Pathway for the management of DVT in primary Care

Pathway for the management of DVT in primary Care Final Version: Approved by NHS DGS CCG: June 2015 This document aims to support practices in DGS CCG in the Management & Treatment of patients with suspected and confirmed DVT. Date of Review: June 2017 Page 1 of 11

Version Control Version Date Comments Contributor Version 1 January 2012 New guidance issued Jabeen Egan Version 2 February 2015 Updated for dxs format Rachna Selvan Jabeen Egan Version 3 June 2015 Addition of Apixaban according to NICE [TA341] Rachna Selvan The following contributed to the development of these guidelines: Dr Janet Hall GP Prescribing Lead NHS DGS CCG Dr D Woodhead GP Governing body NHS DGS CCG Jabeen Egan Lead Pharmacist NHS DGS CCG Rachna Selvan Prescribing Advisor NHS DGS CCG Date of Review: June 2017 Page 2 of 11

Patient Pathway for the management of DVT in primary Care Suspected DVT Clinical assessment according to the Wells Score (if both legs are affected score on the worse leg) Wells Score 1 Wells Score 2 No DVT, STOP TREATMENT Consider alternative diagnosis Negative *Start immediate treatment dose of either LMWH OR NOAC (Rivaroxaban or Apixaban) Ultrasound *Start immediate treatment dose of either LMWH OR NOAC (Rivaroxaban or Apixaban) Ultrasound Negative Reassess Clinical Features of the Patient? Positive Positive Confirmed DVT Follow treatment pathway Confirmed DVT Follow treatment pathway *Check BNF/SPC for any contraindications to treatment before initiating. See Treatment pathway *Consult product literature for details of managing patients with renal impairment *For patients with egfr <30ml/min/1.73m 2 for whom Rivaroxaban is unsuitable Offer unfractionated heparin. If DVT likely use clinical judgment and Repeat ultrasound after 1 week Positive Use clinical judgement to STOP TREATMENT if DVT not likely. Consider alternative diagnosis Negative Confirmed DVT Follow treatment pathway Date of Review: June 2017 Page 3 of 11 Ultrasound negative NO DVT Consider alternative diagnosis.patient to be reassessed as seen fit by the GP

Clinical feature Points Active cancer (treatment ongoing, within 6 months, or palliative) 1 Paralysis, paresis or recent plaster immobilisation of the lower extremities 1 Recently bedridden for 3 days or more or major surgery within 12 weeks 1 requiring general or regional anaesthesia Localised tenderness along the distribution of the deep 1 venous system Entire leg swollen 1 Calf swelling at least 3 cm larger than asymptomatic side 1 Pitting oedema confined to the symptomatic leg 1 Collateral superficial veins (non-varicose) 1 Previously documented DVT 1 An alternative diagnosis is at least as likely as DVT -2 Table 1 Two-level DVT Wells score Clinical probability simplified score DVT likely DVT unlikely 2 points or more 1 point or less Date of Review: June 2017 Page 4 of 11

TREATMENT PATHWAY Patient Pathway confirmed DVT Consider Treatment with either NOAC OR LMWH plus Warfarin Consider NOAC Consider Warfarin -Patients who do not have severe renal impairment <15ml/min (consider product literature for moderate impairment) -Patients on long-term Warfarin who have poor control -Patients with other medical conditions that require regular introductions of medications which interfere with warfarin, e.g. COPD with antibiotics, and cause the need for very frequent INR monitoring/dose changes -Patients who are currently managed on LMWH because of difficulty in INR monitoring Consideration- Warfarin may be more appropriate for: -Patients who are contraindicated to Rivaroxaban (Risk of major bleeding e.g. recent gastro-intestinal ulcer, oesophageal varices, recent brain, spine or ophthalmic surgery, recent intracranial haemorrhage, malignant neoplasms, vascular aneurysm) -Patients who are breastfeeding -Patients whom you wish to monitor their INR to assess compliance to treatment -Patients with poor mobility who find it difficult to attend outpatient clinics and/or require home visits not be able to self-monitor INR -If Patients would benefit from not incurring drug/food interactions (as with warfarin) Treat with NOAC -Counsel Patient fully -Continue with initial treatment: Rivaroxaban: 15mg twice daily with food for 21 days, then for continued treatment and prophylaxis of recurrent deep vein thrombosis 20mg once daily with food. Apixaban: 10mg twice daily for 7 days followed by 5mg twice daily. -The duration of therapy should be individualised after careful assessment of the treatment benefit against risk for bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, and immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE. Treat with Warfarin -Counsel patient fully re: anticoagulation, including information leaflet and anticoagulant card -Prescribe warfarin appropriately to achieve target INR 2.5 for 6 weeks for isolated calf-vein deep vein thrombosis & at least 3 months for unprovoked proximal deep vein thrombosis. -Monitor INR daily or on alternate days of treatment, then at longer intervals (depending on response) then upto every 12 weeks -It is essential that the INR be determined daily or alternate days in early treatment, then at longer intervals (depending on response) then up to every 12 weeks. Date of Review: June 2017 Page 5 of 11

PRESCRIBING INFORMATION Dose Duration Monitoring Comments Daltaparin (Fragmin ) Actual Weight (kg) Dose (units) Syringe Colour 34-35 7,500 GREEN 46-56 10,000 RED 57-68 12,500 ORANGE 69-82 15,000 PURPLE Until adequate Oral Anticoagulatio n established Monitoring not required for once daily treatment Lower doses if should be considered in patients with significant liver/renal failure CrCl <30ml/min >83 18,000 WHITE Enoxaparin (Clexane ) Dosage chart for 1.5mg/kg S/C Actual Weight (kg) Dose mg & Vol. to administer (ml) Syringe Colour 35-38 55mg(0.55ml) Orange 49-41 60mg (0.6ml) 60mg/0.6ml 42-44 65mg(0.65ml) Brown 45-48 70mg(0.7ml) 49-51 75mg(0.75ml) 80mg/0.8ml Until adequate Oral Anticoagulatio n established Monitoring not required for once daily treatment Enoxaparin dose reduced to 1mg/kg ONCE DAILY in patients with renal impairment CrCl<30ml/min 52-54 80mg(0.8ml) 55-58 85mg(0.85ml) BLACK 59-61 90mg(0.9ml) 100mg/1ml 62-64 95mg(0.95ml) 65-68 100mg(1ml) 69-72 105mg(0.7ml) Mauve 73-75 111mg(0.74mg) 120mg/0.8ml 76-78 114mg(0.76ml) 79-82 120mg(0.8ml) 83-85 126mg(0.84) BLUE 86-88 129mg(0.86ml) 150mg/ml 89-92 135mg(0.9) 93-95 141mg(0.94ml) 96-98 144mg(0.96ml) 99-102 150mg(1.0ml) Warfarin Prescribe warfarin appropriately to achieve target INR 2.5 for 6 weeks for isolated calf-vein deep vein thrombosis & at least 3 months for unprovoked proximal deep vein thrombosis. 6 weeks for isolated calfvein deep thrombosis Monitor INR daily or on alternate days of treatment, Counsel Patient on anticoagulatio n with warfarin Date of Review: June 2017 Page 6 of 11

At least 3 months for unprovoked proximal deep vein thrombosis then at longer intervals (depending on response) then up to every 12 weeks fully including drug/drug and food/drug interactions. Issue patients with anticoagulatio n card and information leaflets Rivaroxaban Initial treatment 15mg twice daily with food for 21 days. Continued treatment and prophylaxis of recurrent deep vein thrombosis 20mg once daily with food Individualised after careful assessment of the treatment benefit against risk for bleeding. None Counsel Patient on anticoagulatio n fully CAUTION IN : Creatinine clearance 15-29ml/min Apixaban Initial treatment 10mg twice daily for 7 days followed by 5mg twice daily. Individualised after careful assessment of the treatment benefit against risk for bleeding. None Counsel Patient on anticoagulatio n fully CAUTION IN : Creatinine clearance 15-29ml/min Date of Review: June 2017 Page 7 of 11

SUPPORTING INFORMATION Introduction and Background Venous thrombosis is a condition in which a blood clot (thrombus) forms in a vein. Blood flow through the affected vein can be limited by the clot, causing swelling and pain in the affected limb or area. Venous thrombosis most commonly occurs in the deep veins in the legs, thighs, or pelvis. This is known as a deep vein thrombosis. An embolism is created if a part or all of the blood clot in the deep vein breaks off from the site where it is created and travels through the venous system. If the clot lodges in the lung a very serious condition, pulmonary embolism (PE), arises, which can be life threatening. Venous thrombosis can form in any part of the venous system. However, deep vein thrombosis (DVT) and PE are the most common manifestations of venous thrombosis. DVT and PE are known as venous thromboembolism (VTE). Low Molecular Weight Heparins LMWHs are used in the prevention of venous thromboembolism (prophylaxis) in patients at moderate to high risk, and are given in a low dose. LMWHs are also used in the treatment of venous thromboembolism in patients who develop a DVT or PE and are given in a higher dose. As LMWHs work very quickly, they are used concurrently with warfarin in the first few days of treatment for patients with a DVT or PE, and are continued until the INR is in the target range. Once the INR is in the target range (showing that the Warfarin is working sufficiently) then the LMWH is stopped. However, not all patients can take warfarin and therefore LMWHs are sometimes used for longer periods of time instead of warfarin. When used for prevention of DVT or PE, LMWHs are given for as long as the patient is deemed to be at high risk, and then they are stopped. Novel Oral Anti-coagulants Rivaroxaban Works as a direct inhibitor of activated factor X (Factor Xa). It is given orally for the treatment of DVT and its main advantage is its immediate action negating the need for low molecular weight Heparin (LMWH. Furthermore it does not require routine anticoagulant monitoring (INR tests are unreliable in patients taking Rivaroxaban). Rivaroxaban Contraindications Rivaroxaban is not recommended for use in children below 18 Creatinine clearance <15ml/min Pregnancy Breastfeeding Concomitant treatment with any other anticoagulants, unless switching therapy see guidance below Date of Review: June 2017 Page 8 of 11

Hypersensitivity to the active substance or to any of the excipients listed as the end of this document Avoid in liver disease with coagulopathy Active bleeding; significant risk of major bleeding (e.g. recent gastrointestinal ulcer, oesophageal varices, recent brain, spine or ophthalmic surgery, recent intracranial haemorrhage, malignant neoplasms, vascular aneurysm) Missed doses Day 1-21: If a dose is missed during Day 1-21, the patient should take Rivaroxaban immediately to ensure intake of 30mg per day. In this case two 15mg tablets may be taken at once. The patient should continue with the regular 15mg twice daily intake as recommended on the following day. Day 22 and onwards: The patient should take Rivaroxaban immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose. Renal Impairment Normal renal function Mild renal impairment Renal Function (creatinine clearance 50-80ml/min) Moderate renal impairment (creatinine clearance 30-49ml/min) Severe renal impairment (creatinine clearance 15-29ml/min) Established renal failure (creatinine clearance <15) Recommendations 15mg twice daily for 3 weeks (21days) following diagnosis then 20mg once daily thereafter No dose adjustment required 15mg twice daily for the first 3 weeks. Thereafter 20mg once daily. A reduction of the dose from 20mg to 15mg once daily should be considered if the patients assessed risk for bleeding outweighs the risk for recurrent DVT. The recommendation for 15mg use is based on PK modelling and has not been studied in a clinical setting. Rivaroxaban plasma concentrations significantly increased. Use with caution as moderate renal impairment dosing instructions. Avoid use No dose adjustments are required for body weight or the elderly. Switching Anticoagulant Therapy Converting from Vitamin K Antagonists (VKA) to Rivaroxaban VKA treatment should be stopped and Rivaroxaban therapy should be initiated once the INR <2.5 INR values will be falsely elevated after the intake of Rivaroxaban The INR is not valid to measure the anticoagulant activity of Rivaroxaban and therefore should not be used Converting from Rivaroxaban to Vitamin K Antagonists (VKA) Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. Rivaroxaban can contribute to an elevated INR VKA should be given concurrently until the INR is > 2.0 Date of Review: June 2017 Page 9 of 11

For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing While patients are on both Rivaroxaban and VKA the INR should not be tested earlier than 24hours after the previous dose but prior to the next dose of Rivaroxaban Once Rivaroxaban is discontinued INR testing may be done reliably at least 24hrs after the last dose Converting from parental anticoagulants to Rivaroxaban Discontinue the parenteral anticoagulant and start Rivaroxaban 0 to 2 hours before the time that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product. Converting from Rivaroxaban to parental anticoagulants Give the first dose of parenteral anticoagulant at the time the next Rivaroxaban dose would be taken Rivaroxaban Drug interactions Analgesics (iv diclofenac, ketorolac) Anti-arrhythmics (dronedarone) Antibacterials (rifampicin) Anticoagulants Antidepressants Antiepileptic s Antifungals Antivirals Cobicistat Increased risk of haemorrhage Avoid concomitant use Plasma concentration of Rivaroxaban reduced by rifampicin. Monitor signs of thrombosis. Avoid use Risk of bleeding avoid concomitant use except when switching Plasma concentrations of Rivaroxaban possibly reduced by St John s wort Plasma concentrations of Rivaroxaban possibly reduced by carbamazepine, phenobarbital and phenytoin Avoid concomitant use with Iitraconazole, posaconazole and voriconazole Avoid concomitant use with atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir and lopinavir. Plasma concentration of Rivaroxaban increased by ritnovir Anticoagulant effect of Rivaroxaban possibly enhanced by cobicistat Date of Review: June 2017 Page 10 of 11

References Wells PS et al. (2003) Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis British National Formulary (BNF) Ed. 68 (September 2014) BMJ Publishing Group and RPS Publishing. London Summary of product characteristics. Rivaroxaban (Xarelto ) access via: http://emc.medicines.org.uk Nice TA 261 July2012: Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and Pulmonary embolism. Date of Review: June 2017 Page 11 of 11