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Prescribing outside this formulary should only take place via a New Product Request

Prescribing Guidance: Stroke Prevention in Atrial Fibrillation: Vitamin K antagonists (VKA) and direct acting oral anticoagulants (DOAC) are effective in prevention of stroke in patients with non valvular AF. Guidance on stroke prevention in AF can be found in the NICE guidance (Atrial Fibrillation): For full NICE guidance see link below https://www.nice.org.uk/guidance/CG180 2016 ESC guidance on management of AF developed in collaboration with EACTS. https://academic.oup.com/eurheartj/article/37/38/2893/2334964/2016-ESC-Guidelines-for-the-management-of-atrial#43486436

Doncaster & Bassetlaw Medicines Formulary

Section 2.8.1: Parenteral Anticoagulants

Dalteparin 2500units and 5000units Prefilled Syringes Dalteparin 7500units, 10000units, 12500units, 15000units and 18000units Prefilled Syringes Sodium Heparin 5000units/5ml and 20,000units/20ml Injection Heparinised Saline 50units in 5ml Fondaparinux 2.5mg Injection Section 2.8.2: Oral Anticoagulants

Warfarin 1mg, 3mg and 5mg Tablets Apixaban 2.5mg and 5mg Tablets Rivaroxaban 10mg, 15mg and 20mg Tablets Section 2.8.3: Protamine

Protamine 50mg in 5ml Injection Approved by Drug and Therapeutics Committee: May 2017 Review Date: May 2020

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Before commencing a patient on anticoagulation for stroke prevention it is essential all the baseline investigations are completed (U&E, LFT, Clotting, renal function and BP). It is also important to assess the patients’ risk of stroke and bleeding risks using the CHA2DS2VASc and HASBLED scoring systems and that any contra-indications to anticoagulation have been excluded. The most appropriate anticoagulant should then be selected for the patient taking into consideration patient choice, interacting medication, compliance, renal function etc The Sheffield Guidance on Anticoagulation in Stroke prevention in Non Valvular AF is a useful tool to help you make these choices. The anticoagulant should then be discussed with the patient and as a minimum should include

Options and differences between them

Stroke and bleeding risk

Monitoring

Dosing

What to do if doses missed

Side effects

What to do in event of bleeding/injury

How long anticoagulation will be needed

Patient information leaflets and cards In deciding on best option for your patient the following should be noted

Apixaban is the first line formulary choice of DOAC for patients with Non Valvular AF however others agreed by NICE are available to use on consultant recommendation when evidence, interactions, patent factors deem them to be more suitable on an individual patient basis. The recommended dose of apixaban for the prevention of stroke and systemic embolism in patients with non valvular AF is 5mg twice daily, reduced to 2.5mg twice daily in patients with at least two of the following characteristics: Age ≥ 80 years Weight ≤ 60kg Serum Creatinine ≥ 133micromol/l It should be noted that DOACs are used in a range of different doses depending on the indication. Prescribers should ensure they select the appropriate dosing regime for the patient concerned based on their indication, renal function etc

In patients with renal impairment CrCL <30ml/min warfarin is generally the first line agent (however apixaban can be used at a reduced dose

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of 2.5mg bd if crcl 15-30ml/min-ensure increased monitoring of renal function). Apixaban must not be used if Crcl<15ml/ min. A creatinine clearance can found on the antimicrobial resource site: http://dbhintranetapps/forms/creatinine_clearance.html

In meta-analysis DOACs have been shown to reduce the risk of stroke by 19% compared to warfarin mainly driven by a reduction in the risk of haemorrhagic stroke. Mortality was also 10% lower in the DOAC group.

VKA’s are currently the only oral treatment with established safety in AF patients with rheumatic mitral valve disease and/or a mechanical heart valve prosthesis.

In extremes of body weight (<50kg or >130kg) warfarin may be considered the oral anticoagulant of choice as efficacy and risk of bleeding can be monitored more easily.

It is sometimes necessary to co-prescribe antiplatelet therapy in patients requiring long term anticoagulation. Guidance on this is available in section 2.9 of the formulary and is covered in more detail in the ESC guidance from 2015. The results from the PIONEER AF study may also help guide treatment of patients with ACS and AF-see section 2.9

Patients with poor concordance may be at a greater risk of thromboembolic complications with DOACs as the shorter half-lives of these agents compared to warfarin will potentially result in more time without any degrees of anticoagulation should a dose be missed. Such patients may be better continuing on warfarin.

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Prescribing outside this formulary should only take place via a New Product Request

Treatment of DVT and PE

Guidelines covering antithrombotic therapy in treatment of VTE can be found Trust guidance on the treatment of VTE (PAT/T 44 V3) https://www.dbth.nhs.uk/document/patt44v3/ Journal of Thrombosis and Thrombolysis 2016. Guidance for the treatment of DVT and PE https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715858/ CHEST Guideline for antithrombotic Therapy in VTE-11 key points from ACC http://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/03/02/15/45/antithrombotic-therapy-for-vte-disease NICE Venous thromboembolic disease https://www.nice.org.uk/guidance/cg144 ESC Guidance on treatment of acute PE https://academic.oup.com/eurheartj/article/35/43/3033/503581/2014-ESC-Guidelines-on-the-diagnosis-and The trust guidance on treatment of DVT and PE should be followed and the appropriate IPOC used to guide your treatment.

The choice of anticoagulant should be discussed with the patient and as a minimum should include

Options and differences between them

Bleeding risk

Monitoring

Dosing

What to do if doses missed

Side effects

What to do in event of bleeding/injury

How long anticoagulation will be needed

Patient information leaflets and cards The Sheffield guidance detailed above is a useful tool to help in deciding on appropriate choices of anticoagulation In deciding on best option for your patient the following should be noted

Rivaroxaban is the first line formulary choice of DOAC for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults however others agreed by NICE are available to use on consultant recommendation when evidence, interactions, patent factors deem them to be more suitable on an individual patient basis. It should however be noted that

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apart from rivaroxaban and apixaban the other DOACS currently require 5 days treatment of parenteral anticoagulation before commencing treatment.

Rivaroxaban Dosing Schedule: 15mg twice daily for three weeks with food followed by: 20mg once daily with food for the remainder of the treatment period. The hospital will provide the first four weeks of medication, the GP will provide ongoing prescriptions as necessary. In patients with CrCl 30-50ml/min consideration should be given to reducing the daily dose (day 22 onwards) to 15mg daily if the patients risk of bleeding outweighs the risk of recurrence. However for practical reasons it would be more appropriate to consider switching to apixaban or warfarin in this patient group It should be noted that DOACs are used in a range of different doses depending on the indication. Prescribers should ensure they select the appropriate dosing regime for the patient concerned based on their indication, renal function etc

In those patients were treatment beyond 6 months is anticipated it may be appropriate to decrease the rivaroxaban dose to 10mg daily. This dose reduction would not be appropriate in higher risk patients such as those with bilateral, massive or recurrent PE. Supporting evidence is available via http://www.nejm.org/doi/full/10.1056/NEJMoa1700518 Apixaban is also licensed for the prophylaxis of recurrent DVT/PE after completion of 6 months treatment at a dose of 2.5mg twice daily.

In patients with renal impairment CrCL <30ml/min warfarin is generally the first line agent (A creatinine clearance can found on the antimicrobial resource site: http://dbhintranetapps/forms/creatinine_clearance.html)

In general in the treatment of VTE not associated with cancer DOACS tend to be used first line however each decision needs to be made on an individual patient basis.

VKA’s are currently the only oral treatment with established safety in patients with rheumatic mitral valve disease and/or a mechanical heart valve prosthesis should this condition co-exist

In extemes of body weight (<50kg or >130kg) warfarin may be considered the oral anticoagulant of choice as efficacy and risk of bleeding can be monitored more easily.

It is sometimes necessary to co-prescribe antiplatelet therapy in patients requiring long term anticoagulation. Guidance on this is available in section 2.9 of the formulary and is covered in more detail in the ESC guidance from 2015.

Patients with poor concordance may be at a greater risk of thromboembolic complications with DOACs as the shorter half-lives of these agents compared to warfarin will potentially result in more time without any degrees of anticoagulation should a dose be missed. Such patients may be better continuing on warfarin.

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Prescribing outside this formulary should only take place via a New Product Request

In patients with recurrent VTE despite anticoagulation higher intensity anticoagulation with warfarin at a higher INR or with LMWH may be more appropriate than treatment with a DOAC.

In patients with active cancer LMWH treatment with dalteparin would be the most appropriate choice of anticogaulant

In those on indefinite anticoagulation an annual review should occur which considers the ongoing risk of a event compared to the risk of bleeding for individual patients

When stopping anticoagulation for an unprovoked DVT or PE consideration should be given to the use of aspirin or utilising a lower evidenced based dose of DOAC (apixaban or rivaroxaban)

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Prescribing outside this formulary should only take place via a New Product Request

Warfarin The usual loading dose is 10mg given at 6pm daily for two days and 5mg at 6pm on the third day, maintenance doses are adjusted according to the reported INR. Loading doses may vary depending on the clinical needs of the patient and interacting agents. Prescribers should be familiar with the following guidance Inpatient Anticoagulant Guidelines, a Guideline for Management of Over-Anticoagulation and Guidance on use of Beriplex are available. The following INR range is recommended by the British Committee for Standards in Haematology:

Prophylaxis of DVT; INR 2 to 2.5

Treatment of DVT, PE; prophylaxis of DVT in hip surgery, fractured femur, mitral stenosis with embolism, TIA, atrial fibrillation, extensive anterior MI’s; INR 2 to 3

Recurrent DVT or recurrent pulmonary embolism; INR 3 to 4.0 An e-prescribing user guide is available for Warfarin prescribing via the intranet. It should also be noted that when warfarin is used in the treatment of DVT/PE that at least 5 days treatment with parenteral therapy (usually LMWH) is needed and the INR must be greater than 2 for at least 24 hours before the parenteral therapy is discontinued.

Dalteparin – treatment dose

Patient weight is used as the basis for calculating the treatment dose of dalteparin and should be accurately recorded on the prescription. Dalteparin should be prescribed, with the first dose administered as soon as a diagnosis of probable DVT/PE is made. EXCEPT:

when there is a contraindication to dalteparin therapy (see below)

in acute massive PE in which there is insufficient evidence for its use. Here, alteplase may be appropriate followed by IV unfractionated heparin (IV UFH).

Dosing Table – Treatment of Venous Thromboembolism (VTE): Note: in significant renal impairment*, use unfractionated heparin.

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Prescribing outside this formulary should only take place via a New Product Request

For dosing in obesity – see Dalteparin Dosing Table. For dosing in pregnant patients – see Maternity Service Guidelines No 20.

Body Weight (kg) Daily Dose (units) Syringe Colour

<46 7,500 Green

46-56 10,000 Red

57-68 12,500 Brown

69-82 15,000 Purple

>83 18,000 Grey-Blue

*Significant renal impairment is defined as those with a calculated eGFR less than 20ml/min or those with evidence of acute kidney injury (oliguria over 12 hours or doubling of serum creatinine). Click here to access the online eGFR calculator In liver failure, significant accumulation may occur – specialist advice (from a consultant haematologist and/or gastroenterologist) should be sought and consideration given to IV UFH. Where IV unfractionated heparin is used it should be given as indicated on the procedure outlined on the heparin prescription chart. If Warfarin is to be used as the oral anticoagulant (see guidance below) it should be started once the diagnosis of DVT or PE is confirmed and should be given once daily (at 6.00pm). Dalteparin should be continued for at least five days and until the INR is 2 or more for at least 24 hours, whichever is the longer. In the extended treatment and prophylaxis of VTE in those with solid tumours, continuing dalteparin should be prescribed. After 30 days at the doses above, the dose should be reduced as below:

Body Weight (kg) Daily Dose (units) Syringe Colour

40-56 7,500 Green

57-68 10,000 Red

69-82 12,500 Brown

>83 15,000 Purple

A shared care protocol for dalteparin can be found via the Doncaster PCT Medicines Management website (see shared care protocols in the left hand column and choose the DBHFT protocol as there are differences in protocol over at Sheffield Teaching Hospitals).

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Prescribing outside this formulary should only take place via a New Product Request

Monitoring Requirements when using Heparin or Dalteparin

Platelet count should be monitored at baseline and weekly thereafter. Development of heparin-induced thrombocytopenia does not usually occur until after 6 to 10 days. In patients whose platelet count falls by 50% compared to baseline, heparin should be stopped. Baseline clotting screens are useful if there is a major medical illness or a coagulopathy anticipated. Hyperkalaemia may occur via heparin-induced inhibition of aldosterone secretion. Potassium levels should be monitored at baseline and weekly thereafter in patients at risk of heparin-induced hyperkalaemia. These patients include those with diabetes mellitus, chronic renal impairment and pre-existing metabolic acidosis.

Risk Factors for Bleeding:

• Acute stroke in previous month (haemorrhagic or ischaemic) • Untreated inherited bleeding disorders (such as haemophilia and von Willebrand’s disease)

• Uncontrolled systolic hypertension (230/120 mmHg or higher)

• Severe liver disease (prothrombin time above normal or known varices) • Major bleeding risk, existing anticoagulant therapy • Lumbar puncture/epidural/spinal anaesthesia within the previous 4 hours or next 12 hours.

• Thrombocytopenia (platelets less than 75 x 109/l)

• Active bleeding • Neurosurgery, spinal surgery or eye surgery

Prophylaxis of Venous Thromboembolism

Dalteparin should be prescribed at 6.00pm, where indicated, until the patient is fully mobile. The dose is 5000units daily (usually at 6pm in the evening), although those with significant renal impairment* or weighing less than 46kg should be prescribed 2500units. For dosing in obesity – see Dalteparin Dosing Table. For dosing in pregnant patients – see Maternity Service Guidelines No 20. *Significant renal impairment is defined as those with a calculated eGFR less than 20ml/min or those with evidence of acute kidney injury (oliguria over 12 hours or doubling of serum creatinine). Click here to access the online eGFR calculator

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Prescribing outside this formulary should only take place via a New Product Request

The timing of dalteparin in relation to the insertion of an epidural catheter for epidural/spinal analgesia is critical. The epidural catheter must be removed/inserted 12 hours after the last prophylactic dose of dalteparin (and four hours should be left before administering further doses). For prophylaxis of VTE in orthopaedic patients, see attached guideline. For extended prophylaxis in patients undergoing bowel resection, a 28 day supply of dalteparin will be issued on discharge.

Heparin Flushes

Lumens in continuous or daily use do not usually require flushing to maintain patency, but a ‘Saline-Additive-Saline’ method should be employed during any administration of an additive. Long-term central intravenous catheters used for intermittent drug administration (such as Hickman lines) should be locked weekly with 5ml of heparin 50unit/5ml (e.g. Hepsal/Heplock) when not in daily use. In other situations where a central lumen may be anticipated not to be in continuous or daily use, heparin 50units/5ml may be used to flush the line and lock the line. In all circumstance the use of the flush must be documented by being

prescribed prior to administration or, documented in the patients’ clinical record if the flush is

administered by the prescriber who initiates therapy.

Administration of heparin should be checked in accordance with the Policy for the Safe and Secure Handling of Medicines (PAT/ MM1). Within the Trust these heparin products are only be available as stock for use in Chatsfield suite, ward 18, critical care areas and theatres.

Management of Acute Coronary Syndromes

Fondaparinux is now the antithrombin therapy of choice for this indication – see Fondaparinux Prescribing Guide.

See also ESC guidance for ACS in patients presenting without persistent ST segment elevation and local Thrombolysis Checklist.

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Intravenous Therapeutic Dose Heparin Guidelines for Adults

Therapeutic range for APTT ratio is 1.5 to 2.5 Indications for Therapeutic Intravenous Heparin Infusion include:

As adjunctive therapy to fibrin specific thrombolytic (tenecteplase) in the treatment of ST Elevation Myocardial Infarction (STEMI)

As adjunctive therapy to tirofiban in the treatment of Acute Coronary Syndrome (ACS)

As adjunctive therapy to alteplase in the treatment of Pulmonary Embolism (PE)

In situations where therapeutic anticoagulation with heparin is required but Low Molecular Weight Heparin is unsuitable (e.g. in significant impairment see formulary guidance)

In patients on oral anticoagulants for a recent (within one month) venous/arterial thromboembolic event undergoing surgery

Acute embolic event Adult Loading Dose: 5000units* Sodium Heparin by IV bolus Maintenance Dose: Dosage is based on body weight at 20units/kg/hr* Always use Sodium Heparin at a concentration of 25,000units made up to 50ml with Sodium Chloride 0.9% Suggested starting rates:

Patient weight Heparin required Flow rate (Heparin Sodium 25,000units made up to 50ml with Sodium Chloride 0.9%)

40 kg 800 units/hr 1.6 ml/hr

50 kg 1000 units/hr 2 ml/hr

60 kg 1200 units/hr 2.4 ml/hr

70 kg

1400 units/hr 2.8 ml/hr

80kg or more 1600 units/hr 3.2ml/hr

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*Use in Combination with Tenecteplase For patients weighing 67kg or less an initial intravenous bolus of 4000 units is recommended followed initially by 800 units per hour as an intravenous infusion. For patients weighing more than 67kg, an initial intravenous heparin bolus of 5000 units is recommended followed initially by 1000 units per hour as an intravenous infusion. MONITOR On initiation of infusion, check the APTT RATIO after 4 to 6 hours. Thereafter check the APTT RATIO DAILY (to keep between 1.5 and 2.5) and adjust as shown in the table below according to APTT ratio ADJUSTMENT OF I.V. HEPARIN DOSE

APTT RATIO INFUSION RATE CHANGE

> 7 STOP FOR 30 min – 1 hr and reduce by 500 units/hr (1 ml / hr) 5.1 – 7.0 Reduce by 500 units/hr ( 1 ml / hr ) 4.1 – 5 Reduce by 300 units/hr ( 0.6 ml / hr ) 3.1 – 4 Reduce by 100 units/hr ( 0.2 ml / hr ) 2.6 – 3 Reduce by 50 units/hr ( 0.1 ml / hr ) 1.5 – 2.5 NO CHANGE 1.2 – 1.4 Increase by 200 units/hr ( 0.4 ml / hr ) < 1.2 Increase by 400 units/hr ( 0.8 ml / hr )

After each change wait about 10 hours before next APTT unless ratio is greater than 5 when checks should be made every 4 hours. The full blood count must be checked every week when a patient is on any kind of heparin therapy as there can be a rare but unpredictable development of heparin antibodies with life-threatening thrombocytopenia.

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Protamine

Haemorrhage due to excess heparin is usually treated by stopping the heparin. Protamine is only used when rapid reversal is required, 1mg neutralises 100units of heparin. For an estimation of likely amount of heparin on board if given as an infusion divide the total dose of heparin given in the last 6 hours by 2. A maximum dose of 50mg of protamine can be given by slow IV bolus. Patients with bleeding after receiving treatment doses of dalteparin should receive a single dose of protamine 40mg IV given over 10 minutes, to be repeated once one hour later, if severe bleeding continues. Anti Xa level probably does not contribute in this situation – the effect of treatment should be monitored by the cessation of bleeding. In overdose, protamine can cause bleeding. Management of Bleeding in Patients taking DOACS.

Beriplex is used for the emergency treatment of life-threatening haemorrhage in patients taking oral anticoagulants. Please seek advice from the Consultant Haematologist on call if there is any doubt regarding its use

If Beriplex is to be administered for an indication other than major bleeding on a vitamin K antagonist, then the patient must be discussed with the Consultant Haematologist on call.

For patients on dabigatran a specific reversal agent (idarucizumab) is now available and may be preferred over beriplex in patients admitted on dabigatran needing urgent reversal – seek Consultant haematologist advice

See guidance on beriplex and on management of overanticoagulation for further details

Following discussion with a Consultant Haematologist, Beriplex should be administered as per the protocol below.

Beriplex and Novoseven

Protocols for the use of Beriplex and Novoseven are available.

Bridging Anticoagulation

For peri-operative management of patients on oral anticoagulants, see here.