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
Adapted from Thachil, J
Clin Med 201414;165-75.
Warfarin vs. NOAC
Consideration
• Pregnancy
• Malignancy
Recommendation
• Warfarin/LMWH
• LMWH ?!!!!
• Compliance concerns • Nothing or Warfarin/LMWH
Adapted from Thachil, J
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
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
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
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
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
DBG2919 | September 2011
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
DBG2919 | September 2011
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
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
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
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.
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
DBG2919 | September 2011
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.