New oral New oral anticoagulants:anticoagulants:

an update an update

Julian HolmesJulian Holmes

H+T Pharmacist NUHH+T Pharmacist NUH

Julian.Holmes@nuh.nhs.ukJulian.Holmes@nuh.nhs.uk

Problems with warfarinProblems with warfarin

Variable doseVariable dose INR affected by diet, illness etcINR affected by diet, illness etc Drug interactions can be problematicDrug interactions can be problematic Narrow therapeutic indexNarrow therapeutic index BUT – its cheap!BUT – its cheap! AND – the INR is a good measure of AND – the INR is a good measure of

compliancecompliance

The clotting cascadeThe clotting cascade

New agentsNew agents

Ideally need:Ideally need: Once daily constant dose for all Once daily constant dose for all

patientspatients Predictable kinetics and anticoagulant Predictable kinetics and anticoagulant

effecteffect No problematic drug interactionsNo problematic drug interactions Several new agents – dabigatran, Several new agents – dabigatran,

rivaroxaban and apixaban are most rivaroxaban and apixaban are most advanced threeadvanced three

Dabigatran in AFDabigatran in AF

RELY trialRELY trial Oral direct thrombin inhibitorOral direct thrombin inhibitor Half life 12-17 hoursHalf life 12-17 hours No reversal agentNo reversal agent Contraindicated if CrCl<30ml/minContraindicated if CrCl<30ml/min Substrate of efflux transporter P-Substrate of efflux transporter P-

glycoprotein so levels affected by inducers glycoprotein so levels affected by inducers (St Johns Wort) or inhibitors (amiodarone, (St Johns Wort) or inhibitors (amiodarone, quinidine (C/I), verapamil, clarithromycin) of quinidine (C/I), verapamil, clarithromycin) of thisthis

Dabigatran in AFDabigatran in AF Mortality and haemorrhagic stroke rates Mortality and haemorrhagic stroke rates

favoured dabigatranfavoured dabigatran Time in range ~64% for warfarin ptsTime in range ~64% for warfarin pts Dabigatran slightly more effective than Dabigatran slightly more effective than

warfarin at the higher dosewarfarin at the higher dose Higher MI and GI bleed rates with Higher MI and GI bleed rates with

dabigatrandabigatran Drop out trial rate of ~10% with dyspepsia Drop out trial rate of ~10% with dyspepsia

with dabigatranwith dabigatran Now licensed in UKNow licensed in UK NICE TA249 Mar 2012 – can be used as a NICE TA249 Mar 2012 – can be used as a

treatment optiontreatment option

Dabigatran in AFDabigatran in AF

Dose is 150mg twice daily reduced to Dose is 150mg twice daily reduced to 110mg twice daily if:110mg twice daily if:– Creatinine clearance 30-50ml/minCreatinine clearance 30-50ml/min– Over 80 yearsOver 80 years– Body weight <50kgBody weight <50kg– Increased bleeding riskIncreased bleeding risk– On verapamilOn verapamil– Patients with gastritis, oesophagitis or Patients with gastritis, oesophagitis or

gastoesophageal refluxgastoesophageal reflux– Patients continuing to take aspirin to manage a Patients continuing to take aspirin to manage a

chronic conditionchronic condition

Why Xa inhibitors over TI?Why Xa inhibitors over TI?

Less complicated dosing regimenLess complicated dosing regimen Reduced MI rateReduced MI rate Less GI S/ELess GI S/E MDS issue with dabigatranMDS issue with dabigatran ?easier to reverse?easier to reverse Dabigatran only licensed for AF and Dabigatran only licensed for AF and

not VTE treatmentnot VTE treatment

Rivaroxaban in AFRivaroxaban in AF

Dose 20mg daily (15mg daily if CrCl 30-Dose 20mg daily (15mg daily if CrCl 30-49ml/min or HASBLED score over 3) in 49ml/min or HASBLED score over 3) in ROCKET trial vs warfarin in 14,264 patientsROCKET trial vs warfarin in 14,264 patients

Primary end point of stroke or systemic Primary end point of stroke or systemic embolismembolism

Rates of primary outcome 1.7% per year Rates of primary outcome 1.7% per year rivaroxaban and 2.2% per year warfarinrivaroxaban and 2.2% per year warfarin

Bleeding rates 14.9% per rivaroxaban and Bleeding rates 14.9% per rivaroxaban and 14.5% per year warfarin14.5% per year warfarin

Time in range for warfarin ~55%Time in range for warfarin ~55%

Rivaroxaban in AFRivaroxaban in AF

Intracranial and fatal bleeds favoured Intracranial and fatal bleeds favoured rivaroxabanrivaroxaban

Rivaroxaban non inferior to warfarinRivaroxaban non inferior to warfarin C/I if - CrCl less than 30ml/min, active C/I if - CrCl less than 30ml/min, active

bleeding, hepatic disease (Child’s Pugh B bleeding, hepatic disease (Child’s Pugh B and C), pregnancy and breast feeding and C), pregnancy and breast feeding

Adverse effects – anaemia, dizziness, Adverse effects – anaemia, dizziness, headache, epistaxis, GI s/e, haemorrhage headache, epistaxis, GI s/e, haemorrhage

License application for Dec 2011 and NICE License application for Dec 2011 and NICE appraisal May 2012appraisal May 2012

Rivaroxaban Rivaroxaban Half life 7-11 hoursHalf life 7-11 hours Review use of agents affecting haemostasis (e.g. Review use of agents affecting haemostasis (e.g.

NASIDS and anti platelets)NASIDS and anti platelets) Metabolised by CYP3A4 so interactions could be Metabolised by CYP3A4 so interactions could be

problematic:problematic: InducersInducers – barbiturates, carbamazepine, phenytoin, – barbiturates, carbamazepine, phenytoin,

rifampicin, St Johns Wort – avoid use of strong rifampicin, St Johns Wort – avoid use of strong inducersinducers

InhibitorsInhibitors – clarithromycin, ciclosporine, danazol, – clarithromycin, ciclosporine, danazol, dlitiazem, erythromycin, fluconazole, fluoxetine, dlitiazem, erythromycin, fluconazole, fluoxetine, fluvoxaminefluvoxamine, , indinavir, isoniazidindinavir, isoniazid, , ritonavir, verapamilritonavir, verapamil

Avoid itraconazole, ketoconazoleAvoid itraconazole, ketoconazole, , voriconazole voriconazole and protease inhibitorsand protease inhibitors

Rivaroxaban in DVT (instead of Rivaroxaban in DVT (instead of warfarin/enoxaparin)warfarin/enoxaparin)

Patients must have a recommendation from a Haematology Patients must have a recommendation from a Haematology specialist dose is 15mg BD for 3 weeks then 20mg dailyspecialist dose is 15mg BD for 3 weeks then 20mg daily

Allergy to warfarinAllergy to warfarin Unstable INR controlUnstable INR control Intravenous drug usersIntravenous drug users Liver disease (N.B. All anticoagulants are contraindicated in Liver disease (N.B. All anticoagulants are contraindicated in

established liver cirrhosis including rivaroxaban)established liver cirrhosis including rivaroxaban) Anticoagulation in malignancyAnticoagulation in malignancy

– In this patient group LMWH’s are first line, warfarin and rivaroxaban In this patient group LMWH’s are first line, warfarin and rivaroxaban should only be used if LMWH’s are contraindicated should only be used if LMWH’s are contraindicated

– Newly diagnosed patients with active malignancy should not be Newly diagnosed patients with active malignancy should not be warfarinised until their treatment plan is agreed as control is often very warfarinised until their treatment plan is agreed as control is often very unstable in these patients. unstable in these patients.

– Patients with chronic malignant conditions eg. prostate cancer may be Patients with chronic malignant conditions eg. prostate cancer may be suitable for warfarin, but treatment should be reviewed by the suitable for warfarin, but treatment should be reviewed by the specialist team if liver metastases are present. specialist team if liver metastases are present.

Unable to comply with variable dosing (e.g dementia but with no Unable to comply with variable dosing (e.g dementia but with no support in community)support in community)

Rivaroxaban for SPAF new Rivaroxaban for SPAF new ptspts

Patients must fit the criteria in the Nottinghamshire Patients must fit the criteria in the Nottinghamshire guidance (see guidance (see http://http://www.nottsapc.nhs.uk)) and have a and have a recommendation from a secondary care Consultant recommendation from a secondary care Consultant Haematologist, Consultant in Stroke Medicine , or Haematologist, Consultant in Stroke Medicine , or Consultant Cardiologist. Excluded patient groups are Consultant Cardiologist. Excluded patient groups are those with significant valvular disease and patients those with significant valvular disease and patients suitable for cardioversionsuitable for cardioversion

Patients requiring domiciliary phlebotomy Patients requiring domiciliary phlebotomy Known unpredictable alcohol excess (N.B. All anticoagulants Known unpredictable alcohol excess (N.B. All anticoagulants

are contraindicated in established liver cirrhosis including are contraindicated in established liver cirrhosis including rivaroxaban) rivaroxaban)

Unable to comply with variable dosing schedule Unable to comply with variable dosing schedule Contraindications to warfarin – N.B. many contraindications Contraindications to warfarin – N.B. many contraindications

for warfarin will be contraindications to anticoagulation in for warfarin will be contraindications to anticoagulation in general, and thus are likely to be contraindications for general, and thus are likely to be contraindications for rivaroxaban alsorivaroxaban also

Rivaroxaban switch in pts on Rivaroxaban switch in pts on warfarin warfarin

Patients must fit the criteria in the Patients must fit the criteria in the Nottinghamshire guidance (see Nottinghamshire guidance (see http://http://www.nottsapc.nhs.uk)) and have a and have a recommendation from a secondary care recommendation from a secondary care Consultant Haematologist, Consultant in Stroke Consultant Haematologist, Consultant in Stroke Medicine, or Consultant Cardiologist. Excluded Medicine, or Consultant Cardiologist. Excluded patient groups are those with significant patient groups are those with significant valvular disease and patients suitable for valvular disease and patients suitable for cardioversioncardioversion

TTR<60% after 4 months of VKA in presence of TTR<60% after 4 months of VKA in presence of compliance compliance

Intolerant of VKA (e.g. side effects etc)Intolerant of VKA (e.g. side effects etc) INR>8 without any strong cause (e.g. interacting INR>8 without any strong cause (e.g. interacting

meds) meds) History of significant bleed associated with poor History of significant bleed associated with poor

warfarin controlwarfarin control

Rivaroxaban Rivaroxaban

Classed as amber drug for DVT and AFClassed as amber drug for DVT and AF Secondary care supply first month then Secondary care supply first month then

continues in primary carecontinues in primary care Rebate scheme availableRebate scheme available Can refer pts to NUH anticoag for Can refer pts to NUH anticoag for

counselling etc (as per warfarin)counselling etc (as per warfarin) No INR’s needed – monitor U+E’s according No INR’s needed – monitor U+E’s according

to baseline renal function – see APC to baseline renal function – see APC guidelineguideline

Rivaroxaban and elective Rivaroxaban and elective surgerysurgery

Stop rivaroxaban at least 24 hours before Stop rivaroxaban at least 24 hours before intervention. If procedure cannot be intervention. If procedure cannot be delayed until at least 24 hours post dose, delayed until at least 24 hours post dose, the increased risk of bleeding should be the increased risk of bleeding should be assessed against the urgency of the assessed against the urgency of the intervention. This should be discussed with intervention. This should be discussed with a haematologist. a haematologist.

Rivaroxaban should be re-started post Rivaroxaban should be re-started post procedure when risk of bleeding is judged procedure when risk of bleeding is judged to be lowto be low

Rivaroxaban and emergency Rivaroxaban and emergency surgery/haemorrhagesurgery/haemorrhage

No reversal agentNo reversal agent Can use charcoal if ingested within 1 Can use charcoal if ingested within 1

hrhr Emergency surgery – measure INR Emergency surgery – measure INR

(neoplastin) or Xa level – if low (neoplastin) or Xa level – if low proceed if not delay or give octaplexproceed if not delay or give octaplex

Haemorrhage – as above and use Haemorrhage – as above and use haemorrhage control haemorrhage control measures/tranexamic acid/octaplexmeasures/tranexamic acid/octaplex

Monitoring rivaroxabanMonitoring rivaroxaban Rivaroxaban does not routinely require Rivaroxaban does not routinely require

monitoring of therapeutic response (unlike monitoring of therapeutic response (unlike warfarin). However, if a patient has an episode of warfarin). However, if a patient has an episode of bleeding or requires an invasive procedure, bleeding or requires an invasive procedure, measurement of an anticoagulant effect may be measurement of an anticoagulant effect may be advantageous. advantageous.

A standard clotting screen has not been validated A standard clotting screen has not been validated for assessing the degree of anticoagulation in a for assessing the degree of anticoagulation in a patient taking Rivaroxaban and should not be patient taking Rivaroxaban and should not be used for this purposeused for this purpose

A prothrombin time using a sensitive reagent A prothrombin time using a sensitive reagent such as neoplastin plus or a specific anti Xa can such as neoplastin plus or a specific anti Xa can be used to measure the effect only after be used to measure the effect only after discussion with a haematologist.discussion with a haematologist.

Effect of NOAC on clotting Effect of NOAC on clotting screensscreens

Dabigatran, rivaroxaban and apixaban are Dabigatran, rivaroxaban and apixaban are new oral anticoagulants that are alternatives new oral anticoagulants that are alternatives to coumarins (e.g. warfarin) in selected to coumarins (e.g. warfarin) in selected groups of patients for certain indications. All groups of patients for certain indications. All drugs accumulate in renal impairment. drugs accumulate in renal impairment.

A standard clotting screen has not been A standard clotting screen has not been validated for assessing the degree of validated for assessing the degree of anticoagulation in a patient taking these anticoagulation in a patient taking these agents and should not be used for this agents and should not be used for this purpose. Consult haematology for advicepurpose. Consult haematology for advice

Daily costsDaily costs

Dabigatran and rivaroxaban – Dabigatran and rivaroxaban – community ~£2.60, hospital ~£1.60community ~£2.60, hospital ~£1.60

Warfarin - (+costs of drug, INR, Warfarin - (+costs of drug, INR, monitoring, dosing etc) approx monitoring, dosing etc) approx £0.67-0.83 daily£0.67-0.83 daily

Apixaban likely to be similar other Apixaban likely to be similar other new agentsnew agents

Ongoing trialsOngoing trials

Rivaroxaban in DVT/PE licensed - as Rivaroxaban in DVT/PE licensed - as effective as warfarin and NICE TA – dose is effective as warfarin and NICE TA – dose is 15mg BD for 3 weeks and then 20mg daily15mg BD for 3 weeks and then 20mg daily

Dabigatran now C/I in MHV after trial Dabigatran now C/I in MHV after trial haltedhalted

Apixaban (10mg BD for 5 days then 5mg Apixaban (10mg BD for 5 days then 5mg BD for 6 months then 2.5mg BD) and BD for 6 months then 2.5mg BD) and Dabigatran (150mg BD after 5 days of Dabigatran (150mg BD after 5 days of LMWH) now approved for DVT/PELMWH) now approved for DVT/PE

Cardioversion trial riva vs warfarinCardioversion trial riva vs warfarin

ApixabanApixabanin AFin AF

New oral Xa inhibitorNew oral Xa inhibitor Behind dabigatran and rivaroxaban in Behind dabigatran and rivaroxaban in

development development More effective than aspirin in stroke reductionMore effective than aspirin in stroke reduction C/I if CrCl less than 25ml/minC/I if CrCl less than 25ml/min ARISTOTLE trial – apixaban 5mg twice daily ARISTOTLE trial – apixaban 5mg twice daily

(reduced to 2.5mg BD if any 2 of 3 of: >80yrs, (reduced to 2.5mg BD if any 2 of 3 of: >80yrs, <60kg, Cr>133) vs warfarin in 18, 201 patients<60kg, Cr>133) vs warfarin in 18, 201 patients

Primary endpoint of stroke and systemic Primary endpoint of stroke and systemic embolismembolism

Apixaban in AFApixaban in AF

Warfarin time in range 62%Warfarin time in range 62% Rates of primary outcome 1.27% per year Rates of primary outcome 1.27% per year

apixaban and 1.6% per year warfarin – apixaban and 1.6% per year warfarin – statistically significantstatistically significant

Major bleeds 2.13% per year apixaban and Major bleeds 2.13% per year apixaban and 3.09% warfarin3.09% warfarin

Apixaban superior for stroke prevention and Apixaban superior for stroke prevention and causes less bleedingcauses less bleeding

Drug interactions as per riva avoid strong Drug interactions as per riva avoid strong inhibitors of CYP3A4 or p-gpinhibitors of CYP3A4 or p-gp

But for all new medsBut for all new meds

Higher costs Higher costs How do we reverse if patient is How do we reverse if patient is

actively bleeding and/or needs actively bleeding and/or needs emergency surgery (both companies emergency surgery (both companies recommend rVIIa/PCC – no real in vivo recommend rVIIa/PCC – no real in vivo data)?data)?

Difficult to measure level of Difficult to measure level of anticoagulation (dabigatran ECT/TT, anticoagulation (dabigatran ECT/TT, rivaroxaban PT) which may vary rivaroxaban PT) which may vary according to RF according to RF

But for all new medsBut for all new meds How do we measure compliance with new agents? How do we measure compliance with new agents?

(given data suggests approx 43% average patient (given data suggests approx 43% average patient compliance with new meds – NUH coag service has compliance with new meds – NUH coag service has approx 70% of pts in therapeutic range)approx 70% of pts in therapeutic range)

Peri-operative and emergency surgery issues Peri-operative and emergency surgery issues (cardioversion and emergency surgery) – new (cardioversion and emergency surgery) – new agents have shorter half lives so may be able to agents have shorter half lives so may be able to stop day before pre opstop day before pre op

Pts will need to carry alert cards and be counselled Pts will need to carry alert cards and be counselled (register pts in DAWN) by coag – need to be (register pts in DAWN) by coag – need to be referredreferred

Both C/I for AF treatment if CrCl<30ml/min – what Both C/I for AF treatment if CrCl<30ml/min – what do we do if AKI?do we do if AKI?

Will need to go back onto warfarin if do not Will need to go back onto warfarin if do not tolerate new agents for AFtolerate new agents for AF

Current situationCurrent situation Only using rivaroxaban in selected patients (~400) and Only using rivaroxaban in selected patients (~400) and

those unable to tolerate warfarin – DVT and AFthose unable to tolerate warfarin – DVT and AF Apixaban now has NICE TA and better data for AF – for use Apixaban now has NICE TA and better data for AF – for use

in selected patients as above only by cardiology/strokein selected patients as above only by cardiology/stroke All NOAC C/I in MHVAll NOAC C/I in MHV May decide to use riva in DVT and PE if pts on for up to 6-12 May decide to use riva in DVT and PE if pts on for up to 6-12

months – but ?if long termmonths – but ?if long term Apixaban (10mg BD for 5 days then 5mg BD for 6 months Apixaban (10mg BD for 5 days then 5mg BD for 6 months

then 2.5mg BD) and Dabigatran (150mg BD after 5 days of then 2.5mg BD) and Dabigatran (150mg BD after 5 days of LMWH) now approved for DVT/PELMWH) now approved for DVT/PE

Rivaroxaban vs warfarin in cardioversionRivaroxaban vs warfarin in cardioversion NOAC to amber 3 shortlyNOAC to amber 3 shortly

What do we need to do?What do we need to do?

Check pt has had correct bloods Check pt has had correct bloods (U+E/LFT/clotting/FBC) pre starting and 3 weeks (U+E/LFT/clotting/FBC) pre starting and 3 weeks after then according to guidelines (after then according to guidelines (http://www.nottsapc.nhs.uk/attachments/article/3/http://www.nottsapc.nhs.uk/attachments/article/3/APC%20statement%20re%20NICE%20CG180%20APC%20statement%20re%20NICE%20CG180%20%20Atrial%20fibrillation.pdf%20Atrial%20fibrillation.pdf

Check dose ok according to pts renal functionCheck dose ok according to pts renal function Pt information given and alert cardPt information given and alert card Counselling/DVD – side effects, missed doses, Counselling/DVD – side effects, missed doses,

procedures etcprocedures etc Check interacting meds (antiplatelets)Check interacting meds (antiplatelets)

Questions?Questions?