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Atrial Fibrillation- Anticoagulation

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Atrial 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