Discuss the relative risks and benefits of warfarin and direct-acting oral anticoagulants (DOACs) with patients, with particular reference to the level of INR control.

Categories of patients in whom DOACs may be a useful option:

1. People not taking warfarin because of allergy or intolerance, or where routine INR monitoring may be impractical (monitoring of renal and/or liver function is still required).
2. People currently taking warfarin who, despite evidence of good compliance with medication and monitoring, have poor anticoagulant control.*
   1. Patients should be reviewed individually, taking into consideration their time in the therapeutic range (TTR) on warfarin, to decide whether a DOAC would be an appropriate option. Measures known to improve TTR (such as self-testing or self-management, using a NICE-recommended point-of-care device such as Coaguchek® or INRatio2 PT/INR®) may be the preferred option for some people
   2. Poor anticoagulant control is defined in the NICE AF Clinical Guideline CG180 . NICE recommends that anticoagulant quality is reviewed at least annually.
   3. When reassessing anticoagulation with warfarin, take into account and if possible address the following factors that may contribute to poor anticoagulation control:
      • cognitive function
      • adherence/compliance to prescribed therapy. The yellow NPSA Oral Anticoagulant Therapy information pack may be used to support patient education in patients prescribed warfarin.
      • illness
      • interacting drug therapy
      • lifestyle factors including diet and alcohol consumption
      • access to monitoring, consider domiciliary monitoring for those who cannot travel
   4. Under-anticoagulation due to compliance problems may be more of a concern with a DOAC than with warfarin, given DOACs' much shorter half-life. The dose regimen (irrespective of treatment chosen) should be as simple as possible.
3. People at risk of drug interactions.
   1. A DOAC may be useful where concomitant medication increases the risk of interaction with warfarin.
   2. The main interactions of the DOACs are with P-gp inhibitors and inducers, (refer to BNF/SPC). They should either be avoided or where appropriate, have the dose reduced. Where there is caution or uncertainty about an interaction, the ability to monitor and adjust the warfarin dose based on the INR may make it the preferable anticoagulant.
   3. Always refer to the manufacturers SPC and BNF for specific interactions.
4. People who have never taken warfarin.
   1. Patients are not obliged to have a trial of warfarin but prescribers and patients may feel that a well-established drug may be a more appropriate choice.
   2. Patients with stable, good INR control (an annual TTR of greater than 65%) are much less likely to gain any clinical benefit by switching from warfarin to a DOAC. However the NICE guidance states that even people with very good control should not be refused a DOAC as a potential treatment option. Local expert opinion would be that this category would not be a priority for active switching.

Warfarin may be the preferred option for people who have an eGFR less than 30 mL/min/1.73m².

Patients assessed through the Derriford DVT clinic, acute GP service and Haemostasis clinic, or Torbay hospital DVT clinic will receive initial treatment, the choice of which will depend on individual suitability. If a DOAC is prescribed the clinic will provide the first three weeks of the twice daily dosing regime and then bring the patient back at day 21 for a week of the daily regime. There will then be a communication to the GP requesting that they take over the prescribing.

*National Patient Safety Alert (14 July 2021): Inappropriate anticoagulation of patients with a mechanical heart valve: All patients with prosthetic mechanical heart valves require life-long oral anticoagulation with a vitamin K antagonist (VKA), usually warfarin, and should not be switched to an alternative anticoagulant (e.g. low molecular weight heparin or DOAC)

*NHS England: Management of anticoagulant services during the Coronavirus (COVID-19) pandemic: page 4 includes patient groups who should not be considered for switching from warfarin to DOACs

Dosing regimen guidance can be viewed under the individual drug monographs – see here

Monitoring

• With all the DOACs drug accumulation can occur with impaired renal function.
• Renal function should be checked prior to initiation and monitored when necessary, such as when other drugs with renal effects are introduced or altered, or with dehydration/vomiting/diarrhoea.
• Renal function should be monitored at least annually in patients older than 75 years and in those with renal impairment.
• Liver function may need to be checked prior to initiation and periodically during ongoing treatment. Please refer to individual product SmPCs for more info.

DOACs are associated with increased risk of serious haemorrhage in patients with renal impairment. Assessment of renal function for DOAC use should be based upon creatinine clearance calculated using the Cockcroft-Gault formula.

MHRA Drug Safety Update (October 2019): Using the appropriate estimate of renal function to avoid the risk of adverse drug reactions

Since eGFR is normalised to a standard body surface area (BSA) of 1.73m², there is the potential for under, or over-dosing patients at extremes of body weight (BMI of less than 18.5 kg/m² or greater than 30 kg/m²). This is particularly important for people with reduced muscle mass, including the frail, elderly, or critically ill. Use the Cockcroft-Gault formula to calculate creatinine clearance for determining dose adjustment for DOACs for patients with renal impairment. In all DOAC studies renal function has been expressed in terms of CrCl, no dose recommendation can be made in terms of eGFR.

The Cockcroft & Gault formula:

Estimated Creatinine Clearance (mL/minute) = (140 – Age_yrs) x *Mass_Kg x Constant^# / Serum Creatinine

*Weight (mass) - use actual body weight in the calculation. (In underweight patients, actual body weight should still be used. In overweight patients, ideal body weight should be used)

^#Constant= 1.23 for men, 1.04 in women

The Specialist Pharmacy Service (SPS) and local specialist renal teams recommend the use of a web based application such as MDCalc where actual bodyweight is used to calculate the Cockcroft-Gault CrCl. If height is added the different methods of adjusting for weight can be seen, providing a range of possible values for CrCl.

Where these results cross or are close to a CrCl level that may require a dose change, this can support the clinician making a dosing decision.

For dose adjustments required in renal impairment, refer to individual drug entries:

• Apixaban
• Dabigatran
• Edoxaban
• Rivaroxaban

From warfarin to DOAC

• Apixaban: discontinue warfarin. Start apixaban when INR is below 2.0
• Dabigatran: discontinue warfarin. Start dabigatran once INR is below 2.0
• Edoxaban: discontinue warfarin. Start edoxaban once INR is 2.5 or below
• Rivaroxaban: discontinue warfarin. Start rivaroxaban once INR is 2 to 3.

National Patient Safety Alert (14 July 2021): Inappropriate anticoagulation of patients with a mechanical heart valve: All patients with prosthetic mechanical heart valves require life-long oral anticoagulation with a vitamin K antagonist (VKA), usually warfarin, and should not be switched to an alternative anticoagulant (e.g. low molecular weight heparin or DOAC)

NHS England: Management of anticoagulant services during the Coronavirus (COVID-19) pandemic: page 4 includes patient groups who should not be considered for switching from warfarin to DOACs

From low molecular weight heparin (LMWH) to DOAC

• Apixaban: Stop LMWH. Start apixaban at the time of the next scheduled LMWH dose. They should not be administered simultaneously.
• Dabigatran: Stop LMWH. Start dabigatran 0-2 hours before the next due dose time of LMWH, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH))
• Edoxaban: Stop LMWH. Start edoxaban at the time of the next scheduled dose of LMWH. Where unfractionated heparin infusion being used, stop infusion and wait four hours before starting edoxaban
• Rivaroxaban: Stop LMWH. Start rivaroxaban 0-2 hours before the next due dose time of LMWH, or at the time of discontinuation in case of continuous treatment (e.g. intravenous unfractionated Heparin (UFH))

From DOAC to Warfarin

• Apixaban: Continue apixaban for at least 2 days after starting warfarin. Check INR prior to the next scheduled dose of apixaban; continue apixaban until the INR reaches at least 2.0
• Dabigatran: It may increase INR; readings will be unreliable until dabigatran has been stopped for at least 2 days; interpret values with caution. Adjust the starting time of the warfarin based on CrCl as follows:
  • CrCl above 50 mL/min: discontinue dabigatran 3 days after starting warfarin
  • CrCl 30-50 mL/min: discontinue dabigatran 2 days after starting warfarin
• Edoxaban: Reduce dose from 60mg daily to 30mg (or from 30mg to 15mg if patient was on the reduced dose) once daily when commencing warfarin.
  • Discontinue edoxaban once INR reaches 2 or more; if this is not reached by day 14, stop edoxaban and continue titrating warfarin to achieve an INR between 2 and 3.
  • Do not give a loading dose of warfarin to promptly achieve a stable INR between 2 and 3.
  • Check INR at least 3 times during first 14 days just before edoxaban is given to minimise the effect on INR (edoxaban can increase post-dose INR by up to 46%).
• Rivaroxaban: Continue rivaroxaban for at least 2 days after starting warfarin. Check INR before next scheduled rivaroxaban dose; continue with rivaroxaban until INR reaches at least 2.0

Patients should be aware of the risks and benefits of anticoagulation and should be advised to carry an appropriate anticoagulant alert card. Cards are available for each non-vitamin K oral anticoagulant, and can be obtained from the individual manufacturers:

• Apixaban: (Bristol-Myers Squibb)
  • Telephone 0800 7311736 (Medical Information)
  • Email medical.information@bms.com
  • Download from www.eliquis.co.uk/hcp/resources-for-your-patients/patient-information-booklets
• Dabigatran: (Boehringer Ingelheim)
  • www.pradaxa.co.uk
• Edoxaban: (Daiichi Sankyo UK Limited)
  • Alert card provided in dispensed pack
  • Telephone 0800 028 5122
  • Email medinfo@daiichi-sankyo.co.uk
• Rivaroxaban: (Bayer HealthCare)
  • Telephone 01635 563116 (Medical Information)
  • Email medical.information@bayer.co.uk
  • Download from www.xarelto-info.co.uk

Advise patients to omit their anticoagulant medication and seek medical advice in the event of haemorrhage or significant acute illness. Ensure patients and carers keep a copy of the patient information leaflet.

Missed doses

• Apixaban, edoxaban or rivaroxaban: Forgotten dose should be taken immediately and then continued as normal with the next scheduled dose. No double doses should be taken.
• Dabigatran: Forgotten dose may still be taken up to 6 hours prior to the next scheduled dose, after this point the missed dose should be omitted. No double doses should be taken.

Overdose

• Oral activated charcoal if within 2 hours of ingestion.
• Dabigatran can be dialysed
• An agent to rapidly reverse the anticoagulant effect of dabigatran is available, if required – see "Major bleeding (cerebral or GI)" below

Determining the time since last dose of therapy is vital as interruption of treatment may be sufficient. The estimated time for restoration of haemostasis after cessation of therapeutic doses with adequate renal function is usually within 12 hours for dabigatran and apixaban, and 24 hours for rivaroxaban and edoxaban.

Initiate resuscitation with compression, IV fluids, blood transfusion and other supportive measures as necessary.

Check FBC, U&E's and a coagulation screen (PT, Thrombin Time and APTT). A normal Thrombin Time can be used to exclude any clinical relevant level of dabigatran. However, a normal PT or APTT cannot be used to rule out a therapeutic concentration of the factor Xa inhibitors rivaroxaban, apixaban or edoxaban.

Antidote

An agent to rapidly reverse the anticoagulant effect of dabigatran (idarucizumab [Praxbind] as a single 5g bolus injection) is available.

Dried prothrombin complex (4-factor prothrombin complex concentrate, PCC) may reverse the effect of the factor Xa inhibitors and may be considered (at a dose of 50 IU/kg), but there is very limited clinical experience with its use in patients taking new oral anticoagulants.

MHRA Drug Safety Update (October 2013, September 2016) New oral anticoagulants apixaban, dabigatran and rivaroxaban: risk of serious haemorrhage.

The following contraindications now apply to all DOACs, for all doses and indications:

• A lesion or condition, if considered a significant risk factor for major bleeding. This may include:
  
  • current or recent gastrointestinal ulceration
  • presence of malignant neoplasm at high risk of bleeding
  • recent brain or spinal injury
  • recent brain, spinal, or ophthalmic surgery
  • recent intracranial haemorrhage
  • known or suspected oesophageal varices
  • arteriovenous malformation
  • vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities
• Concomitant treatment with any other anticoagulant agent—e.g unfractionated heparin, low molecular weight heparin (such as enoxaparin or dalteparin), heparin derivatives (such as fondaparinux), or oral anticoagulants (such as warfarin). Exceptions are switching of therapy to or from the medicine, or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter

Additional advice and information for healthcare professionals:

• Special care should be taken when deciding to prescribe these anticoagulant medicines to patients with other conditions, procedures, and concomitant treatments (e.g non-steroidal anti-inflammatory drugs, antiplatelets), which may increase the risk of major bleeding
• Attention should be paid to renal function. Impaired renal function may constitute a contraindication or recommendation not to use the anticoagulant medicine, or may require a dose reduction; recommendations differ for the three medicines
• The contraindications, posology, and warnings and precautions for use specific to each medicine, together with the individual's risk factors for bleeding (e.g renal function), should be considered before prescribing these medicines

Please consult the product information for advice on treatment in the event of bleeding complications, or overdose.

Pregnancy

Women are advised to avoid pregnancy if taking a DOAC

Breast-feeding

Apixaban: Not recommended (secreted into breastmilk)

Dabigatran: Discontinue breastfeeding if taking dabigatran (clinical safety not established)

Edoxaban: Contraindicated. (Secreted into breastmilk; women should consider whether to stop breastfeeding or stop treatment)

Rivaroxaban: Contraindicated in breastfeeding (secreted in breastmilk).

If possible, wait 12 hours (dabigatran) or 24 hours (rivaroxaban, edoxaban and apixaban) after the last dose.

Guidance only, targets and durations should be determined based on individual cases

2.5 (Range 2 – 3)

• Treatment of DVT or PE
• Recurrent VTE whilst off warfarin
• Prophylaxis of stroke in AF
• Cardioversion
• VTE in antiphospholipid syndrome
• Dilated cardiomyopathy
• Mural thrombus following MI or mitral valve disease
• Prosthetic aortic valve (target 2.5 or 3.0)

3.5 (Range 3 – 4)

• Recurrent DVT or PE occurring in patients who were already anticoagulated with INR above 2
• Prosthetic mitral valves (target 3.0 or 3.5)
• Arterial thrombosis in antiphospholipid syndrome

Almost any drug can interact with warfarin. Monitor INR closely when new drugs are started or discontinued.

• Assume all newly prescribed drugs interfere with warfarin control
• Check INR within 3 to 4 days of starting or stopping other drugs
• Be very cautious about prescribing anti-platelet drugs and NSAIDS with warfarin. If antiplatelet drugs are to continue with warfarin this decision must be clearly documented in the medical notes and on the drug chart for inpatients
• Many antibiotics are a common contributing factor to increased INR. Monitor INR closely

Drugs enhancing effect (increase INR)

• Alcohol, anabolic steroids, allopurinol, amiodarone, most antibiotic (particulary erythromycin, clarithromycin & ciprofloxacin), aspirin and other NSAIDs, clopidogrel, dipyridamole, statins, antidepressants, antidiabetics, phenytoin, tamoxifen, levothyroxine, azole antifungals, cranberry juice

Drugs reducing effect (reduce INR)

• Barbiturates, carbamazepine, rifampicin, rifabutin, oral contraceptives, some herbal remedies (e.g. St John's Wort)

Drugs which may enhance or reduce effect

• Phenytoin, corticosteroids, colestyramine

General practitioners may initiate warfarin in the community, usually in older patients with atrial fibrillation, when urgent anticoagulation is not required. This guideline is only intended for initiating warfarin over several weeks in non-acute situations.

Important notes about the guideline

• It is based on a validated protocol for similar patients being warfarinised in a hospital outpatient clinic (Oates et al. A new regimen for starting warfarin therapy in outpatients. Br J Clin Pharm 1998;46:157-161)
• It is intended to give an INR of 2.0-3.0 at 6 weeks. Patients with an INR target outside this range may still begin anticoagulation in this way with further adjustments made after 6 weeks
• INRs are only required at weekly intervals
• The dose of warfarin only changes if the INR is greater than 3.0 or persistently less than 2.0
• The INR at day 14 predicts the maintenance dose – any subsequent changes are based on routine INR checks at days 21, 28, 35 and 42
• Once the INR is stable, the time between monitoring can be increased to 2, then 4, and eventually 12 weeks as recommended by the British National Formulary
• Patients should have their liver function tests [including prothrombin time], urea and electrolytes, creatinine and full blood count measured prior to treatment
• Patients should always be provided with a treatment booklet containing appropriate information about safe use of warfarin

Anticoagulation urgency?

Urgent - seek specialist advice

Non-urgent, warfarin sensitivity likely?

• Interacting drugs (see Drug interactions with warfarin above)
• Liver disease - abnormal liver function or raised PTR
• Other diagnoses - heart failure, low weight, age >80
• Alcohol intake high - raised GGT

If concerned about sensitivity, consider more frequent monitoring or start at lower dose. Consider seeking specialist advice.

Non-urgent, warfarin sensitivity unlikely?

Check INR at days 21, 28, 35 and 42.

Dose adjustment (days 21 - 42)

• INR 1.4 or less - increase dose by 1mg

2 weeks in a row

• INR 1.5-1.9 - increase dose by 0.5mg
• INR 2.0-3.0 - same dose
• INR 3.1-3.5 - reduce dose by 0.5mg
• INR 3.6-4.0 - reduce dose by 1mg
• INR 4.1 or more - stop warfarin for 2 days and reduce dose by 1mg (consider seeking advice)

Once INR is stable, probably weeks 4-6, increase the time between monitoring for 2, then 4 and eventually to 12 weeks

Cautionary Notes

• Check clotting screen, FBC, renal and liver function before starting anticoagulants
• If anticoagulation is urgent, start heparin (usually LMWH) at treatment doses, with warfarin. Give heparin for at least 5 days and until INR has been in therapeutic range for 2 consecutive days
• Use reduced dose loading schedule for AF or if risk factors for bleeding: abnormal baseline clotting, platelets less than 50x10⁹, low body weight (female less than 50kg, male less than 60kg), age over 60, congestive cardiac failure, abnormal LFTs, renal impairment and interacting drugs
• For new patients being loaded on anticoagulant, request daily INRs for the first 4 days
• For AF in the community consider giving 2mg daily and check INR in 4-7 days, see slow induction regimen below

Monitoring INR; in early days of treatment it is essential to determine INR daily or on alternate days, then at longer intervals (depending on response), then up to every 12 weeks.

The main adverse effect of all oral anticoagulants is haemorrhage. The following recommendations (which take into account the recommendations of the British Society for Haematology) are based on the result of the INR and whether there is major or minor bleeding; the recommendations apply to patients taking warfarin:

• Major bleeding: Stop warfarin; give phytomenadione (vitamin K1) 5mg by slow intravenous injection; give dried prothrombin complex (factors II, VII, IX, and X—section 2.11) 25–50 units/kg (if dried prothrombin complex unavailable, fresh frozen plasma 15 mL/kg can be given but is less effective); recombinant factor VIIa is not recommended for emergency anticoagulation reversal
• INR above 8.0 and minor bleeding: stop warfarin; give phytomenadione (vitamin K1) 1–3mg by slow intravenous injection; repeat dose of phytomenadione if INR still too high after 24 hours; restart warfarin when INR below 5.0
• INR above 8.0 with no bleeding: stop warfarin; give phytomenadione (vitamin K1) 1–5 mg by mouth using the IV preparation (unlicensed use); repeat dose of phytomenadione if INR still too high after 24 hours; restart warfarin when INR below 5.0
• INR 5.0–8.0 with minor bleeding: stop warfarin; give phytomenadione (vitamin K1) 1–3 mg by slow intravenous injection; restart warfarin when INR less than5.0
• INR 5.0–8.0 and no bleeding: withhold 1 or 2 doses of warfarin and reduce subsequent maintenance dose
• Unexpected bleeding at therapeutic levels: always investigate possibility of underlying cause e.g. unsuspected renal or gastro-intestinal tract pathology

Primary care management of dental patients on oral anticoagulation

• The risk of significant bleeding in patients on oral anticoagulants and with a stable INR below 4 is very small and the risk of thrombosis may be increased in patients in whom anticoagulants are temporary discontinued. Oral anticoagulants should not be discontinued in the majority of patients requiring out-patient dental extraction.
• For patients who are stably anticoagulated on warfarin, an INR check is recommended 72 hours prior to dental surgery.
• The risk of bleeding may be minimised by:
  • The use of oxidised cellulose (surgical) or collagen sponges or sutures
  • 5% tranexamic acid mouthwash four times daily for 2 days (However this is expensive, difficult to obtain in primary care dental practices and of no more benefit than other local haemostatic measures)
• Patients taking warfarin should not be prescribed NSAIDs for analgesia following dental surgery

Further advice is contained in “BCSH Guidelines for the management of patients on oral anticoagulants requiring dental surgery"