Venous ThromboEmbolism (VTE) prophylaxis in stroke patients

• Aims
• Background
• Risk Assessmnet
• VTE Prevention Approach
• Post Stroke VTE Prophylaxis Flowchart

Aims

Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital with a stroke.

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Background

Hospital-associated thrombosis (HAT), covers all VTE that occurs in hospital and within 90 days after a hospital admission. It is a common and costly public health problem, associated with high morbidity and mortality figures, even in well-established health systems.

‘In 2013 to 2014, there were around 24,700 admissions for pulmonary embolism and 19,400 for DVT in England. In 2013 in England and Wales, there were 2,191 deaths recorded as due to pulmonary embolism and 2,816 due to DVT. HAT accounts for 50% to 60% of all VTE seen.’
NICE NG 89 Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism was issued in March 2018 (Last updated: 13 August 2019)1

Data from the Centers for Disease Control and Prevention in the United States (https://www.cdc.gov/ncbddd/dvt/ha-vte-data.html ) suggest that VTE is a leading cause of preventable hospital death and as many as 70% of cases of hospital associated VTE are preventable with the appropriate measures.

HAT is a potentially preventable problem.

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Risk Assessment

Leeds Teaching Hospitals VTE risk assessment tool on PPM+

All patients should be risk assessed for VTE and bleeding on admission to hospital and by the time of first consultant review.
The electronic VTE prophylaxis form on PPM+ should be completed as soon as possible after admission or by the time of first consultant review and always within 24 hours of admission.

For all stroke patients, updates of the risk assessment and the VTE form are needed on day 14, day 30 and whenever the patient’s clinical picture changes (e.g. new infection, change in mobility, new diagnosis associated with higher thrombotic risk).

All patients should be monitored clinically for signs of VTE, signs of bleeding, and signs of adverse effects of the VTE prophylaxis method that is being used, on a daily basis.

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VTE prevention approach

Venous thromboembolism is the term for deep vein thrombosis (DVT) and pulmonary embolism (PE).

Recommendation No.1

1. Intermittent Pneumatic Compression (IPC) devices (Figure 1) should be used as the first line treatment for ALL acute stroke patients in the first 30 days of admission.

2. Re-assess the VTE risk (VTE risk assessment tool on PPM+) on day 14, consider if prophylactic LMWH needs to be added in higher risk patients (see recommendation No.4 for more details).

Kendall SCDTM sequential compression “Comfort” sleeves is the preferred model of IPC devices for stroke patients.

IPC devices should be applied as soon as possible after admission.
In patients with a delayed acute stroke presentation >72h from last seen well (stroke-symptom free), we would still recommend IPC devices, as soon as possible after admission, as the first line of treatment, provided they have no contra-indications.

IPCs should be taken off (whichever comes first)

• when the patient becomes independently mobile (able to walk to the toilet without the help of another person)
• at discharge from hospital
• if the patient develops any adverse effects (e.g. pressure ulcers on the legs, falls due to the IPCs)
• by 30 days

Contra-indications to IPC devices:
a. severe congestive heart failure with massive leg oedema or pulmonary oedema
b. severe skin problems on legs such as leg ulcers or dermatitis
c. severe peripheral vascular disease (absence of pedal pulses or history of definite intermittent claudication)
d. existing DVT

Explain to the patient or their family members or carers (as appropriate) that IPCs:

• reduce the risk of deep vein thrombosis and may increase their chances of survival
• will not help them recover from stroke, and there may be an associated increased risk of surviving with severe disability.

Check for adherence problems to the IPCs daily.

Evidence to support the recommendation:

In CLOTS ³ trial2, IPC devices (Figure 1) worn on both lower limbs were an effective method of reducing the risk for DVT and improving survival in patients who were immobile (defined as unable to get up from a chair/out of bed and walk to the toilet without the help of another person) after an acute stroke and provided they were applied within 72 hours from stroke onset.

Significantly fewer IPC patients than controls had symptomatic or asymptomatic, popliteal or femoral vein DVTs (8.5% vs. 12.1%; adjusted absolute risk reduction, 3.6%) within 30 days of randomisation.
The protective effect of the IPCs remained significant with the symptomatic or asymptomatic, proximal or calf veins included in the analysis.

Patients on IPCs had non-significantly lower all-cause mortality within 6 months compared to the non-IPC group [IPC, n = 320 (22.3%%), vs. no IPC, n = 365 (25.1%); OR 0.85, 95% CI 0.70 to 1.01].
However, the adjusted Cox proportional hazards model revealed reduced probability of death up to 6 months the IPC group with a hazard ratio of 0.86 (95% CI 0.74 to 0.99; p = 0.042).

The trial switched to the Kendall SCDTM sequential compression “Comfort” sleeves to maximise adherence and these are the IPCs that must be used in patients with acute ischaemic or haemorrhagic stroke who are:

1. for active treatment (i.e. not simply for palliation)
2. immobile (unable to walk independently to the toilet)
3. willing to wear compression sleeves
4. not suffering contraindications to IPC
   a. severe congestive heart failure with massive leg oedema or pulmonary oedema
   b. severe skin problems on legs such as leg ulcers or dermatitis
   c. severe peripheral vascular disease (absence of pedal pulses or history of definite intermittent claudication)
   d. existing DVT

NICE NG89, last updated in August 2019 (NICE NG 89), now states the following on IPC devices:

• Consider intermittent pneumatic compression for VTE prophylaxis for people who are immobile and admitted with acute stroke. If using, start it within 3 days of acute stroke.
• When using intermittent pneumatic compression for people who are admitted with acute stroke, provide it for 30 days or until the person is mobile or discharged, whichever is sooner.
• Explain to the patient or their family members or carers (as appropriate) that IPCs:
  • reduce the risk of deep vein thrombosis and may increase their chances of survival
  • will not help them recover from stroke..

The National Clinical Guideline for Stroke, 5th edition in 2016, by the Royal College of Physicians (NICE accredited) suggests that patients with immobility after an acute stroke should be offered IPC boots within 3 days of admission, for 30 days or until the patient is mobile or discharged, whichever is sooner.³

The NICE guidance [NG128]: Stroke and transient ischaemic attack in over 16s: diagnosis and initial management, published in May 2019 does not make any recommendations on VTE prophylaxis.4

The European Stroke Organisation (ESO) guidelines for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke, published in 2016, also makes a strong recommendation in favour of the IPC use in the acute ischemic stroke period with the exclusion criteria that have been described above.⁵

Recommendation No.2
Graduated Compression Stockings (GCS) (Figure 2): NOT to be used in acute stroke patients who cannot tolerate IPCs.

Graduated compression stockings (GCS) (Figure 2), thigh or knee high, should not be routinely used for VTE prophylaxis in patients with an acute stroke that cannot tolerate IPCs.

Evidence to support the recommendation:

This recommendation is in agreement with The National Clinical Guideline for Stroke, 5th edition in 2016, by the Royal College of Physicians (NICE accredited), the NICE NG 89 Guideline on Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism that was last updated in August 2019 and the ESO guidelines for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke from 2016.^1,3,5

The ESO recommendation is based on a meta-analysis of 2 trials (CLOTS 1 and CLOTS 2) where GCS had no significant effect on death (treatment period and follow up), death or dependency at six months, DVT (symptomatic or asymptomatic) or PE during treatment. Increased risk of skin break was identified in the GCS-treated groups (low level of evidence).

Recommendation No.3
Neuromuscular electrostimulation technology (NES), e.g. GEKO device is an alternative for acute stroke patients who cannot tolerate IPCs in the first 14-30 days. Evidence on their benefit in stroke patients is limited.

Patients who cannot tolerate IPCs should be discussed with a senior member of the clinical team and a decision made as to the most appropriate VTE prophylaxis approach.

For patients with an acute stroke who cannot tolerate IPCs, neuromuscular electrostimulation technology can be an alternative option for VTE prophylaxis.
In LTHT we would suggest considering the use of GEKO device for the first 14 (and up to 30 days) in patients with acute stroke that cannot tolerate IPCs.

Evidence to explain the recommendation:

An audit in 455 in-patients with acute stroke (87.1% ischaemic) admitted in the Acute Stroke Unit at Royal Stoke University Hospital in Stoke-on-Trent, Staffordshire, UK was presented in the 11th World Stroke Congress, 2018.
Subgroups and VTE incidence within 90 days:

• 251 (55.2%) patients treated with IPCs alone – 4 (1.6%) VTEs
• 80 (17.6%) patients treated with IPCs initially but switching to GEKOs due to IPC intolerance – 1 (1.3%) VTE
• 59 (13.0%) patients treated with GEKOs only – No VTEs
• 65 (14.2%) patients treated with primary anticoagulation (due to other comorbidities) – 1 (1.5%) VTE

The NICE medical technologies guidance MTG19: ‘The GEKO device for reducing the risk of venous thromboembolism’ published in June 2014, suggests that GEKO device use is supported in people who have a high risk of venous thromboembolism and for whom other mechanical and pharmacological methods of prophylaxis are impractical or contraindicated.6 The guidance recognises the limited clinical evidence, but acknowledges the likelihood of low risk for harm from a device with potential benefits.
The guidance also suggests that in patients ‘at high risk of venous thromboembolism who would otherwise receive no prophylaxis, using the GEKO device is estimated to be cost saving’ (estimated £197 per patient).⁶
The review of the guidance on 2016 did not lead to any changes in the above recommendations.⁷

The National Clinical Guideline for Stroke, 5th edition in 2016, by the Royal College of Physicians (NICE accredited) and the NICE guidance [NG128]: Stroke and transient ischaemic attack in over 16s: diagnosis and initial management, published in May 2019 do not comment at all on the use of the NES.^3,4

The ESO guideline for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke in 2016 recognises that there is no data available from randomised controlled trials in acute ischaemic stroke patients to suggest that NES reduces VTE risk. The recommendation is that NES for VTE prophylaxis in acute ischaemic stroke should only be used in the context of research.⁵

Recommendation No.4

1. Low molecular weight heparins (LMWHs) or heparinoids or UFH should NOT be routinely used in the first 2 weeks unless on consultant recommendation.

2. Re-assess the VTE risk (VTE risk assessment tool on PPM+) on day 14 and day 30.

3. Between day 14 and 30, if the patient is still assessed to be at very high risk for VTE, consider use of prophylactic LMWH in addition to the IPCs.

4. Between day 14 and 30, if a decision is made to start LMWH in a patient who is on GEKO devices, we would recommend removing the GEKOs.

Patients who cannot tolerate IPCs should be discussed with a senior member of the clinical team and a decision made as to the most appropriate VTE prophylaxis approach.

Patients with an ischaemic stroke but with previous VTEs or with a number of risk factors for VTE should be discussed with a Consultant on the post-take ward round and discussion with the haematology team might be appropriate.

Early use of LMWH is associated with a high risk of symptomatic intracranial haemorrhage (sICH). The greatest risk of haemorrhagic transformation of infarct (HTI) is in the first two weeks.

After that, it is reasonable to give LMWH in a dose that is prophylactic for VTE. Enoxaparin subcutaneously once a day (or twice daily if >100kg) to patients who remain at high risk i.e. those who are immobile, CCF etc. is the Trust’s preferred regime for all LTHT patients, by the publication date of this guidance. Please check the relevant guideline for the prophylactic dosing of enoxaparin:
http://www.leedsformulary.nhs.uk/docs/2.8.1LMWHdosingofenoxaparinInhixa.pdf?UNLID=523637592021422112414
For full prescribing information please refer to the appropriate VTE Prophylaxis Policy, at:
http://nww.lhp.leedsth.nhs.uk/VTE/index.aspx

All heparins are porcine based. If patients do not want a porcine based product consider fondaparinux 2.5mg subcutaneous injection once a day if creatinine clearance > 50ml/min or 1.5mg subcutaneous injection if creatinine clearance 20-50ml/min. Do not use if the patient has a latex allergy.

IPCs and LMWH can be used together in the same patient after day 14 and up to day 30.
This would be expected to be the treating option in a small proportion of (mainly ischemic) stroke patients deemed to be at higher risk of VTE and would not apply to all the admitted stroke patients.
Patients considered to be as higher risk (based on the data from CLOTS 1 and 2) are considered those with at least one of the following:

• dependent in daily life activities prior to stroke
• prior history of DVT
• unable to lift both arms
• unable to lift both legs

As described in recommendation 3, the only available data to support the use of GEKOs come from an audit in 455 in-patients with acute stroke (87.1% ischaemic) admitted in the Acute Stroke Unit at Royal Stoke University Hospital in Stoke-on-Trent, Staffordshire, UK was presented in the 11th World Stroke Congress, 2018. (Please see above)
The NICE medical technologies guidance MTG19 (including the 2016 review) suggests that geko device use is supported in people who have a high risk of venous thromboembolism and for whom other mechanical and pharmacological methods of prophylaxis are impractical or contraindicated.⁶
In view of the above and the high cost of GEKO devices (> £20 per pair, daily, exclusive of VAT), we would recommend withdrawing the GEKO devices once a decision is made to start LMWH.

In the case of primary intracerebral haemorrhage (ICH), VTE prophylaxis with low molecular weight heparin (LMWH) after 2 weeks MAY be indicated after re-risk assessment. This will always be a Consultant led decision.
Although LMWH prevents DVTs in immobile patients with an acute ischaemic stroke, there is a concern on the risk of intracranial haemorrhage especially in the first 2 weeks.

Heparin induced thrombocytopenia (HIT) is a common and serious complication of LMWH treatment affecting 0.5% of individuals exposed to LMWH.
For more details please check the relevant guidance on the intranet:
http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?id=1407

Evidence to support the recommendation:

One meta-analysis has addressed the risk and benefit balance of low-dose LMWH, heparinoids and UFH in acute ischaemic stroke patients.⁸
In the LMWH trials included in this meta-analysis, treatment with LMWH was started within 72h from stroke onset and continued up to a maximum of 16 days (in 7/9 trials treatment was initiated in <48h and treatment duration was limited to ≤14 days).

According to this meta-analysis⁸:

• The risk of symptomatic intracranial haemorrhage (sICH) is higher than the risk of symptomatic PE (sPE) (RR 2.1; 95% confidence interval [CI] 1.03-4.28) with LMWH. No statistically significant difference was noted with heparinoids and UFH.
• Although, in the subgroup analysis, the sICH / sPE risk ratio was not statistically significant, when LMWH was initiated >48h from the ischemic stroke onset, the number of patients was very small to allow for the extraction of safe conclusions.
• The risk ratio for fatal ICH to fatal PE was similar with LMWH (RR 1.71 95% CI 0.53-5.46; p=0.37).
• The risk ratio for fatal ICH to fatal PE was reduced with UFH at a borderline level of statistical significance (RR 0.52 95% CI 0.27-0.99; p=0.05).

The National Clinical Guideline for Stroke, 5th edition, 2016, by the Royal College of Physicians suggests that patients with immobility after an acute stroke should not be routinely given LMWH for VTE prevention.³

The ESO guideline for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke in 2016, based on meta-analysis performed by the panel members makes weak recommendation that:

• Prophylactic anticoagulation with UFH (5000U x2, or x3 daily) or LMWH or heparinoid should be considered in immobile patients with ischaemic stroke in whom the benefits of reducing the risk of venous thromboembolism is high enough to offset the increased risks of intracranial and extracranial bleeding associated with their use.
• Where a judgement has been made that prophylactic anticoagulation is indicated LMWH or heparinoid should be considered instead of UFH because of its greater reduction in risk of DVT, the greater convenience, reduced staff costs and patient comfort associated single daily dose vs. multiple daily injections but these advantages should be weighed against the higher risk of extracranial bleeding, higher drug costs and risks in elderly patients with poor renal function.

In CLOTS 3 trial, a subgroup analysis of the effect of allocation to the IPC group on the primary outcome (the occurrence of either a symptomatic or asymptomatic DVT in the popliteal or femoral veins or a symptomatic DVT in the popliteal or femoral veins, confirmed on imaging within 30 days of randomisation) was performed among individuals with and without at least one of the following prognostic factors at baseline:

• dependent in daily life activities prior to stroke
• prior history of DVT
• unable to lift both arms
• unable to lift both legs

Patients with any of the above features were found to be at greater risk for of proximal DVT in CLOTS 1 and 2 trials. Similarly, in CLOTS3 the risk of DVT in those with at least one of the predefined risk factors was higher compared to those without (13.3%; 257/1927 versus 6.7%; 39/585).²
CLOTS 3 investigators recognise that ‘the lack of a statistically significant interaction between the baseline risk of DVT and the treatment effect may reflect the moderate numbers of patients included in the subgroups because there are marked differences in the effect sizes in the two subgroups’.²
Athough the addition of LMWH was not the treatment regime in CLOTS 3, the investigators recognise that the absence of interaction between the baseline risk of VTE (the higher risk patients) and the treatment effect of IPCs, ‘this may reflect the moderate numbers of patients included in the subgroups because there are marked differences in the effect sizes in the two subgroups.’²

Recommendation No.5
Communication (verbal and written) of the VTE prophylaxis plan, the risks and benefits associated with each option and also the post-discharge symptom identification and actions should adhere to the national guidance rules.

NICE NG89, last updated in August 2019 (NICE NG 89)¹, states (keypoints only listed below):

1. For people admitted to hospital who are at increased risk of VTE, give them and their family members or carers (as appropriate) verbal and written information on the following before offering VTE prophylaxis:
   • the person's risks and possible consequences of VTE
   • the importance of VTE prophylaxis and its possible side effects – for example, pharmacological prophylaxis can increase bleeding risk
   • the correct use of VTE prophylaxis – for example intermittent pneumatic compression
   • how people can reduce their risk of VTE (such as keeping well hydrated and, if possible, exercising and becoming more mobile).
2. As part of the discharge plan, give patients and their family members or carers (as appropriate) verbal and written information on:
   • The signs and symptoms of deep vein thrombosis (DVT) and pulmonary embolism
   • How people can reduce their risk of VTE (such as keeping well hydrated and, if possible, exercising and becoming more mobile)
   • The importance of seeking help if DVT, pulmonary embolism or other adverse events are suspected.
3. Give people discharged with VTE prophylaxis and their family members or carers (as appropriate) verbal and written information on:
   • the importance of using VTE prophylaxis correctly (including the correct administration and disposal of pharmacological prophylaxis)
   • the importance of continuing treatment for the recommended duration
   • the signs and symptoms of adverse events related to VTE prophylaxis
   • the importance of seeking help and who to contact if people have problems using VTE prophylaxis.
4. Notify the person's GP if the person has been discharged with pharmacological and/or mechanical VTE prophylaxis to be used at home.

Figure-1: The Kendall SCDTM Express system, high-length ComfortTM sleeves, used in CLOTS 3 trial. Figure obtained from CLOTS 3 publication and used only for educational purposes here.

Figure-2: Graduated compression stockings. Figure obtained from https://www.ed.ac.uk/research/impact/medicine-vet-medicine/compression-stocking-research and used only for educational purposes here.

Figure-3: The GEKO™ device, powered by OnPulse™, neuromuscular electrostimulation technology. Figure obtained from https://www.gekodevices.com/ and used only for educational purposes here.

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For full prescribing information please refer to the appropriate LTHT VTE Prophylaxis Policy, at:

http://nww.lhp.leedsth.nhs.uk/VTE/index.aspx

Guideline Detail

Ownership (medical and pharmacy team): Dr Vasileios Papavasileiou (Consultant in Stroke), Jeremy Robson (Advanced Clinical Pharmacist in Stroke and Neurology), Katherine Stirling (Consultant Pharmacist - Anticoagulation and Thrombosis)