IS THERE STILL A PLACE FOR VITAMINE K ANTAGONISTS?

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Derick Heath
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1 IS THERE STILL A PLACE FOR VITAMINE K ANTAGONISTS? J.Y. LE HEUZEY Georges Pompidou Hospital, René Descartes University, Paris H E G P Munich, August 27, 2012

2 Disclosure Consultant / Conferences / Advisory Board fees from Bayer, Boehringer - Ingelheim, Bristol Myers Squibb / Pfizer, Daiichi - Sankyo H E G P

3 Total cost : THE COCAF STUDY DISTRIBUTION OF COSTS 3209 per year 8 % 2 % 9 % FR = 2.5 Billion 6 % EU = 25 Billion Hospitalisations Drugs Consultations 23 % Further investigations Paramedical procedures Loss of work Le Heuzey et al., Am. Heart J. 2004, 147 : % H E G P

5 % stroke Stroke rate in non anticoagulated atrial fibrillation patients AFASAK SPAF BAATAF CAFA SPINAF EAFT* * Secondary prevention Hart RG et al. Ann Intern Med ; 131 :

6 Annual stroke rate in patients with atrial fibrillation plus more than one thromboembolic risk factor and not treated by anticoagulants Event rate (%) , ,9 5, < >75 Age (years) Atrial Fibrillation Investigators. Arch Intern Med 1994;154:

7 CHADS 2 SCORE Risk factor Score C = congestive heart failure H = hypertension A = age 1 D = diabetes 1 S = stroke Gage B.F., JAMA 2001; 285 : H E G P

8 Factors for establishing the risk of Stroke

9 Swedish Atrial Fibrillation Cohort Study Friberg L., Rosenqvist M., Lip G.Y., Eur Heart J. 2012; 33 :

10 Stroke is the main complication of Atrial Fibrillation Atrial Fibrillation is associated with a global risk of stroke X 5 Atrial Fibrillation is responsible for 15 % to 20 % of all strokes The risk of stroke is comparable in paroxysmal and permanent atrial Fibrillation Strokes occurring in atrial fibrillation patients are more severe 10

without Atrial Fibrillation 1,0 0,8 0,6 Patients with AF 49.5 % 0,4 0,2 p<0.

11 One year mortality rate due to stroke in patients with Atrial Fibrillation Probability of survival, % The risk of death remains increased after one year as compared with patients without Atrial Fibrillation 1,0 0,8 0,6 Patients with AF 49.5 % 0,4 0,2 p<0.001 Patients without AF 27.1 % 0, Days post stroke 360 Lin HJ et al. Stroke 1996;27:

with AF (n= 869) Patients without AF (n = 2661) 2 p = 0.

12 Cumulated probability of recurrence, % Patients with Atrial Fibrillation have an increasd risk of recurrence Patients with AF (n= 869) Patients without AF (n = 2661) 2 p = Years after the first stroke 12 Marini C et al. Stroke 2005;36:

13 Cumulated survival Cumulated survival Mortality increases in relation to CHADS 2 whatever the type of Atrial Fibrillation ParoxysmalAF All AF 1,0 0 (n = 157) 1,0 0 (n = 405) 0,8 1 (n = 266) 0,8 1 (n = 725) 0,6 0,4 0,2 2 (n = 228) 3 (n = 151) 4 (n = 42) 5 (n = 35) 6 (n= 9) 0,6 0,4 0,2 2 (n = 755) 3 (n = 544) 4 (n = 231) 5 (n = 132) 6 (n= 32) years years Stochkolm Cohort Study of Atrial Fibrillation Friberg L. Eur Heart J. 2007;28:

SPAF BAATAF CAFA SPINAF EAFT Aggregate 100% 50%

14 Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Warfarin better Control better AFASAK SPAF BAATAF CAFA SPINAF EAFT Aggregate 100% 50% 0-50% -100% Hart RG et al, Ann Intern Med 1999;131:492 H E G P

15 Relative risk reduction of stroke in atrial fibrillation ASA compared with placebo Relative risk reduction (95% CI) AFASAK I SPAF I EAFT ESPS II LASAF UK-TIA All trials (n=6) 22% (2% to 38%) ASA better ASA worse H E G P Hart RG, et al. Ann Intern Med 1999;131:

Challenges of Oral Anticoagulation Odds Ratio 15.0 Therapy Narrow efficacy window + complex kinetics + multiple interactions = hard to use/take 10.

16 Challenges of Oral Anticoagulation Odds Ratio 15.0 Therapy Narrow efficacy window + complex kinetics + multiple interactions = hard to use/take 10.0 Stroke Intracranial bleed INR H E G P Hylek EM et al. N Engl J Med 1996;335(8):540-6 Hylek EM et al. Ann Intern Med 1994;120(11):

Limitations of VKA therapy Unpredictable response Narrow therapeutic window (INR range 2 3) Routine coagulation monitoring Slow onset/offset of action VKA therapy has several limitations that make it

17 Limitations of VKA therapy Unpredictable response Narrow therapeutic window (INR range 2 3) Routine coagulation monitoring Slow onset/offset of action VKA therapy has several limitations that make it difficult to use in practice Frequent dose adjustments 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: ; Nutescu EA, et al. Cardiol Clin 2008; 26:

European Heart Journal http://eurheartj.

19 European Heart Journal Eur. Heart J. 2010; 31 :

20 Selected OAC Recommendations

23 Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = 1.46 Dabigatran better HR (95% CI) Warfarin better

Primary Efficacy Outcome Stroke and non-cns Embolism On Treatment N= 14,143 Rivaroxaban Warfarin Event Event Rate Rate 1.70 2.15 HR (95% CI) 0.79 (0.65,0.95) P-value 0.015 ITT N= 14,171 2.

25 Primary Efficacy Outcome Stroke and non-cns Embolism On Treatment N= 14,143 Rivaroxaban Warfarin Event Event Rate Rate HR (95% CI) 0.79 (0.65,0.95) P-value ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Primary Outcome Stroke (ischemic or hemorrhagic) or

26 Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)< % RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P (superiority)=0.011 No. at Risk Apixaban Warfarin

27 WHICH ATRIAL FIBRILLATION PATIENTS WILL NOT RECEIVE NEW ANTICOAGULANTS? Contraindications to anticoagulants (hemorrhagic syndroms) Non indication to anticoagulants (CHADS 2 = 0) Patients with valvular Atrial Fibrillation (rheumatic valvular disease, prosthetic valves) Patients with renal failure (especially elderly) Patients with very stable INRs, without history of thromboembolic and hemorragic event and not willing to change

28 LIMITATIONS OF NEW ANTICOAGULANTS No specific antidote at that time, difficulties in bleeding management Biological tests difficult to interprete Drug-drug interactions (PgP and CYP) Precaution +++ in patients with moderate renal failure (elderly), contraindication if more severe failure (creatinine clearance less than 30 ml/min with the Cockroft method) Therapeutics schemes to redefine in specific situations (for example coronary heart disease) Cost

33 CONCLUSIONS 1- YES, there is still a place for vitamine K antagonists in Main exclusions for new anticoagulants : - valvular atrial fibrillations - renal failure (EPITAF?) - stable INRs in patients not willing to change 3- Economic difficulties for patients, health care systems, countries H E G P

MMS/Mass Coalition Program, Nov. 4, 2008 Patients with AF: Who Should be on Warfarin?

MMS/Mass Coalition Program, Nov. 4, 2008 Patients with AF: Who Should be on Warfarin? Daniel E. Singer, MD Massachusetts General Hospital Harvard Medical School 1 Speaker Disclosure Information DISCLOSURE