Safe and Effective use of Oral AnticoagulantsHSE West RNP Continuing Professional Development Day

18th November 2016

Sarah ClarkeChief II Pharmacist and Programme ManagerHSE Medicines Management Programme (MMP)

www.HSE.ie/yourmedicinessaclarke@stjames.ie

Oral anticoagulants and the MMP

Supporting the SAFE, EFFECTIVE and COST-EFFECTIVE use of medicines

2016•26,000 patients on warfarin•30,000 on NOACs combined

2013•35,000 patients on warfarin•5,000 on NOACs combined

1m/mth

3m/mth

TIME TO REFLECT…..� Do we know all the available oral

anticoagulants?� Are we confident in using them?� Do we understand monitoring and/or

drug interactions?� Do we counsel patients on new

medication and treatment duration and diagnosis (e.g. A Fib or knee replacement)

OPTIONSOral Anticoagulant Mode of ActionWarfarin Vitamin K antagonist (inhibits

factors II, XII, IX, X)Apixaban (Eliquis®) Direct Factor Xa InhibitorEdoxaban (Lixiana®) Direct Factor Xa InhibitorRivaroxaban (Xarelto®) Direct Factor Xa InhibitorDabigatran (Pradaxa®) Direct Thrombin Inhibitor

5 medicines, 4 new, 9 “names” to remember

Indications for AnticoagulationWarfarin

� Prophylaxis of venous thrombosis and pulmonary embolism, and for use in the treatment of these conditions to prevent their extension.

� Prophylaxis of systemic embolisation in patients with rheumatic heart disease and atrial fibrillation.Rivaroxaban

� Prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or TIA

� Treatment of DVT, treatment of PE and prevention of recurrent DVT and PEDabigatran

� Prevention of venous thromboembolism (VTE) in patients post elective hip and knee replacement surgery

� Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation with one or more of the following risk factors:• Previous stroke, transient ischemic attack, or systemic embolism• Left ventricular ejection fraction < 40 %• Symptomatic heart failure, ≥ New York Heart Association (NYHA) Class 2• Age ≥ 75 years• Age ≥ 65 years associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension

Apixaban� Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors,

such as prior stroke or TIA, age ≥75 years, hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II)

Prevention and treatment of VTE and PE

Stroke Prevention in Atrial Fibrillation (NVAF for

newer agents), DVT/PE treatment

ORAL ANTICOAGULANTS• Increased focus on stroke prevention and AF

has resulted in increased treatment of AF at same time as new treatment options come on stream

• Increased treatment => reduced strokes => reduced stroke related costs but => increased drug costs

• Treatment options are becoming more complex and varied => RISK FOR ERRORS

Atrial Fibrillation• Most common sustained cardiac

arrhythmia worldwide • Estimated to affect at least 1% of the

population at the age of 60 and 5% at the age of 70

• 32% of strokes (3200) are attributed to AF • Strokes due to A Fib tend to be more

severe and lead to greater disability and mortality

Atrial fibrillation accounts for 86.9% of all applications for NOACs

Warfarin - Pharmacology� Vitamin K antagonist – Factors II, VII, IX, X� Time to peak effect: 4-5 days� Half-life: 40 hours� Interactions: multiple food and drug

interactions� Monitoring available: Yes, INR� Renal clearance: None

Warfarin: an established therapyBENEFITS• Many years experience • Instantly recognisable (patient/doctor experience)• Can be monitored• Experience with use in invasive procedures

(ablations, pacemaker)• Reversible• Limited renal adjustments needed• Experience with dual antiplatelet agents• COST: 100 x 5mg tablets COST €8.37 (additional

monitoring costs)

Warfarin – the problems� Vitamin K antagonist – many food

interactions� Narrow therapeutic index� Variations in anticoagulant effect� Drug interactions affecting metabolism� Need for regular monitoring� Variation in monitoring services – venous

blood samples to lab, POC devices

New Oral Anti-Coagulants (NOAC’s)

Apixaban (Eliquis®) Rivaroxaban (Xarelto®)

Edoxaban (Lixiana®)Dabigatran (Pradaxa®)

Apixaban - Eliquis®� Direct factor Xa Inhibitor

� Onset: 3-4 hours for max concentration

� Half life: approx 12 hours

� Standard dose in AF 5mg BD € 63.91 (€68.13 for 2.5mg) (28 days)

� Interactions� Adjust dose for: 1) AGE2) Renal Function3) Weight

Dabigatran – Pradaxa®� Direct Thrombin Inhibitor

� Onset: immediate (peak at 2-3 hours)

� Half-life: 12-14 hours� Standard dose in AF150mg BD (€70.01/30 days)� Interactions� Must be stored in original packaging, DO NOT open

capsule

� Adjust dose for: � Age� Renal function� GORD� Interactions (verapamil)

� Reversal agent - Idarucizumab approved

Rivaroxaban - Xarelto®� Factor Xa inhibitor

� Onset: 2-4 hours

� Half-life: 5-9 hours

� Standard dose AF 20mg od (€64.11/28 days)� Adjust dose for Renal function and consider

interactions� Interactions (P-gp and strong CYP 34A inhibitors)

� Ritonavir, lopinavir� Ketoconazole, itraconazole

Edoxaban – Lixiana®

� Direct Factor Xa inhibitor� Onset: 1-3 hours� Half-life: 10-14 hours� Standard dose 60mg once daily (€66.53/28 days)� Interactions� Adjust for:

� Renal function� Body weight� Interactions (ciclosporin, dronedarone,

erythromycin, ketoconazole)

Drug interactions with NOACs

P-glycoprotein transporter (PgP) in intestinal mucosal cells

DigoxinDabigatran Rivaroxaban Apixaban Edoxaban

A drug that is a substrate for P‐glycoprotein (PgP) may have low bioavailability (e.g. dabigatran F% = 6%) as PgP will transport the drug across the intestinal cell membrane and back into the lumen of the intestine

NOAC PgP interactions

P‐glycoprotein transporter (PgP) in intestinal mucosal cells

VerapamilInhibits PgPDigoxinDabigatran   Rivaroxaban   Apixaban

Other  inhibitors of PgP

AmiodaroneDronedaroneClarithromycinErythromycinKetoconazoleItraconazole

� Increased amount of NOAC absorbed

� Increased risk of bleeding

NOAC Metabolism Interactions

LiverMetabolismby CYP3A4enzyme

Rivaroxaban   Apixaban   Edoxaban

Inhibitors of CYP3A4 (↑drug concentration)• Clarithromycin, ketoconazole, itraconazole,

HIV protease inhibitors

Inducers of CYP3A4 (↓ drug concentration)• Carbamazepine, phenytoin, phenobarbitone,

rifampicin, St Johns Wort

� Very few patients with a creatinine clearance < 30 ml/min were studied as this was an exclusion in the RE‐LY study,  such patients were excluded from the  ROCKET ‐ AF study and just 1.5% of patients in the ARISTOTLE study had a CrCl < 30 ml/min as an exclusion criterion was CrCl < 25 ml/min.

�There is no validated rapidly effective antidote to the haemorrhagic complications associated with the factor Xa inhibitors. Major bleeding was observed for all agents in the clinical trials i.e. Dabigatran 2.87% ‐ 3.32%, Rivaroxaban 3.6% Apixaban 2.13%. Major bleeding with warfarin ranged between 3.09% ‐ 3.4% but TTR < 65% in all studies.

� Compliance is an important consideration with these short half‐life drugs and may impact significantly on the anticoagulant effect. 

� Discontinuation rates of approximately 14% at year 1 increasing to over 20% at year two was observed in the NOAC clinical trials.

�Pharmacodynamic drug interactions (antiplatelets, NSAIDS)

NOACs – a closer look at the evidence

Trials versus real world - AGEApixaban Trial Data (ARISTOTLE)Age Category < 80 years 80‐89 years 90+ years TotalNumber 15,765 2352 84 18201% 86.62 12.92 0.46 100Dabigatran Trial Data (RE‐LY)Age Category < 80 years 80‐89 years 90+ years TotalNumber 15,097 2,937 79 18113% 83.35 16.21 0.44 100Rivaroxaban Trial Data (ROCKET‐AF)Age Category < 80 years 80‐89 years 90+ years TotalNumber 11,576 2517 78 14171% 81.69 17.76 0.55 100

All three trials have less than 20% of patients aged 80 years or older.

GMS prescribing database analysis (January 2013 - March 2014) 34.8% of patients treated with dabigatran, 37.5% of patients treated with rivaroxaban and 45.4% of patients treated with apixaban were 80 years or over

Reimbursement Approval form for NOACs – enhancing safety

Applications for reimbursementDrug IndicationRivaroxaban 10mg Limb ischaemia graftApixaban 5mg BD Left ventricular apical thrombusRivaroxaban 20mg No indication, no CHADs score, no GFRRivaroxaban 20mg Post stenting in the legRivaroxaban 10mg Post femoral popliteal bypassRivaroxaban 20mg 6 weeks post femoral neck fractureRivaroxaban 20mg Abdominal aortic aneurysmRivaroxaban 20mg Three weeks tachy-brady syndrome post ICD insertionRivaroxaban 15mg Hypertrophic cardiomyopathyRivaroxaban 20mg thrombophlebitis on the background of brachytherapy for

prostate cancerRivaroxaban 15mg Ventricular thrombus post NSTEMIRivaroxaban 20mg Post endarterectomyRivaroxaban 15mg No indication given, renal failureRivaroxaban 10mg High PlateletsDabigatran 75mg BD No indication givenRivaroxaban 20mg Post surgical femoral artery bypassApixaban 5mg BD SVC obstructionRivaroxaban 10mg AF

Compliance issues� Poor compliance with warfarin should not

be considered a reason for changing patient to NOAC

� No regular monitoring of anticoagulant effect

� Risks of missed dose

New oral anticoagulants – missing dose !

The new oral anticoagulants have short half – lives Missing just one dose can have significant implications for anticoagulant effect.

Plasma conc

50%

25%

100%

75%

12 24 36 48

t½=10 hrs

Rivaroxaban

?

Rivaroxaban

Sample Errors – Knowledge & recognition� Starting on enoxaparin 1.5mg/kg od AND

rivaroxaban 15mg od for PE� Prescribing warfarin for AF when

dabigatran already charted in regular drug chart

� Patient admitted with Hb of 7.4 in A&E, aspirin 75mg put on HOLD, rivaroxaban was prescribed and not held.

� Not prescribed correctly however so could not be given: Rivaroxiban T OD

Adverse Drug Reactions/ Drug Interactions

� Patients presenting with bleeds on rivaroxaban (also on diclofenac, aspirin)

� Patient on dabigatran and rivaroxaban presenting with epistaxis

� Patient confused Zydol® and Xarelto® - took Xarelto BD or TDS post hip replacement – readmission, severe haematoma, surgery

� Patient on prior aspirin, celecoxib had a hip replacement� Rivaroxaban 10mg od and diclofenac 50mg tds prescribed post

surgery – major bleed, 10 days in ICU

� Young lady on phenytoin for epilepsy (enzyme inducer) initiated on rivaroxaban following PE – Extensive stroke 2 weeks later, left with severe disability

� Elderly male started on dronedarone and rivaroxaban for AF – severe haematuria after one week

Adverse Drug Reactions/ Drug Interactions

NOAC monitoring requirements� Renal function (calculate using

Cockroft-Gault equation):(140-age) x weight (kg) x 1.23 (m) or 1.04 (f)

Serum creatinine� Age� Weight� Interacting medicinesDose adjustments may be required over time

Compare VKA and NOACsDischarge prescription (after first diagnosis) should clearly state intended DURATION OF TREATMENT. If rivaroxaban, state how many further days of BD dosing (i.e. 21 days minus number of days doses have already given in hospital) before reducing to once daily and if apixaban, how many further days of 10mg BD before reducing to 5mg BD

TREATMENT OF DEEP VEIN THROMBOSIS (DVT) AND PULMONARY EMBOLISM (PE)

Find us on:ww.hse.ie/yourmedicinessaclarke@stjames.ie