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Recommendations
16.

Offer LMWH to patients with active cancer and confirmed proximal DVT or PE, and continue the LMWH for 6 months(a). At 6 months, assess the risks and benefits of continuing anticoagulation(b).

(a) At the time of publication (June 2012) some types of LMWH do not have UK marketing authorisation for 6 months of treatment of DVT or PE in patients with cancer. Prescribers should consult the summary of product characteristics for the individual LMWH and make appropriate adjustments for severe renal impairment or established renal failure. Informed consent for off-label use should be obtained and documented. (b) Although this use is common in UK clinical practice, at the time of publication (June 2012), none of the anticoagulants has a UK marketing authorisation for the treatment of DVT or PE beyond 6 months for patients with cancer. Informed consent for off-label use should be obtained and documented.
Relative values of different outcomesThe GDG considered recurrent VTE, mortality and major bleeding as the most important outcomes. The other important outcome was quality of life.
Trade off between clinical benefits and harmsReduction in recurrent VTE was considered against major bleeding occurrences, including intracranial bleeding and fatal bleeding.

In patients with cancer, the evidence suggests that anticoagulation for 6 months with LMWH leads to better outcomes compared to switching to a VKA after initial LMWH treatment. There was an important reduction of recurrent VTE in patients who had used LMWH compared to VKA when these were given over 6 months in patients with cancer. The treatment has an overall benefit compared to VKA; all cause mortality and major bleeding were similar for both groups. It is uncertain whether there are any important differences in the quality of life of patients as no studies included this as an outcome.

The option for initial treatment is less clear, as fondaparinux seemed to be favourable compared to UFH in cancer patients with PE, but there was no direct comparison with LMWH in cancer patients.
Economic considerationsData from economic analyses suggest that use of LMWH instead of VKA is cost-effective. As LMWHs are associated with increased costs we would need additional certainty around their cost-effectiveness to recommend them for all patients. Economic studies have shown results to be sensitive to changes in parameters including costs and effectiveness estimates. Since there is stronger evidence of additional benefits of LMWH in patients with cancer, the GDG believe this intervention is likely to be more cost-effective in this group of patients.
Quality of evidenceThe overall quality of evidence was moderate or low. One study, Lee 2003,138 contributes to most of the information about the comparison. Data were only available up to 6 months and only for patients with proximal DVT or PE. The economic evidence has partial applicability and potentially serious limitations.
Other considerationsThe evidence suggested that using LMWH instead of VKAs offered an overall benefit, for patients with proximal DVT or PE and active cancer. However, this means that patients will be having daily subcutaneous injections instead of taking oral tablets. Therefore, patient preference and practicalities, such as whether patients can reliably self-inject or have a carer (such as a relative or district nurse) to help to administer the injection needs to be taken into account. The ability of patients to adhere to the treatment plan is important for its success.
The GDG was concerned that the cost of nurse-delivered injections may limit the availability of this service being available on the NHS and some VTE patients with active cancer may not be offered LMWH. If this is the case, there would be a serious equality of access issue. Patients who need support from nurses and carers should still be offered the LMWH option, and the practicalities of these need to be discussed with them. In the study of using LMWH in cancer patients138, 22% had nurse assistance for injection and only 6% withdrew in the LMWH group, indicating that this is a feasible option for a majority of patients, and should be offered based on the clinical benefits observed in clinical trials for this patient group. Arrangements should be in place for training of patients or carers in the technique of administration of LMWH in order to limit the numbers who require nurse-delivered injections.

At 6 months, the need to continue anticoagulation should be reassessed and discussed with the patient. The current recommendation of international guidelines and UK clinical practice is to continue anticoagulation lifelong in patients with active cancer, based on expert clinical experience, case series and opinion, in the absence of randomised controlled trials122. Therefore, we have made a high priority research recommendation in this area (see research recommendations, section 7.6).

Apart from the availability of evidence to support using LMWH instead of VKA in patients with cancer, the GDG also discussed the potential advantages based on their clinical experience:
  • It is difficult to maintain good INR control (which puts patients at risk of bleeding or more VTE events) while patients are on chemotherapy. This makes it a strong case for the use of LMWH for those patients with new VTE, and active cancer, particularly if undergoing chemotherapy.
  • Patients with cancer have a higher risk of major bleeding on anticoagulation compared to patients without cancer, which may relate to the underlying cancer and propensity for bleeding (e.g. ulcerated gastric cancer).
  • Patients with impaired renal function can receive LMWH at a reduced dose, and would therefore not be excluded. There may be an additional cost to Factor X monitoring for such patients, however probably few actual tests need to be conducted when patients are stabilised.
For the purpose of this recommendation, the GDG considered the evidence available and defined active cancer as: receiving active anti-mitotic treatment; or was diagnosed within last 6 months; or recurrent or metastatic; or where the cancer is inoperable. This definition excludes squamous skin cancer and basal cell carcinoma (BCC).

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.

The potential equalities issues of access to this intervention for patients who are unable to self inject was discussed and documented above.

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).
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