152 THE PHARMACEUTICAL JOURNAL VOL 297 NO 7893 SEPTEMBER 2016 SEPTEMBER 2016 NO 7893 VOL 297 THE PHARMACEUTICAL JOURNAL 153

NEW ORAL ANTICOAGULANTS FOR STROKE PREVENTION IN ATRIAL FIBRILLATIONAround 12,500 strokes are caused by atrial fi brillation (AF) in the UK each year, and 7,100 of these are preventable with appropriate anticoagulation. Four new oral anticoagulants (NOACs) are now available in the UK in addition to warfarin.

DAWN CONNELLY

Sources: “Slow rise of NOACs” – NHS Digital; European Heart Journal; NICE; “Timeline” – New England Journal of Medicine; “The NOACs” – Europace; Summaries of product characteristics; “Deciding which NOAC” – Arrhythmia & Electrophysiology Review.

Editorial adviser: Satinder Bhandal, consultant anticoagulation pharmacist, Buckinghamshire Hospitals Trust

Infographic: MAG

RE-LY trial is published in NEJM showing that dabigatran 150mg BID is superior to warfarin for prevention of stroke and systemic embolism, with no signifi cant diff erences in major bleeding, although gastrointestinal (GI) bleeding was higher.

ROCKET AF trial is published in NEJM showing rivaroxaban is non-inferior to warfarin for the prevention of stroke or systemic embolism, with no diff erences in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. GI bleeding was greater with rivaroxaban.

ARISTOTLE trial is published in NEJM showing apixaban is superior to warfarin in preventing stroke or systemic embolism in patients with AF and results in lower mortality. Patients treated with apixaban had signifi cantly fewer intracranial bleeds, but GI bleedings were similar between both groups.

ENGAGE-AF is published in NEJM showing edoxaban is noninferior to warfarin with respect to the prevention of stroke or systemic embolism and is associated with signifi cantly lower rates of bleeding and death from cardiovascular causes. GI bleeding increased with the 60mg dose of edoxaban.

European Society of Cardiology guidance recommends that NOACs are broadly preferable to warfarin for non-valvular AF

The National Institute for Health and Care Excellence recommends NOACs as an option for non-valvular AF after a discussion about the risks and benefi ts compared with warfarin

Idarucizumab (Praxbind), an antidote to dabigatran

2009 2010 2011

1.69%

2.4%

1.50%2.1%

1.18%1.11%

Dab

igat

ran

Riv

arox

aban

Edox

aban

War

farin

War

farin

War

farin

RATE OF PRIMARY OUTCOME/YEAR:

RATE OF PRIMARY OUTCOME/YEAR:

RATE OF PRIMARY OUTCOME/YEAR:

APPROVAL IN EU

DRUG TRIALS & RATE OF STROKE OR SYSTEMIC EMBOLISM (PRIMARY OUTCOME)

2012 2013

2011 2012 2013 2014

1,538,000

667,000

366,000

2015

1,500,000

1,000,000

500,000

0

2014 2015

DABIGATRAN ETEXILATE (PRADAXA; BOEHRINGER INGELHEIM)Usual dose: 150mg bid. Bioavailability: 3–7%. Peak plasma level: 2hrs. Half-life: 12–17hrs. Renal excretion: 80%. Liver metabolism: no.

Interactions: Use with strong P-gp inhibitors ketoconazole, cyclosporine, itraconazole and dronedarone is contraindicated. Use with P-gp inhibitor verapamil requires dose reduction. Use with P-gp inducers should be avoided.

DABIGATRAN EDOXABANRIVAROXABAN APIXABAN

RIVAROXABAN (XARELTO; BAYER)Usual dose: 20mg od with food. Bioavailability: 66% (without food), almost 100% (with food). Peak plasma level: 2–4 hrs. Half-life: 5–9 hrs (young), 11–13 hrs (elderly). Renal excretion: 35%. Liver metabolism: yes.

Interactions: Use with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics or HIV protease inhibitors, is not recommended. Co-administration with dronedarone and strong CYP3A4 inducers should be avoided.

RivaroxabanDabigatranApixaban

WARFARIN Usual dose: 1–10mg od. Bioavailability: 99%.

Peak plasma level: 72–96 hrs. Half-life: 20–60 hrs. Renal excretion: <1%. Liver metabolism: yes.Drug-drug and drug-food interactions: numerous.

THE NOACsANTICOAGULANT EFFECT OF NOACs

DECIDING WHICH NOAC

SLOW RISE OF NOACs

All NOACs are indicated for the prevention of stroke and systemic embolism in adults with nonvalvular AF who have one or more risk factors, such as prior stroke or transient ischaemic attack; age ≥ 75 years; hypertension; diabetes mellitus and symptomatic heart failure. Unlike warfarin, the NOACs have a predictable therapeutic response, rapid onset of action, few drug interactions and no requirement for regular coagulation monitoring.

The coagulation cascade is a series of reactions involving coagulation factors that ultimately results in the formation of a blood clot. The NOACs directly inhibit one specifi c coagulation factor in the cascade, whereas warfarin prevents the coagulation process by suppressing the synthesis of several vitamin K-dependent coagulation factors.

Several patient characteristics may be considered when deciding on which NOAC to recommend. Patient preference for once daily dosing may also be taken into account. CAD: coronary artery disease, MI: myocardial infarction, ACS: acute coronary syndrome.

Prescription items dispensed in the community in England. Edoxaban was approved in 2015.

INTRINSIC (CONTACT ACTIVATION) PATHWAYActivated by contact of the vessel wall with

lipoprotein particles or bacteriaActivated in response to tissue injuryEXTRINSIC (TISSUE FACTOR) PATHWAY

Cross-linked Fibrin clot

have a predictable therapeutic response, rapid onset of action, few drug interactions and no requirement for regular coagulation monitoring.

EDOXABAN (LIXIANA; DAIICHI SANKYO UK)Usual dose: 60 mg od. Bioavailability: 62%. Peak plasma level: 1–2 hrs. Half-life: 10–14 hrs. Renal excretion: 50%. Liver metabolism: minimal.

Interactions: Use with the P-gp inhibitors ciclosporin, dronedarone, erythromycin or ketoconazole requires dose reduction to 30mg once daily. Use with caution concomitantly with P-gp inducers (e.g. rifampicin).

APIXABAN (ELIQUIS; BRISTOL-MYERS SQUIBB-PFIZER)Usual dose: 5mg bid. Bioavailability: 50%. Peak plasma level: 1–4 hrs. Half-life: 12 hrs. Renal excretion: 27%. Liver metabolism: yes.

Interactions: Use with strong inhibitors of CYP3A4 or P-glycoprotein (P-gp) is not recommended. Use with strong inducers of CYP3A4 and P-gp requires caution.

I NFOGRAPH ICINFOGRAPH IC

DABIGATRAN

Factor Xa

Fibrinogen(Factor I)

Factor VII Tissue factorFactors IX Factors XI, XII

Factor XFactor X

Thrombin (Factor IIa)

Fibrin (Factor Ia)

Prothrombin (Factor II)

RIVAROXABAN

APIXABAN

WARFARIN

EDOXABAN

PREVIOUS, OR HIGH RISK OF,GI BLEED

HIGH ISCHAEMIC STROKE RISK, LOW BLEEDING RISK

CAD, PREVIOUS MI OR HIGH RISK FOR ACS/MI

RENAL IMPAIRMENT

DIARRHOEA DISORDERS

Warfarin usage in 2015: 11,551,000

1.60%1.27%

Api

xaba

n

War

farin

RATE OF PRIMARY OUTCOME/YEAR: