anticoagulation - which patients should be on novel oral ... ellis - noacs - wpcc.pdf · af...

Anticoagulation - which patients should

be on Novel Oral Anticoagulants

(NOAC)?

Welsh Primary Cardiovascular ConferenceWelsh Primary Cardiovascular ConferenceAbertawe, Mai 2014

Gethin Ellis Cardiologist Cwm Taf UHB

Declaration (?conflicts) of interest....

• Advisory boards:

Boehringer, Pfizer,

Bayer

• My personal

experiences…..

• Many free pens,

sandwiches, crisps,

USB sticks, laser

pens, car

accessories, key

rings, ……

• My clinical

experience as a

warfarin

prescriber….

VKA ‘NOAC/ODI/DOA/NVKA’

V.

‘Novel’ Oral Anticoagulants

Oral Direct Inhibitors

Direct Oral Anticoagulants

Non-vitamin K anticoagulants

Narrow therapeutic range with VKA

Target INR

(2.0-3.0)

60

80

Even

ts /

1000 p

ati

en

t years

Intracranial haemorrhage

Ischaemic stroke

The anticoagulant

effect of vitamin K

International Normalised Ratio (INR)

<1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6-4.0 4.1-4.5 >4.50

20

40

Even

ts /

1000 p

ati

en

t years

antagonists are

optimized when

therapeutic doses are

maintained within a

very narrow range

1. Hylek EM, et al. N Eng J Med 2003; 349:1019-1026.

Novel oral anticoagulants - NOAC

• Direct thrombin inhibitors – dabigatran1, ximelagatran

• Factor Xa inhibitors – rivaroxaban2, apixaban3, edoxaban4, betrixaban, idraparinux

• Factor IXa inhibitor – TTP889

• Glycosaminoglycan enhancer - odiparcil1.RELY. 2.ROCKET-AF. 3.ARISTOTLE.4.ENGAGE.www.nice.org

Licensed indications for NOAC

NOAC Stroke prevention in non-valvular AF

DVT treatment

PE treatment

Prevention of recurrent DVT/PE

Prophylaxis VTE following knee and hip surgery

Dabigatran Y N N N Y

Rivaroxaban Y Y Y Y Y

Apixiban Y N N N Y

AF increases the risk of stroke

• AF is associated with a pro-thrombotic state– ~5 fold increase in stroke risk1

• Risk of stroke is the same in AF patients regardless of

whether they have paroxysmal or sustained AF2,3whether they have paroxysmal or sustained AF2,3

• Cardioembolic stroke has a 30-day mortality

of 25%4

• AF-related stroke has a 1-year mortality of ~50%5

1. Wolf PA, et al. Stroke 1991;22:983-988; 2. Rosamond W et al. Circulation. 2008;117:e25–146; 3.Hart RG, et al. J Am Coll Cardiol 2000;35:183-187;

4. Lin H-J, et al. Stroke 1996; 27:1760-1764; 5. Marini C, et al. Stroke 2005;36:1115-1119.

Stroke risk assessment with CHADS2

CHADS2 criteria Score

Congestive heart

failure1

Hypertension 1

16

20

Adjusted stroke risk

NR

AF

ad

juste

d s

tro

ke r

ate

p

er

100 p

ati

en

t years

, w

ith

ou

t asp

irin

Hypertension 1

Age >75 yrs 1

Diabetes mellitus 1

Stroke / transient

ischaemic attack2

1 Gage BF et al. JAMA 2001;285:2864–70.

2 Based on data from Gage BF et al. JAMA 2001;285:2864–70.

0

4

8

12

0 1 2 3 4 5 6

CHADS2 score

NR

AF

ad

juste

d s

tro

ke r

ate

p

er

100 p

ati

en

t years

, w

ith

ou

t asp

irin

Car Parking at the Liberty Stadium

Stroke risk assessment with CHA2DS2-VASc

CHA2DS2-VASc criteria Score

Congestive heart failure/left ventricular dysfunction

1

Hypertension 1

Age ≥≥≥≥75 yrs 2

Diabetes mellitus 1

Stroke/transient ischaemic attack/TE

2

CHA2DS2-VASc total score

Rate of stroke/other TE (%/year)*

0 0.0

1 1.3

2 2.2

3 3.2

4 4.0

DBG2919 | September 2011

attack/TE

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

1

Age 65–74 yrs 1

Sex category (i.e. female gender)

1

4 4.0

5 6.7

6 9.8

7 9.6

8 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

Intracranial

bleeding vs

warfarin

%/yrWarfarin

%/yrHR

(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)

New agents: Intracranial bleeding vs warfarin

Rivaroxaban 0.5 0.7 0.67 (0.47-0.93)

Apixaban 0.33 0.80 0.42 (0.30-0.58)

0 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.

Favoursnew orals

Favourswarfarin

www.escardio.org/guidelines

European Society of Cardiology

www.escardio.org/EHRA

AWMSG -NOAC for SPAF 2012

AF patients with previous TIA or ischaemic stroke, considered to be suitable for

anticoagulation and admitted with acute ischaemic stroke (Ontario 2003–2007)

Warfarin –

therapeutic, 18%

Dual antiplatelet

therapy, 3%

No antithrombotics, 15%

Warfarin –

Sub-therapeutic, 39%

Single

antiplatelet

agent, 25%

therapy, 3%

n=323

Adapted from Gladstone et al. Stroke 2009;40:235–40.

Antiplatelet/antcoagulants in stroke patients with AF (Wales)

Patients on the practice register with AF - nurse triaged and 47 reviewed by Cardiologist (Dr Richard Anderson)

Therapeutic

warfarin - 32Dual

antiplatelet

No antithrombotic - 12

2014 – Practice in Cardiff (Dr Armon Daniels)

Sub- therapeutic

warfarin - 12

Single antiplatelet

agent - 20

antiplatelet

therapy - 2

Changes….

• 6 switches from Warfarin to NOAC

• 7 switches from ASA/nil to Warfarin

• 2 switches from ASA/nil to NOAC

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.

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.

(in atrial fibrillation)

MetabolismEsterase catalysed hydrolysis

CYP P450 dependant and independent mechanisms

CYP P450

Excretion 85% Renal1/3 Renal2/3 Hepatic

1/4 Renal3/4 Non Renal

Form Capsule Tablet Tablet

Dose150 mg110 mg (>80 yrs, verapamil or

increased bleeding risk)

20 mg15 mg (CrCL 30-49 ml/min)

5 mg2.5 mg (2 or more:

>80yr; weight <60 kg;

Cr >1.5 mg/dL)

B.D. = twice daily; O.D. = once daily

Drug interactions – effect on NOAC plasma levels

Dabigatran Apixiban Rivaroxaban

Atorvastatin +18% No data yet No effect

Verapamil +12-180% No data yet Minor effectVerapamil +12-180% No data yet Minor effect

Diltiazem No effect +40% Minor effect

Amiodarone +12-60% No data yet Minor effect

Clari/erythromycin +15-20% No data yet +30-54%

CBZ, Rifampicin -66% -54% -50%

Warfarin vs. NOAC

Consideration

• Valvular heart disease

• Severe hepatic impairment with associated coagulopathy

Recommendation• Warfarin

• Warfarin or LMWH

• Extremes of weight

• CrCl<15ml/min

• Needs triple therapy (AC+DAPT)

• Patient requires high level of AC (eg antiphospholipid Sx)

• Warfarin

• Warfarin

• Warfarin

• Warfarin (studies with NOAC underway)

Adapted from Thachil, J

Clin Med 201414;165-75.

Warfarin vs. NOAC

Consideration

• CrCl >15 - <30ml/min

• History of MI

Recommendation

• Warfarin or R. or A.

• Warfarin or R. or A.

• Recent ischaemic stroke on Warfarin

• DVT or PE

• Dabigatran 150mg bd

• Rivoraxaban


Clin Med 201414;165-75.

Warfarin vs. NOAC

Consideration

• Pregnancy

• Malignancy

Recommendation

• Warfarin/LMWH

• LMWH ?!!!!

• Compliance concerns • Nothing or Warfarin/LMWH


Clin Med 201414;165-75.

Predicting warfarin response in AF

- SAMe-TT2R2Acronym Definitions Points

S Sex (female) 1

A Age (<60 years) 1

Me Medical history* 1

T Treatment 1

T Tobacco use 2

R Race (non-Caucasian) 2

*Two of following: HT, DM, CAD/PVD/CVD, CHF,

pulmonary disease, hepatic or renal disease

‘0-1 Likely to do well on Warfarin≥ 2 More likely to have poor INR control’

Chest 2013;144: 1555-1563.

Warfarin vs. NOAC chat

• 60 years vs. 6 years

• Long term effects -

MI signal?

• Monitoring

• Weekly-monthly vs.

1-3 times/year

• Bleeding risk-

intracranial/GI

bleeds

• Reversal strategies

• Drug/lifestyle

interactions

Compliance..!!

Diolch

New agents: Ischaemic stroke vs warfarin

Ischaemic stroke vs warfarin

%/yrWarfarin

%/yrHR

(95% CI)

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 1 1.5*Ischaemic or uncertain type of stroke

Favoursnew orals

Favourswarfarin


Major bleeding

vs warfarin%/yr

Warf

%/yr

HR

(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 (0.90-1.20

New agents: Major bleeding vs warfarin

Rivaroxaban 3.6 3.4 1.04 (0.90-1.20

Apixaban 2.13 3.09 0.69 (0.60-0.80)

0.5 1 1.5


Favoursnew orals

Favourswarfarin

Pharmacodynamic and kinetic factors

Age ≥75 years

Factors increasingdabigatran plasma levels

Major:

•Moderate renal impairment (30–50 ml/min CrCL)

•P-gp inhibitor co-medication

Minor:

•Low body weight (<50 kg)

Pharmacodynamicinteractions

• ASA

• NSAID

Factors which may increase the haemorrhagic risk


interactions • NSAID

• Clopidogrel

Diseases / procedureswith special haemorrhagic risks

• Congenital or acquired coagulation disorders

• Thrombocytopenia or functional platelet defects

• Active ulcerative GI disease

• Recent gastro-intestinal bleeding

• Recent biopsy or major trauma

• Recent ICH

• Brain, spinal or ophthalmic surgery

• Bacterial endocarditis

Practical points re. NOAC

• Patient selection and information/discussion

• Renal function-baseline ~ 1-3x year • Renal function-baseline ~ 1-3x year

• Dose decision

• Switching

• Concurrent medication

Bleeding advice using NOAC

for SPAF

• Minor bleeding • Omit ≥ 1dose of

drug

• Restart once • Restart once

bleeding settled

• Consider lower dose

Warfarin vs. NOAC in SPAF

• Not licensed with

prosthetic

valves/valvular HD

• Dabigatran may cause

dyspepsia/ increase GI

• Fewer drug/food

interactions

• Little/no monitoringdyspepsia/ increase GI

bleeding risk

• Stopping abruptly relies

predominantly on short

half-life (currently)

• Long term effects

unknown

• Warfarin may be

protective post-ACS

• May be better

• May have lower major

bleeding risk

Practical considerations when initiating Pradaxa®

Defined process to switch patients from warfarin

Initiation for new patients•Initiate Pradaxa®

•Onset of effect starts shortly after dosing with peak plasma concentrations and maximal anticoagulant effects achieved within 0.5–2 hours•No need to give an interim dose of low molecular weight heparin


Defined process to switch patients from warfarin•Discontinue warfarin•Initiate Pradaxa® once the patient’s INR is below 2.0

• The time this takes will vary from patient to patient

Switching patients taking aspirin for SPAF•Discontinue aspirin•Initiate Pradaxa®

An educational pack has been developed to support the prescribing of Pradaxa® for stroke prevention in atrial fibrillation

Myocardial

infarction vs

warfarin

%/yrWarfarin

%/yrHR

(95% CI)

Dabigatran 150 mg 0.81 0.64 1.27 (0.94-1.71)

Dabigatran 110 mg 0.82 0.64 1.29 (0.96-1.75)

New agents: Myocardial infarction vs warfarin

Rivaroxaban 0.91 1.12 0.81 (0.63-1.06)

Apixaban 0.53 0.61 0.88 (0.66-1.17)

0.2 1 1.8


Favoursnew orals

Favourswarfarin

All cause

mortality vs

warfarin

%/yrWarf

%/yr

HR

(95% CI)

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)

New agents: All cause mortality vs warfarin

Rivaroxaban 1.87 2.21 0.85 (0.70-1.02)

Apixaban 3.52 3.94 0.89 (0.80-0.99)

0.5 1 1.5


Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.

Favoursnew orals

Favourswarfarin

Why time in therapeutic range (TTR) matters

0.8

0.9

1.0C

um

ula

tive s

urv

ival

71–100%

Warfarin group

61–70%

51–60%

41–50%

31–40%

<30%

Non warfarin


0 500 1000 1500 2000

Survival to stroke (days)

0.6

0.7

0.8

Cu

mu

lati

ve s

urv

ival

Non warfarin

Morgan CL et al. Thrombosis Research 2009;124:37–41.

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