GGC Medicines


Adult Therapeutics Handbook

Diagnosis and Treatment of Venous Thromboembolism

Diagnosis and Treatment of Venous Thromboembolism

For suspected venous thromboembolism (VTE) in pregnant patients, refer to separate guideline here

Introduction

Fifty percent of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) arise spontaneously, without any obvious triggering event; there are many risk factors which are particularly common in hospitalised patients.

Early recognition and treatment of an acute venous thromboembolism (VTE) is essential to reduce the risk of early fatal PE. It is estimated that deaths from healthcare associated PE far exceed those from healthcare associated infection.

Diagnosis of acute VTE

Signs and symptoms which may accompany an acute DVT or PE include:

  • Calf warmth, tenderness, swelling, pitting oedema, erythema
  • Chest pain (often pleuritic), cyanosis, breathlessness, haemoptysis, collapse
  • Tachycardia / hypotension, raised JVP, hypoxia, tachypnoea

In almost all suspected cases positive radiological confirmation will be required. However, for those presenting from the community it may be possible to rule out such a diagnosis by use of pre-test clinical probability scoring schemes in conjunction with measurement of fibrin D-dimer levels, which are almost invariably increased in cases of acute VTE (see decision algorithms for suspected DVT and PE below). D-Dimer measurement is not useful in the diagnosis of VTE in pregnant women or already hospitalised patients and should not be measured in these patient groups.

If DVT or PE is not excluded by the above, or the patient is already hospitalised then:

  • Check baseline coagulation screen, FBC, U&Es and LFTs.
  • Unless contraindicated, commence anticoagulant therapy with low molecular weight heparin (LMWH) – Drug therapy / treatment options section below.
  • Arrange objective radiological imaging (e.g. compression ultrasound leg or CTPA chest or V/Q lung scan).

Diagnosis and early management of suspected massive PE

Brief guidance is given below. Full guidance on the diagnosis and early management of a suspected massive PE can be found on NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search for 'Suspected Massive PE' guideline.

Definition of massive PE

PE associated with a systolic blood pressure <90mmHg or a drop in systolic blood pressure of >40mmHg from baseline for a period >15 minutes (not otherwise explained by hypovolaemia, sepsis or new arrhythmia)

Initial management

  • Seek immediate senior advice as patient may need transfer to CCU / ICU / HDU / Resus
  • Heparinise with IV unfractionated heparin bolus (5,000units) then IV infusion (18units/kg/hour adjusted to maintain APTT ratio of 1.8–2.8) – see Drug therapy / treatment options section below.
  • O2
  • IV fluids and inotropic support
  • Perform urgent CTPA or cardiac ECHO (if CTPA not possible / not available).
  • If pregnant, inform on-call obstetric team immediately for consideration of early delivery
  • If there is persistent hypotension (SBP <90mmHg) and either CTPA confirms PE, cardiac ECHO demonstrates RV dilatation / dysfunction or patient is in peri-arrest, then consider thrombolysis as follows:
    • Alteplase IV 10mg over 1–2 minutes followed by 90mg over 2 hours (max 1.5mg/kg if <65kg); if this is not available, consider using local regimen for MI (unlicensed for PE).
    • Continue heparin to maintain APTT ratio 1.8–2.8

If thrombolysis contraindicated, consider percutaneous catheter fragmentation or surgical embolectomy. Be aware that when considering thrombolysis the risk of major haemorrhage is significantly increased in the older patient.

Diagnostic algorithm for out-patients with suspected DVT

Patients with chronic heart failure or suspected bilateral DVT and patients at extremes of weight or with renal impairment (i.e. CrCl <30ml/minute) preventing the safe use of LMWH, may not be suitable for out-patient investigation and management of suspected VTE.

Table 1 – Wells Clinical Score

Active cancer (treatment ongoing, within previous 6 months or palliative) 1
Paralysis, paresis or recent plaster immobilisation of lower extremities 1
Recently bedridden for ≥3 days or major surgery within 12 weeks 1
Localised tenderness along distribution of deep venous system 1
Entire leg swollen 1
Calf swollen by ≥3cm compared to asymptomatic leg (10cm below tibial tuberosity) 1
Pitting oedema (greater in symptomatic leg) 1
Collateral superficial veins (non-varicose) 1
Previously documented DVT 1
Alternative diagnosis as likely or greater than that of DVT -2
TOTAL:  
From The New England Journal of Medicine, Philip S. Wells, David R. Anderson, Marc Rodger, et al., Evaluation of D-Dimer in the Diagnosis of Suspected Deep-Vein Thrombosis, 349(13), 1227-35. Copyright © (2013) Massachusetts Medical Society. Adapted with permission from Massachusetts Medical Society.

Score < 2: DVT unlikely

Score ≥2: DVT possible

Wells Clinical score should be utilised in all NHSGGC hospitals when DVT is suspected in out-patients

Figure 1 – Suspected DVT

Possible DVT
(use Wells clinical score, table 1 above)

Wells clinical score <2 and D-dimer negative – DVT unlikely. Consider other diagnosis before discharge and issue patient information sheet.

Wells clinical score <2 and D-dimer positive – continue below

Wells clinical score ≥2 (irrespective of D-dimer) – continue below

Treat as DVT until ultrasound result available.

Is patient suitable for out-patient management? If IV drug misuser, follow specific guidance on NHSGGC StaffNet.

Out-patients who have a negative ultrasound should discontinue anticoagulation and be considered for a repeat scan at 5–7 days if there is no likely alternative diagnosis for their leg symptoms.

Diagnostic algorithm for out-patients with suspected PE

      • Assess predictive risk score using following scoring tool
      • Identify risk of PE and follow guidance in flow-chart
      • If patient is haemodynamically unstable consider massive PE and refer to brief guidance above and the full guideline on StaffNet.

Table 2 – Revised Geneva Predictive Risk Score

Age >65 years 1
Previous DVT / PE 3
Recent surgery or recent lower limb fracture (≤1 month) 2
Malignant disease (active or cured ≤1 year) 2
Unilateral lower limb pain 3
Haemoptysis 2
Heart rate 74–94bpm 3
Heart rate ≥95bpm 5
Pain on deep venous palpitation of leg and unilateral oedema 4
TOTAL:  
Le Gal G, Righini M, Roy PM, et al. (February 2006). Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Annals of Internal Medicine 144(3); 165-171. Copyright © 2013 The American College of Physicians. All Rights Reserved. Adapted with permission from The American College of Physicians.

Perform D-dimer and troponin

Full guidance is available on StaffNet in the Clinical Guideline Electronic Resource Directory in the Haematology section under 'Suspected PE non massive'.

Figure 2 – Pulmonary embolism – risk stratification and management

Perform D-dimer and troponin

Revised Geneva predictive risk score (table 2):

Low risk (score 0–3) – continue below.

Intermediate risk (score 4–10) – continue below.

High risk (score ≥11)see here.

D-dimer negative – PE not likely, consider other diagnosis.

D-dimer positive – administer LMWH treatment dose and continue below.

CTPA

If this is not readily available and patient is clinically stable with normal CXR and no underlying lung disease, then V/Q scan may be an alternative diagnostic option.

No PE – consider other diagnosis.

PE present – commence apixaban or warfarin and continue below.

Risk stratify according to troponin and RV size (from CTPA or by echo)

RV normal, troponin normal – low 30-day mortality. Consider early discharge and OP management.

RV dilated, troponin normal – intermediate 30-day mortality.

RV dilated or RV thrombus and troponin elevated – high 30-day mortality.

General Management

A duration of 3 months of therapeutic anticoagulation should be sufficient for most patients (longer term anticoagulation should be considered for those who have had recurrent thrombosis or are considered at high risk of a recurrent event), normally using either oral apixaban or LMWH initially followed by oral warfarin (with an overlap of at least 5 days) for 3 months. For details on the use of apixaban in acute DVT or PE, see Drug therapy / treatment options section below.

Special cases where management may differ include:

Pregnant patients

      • Both diagnostic and management strategies differ (see separate guideline here)

Patients with active cancer

      • These patients should be managed with LMWH only, due to their high risk of bleeding and risk of early recurrent thrombosis. Seek advice and discuss with patient and their cancer team. Full guidance is available on NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search for 'Treatment of venous thrombosis in patients with malignant disease' guideline.

Patients with superficial thrombophlebitis

Some patients with extensive superficial thrombophlebitis proximal to the knee can be considered for 6 weeks of anticoagulation with prophylactic dose LMWH (i.e. enoxaparin 40mg once daily). A full guideline pertaining to this management is available on NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search for 'superficial thrombophlebitis' guideline.

IV Drug Misusers

      • Given their chaotic lifestyles and habits, these patients may be considered at high risk of bleeding complications from therapeutic anticoagulant therapy, particularly warfarin therapy which demands careful compliance with monitoring and avoidance of interacting drugs (including alcohol).
      • For these patients an individualised risk / benefit assessment is required, and there are three possible approaches to outpatient management of DVT in these patients:
        1. No anticoagulant therapy
        2. LMWH or oral apixaban for 6 weeks
        3. Apixaban or warfarin treatment for 3 months

An algorithm to inform the decision as to which treatment option is the most suitable and with details of treatment for related conditions (e.g. cellulitis) is available on NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search for 'IVDU'. If it is perceived that the patient will be more compliant with once-daily dosing then rivaroxaban should be considered in place of apixaban.

Screening for cancer in patients with unprovoked venous thrombosis

Investigation for occult malignancy in unprovoked VTE, in patients over 40 years old, should involve full clinical history and examination, basic laboratory testing, chest x-ray, urinalysis and any age-appropriate cancer screening if not already performed. Routine extensive screening is not recommended. Rather, investigation for occult malignancy in VTE should be directed by, and be appropriate to, clinical signs and symptoms presented at diagnosis.

Thrombophilia testing

Thrombophilia testing is warranted in some patients who experience a VTE but should not be performed at the time of the acute event or during anticoagulation therapy.

Drug therapy / treatment options

Subcutaneous LMWH (see separate guideline here for dosing in pregnant patients).

Dalteparin is the LMWH of choice across NHSGGC for the initial treatment of VTE unless the patient is pregnant, has specific contraindications to dalteparin, or is to be treated with apixaban. Most patients with cancer should continue treatment with LMWH for the duration that anticoagulation is required.

Continue with dalteparin until:

  • The diagnosis is disproved or
  • The diagnosis is confirmed and either apixaban (or other direct oral anticoagulant) is commenced or dalteparin has been over-lapped with warfarin for at least 5 days and the INR has been ≥2 for two consecutive days.
  • Dalteparin does not require laboratory monitoring (APTT is inappropriate, though if significant renal impairment or exceptionally low or high body weight, consider assessing anti-factor Xa activity after 2–3 consecutive doses of dalteparin, at 4 hours post dose (when target would be 0.5–1units/ml)). Guidelines on appropriate use of LMWH at extremes of body weight and with renal impairment (CrCl <30ml/minute) are available on StaffNet, Clinical Guideline Electronic Resource Directory and search in the 'Haematology' section.

Dalteparin

Dose is 200units/kg subcutaneously once daily. 18,000units is the maximum recommended daily dose.

Table 3 – Dalteparin dosing

Actual weight (kg) Dalteparin daily dose (units) using pre-filled syringes Dalteparin Syringe Colour
34–45 7,500 Green
46–56 10,000 Red
57–68 12,500 Brown
69–82 15,000 Purple
≥83 18,000 Grey

NOTES

  • Guidance on heparin dose adjustment for patients with significant renal impairment or weighing >120kg are available in the Clinical Guideline Electronic Resource Directory on StaffNet.
  • If there is concern about efficacy in patients weighing >95kg, anti-factor Xa activity should be checked after 2–3 consecutive doses of dalteparin, at 4 hours after a dose.
  • Lower doses of dalteparin should be considered in patients with significant liver and/or renal failure (CrCl <30ml/minute).

Unfractionated Heparin (Sodium Heparin)

  • Used in treatment of DVT / PE if rapid anticoagulation is deemed appropriate (e.g. massive PE) or patients thought to be at particularly high bleeding risk (e.g. recent surgery/trauma)
  • There are different concentrations of unfractionated heparin currently available – only the 1000units/ml preparation should be used at all times
  • Loading Dose: 5,000units by IV bolus over 5 minutes – use one 5ml vial of 1000units/ml (total concentration 5000units/5 ml)
  • Maintenance Infusion: 18units/kg/hour (usually ∼ 1,200units (1.2ml) per hour for a 70kg patient). If patient is at high risk of bleeding, start at 1000units/hour. Use one 20ml vial of 1000units/ml (total concentration 20,000units/20ml). Replace the syringe at least every 24 hours, until treatment is discontinued.
  • Monitoring – Check APTT ratio after 6 hours and 4 hours after any change in infusion rate, then daily.
  • Adjust infusion rate according to APTT ratio (see table 4 below).

Table 4 – Unfractionated heparin dose adjustment

APTT ratio Sodium Heparin Infusion Rate Change
>4 Stop for 60 minutes and recheck APTT ratio, before recommencing at a rate reduced by 300–500units/hour
3.5–4 Stop for 60 minutes and reduce heparin by 200units/hour
2.9–3.4 Stop for 30 minutes and reduce heparin by 100units/hour
1.8–2.8 No change
1.2–1.7 Increase heparin by 200units/hour
<1.2 Increase heparin by 400units/hour and consider further bolus of 5,000units heparin

NOTES

  • Monitoring - check APTT ratio 4 hours after any change in infusion rate.
  • Rarely should patients require infusion rates >1.6–2ml/hour. If target APTT ratio of 1.8–2.8 is not being achieved with a dose of 1.6ml/hour, then monitor anti-factor Xa level (target 0.35–0.7units/ml).
  • Routine platelet count monitoring for Heparin Induced Thrombocytopenia is not required unless unfractionated heparin is being administered within 3 months of recent surgery.

Direct Oral Anticoagulants (DOACs)

Apixaban is curently the NHSGGC preferred DOAC for acute treatment and long-term secondary prevention of DVT and/or PE. Rivaroxaban and dabigatran remain on formulary as an option for acute treatment of DVT and/or PE in patients where these drugs are thought to be preferable (see separate guidance see NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search for 'rivaroxaban for the treatment of acute DVT or PE' guideline).

Apixaban and rivaroxaban are oral direct factor Xa inhibitors and dabigatran is an oral direct factor IIa inhibitor. All three have shown to be as effective as LMWH followed by warfarin in the treatment of acute PE and/or DVT. No monitoring of the anticoagulant effect of any of these medications is required, and although all have a short half-life, only dabigatran has a reversing agent, idarucizumab (Praxbind®).

Patients with acute PE and/or DVT deemed suitable for apixaban therapy:
  • Should be treated with LMWH (dalteparin) until the diagnosis has been objectively confirmed.
  • Apixaban use is not recommended if CrCl is <15ml/minute, and should be used with caution if CrCl is 15–29ml/minute.
  • Start apixaban 22–24 hours after the last dose of dalteparin.
  • Give apixaban oral 10mg twice daily for the first 7 days and then 5mg twice daily for the remaining duration of acute treatment (i.e. 3 or 6 months).
  • If for long-term anticoagulation, the dose of apixaban should be reduced to 2.5mg twice daily after 6 months.
Exclusion for apixaban treatment includes:
  • Creatinine clearance <15ml/minute
  • Liver disease associated with cirrhosis or coagulopathy
  • Pregnancy or breast feeding
  • Concurrent therapy with azoles (except fluconazole), protease inhibitors or strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbitol or St John's Wort)
  • Patients perceived to be at high bleeding risk who would not be suitable for any therapeutic anticoagulant therapy.
Patients being discharged on apixaban:
  • The initial 21 days of treatment (56 x 5mg tablets: 10mg twice daily for 7 days followed by 5mg twice daily for 2 weeks) should be provided from hospital pharmacy.
  • Patients on apixaban do not require referral to an anticoagulant clinic.
  • The GP copy of the patient discharge medications should be accompanied with clear written information for the GP regarding the ongoing time-restricted prescription of this medication and its important contraindications. A GP proforma letter regarding post-discharge apixaban instructions is available on StaffNet, Clinical Guidelines Electronic Resource Directory, 'Haematology' section, under 'Apixaban for the treatment of deep vein thrombosis and/or pulmonary embolism'.
  • Any patient commenced on apixaban should be issued with an apixaban Patient Alert card and offered counselling about this anticoagulant medication.

Warfarin

  • Used as follow-on from LMWH in intermediate and long-term treatment of DVT and PE (except in pregnant patients and some IVDU and cancer patients).
  • Induction treatment with warfarin should always follow a validated induction dosing algorithm suitable to the patient, and be accompanied by INR testing on the specified days.
  • The age-adjusted Fennerty regimen algorithm is suitable for most inpatients who require to quickly achieve a therapeutic INR of 2–3. Daily INR testing is required with this algorithm.
  • The use of alternative 'slower' induction regimens (with less intense monitoring) should be considered in outpatients and the elderly (see NHSGGC StaffNet / Clinical Info / Clinical Guideline Directory and search for 'warfarin induction protocols').
  • Warfarin should be administered orally, once daily at 6pm.

The warfarin flexible induction (Age-adjusted Fennerty) regimen (see NHSGGC StaffNet / Clinical Info / Clinical Guideline Directory and search for 'warfarin induction protocols') gives dosing advice for the first 4 days of warfarin initiation only. It is not appropriate for dosing from day 5 onwards which should be undertaken manually using clinical judgement.