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Treatment of VTE (DVT/PE)
Initial Management of VTE (DVT/PE)
The initial management of DVT consists of LMWH and warfarin (see Initial Dosage of Heparin and Warfarin).
The initial management of PE is:
Heparin and Warfarin Therapy
Note: The following information needs to be considered before starting heparin/warfarin therapy.
- CBC + diff.
- Na, K, creatinine, alb, bili, ALP, GGT, ALT, AST.
- INR/APTT in all patients. In patients under 45, consider taking 2 extra citrate (blue top) tubes for anticardiolipin antibodies, lupus anticoagulant, protein C, protein S, APC resistance and antithrombin III (thrombophilia screen). Consider also prothrombin gene mutation.
Initial Dosage of Heparin and Warfarin
Initial Dosage of Heparin and Warfarin
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- Low molecular weight heparin (LMWH), e.g., enoxaparin 1 mg/kg q12h subcut. On discharge, if LMWH is still required, change to 1.5 mg/kg subcut q24h. If necessary, adjust dosage according to the anti-Xa levels and/or renal function. See below for dosage modifications in renal impairment and for extremes of weight. For information about anti-Xa monitoring, see below.
- Duration: until INR >2 for 2 consecutive days (normally given for at least 5 days).
- Monitoring: Not usually required for LMWH but may be needed. See LMWH Dosage and Monitoring section.
and
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Treatment of DVT/PE in pregnancy
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- Warfarin is teratogenic. Start the patient on LMWH in therapeutic dosage and seek advice from an Obstetric Physician.
- Anti-Xa monitoring should be used when LMWH is given for the treatment of DVT/PE in pregnancy.
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ACCP Antithrombotic Guidelines 9th edition. Chest 2012; 141:7S-47S.
Low Molecular Weight Heparin (LMWH) Dosage and Monitoring
- Low molecular weight heparins (LMWH) have more predictable pharmacokinetics, a longer half-life compared to unfractionated heparin, and a lower rate of thrombocytopaenia (HIT).
- The risk of haemorrhagic complications is also less compared with unfractionated heparin, but it is still a significant problem and fatal haemorrhage may occur.
- A number of low molecular weight heparins are currently available for the treatment of DVT. CDHB recommends enoxaparin.
- Dose reduction of LMWH is required in certain situations.
- Studies have shown that outpatient treatment of DVT and less extensive PE with LMWH is safe and effective. Use the referral form provided and contact the Haemostasis Nurse (
81246) for this service.
Dosage in renal impairment
- If the creatinine clearance (CrCl) is <60 mL/minute, then treat as follows:
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LMWH dosage in renal impairment
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CrCl (mL/min)
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Dosage of LMWH recommended
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>60
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full dose
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50-60
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70% of the weight-based dose
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40-50
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60% of the weight-based dose
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30-40
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50% of the weight-based dose
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<30
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Use unfractionated heparin(1)
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- If the creatinine clearance is <30 mL/minute, discuss with Consultant. Unfractionated heparin should be given in this situation with close monitoring (see below). Unfractionated heparin can be reliably reversed by protamine sulphate if abnormal bleeding occurs. See Heparin Overdosage.
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Dosage in extremes of weight
- This is controversial with conflicting evidence in the medical literature. We have adopted a pragmatic approach and tried to avoid over- or under-dosage and to avoid giving too large a single dose.
- For patients at extremes of weight, we recommend using anti-Xa levels to guide dosage after the third dose.
LMWH dosage in extremes of weight
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- Weight <45 kg or >130 kg.
- 1 mg/kg q12h subcut for 3 doses based on actual weight. The second and third doses will need to be modified if there is renal impairment as above.
- An anti-Xa peak level should be taken three hours after the 3rd dose. The urgent testing required on this sample needs to be arranged with the laboratory.
- Subsequent dosage, i.e., from the 4th dose onwards, may need to be modified when the anti-Xa result is known.
- If still on LMWH at discharge it may be impractical to continue with q12h doses. Change to q24h dosage. Continue to monitor anti-Xa levels to guide dosage.
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LMWH monitoring
- This is done using anti factor-Xa (anti-Xa) levels.
- Indications: LMWH therapy for >7 days; extremes of weight; pregnancy.
- Use a citrate (blue) tube for blood samples. Samples for anti-Xa levels should be taken 4 hours after enoxaparin administration (i.e., peak) and at steady state, e.g., after the first 3 doses when initiating enoxaparin therapy.
- Turnaround at the laboratory can be up to 4 days. Urgent testing (as little as 2 hours' turnaround) may be arranged by calling the laboratory.
Note: Interpretation of anti-Xa levels. This is a controversial area as the correlation between anti-Xa levels and the risk of bleeding or recurrent thrombosis is not exact. There is general agreement that in the treatment of DVT with LMWH the anti-Xa level should be between 0.3 and 1 unit/mL. Consult Haematology for advice if anti-Xa levels and the clinical findings appear inconsistent.
Unfractionated Heparin Dosage
- Use the Unfractionated Heparin Intravenous Infusion Via Syringe Pump chart (search for "C160010" on the CDHB intranet). This gives full guidelines for prescribing IV unfractionated heparin.
- Check INR and APTT before starting treatment.
- Give loading dose (IV bolus) of 80 units/kg (max 10,000 units) then an initial maintenance infusion of 18 units/kg/hr (max 1,800 units/hr).
- Check APTT 6 hourly until in the "therapeutic range". This is approximately 2 - 2.5 times the upper normal range for APTT. The laboratory will indicate their recommended therapeutic range on the report if you state that the patient is on unfractionated heparin.
- Unfractionated heparin dosage should not be altered in relation to renal function and should be monitored with APTT testing.
- Unfractionated heparin effects can be reversed by protamine sulphate.
Warfarin Dosage - the First 5 Days, Recommended INR Levels
- Check INR and APTT before starting treatment.
- Anticoagulant action begins in hours to days relative to the half-lives of the factors affected (II, VII, IX, X). Antithrombotic action takes some days to achieve.
- Aim to start warfarin 5 days before it is planned to stop heparin. During this time check INR daily.
- Patients may be more sensitive to warfarin if they are over 65, and/or have low body weight, altered liver function tests, or are on drugs known to increase sensitivity to warfarin.
- Patients who are generally well, relatively young, and with no comorbidities can be started on warfarin 10 mg on day 1 and 10 mg on day 2 if INR <1.5. Otherwise follow the nomogram below.
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Nomogram for the first 5 days of warfarin treatment
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Day:
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INR:
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Warfarin Dose
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1
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Within normal range
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5 mg or 10 mg, see text
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2
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<1.5
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5 mg or 10 mg, see text
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1.5-1.9
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3 mg
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2.0-2.5
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1 mg
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>2.5
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seek advice
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3
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<1.5
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5 mg
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1.5-1.9
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3 mg
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2.0-2.5
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2 mg
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2.5-3.0
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1 mg
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>3.0
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seek advice
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4
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<1.5
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10 mg
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1.5-1.9
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6 mg
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2.0-3.0
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2 mg
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>3.0
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seek advice
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5
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<1.5
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seek advice
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1.5-1.9
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8 mg
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2.0-3.0
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3 mg
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>3.0
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seek advice
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- Two commercial preparations of warfarin are available in New Zealand - Marevan 1, 3, and 5 mg tablets and Coumadin 1, 2, and 5 mg tablets. They are not pharmacologically interchangeable! i.e., 1 mg of one may not equate to 1 mg of the other. The CDHB uses Marevan.
- We suggest for inpatients and at discharge only 1 mg tablets of warfarin are prescribed, to minimize confusion over dosage and tablet size.
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Recommended INR Levels for Warfarin Treatment
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Prothrombin Ratio (INR)
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Duration
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Pre and perioperative anticoagulation
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1.5-2
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Days
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Treatment of calf DVT
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2-3
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4-6 weeks
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Treatment of provoked DVT
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2-3
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12-26 weeks(1)
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Treatment of provoked PE or massive DVT
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2-3
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26-52 weeks(1)
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Treatment of unprovoked PE or DVT
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2-3
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life long(2)
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Treatment of recurrent PE or DVT(3)
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3-4
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life long
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Atrial fibrillation
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2-3
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life long
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Mechanical valves:
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2-2.5
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life long
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2.5-3
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life long
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Arterial disease
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3-4
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life long
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- This assumes that any transient cause for DVT/PE has resolved. The presence of an inherited prothrombotic defect does not, of itself, influence the duration of anticoagulation in this instance.
- If there is a low risk of bleeding and if this is consistent with the patient's preference. The decision to give life long oral anticoagulants should be taken at a formal assessment of the patient at 6-12 months after the initial thrombosis.
- Recurrence despite prothrombin ratio between 2 and 3.
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Warfarin - Drug Interactions
Many factors influence the individual's response to warfarin. Other drugs may inhibit or induce the enzymes that metabolize warfarin, and these enzymes may show inherited variation in activity. The anticoagulant effect of warfarin may also be influenced by diet, various disease states, and vitamin K metabolism.
Some drugs expected to potentiate warfarin effect
- Antimicrobials: azole antifungal drugs, cephalosporins, cotrimoxazole, isoniazid, macrolides, metronidazole, penicillins, quinolones, tetracycline
- Cardiovascular: amiodarone, diltiazem, fibrates, verapamil.
- Central Nervous: antidepressants (tricyclics, SSRIs, SNRIs).
- Gastrointestinal: omeprazole.
Some drugs expected to decrease warfarin effect
- Antibacterials: rifampicin.
- Cardiovascular: cholestyramine.
- Central Nervous: barbiturates, carbamazepine, phenytoin.
Other factors that may influence warfarin effect:
- Vitamin K, vitamin K rich foods, e.g., avocados, broccoli, will decrease the effect of warfarin.
- Herbal medicines may interact with warfarin. Increased effect - gingko, fish oils; decreased effect - St. John's wort, ginseng.
Note: These lists are not exhaustive. If an unfamiliar drug or complementary medicine is being combined with warfarin, look it up (e.g., UpToDate online), or seek advice from the ward pharmacist or the Drug Information Service, 80900.
Thrombolytic Therapy for PE
- Thrombolytic agents should be considered in life-threatening PE.
- Thrombolysis should not be used as first line treatment in non-massive PE.
- A massive PE is defined as having:
- Haemodynamic compromise, and right heart strain, i.e., raised JVP, RV dilatation on CT, and an echo showing pulmonary hypertension.
In this situation, the recommended practice is to use thrombolysis, the earlier the better. In patients with right heart thrombus, mortality with thrombolysis is a third of that with heparin.
- Such patients should be in either CCU or ICU.
- If the investigations have confirmed PE and the above criteria are satisfied, give r-tPA (tenecteplase). Give single bolus IV, dosage according to weight:
Weight
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Dose of Tenecteplase
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<60 kg
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30 mg
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60 - 70 kg
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35 mg
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70 - 80 kg
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40 mg
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80 - 90 kg
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45 mg
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>90 kg
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50 mg
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The combination of thrombolysis concurrent with low molecular weight heparin increases the bleeding risk.
- If no abnormal bleeding occurs with tenecteplase, follow with low molecular weight heparin and warfarin as recommended in Drug Therapy for DVT or PE.
Contraindications to Thrombolysis
Absolute Contraindications:
- Any prior intracranial haemorrhage.
- Known structural cerebral vascular lesion.
- Known malignant intracranial or spinal neoplasm or arteriovenous malformation.
- Ischaemic stroke within 3 months, except if ischaemic stroke is being treated by thrombolysis.
- Neurosurgery within 6 months.
- Suspected aortic dissection.
- Active bleeding or bleeding diathesis (excluding menses).
- Significant closed-head or facial trauma within 3 months.
- Uncontrolled hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg).
- Recent internal bleeding within 6 weeks.
- Major surgery or major trauma <2 weeks.
Relative Contraindications (to be discussed with Physician):
- Transient ischaemic attack <6 months.
- Traumatic cardiopulmonary resuscitation <2 weeks.
- Non-compressible vascular puncture.
- Pregnancy.
- Active peptic ulcer.
- Current use of anticoagulants (e.g., warfarin with an INR >2: the higher the INR, the higher the risk of bleeding).
Note: Long term benefits of fibrinolysis for life-threatening PE are not yet clearly defined. The risk of bleeding is higher with thrombolysis than heparin and it is less easily reversed.
ACCP Antithrombotic Guidelines 9th edition. Chest 2012; 141:7S-47S.
Topic Code: 1706