hospital, Imperial College Healthcare NHS Trust, and honorary senior lecturer at Imperial College London. Dr Howard has been a consultant physician in the National Pulmonary Hypertension Service, which manages approximately 1000 patients with pulmonary hypertension, since 2006. He also has specialist interests in exercise physiology and pulmonary embolism, chairing the British Thoracic Society Guideline on Ambulatory Care Management of Pulmonary Embolism.

Welcome to the September 2015 edition of the Thrombosis Adviser newsletter.

Dear Thrombosis Adviser user,

Pulmonary embolism (PE) is the most serious clinical presentation of venous thromboembolism (VTE) and a major cause of mortality, morbidity and hospitalization worldwide. In serious cases, PE can result in circulatory collapse and cardiac arrest, and death has been reported in up to 17% of patients with PE within 3 months of the index event. Fast, effective treatment is therefore essential to prevent long-term complications, recurrent VTE and death. Nonetheless, the clinical presentation of PE is highly variable and easily mistaken for other disorders, and physicians must select the optimal management strategy carefully and on a case-by-case basis. Novel oral anticoagulants (NOACs) provide an alternative treatment option to previously favoured vitamin K antagonists (VKAs), and have an important role to play in the treatment of risk-stratified PE patients.

Risk stratification can help to achieve the best outcome for patients with pulmonary embolism

To determine an optimal treatment strategy, the 2014 update of the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for the diagnosis and management of PE recommends formal risk stratification based on an individual assessment of early mortality risk (death in-hospital or within 30 days):

  • Patients with suspected PE who present with shock and/or hypotension should be immediately identified as ‘high-risk’ patients. These patients require emergency diagnosis followed by primary reperfusion treatment, usually thrombolysis, once diagnosis has been confirmed. Thrombolytic therapy is also recommended for haemodynamically unstable (but not stable) patients by the 2012 UK National Institute for Health and Care Excellence (NICE) guidelines and the 2012 American College of Chest Physicians (ACCP) guidelines
  • Patients identified as having a ‘low risk’ of 30-day mortality (Pulmonary Embolism Severity Index [PESI] class I–II or simplified PESI [sPESI] = 0) can be considered for at-home treatment
  • Further risk stratification can help to identify ‘intermediate-high’-risk patients, who are in need of close monitoring for haemodynamic decompensation
  • Anticoagulation is the primary treatment choice for all patients with low-to-intermediate-risk PE (unless contraindicated)

The sPESI score was shown to have similar prognostic accuracy, clinical utility and greater ease of use compared with its predecessor, thus guiding physicians to make straightforward treatment decisions. sPESI assigns 1 point to each of the following variables: age >80 years; history of cancer; history of heart failure or chronic lung disease; pulse ≥110 beats per minute; systolic blood pressure <100 mm Hg; and arterial oxyhaemoglobin saturation level <90%. Any patient with a total score of ≥1 point is at high risk, whereas those with a score of 0 are considered as low risk. In a post hoc analysis of the phase III EINSTEIN PE study of patients treated with rivaroxaban or standard enoxaparin/VKA therapy, patients with sPESI scores of 0 or 1 had a low incidence of fatal PE, all-cause mortality and other adverse outcomes within the first 30 days, whereas adverse outcomes were more common in those with scores of ≥2. Early hospital discharge of patients at low risk of mortality is often a priority for healthcare systems, and although the sPESI score is a powerful predictor of short-term mortality, additional medical and social factors which may necessitate hospital admission should be taken into account, such as those included in the Hestia criteria.

Novel oral anticoagulants: alternatives to vitamin K antagonist therapy for the treatment of risk-stratified patients with pulmonary embolism

Oral anticoagulant treatment choice, previously limited to VKAs, has expanded to include the NOACs apixaban, edoxaban, rivaroxaban (direct Factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor). NOACs provide an important treatment alternative in light of the many limitations associated with VKA therapy, and their improved convenience has been demonstrated to have a positive impact on clinical outcomes. For example, rivaroxaban has been associated with reductions in the length of hospital stay and improved patient-reported treatment satisfaction compared with standard therapy.

The updated ESC/ERS guidelines now endorse the NOACs as therapeutic options for the treatment of acute PE in patients with a low to intermediate risk of early mortality. This recommendation is based on the success of the large phase III studies (AMPLIFY, Hokusai-VTE, EINSTEIN and RE-COVER). All four NOACs received the 1B class of recommendation, meaning that they are equivalent to the established standard of care (i.e. VKAs).* For extended secondary prevention of VTE after an initial PE event, the 2014 ESC/ERS guidelines state that apixaban (AMPLIFY-EXT), dabigatran (RE-SONATE and RE-MEDY) and rivaroxaban (EINSTEIN EXT) should be considered as alternatives to VKA therapy for extended anticoagulation therapy in patients with PE, unless contraindicated.

With the increased use of NOACs in everyday clinical practice, real-life effectiveness and safety data are expected to accumulate. To date, the Dresden NOAC Registry has shown that rates of major bleeding in patients prescribed rivaroxaban for the treatment of VTE or the prevention of stroke in non-valvular atrial fibrillation in everyday clinical practice may be significantly lower than in patients prescribed VKA. Furthermore, most events (~62%) were managed conservatively (i.e. without surgery or interventional treatment).

*The recommendation for edoxaban therapy is subject to regulatory review for the treatment of VTE in the EU.

Periodic benefit–risk assessment should be used to determine the duration of anticoagulation therapy

Intuitively, physicians will regard patients with PE as needing longer anticoagulation treatment than those with deep vein thrombosis (DVT). However, it is the cause of PE/DVT that more strongly predicts the risk of recurrence, the prevention of which is the primary aim of anticoagulation therapy. Evidence-based guidelines (NICE 2012, 2014 ESC/ERS and 2012 ACCP) recommend anticoagulation therapy for 3 months for patients with VTE provoked by surgical or non-surgical risk factors, providing that the transient risk factor does not persist. Because unprovoked VTE is associated with a more than twofold increased risk of recurrence compared with provoked VTE, these patients should be treated for at least 3 months, with indefinite anticoagulation therapy considered if the bleeding risk is low, or if the patient has a second unprovoked event.

The decision to continue or withdraw anticoagulation therapy should be periodically reassessed, and several risk-stratification scores exist to aid physician decision making. For example, the DASH (D-dimer, Age, Sex, Hormones) score can be used to assess the need for extended therapy in patients with a first unprovoked VTE who have received at least 3 months of anticoagulation therapy.

DASH item Points
D-dimer abnormal +2
Age ≤50 years old +1
Male patient +1
Hormone use at VTE onset –2

Total points Predicted annual recurrence rate (%) Recommendation
-2 1.8 DASH ≤1: consider discontinuing anticoagulation therapy after 3–6 months of anticoagulation
0 2.4
1 3.9
2 6.3 DASH ≥2: consider continuing anticoagulation therapy unless a significant risk of bleeding is present
3 10.8
4 19.9

DASH prediction score for recurrent venous thromboembolism

Currently, there are no validated/guideline-endorsed bleeding risk scores for patients receiving anticoagulant treatment for VTE. However, the HAS-BLED score has recently been shown to successfully identify patients with acute VTE at high risk of anticoagulation-related major bleeding, and may be useful in identifying correctable risk factors for bleeding. Cumulative incidences of major bleeding events were 1.3% in the non-high-risk group (HAS-BLED <3) and 9.6% in the high-risk group (HAS-BLED ≥3) (p<0.0001 by log-rank test).

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