Recommendations
19.

Consider extending the VKA beyond 3 months for patients with unprovoked proximal DVT if their risk of VTE recurrence is high and there is no additional risk of major bleeding. Discuss with the patient the benefits and risks of extending their VKA treatment.

Relative values of different outcomesRecurrent VTE and major bleeding (such as fatal bleeding and intracranial bleeding) were considered the most important outcomes. All cause mortality, VTE related mortality, quality of life and PTS were also considered to be important.
Trade off between clinical benefits and harmsThe balance between a decrease in recurrent VTE and occurrence of major bleeding was considered.
An economic model was conducted to incorporate the trade off between the benefits and harms (see economic considerations below). The model found that long-term treatment is not cost-effective in patients with unprovoked proximal DVT unless the risk of VTE recurrence is increased. In patients with an initial presentation of unprovoked proximal DVT, long-term treatment is likely to be beneficial only for patients with an increased risk of VTE recurrence and with no increased risk of major bleeding. Therefore VKA anticoagulation should be considered for patients with unprovoked proximal DVT only if they have an increased risk of VTE recurrence and no increased risk of major bleeding. For example, patients with twice the baseline risk of VTE recurrence will have an overall benefit from continuing treatment if there is no increase in risk of major bleeding. However they will have more potential harm than benefit if they have risk factors that put them at an increased risk of major bleeding. The individual risk factors need to be considered carefully; the risk of bleeding has to be assessed because any increase in risk of bleeding is likely to outweigh any benefits from extended treatment, even in the presence of risk factors for VTE recurrence.
Economic considerationsAn original economic model was conducted. In the base case analysis where the risk of VTE recurrence was 8.4% in patients with an initial proximal DVT and 7.4% in patients with an initial PE; however, the proportion of recurrences as PE was higher in the PE group (50%) compared to the proximal DVT group (15%). Given the high burden of PE episodes in terms of costs and increased mortality, in the base case analysis extending treatment beyond three months is cost-effective in patients after an initial idiopathic PE episode but it is not cost-effective in patients after an initial proximal DVT episode. We conducted a two-way sensitivity analysis and a threshold analysis to analyse the impact of the risk of major bleeding and VTE recurrence on the final results. In patients with proximal DVT long-term treatment becomes cost-effective when there is an increased risk of VTE recurrence and no increased risk of major bleeding. For example, in patients with twice the baseline risk of VTE recurrence, long-term treatment is cost-effective if there is no increase in risk of major bleeding. However, it is not cost-effective if patients have risk factors that put them at an increased risk of major bleeding.
Quality of evidenceModerate to low quality evidence suggests that long-term anticoagulant treatment may benefit some groups of patients with unprovoked proximal DVT. There was concern over heterogeneous populations in the studies and the differing length of treatment and follow up.
The economic evidence had some potentially serious limitations and partial applicability. The model was based on limited clinical evidence (only one RCT for the estimate of effectiveness) and there could be some heterogeneity in the population of the studies informing different parameters. In addition, the model required a lifetime extrapolation on short-term data. Some parameters (for example risk of major bleeding while on treatment) were obtained from a slightly different population (patients treated with anticoagulants for non rheumatic atrial fibrillation).
Other considerationsVKA anticoagulation only offers prevention while on treatment and therefore this may have to be extended as long as the underlying risk factor(s) remain(s). Correctly identifying “unprovoked” proximal DVT and where there may be permanent underlying risk factors as opposed to “provoked” proximal DVT where the risk factors are more likely to be temporary (for example, surgery, immobilisation) is the first step.

The following are the main reasons for a more cautious recommendation of “considering” long-term VKA treatment for patients who had unprovoked proximal DVT:
  • The economic model showed that it is not cost effective, unless a patient has factors which further increase the risk of recurrence. The GDG discussed that men with unprovoked VTE have been reported to have higher risk of VTE recurrence.56,158,206 The other potential factors include PTS206,232 and a raised D-dimer after stopping anticoagulation.182,255
  • The risk of recurrence as PE is lower in these patients, and therefore there is potentially less morbidity and recurrence is less likely to be life-threatening than in patients with PE (who have proportionately more recurrences as PE).
The GDG recognised that identifying which patients should have extended VKA treatment beyond 3 months is a pertinent clinical issue. Conducting a risk assessment may have clinical, resource and/or economic implications to the NHS and the decision will often be taken in a secondary care setting. However, this is necessary because there are no valid and reliable tools to accurately predict risk of bleeding or VTE recurrence. This recommendation emphasised discussion with the patient because the risk benefit is very patient specific and patient preferences are particularly important here. Unlike patients who presented with unprovoked PE, long-term VKA anticoagulation beyond 3 months will only be cost effective to patients who have above average risk of recurrence (compared to other unprovoked DVT/VTE patients), and do not have risk factors (apart from VKA treatment) which put them at higher risk of bleeding.

The risk of thrombosis and bleeding may change over time and it is important to have a review annually and if circumstances change for patients who are continuing on treatment.

The likelihood of patient adherence to the treatment and the monitoring of INR to maintain good anticoagulation control are also important considerations. Groups at risk of poor adherence and/or poor INR control include patients with mental health or cognitive problems and IV drug abusers.

The GDG have prioritised this recommendation as a key priority for implementation as they considered that it has a high impact on outcomes that are important to patients, a high impact on reducing variation in care and outcomes, leads to a more efficient use of NHS resources, promotes patient choice, promotes equalities and means patients reach critical points in the care pathway more quickly.

From: 7, Pharmacological interventions

Cover of Venous Thromboembolic Diseases
Venous Thromboembolic Diseases: The Management of Venous Thromboembolic Diseases and the Role of Thrombophilia Testing [Internet].
NICE Clinical Guidelines, No. 144.
National Clinical Guideline Centre (UK).
Copyright © 2012, National Clinical Guideline Centre.

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