Atrial Fibrillation- Anticoagulation
.pdfAtrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Stroke Prevention & Atherosclerosis
Research Centre
Robarts Research Institute
London, Canada
dspence@robarts.ca
http://www.imaging.robarts.ca/sparc
1
Stroke series
Perspective and Pathogenesis
1.Cerebrovascular disease: introduction and perspective (41 mins) Prof. Vladimir Hachinski – Western University, Canada
2.Basic anatomy, physiology and pathophysiology of the cerebral circulation for the physician
(32 mins) Prof. Jean-Claude Baron – Cambridge University Hospitals, UK
3. Pathophysiology of cerebral ischemia (43 mins) Prof. Wolf-Dieter Heiss – Max Planck Institute for Neurological Research, Germany
Diagnosis
4.The clinical diagnosis of stroke and stroke subtypes (42 mins) Prof. Louis Caplan – Beth Israel Deaconess Medical Center and Harvard University, USA
5.The investigation of stroke (30 mins) Dr. Bart Demaerschalk – Mayo Clinic Arizona, USA
Treatment
6. General management (27 mins) Prof. Bo Norrving – Lund University Hospital, Sweden
7.The treatment of stroke: specific management - thrombolysis plus (35 mins) Prof. Nils Wahlgren
– Karolinska University Hospital, Sweden
8.The deteriorating stroke (36 mins) Prof. Werner Hacke – University of Heidelberg, Germany
Rehabilitation
9.Stroke rehabilitation (42 mins) Prof. Robert Teasell – University of Western Ontario, Canada
10.Rehabilitation: the chronic phase (42 mins) Prof. Lalit Kalra – King’s College London School 2 of Medicine
Disclosures
•Interest in vascularis.com
•Lecture honoraria/travel support from Bayer, Merck, Boehringer-Ingelheim, Pfizer
•Research support for investigator-initiated projects from Pfizer
•Contract research with many pharma/device companies: all of the above, plus Takeda, BMS, Servier, Wyeth, Miles, Roussel, NMT, AGA, Gore
•Grants from CIHR, Heart & Stroke Foundation, NIH/NINDS
3
The screen versions of these slides have full details of copyright and acknowledgements |
1 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Stroke and aging population
|
14 |
Stroke |
|
|
12 |
||
Percent |
10 |
|
|
8 |
Men |
||
|
|||
|
6 |
Women |
|
|
4 |
|
2
0
20-34 35-44 45-54 55-64 65-74 75+
41. Economist 2014 2. AHA Statistics 2007
Percent
18
16 CAD
14
12
10
8
6
4
2
0
20-34 35-44 45-54 55-64 65-74 75+
Atrial fibrillation and age
•At age 50: 1.5% of stroke
•At age 80-89: 23.5% of stroke (probably a higher proportion now)
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke:
5the Framingham Study Stroke. 1991; 22: 983-8
Projected number of adults
with atrial fibrillation in the United States between 1995 and 2050
•1995: 2,080,000
•2050 (expected):5,610,000
6Bsaed on: Go AS et al. JAMA 2001; 285: 2370-2375
The screen versions of these slides have full details of copyright and acknowledgements |
2 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Diagnosing cardioembolic stroke
•Negative evidence
‒Normal arteries, normal blood pressure
‒Not lacunar
‒No indication of vasculitis
•Positive evidence
‒Clinically embolic
‒Multiple vascular territories
‒Echo, Holter, TCD bubble study
7
Baseline carotid plaque area as a predictor of 5-year risk of stroke, MI, death
(after adjustment for risk factors*)
*Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BP
8Stroke 2002; 33: 2916-2922
Cryptogenic stroke
“Normal arteries”
•Not just no stenosis: also little plaque
•Not just young people
•Plaque measurement very useful
79 y.o. woman |
72 y.o. man |
9 |
Composite drawing of all plaques in extracranial carotids |
The screen versions of these slides have full details of copyright and acknowledgements |
3 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Ischemic stroke subtypes are changing
•Better BP control
•More statins
10Bogiatzi C ….Spence JD. Stroke. 2014 Sep 11
Ischemic stroke subtypes are changing
Before 2005 |
After 2009 |
• Cardioembolic strokes more common, large artery strokes less common
11Bogiatzi C ….Spence JD. Stroke. 2014; 45: 3208-13
Treat early on clinical grounds
Anticoagulate pending the result of echo, Holter etc.
12Purroy F et al.
Stroke 2007; 38; 3225-3229
The screen versions of these slides have full details of copyright and acknowledgements |
4 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
AF, aging and under-anticoagulation
Medicare: only 2/3 of appropriate candidates receive warfarin1
Canadian Stroke Registry2: Patients who should have been on warfarin
• Only 40% were receiving warfarin
• 30% were on antiplatelet therapy
• 29% were receiving neither
• Only 10% of patients admitted with stroke and known AF were anticoagulated appropriately to an INR of 2 to 3
• Even with AF and previous stroke/TIA, only 18% appropriately anticoagulated
• New anticoagulants (e.g. dabigatran, rivaroxaban) may help3
1. Birman-Deych E et al, Stroke 2006; 37: 1070-4 2. Gladstone, DJ. et al. Stroke 40, 235-240 (2009)
13. Spence JD. Nature Reviews Cardiology 2009; 6: 448 – 450
Antiplatelet agents are not anticoagulants
14
Activated platelets
15
The screen versions of these slides have full details of copyright and acknowledgements |
5 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Retinal embolus of platelet aggregates
16Fisher CM. Neurology. 1959 May; 9(5): 333-47
White thrombus vs. red thrombus
•White thrombus: platelet aggregates
‒Fast flow, arteries
‒Treatment: antiplatelet agents
•Red thrombus: fibrin polymer with entrapped RBCs
‒Stasis, veins, AF, recent MI, ventricular aneurysm
‒Treatment: anticoagulants
Deykin D. New Engl J Med 1967; 276: 622-628
17Caplan L. Rev Neurol Dis 2007; 4: 113-121
Antiplatelet agents don’t work in atrial fibrillation
Adding clopidogrel to ASA only reduces stroke risk by 0.67%, NNT 149
18Connolly SJ et al. Ann Intern Med 2011 155: 579–586
The screen versions of these slides have full details of copyright and acknowledgements |
6 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Adjusted dose warfarin
vs. low-dose warfarin plus aspirin
It’s all about INR
19SPAF III Lancet 1996; 348(9028): 633-638
ASA vs. warfarin in elderly: BAFTA study
•973 patients with AF age > 75
•Annual stroke risk 3.4% with ASA, 1.6% with warfarin
p=0·003
•Fatal or disabling stroke, intracranial haemorrhage, or clinically significant arterial embolism
•No significant increase in bleeding with warfarin
Mant J et al. Lancet 2007; 370: 493–503
ASA less effective than warfarin for stroke prevention in ASA trials
Warfarin reduces stroke by ~ 50%, compared to aspirin
21Adapted from Hart et al. Ann Intern Med 2007; 147: 590-592
The screen versions of these slides have full details of copyright and acknowledgements |
7 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Poor INR control increases risk of stroke in the real world
Stroke survival in 37,907 AF patients – UK General Practice Research Database (27,458 warfarin users and 10,449 not treated with an antithrombotic)
% of patients without stroke
100
95
%TTR
90
> 70
85 |
|
|
|
|
61-70 |
|
|
|
|
|
|
|
|
|
|
|
51-60 |
80 |
|
|
|
|
41-50 |
|
No warfarin |
|
|
|
31-40 |
75 |
|
|
|
< 30 |
|
|
|
|
|
||
|
|
|
|
|
|
I |
I |
I |
I |
I |
I |
0 |
20 |
40 |
60 |
80 |
100 |
Months
22Adapted from Gallagher et al. Thromb Haemost 2011; 106: 968-77
Warfarin will continue to be used
Dabigatran Warfarin
•Cost
•Prosthetic valves
•Renal failure
So we still need to do better with it
23Spence JD. J Neural Transmission: 2013; 120: 1447-1451
Narrow therapeutic range
Adjusted odds ratio for ischaemic stroke and intracranial bleeding in relation to INR
Odds ratio
Ischaemic |
Intracranial |
stroke risk |
bleeding risk |
20 |
|
|
Ischaemic stroke risk |
15 |
Intracranial bleeding risk |
10
5
1
1.0 |
2.0 |
3.0 |
4.0 |
5.0 |
6.0 |
7.0 |
8.0 |
INR |
Adapted from: Fuster et al. Circulation 2011; 123: e269-e367. / Hylek and Singer. Ann Intern Med 1994; 24120: 897-902 / Oden et al. Thromb Res 2006; 117: 493-9
The screen versions of these slides have full details of copyright and acknowledgements |
8 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Genetics of warfarin response
Schwarz, U.I. et al. N. Engl. J. Med. 2008; 358: 999-1008
•Polymorphism of warfarin response VKORC1 (vitamin K receptor)
•Polymorphism of warfarin metabolism CYP2C9
•Huge range of inter-individual differences
in both metabolism and response to warfarin
•Individualized therapy better using genotyping
25
Receptor polymorphism
•VKORC1 haplotype had a significant effect on the time that was required to reach the first INR
within the therapeutic range (P = 0.02) and the time to the first INR of more than 4 (P = 0.003)
‒A/A: 32
‒A/non-A: 129
‒Non-A/non-A: 135
•There was much more bleeding among patients with polymorphism
26Schwarz,U.I. et al. N. Engl. J. Med. 2008; 358: 999-1008
Metabolism polymorphism
•CYP2C9 genotype did not significantly affect the time to the first INR within the therapeutic range
•Carriers of CYP2C9*2 and CYP2C9*3 variant alleles
did reach a first INR of more than 4 earlier than did patients with the wild-type allele (P = 0.03)
‒*1/*1: 204
‒*1/*2 or *1/*3: 79
‒*2/*2, *3/*3 or *2/*3: 1
•The time to a high INR was earlier in patients with polymorphisms
27Schwarz,U.I. et al. N. Engl. J. Med. 2008; 358: 999-1008
The screen versions of these slides have full details of copyright and acknowledgements |
9 |
Atrial Fibrillation, Anticoagulation
and Vitamins for Homocysteine
Prof. J. David Spence M.D.
Aspirin vs. apixaban in AF: AVERROES trial
Stroke or systemic embolism:
hazard ratio with apixaban, 0.45 (95% CI, 0.32–0.62)
28Connelly SJ et al. N Engl J Med. 2011 Mar 3; 364(9): 806-17
Aspirin vs. apixaban in AF
Major bleeding:
hazard ratio with apixaban, 1.13 (95% CI, 0.74–1.75)
29Connelly SJ et al. N Engl J Med. 2011 Mar 3; 364(9): 806-17
Apixaban vs. ASA in TIA/stroke
|
|
No TIA/stroke |
|
|
Aspirin |
Stroke |
hazard |
Apixaban |
|
||
or systemic |
Cumulative |
HR 0.51 (95% CI 0.35-0.74) |
embolism |
|
|
|
|
|
|
hazard |
HR 1.08 (95% CI 0.64-1.80) |
Major |
|
|
|
|
|
Bleeding |
Cumulative |
|
|
|
30
Time (months)
Diener H-C et al. Lancet Neurol 2012; 11: 225–31
TIA/stroke
HR 0.29 (95%
CI 0.15-0.60)
HR 1.28 (95% CI 0.58-2.82)
Time (months)
The screen versions of these slides have full details of copyright and acknowledgements |
10 |