Stroke prevention in AF Dr Ronald M Jardine Linmed Hospital, Benoni 25 October 2015
Stroke prevention in AF - 2015 Dr Ronald M Jardine Linmed Hospital, Benoni 25 October 2015
AF increases the risk of stroke o AF is associated with a...
Stroke prevention in AF - 2015 Dr Ronald M Jardine Linmed Hospital, Benoni 25 October 2015
AF increases the risk of stroke o AF is associated with a ~5 fold increase in stroke risk i.e. to ~5% per year1 o Risk of stroke is the same in AF regardless of whether it is paroxysmal / persistent / permanent 2,3
o AF is associated with 15-20% of all strokes o Up to 3 million people suffer AF related stroke each year worldwide4 1. Wolf PA et al. Stroke 1991; 22: 983-8. 2. Rosamond W et al. Circulation 2008; 117: e25–146. 3.Hart RG et al. J Am Coll Cardiol 2000; 35: 183-187. 4. Atlas of Heart disease and Stroke, World Health Organisation, September 2004. http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf
Stroke severity in AF AF-related strokes tend to be especially severe and disabling o 30-day mortality = 25%1 o 1-year mortality = 50%2 1. Lin HJ et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27: 1760-4. 2. Marini C et al. Stroke 2005; 36: 1115-9.
Stroke severity in patients with AF Effect of first ischaemic stroke in patients with AF (n=597)1 60%
% of patients
50% 40% 30% 20% 10%
0% Disabling Gladstone DJ et al. Stroke 2009; 40: 235-240.
Fatal
Economic burden of AF The American Heart Association estimates that the direct and indirect cost of stroke in the US is $65.5 billion pa1
A German Registry has shown that the overall first-year cost of AF is €18,5172
A 15% reduction in stroke-related hospital admissions in the UK would save an estimated £30 million/year3
1. Rosamond W et al. Circulation 2008; 117: e25–146. 2. Kolominsky-Rabas PL et al. Stroke 2006; 37: 1179–83. 3. Stewart S et al. Heart 2004; 90: 286–292.
Thrombo-embolism in AF o Thrombus from LA / LAA
Thrombus from LA/LAA Virchow’s triad o Stasis
o Endothelial dysfunction o Hyper-coagulable state
Watson T et al. Lancet 2009; 373: 155-66.
Thrombo-embolism in AF o Thrombus from LA / LAA (only 75%) o Other cardio-embolic, e.g. prosthetic valve, LV aneurysm o Aortic atheroma o Cerebro-vascular disease
CHA DSVASc score o o o o o o o o
Risk factor Score CHF / LV dysfunction 1 Hypertension 1 Age > 75 2 Diabetes mellitus 1 Stroke/TIA/other embolism 2 Vascular disease 1 Age 65-74 1 Sex category (female) 1 Max score 9
Stroke rate according to CHADSVASc Score 0 1 2 3 4 5 6 7 8 9
% per annum 0 1.3 2.2 3.2 4.0 6.7 9.8 9.6 6.7 15.2
ESC recommendations o CHADSVASc score = 0 Aspirin or nothing Preferrably nothing o CHADSVASc score = 1 Consider Oral Anticoagulant (OAC) Preferrably Novel OAC (NOAC) o CHADSVASc score = 2 or more Oral Anticoagulant mandatory Preferrably Novel OAC
HAS-BLED score o o o o o o o
Risk factor Hypertension Abn renal/liver function Stroke Bleeding Labile INR Elderly (>65) Drugs / alcohol Max score
Score 1 1-2 1 1 1 1 1-2 9
ESC Guideline 2012.
Coagulation cascade
Vit K Antagonists II VII IX X
Anti-thrombotic therapy in AF
64
Hart RG et al. Ann Intern Med 2007; 146: 857-67.
Anti-thrombotic therapy in AF
22
Hart RG et al. Ann Intern Med 2007; 146: 857-67.
Anti-thrombotic therapy in AF
38
Hart RG et al. Ann Intern Med 2007; 146: 857-67.
Brush up on Warfarin - 1 o Anti-coagulate all those who require it o Educate patients starting warfarin o Understand the reason for treatment o Understand what warfarin does o The meaning of the INR o Appropriate response to bleeding o Vitamin K and other antidotes o Drug-drug (especially non-prescription) and food-drug interactions o MedicAlert bracelet o Frequency of INR monitoring and a log book Dalby AJ, Wessels P and Opie LH. S Afr Med J 2013; 103: 901-4.
Brush up on Warfarin - 2 o Take steps to ensure patient compliance
o System to ensure regular monitoring of INR -Lab -Patient self-monitoring? o Use an algorithm to guide dose adjustment. Algorithm consistent dosing relates to better TTR, which in turn relates strongly to thromboembolic and bleeding outcomes o Follow an accepted protocol for bridging the peri-operative period
RE-LY algorithm INR
Dose adjustment
9.00, give Vitamin K 2.5 mg p.o.) van Spall HGC, Wallentin L, Yusuf S et al. Circulation 2012; 126: 2309-16.
Bridging therapy: Cleveland Clinic Timing
Action
Day 5 before surgery if INR 2-3 Day 6 before surgery if INR 3-4.5
Peri-operative bridging anticoagulation in patients with atrial fibrillation BRIDGE trial In patients with AF who had warfarin treatment interrupted for an elective operation or other invasive procedure, forgoing bridging anticoagulation o was noninferior to peri-operative bridging with LMWH for the prevention of arterial thromboembolism and o decreased the risk of major bleeding. Douketis JD et al. N Engl J Med 2015; DOI:10.1056/NEJMoa1501035
When is it not necessary to stop warfarin?
Jaffer AK. Cleveland Clinic J Med 2009; 76(supp 4): S37-S44.
Limitations of VKA therapy Unpredictable response Narrow therapeutic window (INR range 2-3)
Routine coagulation monitoring
Slow onset/offset of action
Frequent dose adjustments
VKA therapy has several limitations that make it difficult to use in practice
Numerous food-drug interactions
Numerous drug-drug interactions
Warfarin resistance
1. Ansell J et al. Chest 2008; 133: 160S-198S. 2. Umer Ushman MH et al. J Interv Card Electrophysiol 2008; 22: 129-37. 3. Nutescu EA et al. Cardiol Clin 2008; 26: 169-87.
Narrow therapeutic range with VKA Target INR
(2.0-3.0)
Ischaemic stroke Intracranial haemorrhage
Events / 1000 patient years
80
The anticoagulant effect of vitamin K antagonists is optimized when therapeutic doses are maintained within a very narrow range
60
40
20
0 4.5
ACTIVE-W trial: mean TTR by country
Connolly SJ et al. Circulation 2008; 118: 2029-37.
0
Country
Wallentin L et al. Lancet 2010; 376: 975–83. 71 72 72 72 70 70 70 71
*Connolly SJ et al. N Engl J Med 2009; 361: 1139-51. **Patel MR et al. N Engl J Med 2011; 365: 883-91. ***Granger C et al. N Engl J Med 2011; 365: 981-92. ****Giugliano RP et al. N Engl J Med 2013; 369: 2093-104.
NOAC – 4 landmark trials o RE-LY dabigatran 150mg BD dabigatran 110mg BD o ROCKET-AF rivaroxaban 20mg OD o ARISTOTLE apixaban 5mg BD o ENGAGE –AF edoxaban 60mg OD edoxaban 30mg OD (All vs dose-adjusted warfarin INR 2-3) Total
19 013 14 263 18 201 21 105
71 683
NOAC trials – Primary end-point
Stroke or systemic embolism
Ruff CT, Giugliano RP, Braunwald E et al. Lancet 2014; 383: 955-62.
Secondary efficacy and safety outcomes
Ruff CT, Giugliano RP, Braunwald E et al. Lancet 2014; 383: 955-62.
Major bleeding
Ruff CT, Giugliano RP, Braunwald E et al. Lancet 2014; 383: 955-62.
Practical issues with NOACs: - pharmacological - co-morbidity
Practical issues - pharmacological o o o o o o o o
Patient selection Drug selection Dose selection Adherence errors Switching Warfarin to NOAC Switching NOAC to Warfarin Measuring anti-coagulant effect Drug interactions
Patient selection New AF patients o All Existing Warfarin patients o TTR 80 years old Patients 75-80 with HAS-BLED score >3 Body weight < 60kg Moderate renal dysfunction (Cr Cl 30-50ml/min) GORD (with dabigatran)
Dose selection o Full dose = dabigatran 150mg BD rivaroxaban 20mg OD apixaban 5mg BD edoxaban 60mg OD o Reduced dose = dabigatran 110mg BD rivaroxaban 15mg OD apixaban 2.5mg BD edoxaban 30mg OD
Adherence errors o Missed dose o Double dose o Uncertainty
If a patient misses a dose….. The half-way rule Time since missed dose
Recommendation
half-way*
The patient should wait until their next scheduled dose
*Half-way = 6 hours for dabigatran and apixaban, 12 hours for rivaroxaban and edoxaban
Huisman M et al. Thromb Haemost 2012; 107: 838-47.
46
Adherence errors o Missed dose
half-way rule
o Double dose
BD skip next dose OD take next dose
o Uncertainty
BD no stat dose OD stat dose
Switching patients to NOAC Warfarin to NOAC
Stop warfarin
Allow INR to fall below 2.0
Start NOAC
Parenteral to NOAC Start NOAC up to 2 hours before next parenteral drug dose Continuous infusions to NOAC Start NOAC at time of discontinuation of Huisman M et al. continuous Thromb Haemost 2012; 107: 838-47, infusion
48
Switching from Xa inhibitors o Start warfarin 3 days before stopping Xa
Switching patients from dabigatran Start Warfarin based on renal function: CrCl in mL/min
Recommendation
≥50
Start VKA 3 days before stopping NOAC
≥30 to 80 seconds at trough (when the next dose is due) is associated with a higher risk of bleeding1,3
1. Van Ryn J et al. Thromb Haemost 2010; 103: 1116–1127. 2. Liesenfeld K-H et al. Br J Clin Pharmacol 2006; 62: 527–537. 3. Huisman M et al. Thromb Haemost 2012; 107: 838-47.
53
Measuring anti-coagulant effect Xa inhibitors o Qualitative Prothrombin time (PT) (not INR) o Quantitative Anti-Xa chromogenic assay 54
Drug interactions
Drug interactions o Few o Verapamil – strongly accentuates dabigatran and edoxaban
o HIV protease inhibitors – strongly accentuates rivaroxaban and apixaban
Chronic kidney disease o CKD is an independent risk factor for stroke in AF o CKD is a risk factor for bleeding on OAC o All NOACs are excreted by kidneys dabi>edoxa>rivaroxa>apixa o Monitor renal function o No NOACs if on haemodialysis (Rx warfarin)
Interruption for surgery o Bridging is never necessary o When to stop? o When to restart?
Interruption for surgery – when to stop? o Emergency / elective o Bleeding risk of the procedure
o Renal function in the case of dabigatran
Classification of bleeding risk o No bleeding risk o Low bleeding risk o High bleeding risk
No bleeding risk
No interruption necessary – operate at trough concentration
Low and high bleeding risk
Interruption for surgery – when to stop? o Dabigatran CrCl >80 50-80 30-50 30 15-30
