Dr. Khalid KhanConsultant Cardiologist

BCUHB  (Wrexham)BCUHB  (Wrexham)

WCS Spring Meeting 2012

“When the pulse is irregular and p gtremulous and the beats occur at intervals, then the impulse of life fades; when the then the impulse of life fades; when the pulse is slender (smaller than feeble, but 

still perceptible  thin like a silk thread)  then still perceptible, thin like a silk thread), then the impulse of life is small."

~2000 BC  ‐Huang TiNei Ching Su Wen

In the next 4 hours itis estimated that…

10 patients with AF willhave suffered a stroke…

Of these…

ld h8 patients would havebeen at high risk of stroke…

6 patients should havebeen on warfarin…

5 patients will end up inresidential care…

3 patients will go home…

2 patients will die…

www.spafacademy.org.uk

p

VFVF

StrokeStroke

Back door...

CHA2DS2‐VASc criteria Score

Congestive heart failure/left ventricular dysfunction

1

CHA2DS2‐VASc total score

Rate of stroke/other TE (%/year)*

0 0.0Hypertension 1

Age ≥75 yrs 2

Diabetes mellitus 1

1 1.3

2 2.2Diabetes mellitus 1

Stroke/transient ischaemicattack/TE

2

Vascular disease 1

3 3.2

4 4.0

5 6 7Vascular disease(prior myocardial infarction, peripheral artery disease or aortic plaque)

1 5 6.7

6 9.8

7 9.6Age 65–74 yrs 1

Sex category (i.e. female gender)

18 6.7

9 15.2

* Theoretical rates without therapy: assuming that warfarin provides a 64% relative reduction in TE risk (2.7% ARR), based on Hart et al. 

1 Lip GYH et al. Stroke 2010;41:2731–2738.2 Hart RG et al. Ann Intern Med 2007;146:857–67.TE = thromboembolism

The best or the worst drug in Cardiology

Warfarin better Placebo better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100 10050 0 50

All trialsRRR 64%*, ARR 2.7%(95% CI: 49–74%)

Random effects model;

RRR (%)†100 –10050 0 –50

Compared to a 19% RRR, 0.7% ARR for aspirin

Error bars = 95% CI;* p>0.2 for homogeneity;† Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)

Hart RG et al. Ann Intern Med 2007;146:857–67.

50% AF in over  25% low risk patients 75yrs pat e ts

anticoagulated

Only 50% high  Only 20% high y 5 grisk patients on warfarin

y grisk over 75yr on warfarin

P d i i di ti i ti t ith k t i lPreadmission medications in patients with known atrial fibrillation who were admitted with acute ischaemic stroke

(high-risk cohort, n=597)( g , )

Sub‐ therapeuticwarfarin, 29%

No antithrombotic29%

Dual antiplatelet

Therapeutic f i   %

antiplatelettherapy, 2%

Gladstone DJ et al. Stroke 2009;40:235–240.

warfarin, 10% Single antiplateletagent, 29%

P ib  Prescriber reluctance

Patient l t

Genuine Problem! reluctanceProblem!

TherapeuticTherapeuticrange20

Requires dose adjustmentand regular monitoring

Ischaemic stroke

15and regular monitoringstroke

dds ratio

10Intracranial bleed

Od

5

01

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–e354.

1International normalized ratio (INR)2 83 4 5 6 7

Patient Lifestyle• ComplianceCompliance• Dietary intake of vitamin K• Alcohol intake

M di l IMedical Issues• Numerous drug interactions• Hepatic dysfunctionHepatic dysfunction• Changes in the gut flora

Pharmacogenetics• CYP 2C9 & VKORC1 genes• Tailored therapy

P ib !Prescribers!

“Do you really want some of that rat poison, which means loads of blood tests  you can’t drink and you might tests, you can t drink and you might bleed to death or perhaps you might p p y gprefer a baby aspirin which is very 

d t ”good too....”

Simple dosing (one size for all)Simple administrationSimple administrationNo / minimal monitoring required

d h dWide therapeutic indexHigh benefitgLow bleeding

Minimal drug / food interactionsMinimal drug / food interactionsPredictable pharmacokinetics

Summary and comparisons

Dabigatran1‐3 Rivaroxaban4,5 Apixaban6,7

Mode of action Factor II Factor X Factor X

Half life 12‐14 hrs 7‐11 hrs 12 hrs

Dosing(in atrial fibrillation)

B.D. O.D. B.D.( )

MetabolismEsterase catalysed hydrolysis

CYP P450 dependant and independent mechanisms

CYP P450

Excretion 85% Renal1/3 Renal 1/4 Renal

Excretion 85% Renal2/3 Hepatic 3/4 Non Renal

Form Capsule Tablet Tablet

150 mg 5 mg

Dose150 mg110 mg (>80 yrs, verapamil or increased bleeding risk)

20 mg15 mg (CrCL 30‐49 ml/min)

5 g2.5 mg (2 or more:>80yr; weight <60 kg;Cr >1.5 mg/dL)

B.D. = twice daily; O.D. = once daily

1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4. Rocket Investigators. Am Heart J 2010;159:340‐347; 5. Patel MR et al. NEJM 

2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331‐9; 7. Granger et al. N Eng J Med 2011;365:981‐92.

y; y

Dabigatran1‐3 Rivaroxaban4,5 Apixaban6,7

Study RE‐LY ROCKET‐AF ARISTOTLE

Design PROBE Double Blind Double Blind

Follow up 2 yrs 1.5 yrs 1.5 yrs

Population size >18,000 >14,000 >18,000

InclusionNonvalvular AF + 1 risk factor

Nonvalvular AF + 2 risk factors (i.e. moderate to high risk)

Nonvalvular AF + 1 risk factor

Inclusion (CHADS) 2.1 3.5 2.1

Primary EndpointStroke and systemicembolism 

Stroke and systemicembolism 

Stroke and systemicembolism 

Warfarin comparator INR control (mean TTR)

64% 55% 62%

PROBE   prospective randomised open blinded end point  INR   international normalised ratio  TTR   time in therapeutic range

1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4. Rocket Investigators. Am Heart J 2010;159:340‐347; 5. Patel MR et al. NEJM 

2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331‐9; 7. Granger et al. N Eng J Med 2011;365:981‐92.

PROBE = prospective randomised open blinded end‐point; INR = international normalised ratio; TTR = time in therapeutic range

SSE vs. warfarin(ITT population)

%/yr Warfarin%/yr

HR(95% CI)

Dabigatran 150 mg 1.11 1.710.65 (0.52‐

0.81)

Dabigatran 110 mg 1 54 1 710.90 (0.74‐

Dabigatran 110 mg 1.54 1.711.10)

Rivaroxaban 2.1 2.40.88 (0.75‐

1.03)

Apixaban 1.27 1.600.79 (0.66‐

0.95)

0.5 1 1.5SSE = stroke and systemic embolism 

Favours new orals        Favours warfarin5 5

1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3.Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix;

4.Granger et al. N Eng J Med 2011;365:981‐92.

Ischaemic stroke vs. Warfarin

%/yrWarfarin%/yr

HR(95% CI)y

Dabigatran 150 mg 0.86 1.14 0.75 (0.58‐0.97)

Dabigatran 110 mg 1.28 1.14 1.13 (0.89‐1.42)

Rivaroxaban 1.34 1.42 0.94 (0.75‐1.17)Rivaroxaban 1.34 1.42 0.94 (0.75 1.17)

Apixaban* 0.97 1.05 0.92 (0.74‐1.13)

0.5 1Favours new orals          Favours warfarin

1.5*Ischaemic or uncertain type of stroke

1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix;

4.Granger et al. N Eng J Med 2011;365:981‐92.

Haemorrhagic stroke vs  warfarin

%/yrWarfarin%/yr

HR(95% CI)stroke vs. warfarin %/yr (95% CI)

Dabigatran 150 mg 0.10 0.380.26 (0.14‐

0.49)

Dabigatran 110 mg 0.12 0.38 0.31 (0.17‐0.56)

Rivaroxaban 0.26 0.44 0.59 (0.37‐0.93)

Apixaban 0.24 0.47 0.51 (0.35‐0.75)

Favours new orals              Favours warfarin0 1 2.0

1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix;

4.Granger et al. N Eng J Med 2011;365:981‐92.

All cause mortality vswarfarin

%/yrWarfarin%/yr

HR(95% CI)

warfariny 95

Dabigatran 150 mg 3.64 4.13 0.88 (0.77‐1.00)

Dabigatran 110 mg 3.75 4.13 0.91 (0.80‐1.03)

Rivaroxaban 1.87 2.21 0.85 (0.70‐1.02)

Apixaban 3.52 3.94 0.89 (0.80‐0.99)

0.5 1Favours new orals            Favours warfarin

1.5

1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix;

4.Granger et al. N Eng J Med 2011;365:981‐92.

Major bleeding vswarfarin

%/yrWarfarin%/yr

HR(95% CI)warfarin %/yr (95% CI)

Dabigatran 150 mg 3.32 3.57 0.93 (0.81‐1.07)

Dabigatran 110 mg 2.87 3.57 0.80 (0.70‐0.93)

Rivaroxaban 3.6 3.4 1.04 (0.90‐1.203 3 4 4 ( 9

Apixaban 2.13 3.09 0.69 (0.60‐0.80)

0.5 1Favours new orals            Favours warfarin

1.5

1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix;

4.Granger et al. N Eng J Med 2011;365:981‐92.

Intracranial bleeding vs %/yr

Warfarin%/yr

HR(95% CI)

gwarfarin

y%/yr (95% CI)

Dabigatran 150 mg 0.32 0.76 0.41 (0.28‐0.60)

Dabigatran 110 mg 0.23 0.76 0.30 (0.19‐0.45)

Rivaroxaban 0 5 0 7 0 67 (0 47 0 93)Rivaroxaban 0.5 0.7 0.67 (0.47‐0.93)

Apixaban 0.33 0.80 0.42 (0.30‐0.58)

Favours new orals              Favours warfarin0 1 2.0

1. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 3. Patel MR et al. NEJM 2011;365:883–91 and Supplementary Appendix;

4.Granger et al. N Eng J Med 2011;365:981‐92.

Patients asking for NOACsA      t i l   bli h dAs soon as trials publishedFollowing approvalsAware of NICE guidelines

Empowered patientp pClear agenda coming in to clinicGood  nderstanding of cost and other iss esGood understanding of cost and other issuesAFA and other ‘professional’ website

• Aug 2009 – RELY trial• Sept 2011 – EMA approvalDabigatran • Sept 2011 – EMA approval• March 2012 – NICE TA299

Dabigatran

• Nov 2010 – ROCKET‐AF trial• Dec 2011 – EMA approvalRivaroxaban pp• March 2012 – NICE FAD

Rivaroxaban

• Aug 2011 –ARISTOTLE trial• Not licensed yetApixaban• ?August – NICE

p

The aim of this advice is to promote the safe and effective use of ▼dabigatran within its licensed indication inThe aim of this advice is to promote the safe and effective use of ▼dabigatran within its licensed indication in BCUHB for the prevention of stroke and systemic embolism for patients with nonvalvular atrial fibrillation.The advice:1 Warfarin with dose titrated to a target INR of 2 to 3 remains the anticoagulant of choice for stroke1. Warfarin, with dose titrated to a target INR of 2 to 3, remains the anticoagulant of choice for stroke

prevention in AF. The focus of AF management should be to identify patients with AF and undertake stroke risk assessment using the CHADS2 risk assessment tool, or more recently introduced CHA2DS2-VASc risk assessment tool (see Appendix 1).

Patients ith a CHADS / CHA DS VASc score ≥ 2 sho ld be initiated on arfarin in the first instancePatients with a CHADS2 / CHA2DS2-VASc score ≥ 2 should be initiated on warfarin in the first instance, unless contraindicated.

2. In warfarin naive patients, if there are compelling reasons (see below) not to initiate warfarin then ▼dabigatran initiation should be undertaken only by Secondary Care clinicians specialising in stroke g y y y p gprevention in AF (eg Cardiology or the Stroke team). However in this group of patients continued prescribing by General Practitioners is appropriate i.e. ▼dabigatran's BRAG List designation for stroke prevention in AF is AMBER WITHOUT SHARED CARE. Compelling reasons include patients who are:

Unable to take warfarin due to allergy or contraindications (that is not otherwise a contraindication gy (to anti-coagulant therapy in general). Note that a bleeding risk that would lead to contra-indication of warfarin would also contra-indicate dabigatran.

3. For patients prescribed warfarin previously ▼ dabigatran will only be considered as an alternative to warfarin for stroke prevention in AF in patients who are:warfarin for stroke prevention in AF in patients who are:

Unable to achieve an INR within the target therapeutic range (TTR) for at least 50% of the time over a period of 6 months (excluding first month after initiation) on warfarin. The TTR can be calculated automatically with most INR monitoring software systems.

Travel IssuesInternational businessmanRemote residence  can’t easily get to hospitalRemote residence – can’t easily get to hospital

Dosing difficultiesInnumerate Can’t do /Confused changing doses warfarinPill boxes

d

Can t do /won’t doW f iFear adverse events

Family members problemsRisk of intracranial bleeds

Warfarin

Risk of intracranial bleedsRefusal 

QOL dietary restrictions

‘Good’ pt vs. ‘Bad’ patient (rewarded)

‘Simple’ defined population type

Good clinical trial  Approval for use

Select difficult patients (outside trial)

Uncertain / poor outcomes/ p

Lack of confidence/ drug experienceLack of confidence/ drug experience

High bleeding risk/event

High risk but not anticoagulated

Professional reluctanceanticoagulated

Patient reluctance New Agents

Patient difficulty warfarin

g

On WarfarinContinue onWarfarinWarfarin

Loss of income / service primary care?Will  t  li i t   ti l ti   li i  Will not eliminate anti‐coagulation clinics (immediately)Other conditions needing warfarin (presently)True bleeding or high unacceptable riskTrue bleeding or high unacceptable riskLow risk patientsPatients happy and stable on current Rx

ReversibilityI  thi   ll    bi  i ?• Is this really a big issue?

• Antidotes in development

Monitoring?Monitoring?• Don’t do for most other anti‐thrombotics• Crude assessments possible• Crude assessments possible

Clinical scenarios• Cardioversion• EP studies• ACS & PCI – difficult areaACS & PCI  difficult area• Confusion doses for other indications (e.g. VTE prophylaxis, DVT/PE Rx)

Duty of care to patientInformed consentInformed consentLaying out of all options – balanced & objectiveRisk and benefits as applicable to patient

Patient choice and partnershipp pLegal status of NICE / AWMSG decisionCannot force warfarin on a patientCannot force warfarin on a patientCan we deny any other treatment i.e. none?Yet to be tested in court…

SPAF remains an unmet needWarfarin remains a good option (tried & tested)Warfarin remains a good option (tried & tested)But for many patients ( & prescribers) not acceptable

N   l  ti l t   ffNew oral anticoagulants offerEquivalent / greater efficacy in SPAF cf. warfarinGreater safety for intracranial bleedsSignificant QOL benefits for many patients

Challenge implementation: Patient vs. Clinician vs. OrganisationgIssue for today – 5 years NOACs will be routine