Atrial Fibrillation- Anticoagulation

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Reversal with perosphere

In a clinical trial in healthy volunteers, there was a marked reduction in clotting time with a dose response

61Ansell JE et al. N Engl J Med. 2014 371(22): 2141-2

Homocysteine: alive again

•MI ≠ STROKE

•MI – almost all due to plaque rupture; thrombosis is secondary to occlusion

•STROKE: atheroembolic, dissection, vasculitis, small vessel disease (lacunar infarctions), cerebral vein thrombosis

–Coagulation more important

–Cardiac emboli

AF, MI, ventricular aneurysm

Paradoxical embolism

62Spence JD. Lancet Neurology 2007; 7: 830-838

Homocysteine: steep dose-response curve

(schematic)

Risk of cardiovascular event

Homocysteine blood levels

63Based on: Nygård O et al. N.Engl.J.Med. 1997; 337: 230-6

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Biological plausibility is overwhelming

•Increased thrombosis

•Impaired endothelial function

•LDL, HDL synthesis

•Oxidative stress including oxidized LDL

•Causal in animal models1

641. Zhou J et al. Atherosclerosis. 2003; 168: 255-62

Homocysteine and venous thrombosis

•Excess of high tHcy and prothrombin gene mutation in cerebral venous thrombosis1

•High tHcy a risk factor for venous thrombosis2

•High tHcy a risk factor for retinal vein occlusion3

1.Ventura P. Cerebrovasc Dis. 2004; 17(2-3): 153-9

2.den Heijer M. Clin Chem Lab Med. 2003; 41: 1404-7 653. Chua B et al. Am J Ophthalmol. 2005 Jan; 139(1): 181-2

Homocysteine and atrial fibrillation

•In patients with AF

•Stroke risk is 4-5 fold higher with tHcy > 14

66

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Homocysteine increases risk in atrial fibrillation

Homocysteine>90th percentile

p=0.006

Homocysteine<90th percentile

Time (days)

67Poli D et al. Stroke 2005; 10: 2159-63

Vitamin B12 deficiency

• There are about 8 ways for B12 absorption to go wrong:

‒ Terminal ileum: Crohn’s etc.

‒ 2 transport proteins: transcobalamin II

 Genetic deficiency, antibodies

• In Framingham, 40% of elderly have levels <258 pmol/L1, which represents insufficient B12 to maintain normal MMA

• 20% of elderly have B12 deficiency2

1. Lindenbaum J et al. Am J Clin Nutr 1994; 60: 2-11 682. Andres E. et al. CMAJ 2004 Aug 3; 171(3): 251-9

Baseline tHcy by serum B12 (pmol/L), adjusted for age, sex, smoking and GFR (NHANES)

Segmented

regression

69Bang H, Mazumdar M, Spence D. Neuroepidemiology. 2006; 27(4): 188-200

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Threshold B12 level for MMA and tHcy

Hordaland study n=6946

70Vogiatzoglou A … Refsum H. Clinical Chemistry 2009; 55: 12 2198–2206

Metabolic B12 deficiency in the stroke prevention clinic

•Proportion of patients

with various B12 levels in the Stroke

Prevention Clinic

•Only 26%

had serum B12 in the clearly

adequate range above 400 pmol/L

72

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Metabolic B12 deficiency in vascular patients

•Define by methylmalonic acid (or tHcy in folate-replete state)

•11% age <50

•12% age 51-71

•30% age >71

73Spence JD. Stroke 2006; 37: 2430-5

tHcy>14 μmol/L by age

n= 2372 - patients referred to stroke prevention clinic

74Spence JD. Lancet 2009; 373: 1006

Follow up time in days

75Spence JD et al. Stroke. 2005; 36: 2404-2409

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

HOPE-2 trial

23% reduction of stroke in the HOPE-2 trial (p=0.03) – first study to use 1 mg of vitamin B12

76Based on: Refsum H, Smith AD. N Engl J Med. 2006; 355: 207

Reduction of stroke in SuFolOM3 trial

p=0.04

Galan P, et al. BMJ. 2010; 341: c6273

VITATOPS

•n= 1463 not on antiplatelet therapy

•HR 0·76 (0·60–0·96)

for stroke/MI/vascular death

78Hankey GJ et al. Lancet Neurol 2012; 11: 512–20

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

VITATOPS stratified by GFR

Cyanocobalamin dose was lower in VITATOPS – 500 mcg

79Yi Q, Hankey G, Spence JD. Unpublished data

JAMA. 2010; 303(16): 1603-1609

80

Stroke, MI, death1

The greatest harm of vitamin therapy was in patients with GFR<502

1. JAMA. 2010; 303(16): 1603-1609

812. JAMA. 2010; 304(6): 636-637

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

Possible harmful effects of folic acid

Folic acid does not reverse the increase

in asymmetric dimethylarginine that accompanies high homocysteine levels

82Based on: Loscalzo, J N Engl J Med 2006; 345: 1629-32

Cyanide from B12

83Koyama K et al. Nephrol Dial Transplant. 1997; 12: 1622-8

Interesting lessons

•Clinical trials are blunt instruments for studying vascular biology

•Subgroup analyses can be very informative

•We should probably be using methylcobalamin or hydroxycobalamin instead of cyanocobalamin

•? Tetrahydrofolate instead of folic acid (particularly

where folic acid fortification of the grain supply is in effect)

84Spence JD, Stampfer M. JAMA 2011; 306: 1260-1261

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

What’s the secret?

To select the appropriate treatment, find the cause of the TIA/stroke

85

Find the cause, and treat it

•U/S: symptomatic severe (moderate) carotid stenosis – endarterectomy

•MRA/CTA: basilar occlusion ?anticoagulate

–Intracranial stenosis ?ASA/clopidogrel

•ECG/Echo/Holter/TCD: cardiac source: anticoagulate

•Vasculitis (e.g. giant cell arteritis – prednisone)

•TCD – intracranial stenosis ?Anticoagulate

•TCD with bubble test for paradoxical embolusanticoagulate or ?close PFO

•Aortic atheroma - intensive medical Rx,

86 ?anticoagulate, ??surgery

87http://www.imaging.robarts.ca/SPARC/ dspence@robarts.ca

Atrial Fibrillation, Anticoagulation

and Vitamins for Homocysteine

Prof. J. David Spence M.D.

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