Recommendations for research
- 1 Diagnosis of deep vein thrombosis
- 2 Long-term versus 3‑month oral anticoagulation treatment in subgroups of patients at increased risk of VTE recurrence
- 3 Long‑term anticoagulation treatment with low molecular weight heparin versus a vitamin K antagonist in patients with VTE and active cancer
- 4 Thrombolytic therapy for DVT
- 5 Systemic pharmacological thrombolysis compared with standard anticoagulation treatment in patients with pulmonary embolism and right ventricular dysfunction
- 6 Thrombolysis for patients with acute PE and right ventricular dysfunction
- 7 Lower-dose thrombolysis for patients with acute PE and right ventricular dysfunction
- 8 Stockings for preventing post‑thrombotic syndrome in patients with DVT
In 2012, the Guideline Development Group made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline.
What is the clinical and cost effectiveness of a whole‑leg ultrasound scan compared with a proximal leg vein ultrasound scan in the diagnosis of acute deep vein thrombosis (DVT)?
The Guideline Development Group noted that proximal leg vein ultrasound scans will not identify an isolated calf vein thrombus but that a repeat scan 1 week later will identify the clinically important thrombi that have extended. If a whole‑leg scan is conducted initially, no repeat ultrasound at 1 week is required, but more patients may need anticoagulation therapy. More DVTs are identified by a whole‑leg scan but this is more time‑consuming and the impact on patient outcomes is unknown. Whole‑leg scans are also more difficult technically and are subject to variability because there are more veins within the calf and they are considerably smaller; therefore there is still a risk of missing a calf vein thrombus. Repeating the proximal leg vein ultrasound scan after 1 week necessitates 2 scans, which is also time‑consuming. A randomised controlled trial (RCT) with cost‑effectiveness analysis could answer the crucial question of whether full‑leg ultrasound improves patient outcomes and allow for more effective use of NHS resources. Primary outcomes should include objectively confirmed 3‑month incidence of symptomatic venous thromboembolism (VTE) in patients with an initially normal diagnostic work‑up, mortality and major bleeding. 
2 Long-term versus 3‑month oral anticoagulation treatment in subgroups of patients at increased risk of VTE recurrence
What is the clinical and cost effectiveness of long‑term oral anticoagulation treatment in specific subgroups of patients with a first unprovoked VTE?
There is evidence that some risk factors, such as male sex, raised D‑dimer or the presence of post-thrombotic syndrome, are associated with a greater risk of VTE recurrence than others. Although it is thought that subgroups with these risk factors are at increased risk of VTE recurrence, high‑quality evidence on the benefits of extending anticoagulation treatment in these subgroups is lacking. An RCT comparing long‑term oral anticoagulation with 3 months of oral anticoagulation treatment in patients with a first unprovoked VTE is needed to determine the relative benefits and risks of long‑term oral anticoagulation treatment in these subgroups. The trial should include initial presentation because, compared with a DVT, a pulmonary embolism (PE) is a stronger predictor of a future PE, and therefore initial presentation is likely to be a factor in the decision to offer long‑term oral anticoagulation. The trial should include the following outcomes: all‑cause mortality, recurrence of VTE, major bleeding and quality of life. Follow‑up should be for 5 years. The results would inform the recommendation in this guideline on continuing oral anticoagulation treatment beyond 3 months. 
3 Long‑term anticoagulation treatment with low molecular weight heparin versus a vitamin K antagonist in patients with VTE and active cancer
In patients with VTE and active cancer who have had 6 months of anticoagulation treatment with low molecular weight heparin (LMWH), what is the clinical benefit (in terms of VTE recurrence rates, all‑cause mortality and major bleeding) and cost effectiveness of continued anticoagulation treatment with LMWH versus a vitamin K antagonist (VKA)?
Determining whether LMWH or a VKA should be used for anticoagulation treatment in patients with cancer beyond the initial 6 months of LMWH therapy is critically important. The current recommendation for use of LMWH for the initial 6 months is based on a systematic review that showed LMWH to be advantageous compared with VKA; however, evidence was available only up to 6 months of anticoagulation with VKA. The relative benefits of LMWH or a VKA beyond the initial 6 months are therefore unknown. An RCT is urgently needed to answer this question. The trial should recruit patients with VTE associated with cancer who have completed 6 months of LMWH treatment, in whom long‑term treatment is planned, and who have no contraindications to further anticoagulation treatment with either LMWH or a VKA. Patients should be randomised to treatment with either LMWH or a VKA. The primary outcome measure should be VTE recurrence rates. Secondary outcomes should include cost effectiveness and quality of life. Such a trial will provide an evidence‑based understanding of the relative benefits and risks of long‑term treatment with LMWH versus long‑term treatment with a VKA, inform patient and clinician choice and enable development of clear guidelines to minimise variability in care and make the best use of NHS resources. 
What is the clinical and cost effectiveness of clot removal using catheter‑directed thrombolytic therapy or pharmacomechanical thrombolysis compared with standard anticoagulation therapy for the treatment of acute proximal DVT?
Clot removal strategies such as catheter‑directed thrombolysis might be more effective than standard anticoagulation treatment in reducing post‑thrombotic syndrome. However, there is an increased risk of major bleeding with these strategies. Evidence was identified on outcomes (mortality, major bleeding, post‑thrombotic syndrome and recurrent DVT) related to clot removal strategies for the treatment of acute (less than 14 days' duration) proximal DVT. However, the studies had important methodological limitations and the follow‑up periods were only 6 months. It is important to have longer‑term (at least 2 years) and higher‑quality evidence from RCTs to inform the decision on whether to use clot removal strategies for the treatment of acute proximal DVT. Catheter‑directed or pharmacomechanical thrombolysis should be compared with standard anticoagulation therapy (LMWH or fondaparinux). The primary outcome measures should be mortality, major bleeding, VTE recurrence at 3 months, incidence and severity of post‑thrombotic syndrome at 2 years (measured by a validated tool) and quality of life. 
5 Systemic pharmacological thrombolysis compared with standard anticoagulation treatment in patients with pulmonary embolism and right ventricular dysfunction
What is the clinical and cost effectiveness of systemic pharmacological thrombolysis compared with standard initial anticoagulation therapy in patients with confirmed PE and haemodynamic stability who present with right ventricular dysfunction?
It is unclear from the evidence identified in the review whether there are subgroups of patients with PE and haemodynamic stability who have a significant risk of PE‑related mortality and morbidity and who would benefit from systemic thrombolysis. No evidence was found in the clinical review for the safety and effectiveness of pharmacological thrombolysis in patients with confirmed PE and haemodynamic stability who present with right ventricular dysfunction. An RCT is needed to compare pharmacological thrombolysis (for example, with alteplase) with standard initial anticoagulation therapy (with LMWH or fondaparinux) in these patients. The important outcomes would be all‑cause mortality, VTE‑related mortality, cardiopulmonary resuscitation, major bleeding, VTE recurrence and chronic thromboembolic pulmonary hypertension. This research could improve early outcomes and survival, and reduce complications such as chronic thromboembolic pulmonary hypertension, and would inform an update of this guideline. Currently the guideline does not recommend systemic thrombolysis for these patients. 
As part of the 2015 update, the Standing Committee made additional research recommendations on thrombolysis for patients with acute PE and right ventricular dysfunction, and stockings for preventing post‑thrombotic syndrome in people with confirmed DVT.
Does thrombolysis in patients with acute PE and right ventricular dysfunction improve long‑term quality of life and/or reduce the incidence of chronic thromboembolic pulmonary hypertension (CTEPH)?
PE may affect patients' long‑term quality of life and functional capacity. Because of the short timeframes of previous studies, there is currently insufficient evidence to determine whether thrombolysis confers additional longer‑term benefits compared with anticoagulation alone in patients with acute PE who are haemodynamically stable with right ventricular dysfunction. [new 2015]
Does lower-dose thrombolysis reduce the risk of major bleeding and improve outcomes in patients with acute PE and right ventricular dysfunction?
What is the effectiveness of stockings, when adherence is adequate, for preventing post‑thrombotic syndrome in people with confirmed deep vein thrombosis?
While there have been trials of elastic graduated compression stockings for preventing PTS following proximal DVT, there are aspects of these studies that make it difficult to be certain about the outcomes. In addition, these studies have differed considerably on whether or not the use of these stockings is effective. The Committee noted the importance of ensuring adherence in research on any possible preventative role of elastic compression stockings.
The Committee concluded that the currently available research evidence does not aid decision-making, due to the uncertainty of the output. [new 2015]