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Recommendations
15.

Offer a choice of low molecular weight heparin (LMWH) or fondaparinux to patients with confirmed proximal DVT or PE, taking into account comorbidities, contraindications and drug costs, with the following exceptions:

  • For patients with severe renal impairment or established renal failure (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m2) offer unfractionated heparin (UFH) with dose adjustments based on the APTT (activated partial thromboplastin time) or LMWH with dose adjustments based on an anti-Xa assay.
  • For patients with an increased risk of bleeding consider UFH.
  • For patients with PE and haemodynamic instability, offer UFH and consider thrombolytic therapy (see recommendations 21 and 22).

Start the LMWH, fondaparinux or UFH as soon as possible and continue it for at least 5 days or until the international normalised ratio (INR) (adjusted by a vitamin K antagonist [VKA]; see recommendation 17) is 2 or above for at least 24 hours, whichever is longer.

Relative values of different outcomesAll cause mortality, VTE related mortality, and recurrent VTE and major bleeding were considered the most important outcomes. The other important outcomes were: intracranial bleeding, fatal bleeding, quality of life, PTS and heparin induced thrombocytopenia (HIT).
Trade off between clinical benefits and harmsReduction in VTE related mortality and recurrent VTE were considered against major bleeding occurrences, including intracranial bleeding and fatal bleeding.

No RCT evidence was available for important longer term outcomes such as PTS and quality of life and it is uncertain whether there are any important differences between these intervention options. The specific tradeoffs between each intervention option are summarised below:

LMWH vs UFH
Overall, the meta-analysis showed that LMWH had more favourable outcomes than UFH, in both benefits and harms from treatment. There were fewer deaths and recurrent VTE in the LMWH group compared to the UFH group, and also less major bleeding. The rates of HIT were similar (about 0.4%) in both arms.

LMWH vs fondaparinux
There were no observed differences in major bleeding and recurrent VTE outcomes, but it is very uncertain whether the patients on fondaparinux have a higher mortality rate (all cause, and fatal bleeding); the CIs for the relative risks were very wide for these outcomes, but the difference in absolute rates is low. Evidence was only available for DVT patients for this comparison. There were no data for safety and efficacy of fondaparinux compared to LMWH in patients with PE.

Fondaparinux vs UFH
There might be some advantages in using fondaparinux compared to UFH; major bleeding and recurrent VTE rates may be lower, particularly in patients with cancer. However, it is uncertain whether the patients on fondaparinux have a higher mortality rate (all cause, and fatal bleeding); the CIs were very wide for these outcomes and the difference in absolute rates is low. However, data were only available from one study conducted only in patients with PE. There were no data for safety and efficacy of fondaparinux compared to LMWH in patients with proximal DVT.

Overall comparison between LMWH, UFH and fondaparinux
There was more evidence available for LMWH compared to UFH, and it showed that LMWHs generally have a slight advantage over UFH in all outcomes considered. However, the benefits vs harms of fondaparinux vs LMWH are less clear. There were also no data in PE patients for this comparison. The only study which compared these two interventions used a LMWH dose which is higher than UK dose, making it particularly hard to draw a firm conclusion and interpret the slightly increased fatal bleeding and all cause mortality rate, particularly when the CIs are very wide.

Patients with renal problems or haemodynamically unstable PE
UFH, which has a shorter half life, may have an advantage in patients with renal impairment because there is less risk of accumulation of the drug. The effect can be more quickly reversed, and therefore it is considered a better option if there is an uncertain risk of bleeding, such as when thrombolysis or surgery may be required. It is also the only licensed product for patients with PE who are haemodynamically unstable.

Starting treatment as soon as possible
It is important that parenteral anticoagulation is achieved quickly for patients with VTE in order to reduce the risk of clot propagation or further embolic events.
Economic considerationsThe economic evidence shows that LMWH is more cost-effective or cost-saving compared to UFH as a short-term treatment for PE or DVT. This conclusion is reinforced if more patients are treated with LMWH as outpatients. No evidence was found on fondaparinux; a simple cost analysis considering only the acquisition costs shows that the average treatment with fondaparinux is more costly compared to LMWH and UFH. Since some hospitals might be able to obtain the different products at different costs, and since the clinical review did not show any difference between fondaparinux and LMWH, they could both be viable options based on local costs.
Quality of evidenceDirect comparisons were available for all three groups of pharmacological agents available for the initial anticoagulation of VTE: LMWH vs UFH, fondaparinux vs UFH and fondaparinux vs LMWH, but not for both patients with PE and DVT. All studies excluded patients at increased risk of bleeding, and there was no specific evidence for patients with increased risk of bleeding, renal impairment or haemodynamically unstable PE.

LMWH vs UFH
For LMWH compared to UFH the quality of evidence was low for most outcomes, despite the abundance of RCTs in this area. For studies comparing LMWH and UFH, there were some limitations in the design of studies. Many of these studies were published more than ten years ago, and there were some concerns about studies which were not using the doses of heparin currently licensed in the UK. There were also variations in the definition of “bleeding” and potential publication bias. Outcomes such as fatal bleeding, intracranial bleeding and VTE related deaths were not consistently reported. Quality of life data were only reported by one study, and it was uncertain whether the instrument was validated. There was no reported data for frequency of HIT in the studies reviewed.

Fondaparinux
Only two studies were found for fondaparinux. One compared fondaparinux vs UFH in patients with PE, while the other compared fondaparinux with LMWH in patients with DVT. The quality of evidence was low. Although these trials are relatively large, these were still serious imprecision for most of the outcomes. The fondaparinux vs UFH comparison also had serious study limitations (unclear allocation concealment and randomisation procedure). There was a subgroup analysis for patients with cancer in the study comparing against UFH, suggesting that in this subgroup there may be a lower risk of VTE recurrence or bleeding in patients treated with fondaparinux.

The economic evidence has potentially serious limitations and partial applicability.
Other considerationsIn addition to the clinical evidence available, the GDG also discussed important practical advantages of using LMWH and fondaparinux over UFH.
  • LMWH or fondaparinux are administered by subcutaneous injections, while UFH is usually administered by continuous intravenous infusions. Because a cannula is inserted for the UFH infusion, patients are at risk of vascular access related problems (such as local infections and bacteraemia). Not being attached to an infusion device also promotes mobility and patient independence.
  • Patients on LMWH or fondaparinux do not require APTT monitoring.
With these advantages, patients on LMWH or fondaparinux often have a shorter hospital stay than patients receiving UFH. Use of LMWH or fondaparinux could also facilitate the option of outpatient initial management of DVT and haemodynamically stable PE in some patients.

The GDG noted that it is very important to consider the individual patient circumstances, such as comorbidities and contraindications in order to offer the most suitable agent for the patient. Important considerations include:
  • Renal status: Dose adjustment and monitoring may be required as patients with renal impairment may accumulate excessive amounts of these drugs in the body. LMWH and fondaparinux should be used with caution for people with renal impairment, and UFH should be considered as an alternative. UFH has a short half-life and is predominantly metabolised in the liver compared to LMWHs that are predominantly excreted through the kidneys. UFH therefore may be more suitable for patients who are at risk of bleeding or have renal impairment.
  • Risk of bleeding or need for surgery or thrombolysis: As in renal impairment patients, UFH is an alternative option for patients with uncertain risk of bleeding or if the patient may have to undergo surgical procedures or thrombolysis. Unfractionated heparin has a shorter half life and is more easily reversed if required.
  • Risk of HIT: Although the review did not show any difference between LMWH and UFH in the risk of heparin induced thrombocytopenia (HIT), the quality of evidence is very low. However, the GDG considered that there may be a lower risk of HIT in people receiving LMWH compared to UFH based on their clinical experience. However, if the patient has a history of HIT, fondaparinux is an alternative option because it is a synthetic pentasaccharide and not associated with HIT.
  • Appropriate dose: Dosing errors in administering LMWH to patients have been the subject of a National Patient Safety Agency alert (NPSA Rapid Response Report 14170); doses were frequently not adjusted to the appropriate clinical indication, weight or renal function. Patients should be weighed prior to receiving LMWH to ensure that they are prescribed the correct dose, especially in obese patients. Renal function should also be considered in all patients, although renal function testing should not delay the first dose it should be taken into account for subsequent doses.
  • Patient preferences: Both UFH and LMWH are of porcine origin. This may be a concern to some patients. If this is a concern, fondaparinux may be considered as a suitable alternative for some of these patients.
  • Route of administration for UFH: Both the intravenous route and the subcutaneous route were included for UFH in the evidence review. However, the main group of patients where UFH is likely to be used are those with risk of bleeding or accumulation due to severe renal impairment. The intravenous route has advantages over the subcutaneous route in patients where accumulation or bleeding may be problematic. If problems arise, the action of UFH can be limited by turning off the infusion. Protamine sulphate can be administered as indicated.
LMWH and fondaparinux are not licensed for the treatment of haemodynamically unstable PE. These patients may also undergo thrombolysis (and therefore may be at a higher bleeding risk) and so only UFH is recommended for these patients.

The recommendation emphasises that treatment is started as soon as possible. It is important that parenteral anticoagulation is achieved quickly for patients with VTE in order to reduce the risk of clot propagation or further embolic events. Initial treatment should be commenced without delay in patients diagnosed with DVT/PE and if necessary even prior to the confirmation of the diagnosis by imaging.

As oral VKAs may take a few days to reach a level which is effective for anticoagulation, it is important to continue the initial parenteral treatment with heparins for fondaparinux until the INR is 2 or above for at least 24 hours, or 5 days, whichever is longer. This is to ensure adequate anticoagulation at all times.

The GDG also noted that there are wide variations in the purchasing costs between various NHS organisations for LMWH and fondaparinux. Some organisations may be able to obtain fondaparinux at an equivalent or lower cost than LMWH, and this could be a consideration in the choice of agents.

The GDG have prioritised this recommendation as a key priority for implementation. 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.

Linked recommendations:
Thrombolytic recommendations in section 8.2 and 0.
Recommendations 3 and 5 in the DVT diagnosis chapter 5 and recommendations 11 and 13 in the PE diagnosis chapter 6.
Recommendation 30 in the patient information chapter 11 which refers to LMWH being of porcine origin.

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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