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Prospects for improving thrombosis management in atrial fibrillation

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1 Prospects for improving thrombosis management in atrial fibrillation
Lessons from Large Randomised Trials Hemmaridge Dimentja Fasit Haai_arki M. Duytschaever, P. Debonnaire, Y.Vandekerckhove and R. Tavernier St Jan Hospital, Bruges EHRA Training Centre for Electrophysiology University Hospital Ghent

2 Presenter Disclosure Information of Mattias Duytschaever
Biosense Webster Consultant Medtronic Sanofi Advisory Board 2

3 At 55y Life time risk for AF = 23.8%
Epidemiology of Atrial Fibrillation Prevalence and Incidence of AF Prevalence (%) Incidence/1000 person-years 17.8% Framingham Study Mayo Clinic Study CHS Rotterdam Study 60 Framingham Study (men) 15 CHS (men) Mayo Clinic (men) 40 10 1 to 1.5% 20 5 Prevalence in the General Population 1 to 1,5% (Based on these data Estimated Prevalence Pool of 3 milj Europe, 2,3 in the US) Miyaska: cijfers bij dames ligt iets lager (niet geplot) Cijfers bij blanken ook hoger Rotterdam Study >55y: °Prevalence 5.5% °Life Time Risk to Develop AF was 23.8% >85 y: Prevalence 17.8% 40 50 60 70 80 40 50 60 70 80 90 Age (yrs) Age (yrs) At 55y Life time risk for AF = 23.8% Miyasaka et al, Circ 2006;114: Heeringa et al, EHJ 2006;27:

4 Impact of Atrial Fibrillation on Stroke
Stroke Prevention in AF is a Pressing Health Concern Yearly Risk of Stroke in Non-valvular AF is 5% AF is Associated with a 6-fold Increased Risk for Stroke Over 87% of strokes are Thromboembolic 40% of Patients with AF have Silent Brain Infarction In Patients with AF there is Twice as much Cognitive Dysfunction or Dementia Strokes by AF are Twice as Fatal or Disabling, and are more Likely to Recur compared to other causes Incidence of Dementia/1000 person-years 80 60 Men with AF 40 Strokes are more disabling beacuse clots are well preformed and not break up before going to the brain General Men 20 50 60 70 80 90 Age (yrs) Miyasaka et al, European Heart J 2007;28:

5 Impact of Atrial Fibrillation on Stroke
Stroke due to AF is more Severe Stroke due to AF Mortality after Stroke (%) Other Stroke 63% 60 40 34% 25% Strokes are more disabling beacuse clots are well preformed and not break up before going to the brain In comparison: ICH has bad prognosis: 1 year mortaity 50%, sequella 100% 20 14% 30 days After 1 year Marini et al , Stroke 2005

6 Prospects for improving thrombosis management in atrial fibrillation
Atrial Fibrillation and Stroke Risk Factors for Stroke in AF Warfarin and Aspirin Dual Antiplatelet Strategy Novel Antithrombotic Strategies Control of Risk Factors Non-pharmacological Strategies New Oral Anti-thrombotic Drugs

7 Atrial Fibrillation on Stroke
Virchow’s Triad* Circulatory stasis Endothelial injury Thrombosis An adaptation of the relevance of Virchow’s triad to AF and ACS is shown in this slide Key message Virchow’s triad key pathogenic factors in the coagulation process are involved in arterial thrombosis associated with AF and ACS: BLOOD VESSEL STASIS *>90% of thrombus accumulation originates in the Left Atrial Appendage (LAA) Hypercoagulable state 7

8 Risk Factors for Stroke in Pts with Afib
Long-Term Outcome in Pts with Lone AF: a 30-year Follow-Up Study Survival Free of Stroke/TIA (%) Survival Free of Death (%) 100 96% 100 92% observed 89% 85% 94% 80 80 68% 88% 86% 72%* 60 60 expected expected 57% 40 observed 40 20 Interaction of Lone AF with ageing and developing risk factors Predictors for stroke and detah: Older Age >45y (multivariate) st episode of AF (3623) 76 pts with lone AF (2%), 44.2+/-11.7y, 78% male, FU 25+/-9.5 5 permanent, 71 recurrent 22 out of 71 with 30y cumulative probbability of 29% progressie naar permanent AF (low risk of progression) Invasive therapies shoud be reserved for symptomatic patients, After a young patient with lone atrial fibrillation ages or develops hypertension, heart failure, or diabetes, thromboembolic risk increases. Therefore, screening for comorbidities is essential in this group Overall Survivial: duidelijk Stroke: Initial 25y similar risk (After a young patient with lone atrial fibrillation ages or develops hypertension, heart failure, or diabetes, thromboembolic risk increases. Therefore, screening for comorbidities is essential in this group, however everybody becomes old) mean age 74y 17 developed stroke/TIA over 30-years (5 strokes –12 TIA) 7 recurrent, 10 permanent 7 embolic, 10 non-embolic All pts who developed stroke/TIA had developed >1 RF for Trombo-embolism Chf 4, Hypertensie 12, Diabetes 3 (also in the age and sex matched population denk ik dan) (relatie met development of permanent AF?) 25 year is misschien geen gerusstelling voor man van 40 jaar? 20 10 20 30 10 20 30 Years Years Jahangir et al, Circulation 2007;115:

9 Risk Factors for Stroke in Pts with Afib
AF and Stroke: Framingham Study, 30-year FU Stroke rate (% year) Age Prev AF Strokes per 1000PYctrl Strokes per 1000PYAF RR 7 60-69 1.8% 4.5 21 4.7 5 70-79 4.7% 9.0 49 5.4 3 80-89 10.2% 14 71 5.0 1 In general, AF is Associated with a 6-fold Increased Risk for Stroke Age (yrs) 40-49 50-59 60-69 70-79 80-89 In general AF is Associated with a 6-fold Increased Risk for Stroke The risk of Stroke increases Exponential with Age Wolf et al. Jacc 2001 and Arch Intern Med 1987

10 Risk Factors for Stroke in Pts with Afib
Risk Factors for Stroke in Non-valvular AF: CHADS Criteria Fuster et al, Circulation 2006;114:

11 Risk Factors for Stroke in Pts with Afib
Risk Factors for Stroke in Non-valvular AF: CHADS2 Score C—CHF 1 H—Hypertension 1 A—Age >75 1 D—Diabetes mellitus 1 S2—TIA/stroke 2 20 18.2 15 12.5 Stroke rate (% per year) 10 8.5 5.9 5 4 2.8 1.9 n=120 n=463 n=523 n=337 n=220 n=65 n=5 1 2 3 4 5 6 CHADS2 score Overall Yearly Risk of Stroke in Non-valvular AF is 5% Fuster et al, Circulation 2006;114:

12 Risk Factors for Stroke in Pts with Afib
How to Improve Risk Stratification? CHADS2 criteria and other mild risk factors (female, diastolic dysfunction, LA dilatation, mild VHD, PAOD, CAD, renal failure) Any of the risk factor (pacemakjer, valvular heart disease,n…): 5 fold increase in stroke risk AUC for CHADS2 is close to 0.6. all scores 0.5 is like flipping a coin Other scores take into consideration other factors like = female, LAD, diastolic, PAO, CAD, VHD, renal failure.... Asn also fail. Do we miss some: Parox vs persitent: no Flutter vs AF: no Duration of AF: maybe Fang et al, JACC 2008;51:810-5

13 Risk Factors for Stroke in Pts with Afib
Is there a critical value of daily burden that raises stroke risk? burden Annual TE Rate (unadjusted) 95% CI Hazard Ratio P- value Zero burden 1.1% ( ) Low burden <5.5hrs 1.1% ( ) 0.98 0.97 The results suggest that device detetecd AF/AT burden >5.5hrs on any day doubles the risk for TE, independent of known risk factors and antithrombitic therapy High burden >5.5hrs 2.4% ( ) 2.2 0.06 device detetecd AF/AT burden >5.5hrs on any day doubles the risk for TE Glotzer et al, TRENDS Study, Circulation Arrhythmia Electrophysiol 2009;2:474

14 Prospects for improving thrombosis management in atrial fibrillation
Atrial Fibrillation and Stroke Risk Factors for Stroke in AF Warfarin and Aspirin Dual Antiplatelet Strategy Novel Antithrombotic Strategies Control of Risk Factors Non-pharmacological Strategies New Oral Anti-thrombotic Drugs

15 Antithrombotic Therapies in AF
Warfarin in Non-valvular AF Risk Patients (Pooled 1° RCT) RR Reduction (95% CI) Relative Risk Reduction 68% (to placebo) Absolute Risk Reduction 3.1% per year Annual Rate of Major Bleeding 2% Annual Rate of ICH 0.3% AFASAK SPAF BAATAF CAFA SPINAF Warfarin broadly inhibit coagulation (inhibiting factors II, X, VII, IX, and protein C and S. Actual Strioke rate taking warfarin is reduced to 1.6% (Rely study) 1.4% (Active W) to 2% cfr also slide on BD and reduced stroke The cumulative N of events is dus 2% stroke and 2% bleeding (soortement van net clinical benefit berekeking) Relative Risk Reduction 41% (to ASA) Warfarine in Rely: 0.48% (in t algmeen, 2* zoveel ICH als aspirine, dus hier mocht er wel verbetering zijn 1° is first generation ICH has bad prognosis: 1 year mortaity 50%, sequella 100% 1 EAFT All Trials (6) 50% -50% Warfarin Better Warfarin Worse Hart et al, Arch Intern Med 1999;131:492

16 Antithrombotic Therapies in AF
Net Clinical Benefit of Warfarin Anticoagulation in AF Assuming 51 ischemic strokes/1000 pt-yr Adjusted standard dose warfarin prevented 28 strokes at expense of 11 fatal bleeds Cooper: Arch Int Med 166, 2006 Lip: Thromb Res 118, 2006 Assuming 5% anuual stroke rate in CHADS +patients Weighting facto of 1.5 because ICH (=ICB) is worse than ischemic stroke ICH has bad prognosis: 1 year mortaity 50%, sequella 100% Bij Rely wordt Netto klinisch benefit uigedrukt als aantal cumulatieve events (ipv uitgespaarde events) nl TE events + bloedingen: Zo bvb +/7% Bij warfarine: Strioke rate under warfarin is reduced to 1.4% (Active W) to 2% cfr slide on BD and reduced stroke The cumulative N of events is dus 2% stroke and 2% bleeding (soortement van net clinical benefit berekeking) TEs prevented minus ICHs induced (TE rate off warfarin – TE rate on warfarin) minus 1.5 (ICH rate off warfarin – ICH rate on warfarin)

17 Antithrombotic Therapies in AF
Net Clinical Benefit of Warfarin Anticoagulation in AF This is a forrest plot Singer et al Annals of Int Med 2009;151:

18 Antithrombotic Therapies in AF
Aspirin in Non-valvular AF Risk Patients RR Reduction (95% CI) AFASAK (75mg) Relative Risk Reduction 21% (to placebo) Aspirin prevented 16 strokes at expense of 6 fatal bleeds Warfarin vs ASA: Relative Risk Reduction 41% SPAF I (325mg) EAFT (300mg) ESPS II LASAF BELANGRIJK MATTIE Assuming 51 ischemic strokes/1000 pt-yr Adjusted standard dose warfarin prevented 28 strokes at expense of 11 fatal bleeds Aspirin prevented 16 strokes at expense of 6 fatal bleeds Dus met asirine toch wat minder bloedingen blijkt uit bovenstaande data (enkel in contrast met BAFTA) (komt ook overeen met lage frequentie van bloedingen in Active A study; komt ook overeen met feit dat Warfarin tav aspirine tweemaal zoveel ICH geeft De gap 16 – 1.5 * 6 (9 prvented) toch blijkbaar minder positief dan *11 (12 prevented) UK-TIA All Trials (6) 50% -50% Aspirin Better Aspirin Worse JACC 2001;38(4):1-70

19 Antithrombotic Therapies in AF
Warfarin vs Aspirin in the Elderly (BAFTA Study) N=973 >75y (Mean Age 81y) Controlled Randomised Trial Aspririn 75mg vs Warfarin INR 2-3 40% Warfarin at entry Primary Event: stroke, IC hemorraghe, arterial embolism Aspirin Warfarin Superiority also clear in elderly. However these pts were randomisable, therefore not representin the whole elederly population (number neeeded to treat to prevent one event per year) Bij de oudere geeft aspirine eveneveel bloedingen als warfarin Given aging of the Population, 50% >80y BAFTA = Birmingham AF Treatment of the Aged N= 973 >75 years (mean age 81 years) Controlled Randomised Trial: Aspirin 75mg vs Warfarin INR 2_3 In the Warfarin group: Primary event (stroke, hemorraghe, embolism) Annual rate 1.8% (vs 3.8% aspirin) Major Bleeding: Annual rate 1.9% (vs 2.0% aspirin) Annual Rate of Primary Event 3.8% 1.8% Annual Rate of Major Bleeding 2.0% 1.9% NTT = 50 Mant et al, Lancet 2007;370:

20 Antithrombotic Therapies in AF
ACC/AHA/ESC Practice Guidelines for the management of AF (CHADS2 0) (CHADS2 1) (CHADS2 2 or more) - Fuster et al, Circulation 2006;114:

21 Antithrombotic Therapies in AF
ACC/AHA/ESC Practice Guidelines for the management of AF (“not tabloids from the mountains”) CHADS2 criteria and other mild risk factors (female, diastolic dysfunction, LA dilatation, mild VHD, PAOD, CAD, renal failure) CHADS2 0 - nothing CHADS2 0 + Aspirin 81mg to 325mg daily - CHADS2 1 - Aspirin 81mg to 325mg daily CHADS2 1 + Warfarin (INR 2.0 to 3.0)

22 Antithrombotic Therapies in AF
Warfarin Treatment in European Countries (Euro Heart Survey) % of Patients 100 No antithrombotic antiplatelet OAC+ antiplatelet 75 OAC 50 Despite the Guidelines: Over-utilisation (49%) Under-utilisation (33%) 67% The previous Data should encourage us to use warfarin and follow the guidelines, wouldnt it? Waht do we see? Explanantion? Difficult to Manage (compliance, routine INR checks, polypharmacy vigilance, alochol temperance) Clinicians Beleiev that Published rates of Hemorrgahe may not reflect real-world practice, especially not in the elderly (all pts were randomisable dont forget) 49% 25 Non Eligible (N=517) Eligible (N=4736) Nieuwlaat et al, Eur Heart J 2005;26:2422 (Euro Heart Survey)

23 Antithrombotic Therapies in AF
Dose-Adjusted Warfarin (INR 2-3) Odds Ratio Patients with INR 2-3 (%) 20 Stroke 70 Bleeding 15 60 50 10 40 The importance of TTR is proven in the SPORTIF III and V trial 30 5 At INR >2 prevention of stroke but also clear reduction of sevrity of stroke A Recent Meta-analysis demonstrated that Treating 1000 Patients with AF for 1 year With Warfarin vs Aspirin Prevented 23 Ischemic Strokes but Caused 9 Additional Major Bleeds TTR : Time in Target INR 20 10 1 1 2 3 4 5 6 7 2 4 6 8 10 12 International Normalised Ratio Weeks on Treatment JACC 2001;38(4):1-70 Sportif II Trial

24 Antithrombotic Therapies in AF
Major Hemorrhage in the 1st Year of Warfarin R/ Among AF>65y Cumulative Proportion with Major Hemorraghe Annual Rate of Major Hemorr Warfarin at entry Mean Age >80y Trial 0.10 AFI (1994) 1.3 N.R. 69y 72y 80y 70y 77y 0.08 SPORTIF III (2003) 2.2 73% 0.06 <80y SPORTIF V (2005) 3.4 85% 0.04 (1) New and startling information from Hylek (quote unquote Wyse et al): the gap between the 10% stroke rate and the 7.2% ICH rate begets smallerbut still yet benefit (2) Not an efficay study Hylek et al: Introduction: Rates of hemorraghe are re-assuringly low (however hom many old people, only few cohort studies include inlude the initial pahse of therapy (which is reported to convey the highest risk) 472 pts >65 years, 91% >=1RF, Warfarin at entry = 0% FU 1 year after start of warfarin (early phase of R/) = INCEPTION COHORT EP= major hemorraghe Global <80y: Cumulative incidence of major hemorrhage =4.75 per 100 person-years N=150 >80y Cumulative incidence of major hemorrhage =13.1 per 100 person-years °Time dependent Risk °°Higher Age °°°Warfarin-naive Pâtients (3) AFI 1994: pooled analysis of the 1st 5 randomised trials only 20 pts above 75y old (4) Editorial van Wyse et al from bad to worse The Guidelines Process Can Not Keep Up with the Pace of Emerging New Information The most difficult obstacle to a net benefit scheme is agreement about a hierarchy or a ranking for comparin stroke and bleeding events F;e; stroke (ischemic or hemoraghic) can be ranked by a Rankin Scale score SPAF II >75 (1994) 0.02 4.2 0% 0.00 Hylek (2007) 7.2 0% 100 200 300 400 Days on Warfarin Hylek et al, Circulation 2007;115:2689

25 Antithrombotic Therapies in AF
Core Findings Warfarin is cornerstone of therapy Anticoag at INR very effective generally safe moderately burdensome Aspirin is much less effective Under-utilisation of Warfarin: Narrow therapeutic spectrum Need for monitoring (with 65% TTR to 50% real-life) Drug and Diet Interactions Study Pts vs Real World Pts (elderly, warfarin naieve) No warfarin (Prohibitive) if non Compliancve, Active bleeding, Recent IC hemorraghe) Intermediate (Age >80, History of fall) Low (None of the above) 25

26 Antithrombotic Therapies in AF
Vit K Antagonists or Coumadin Sintrom 1-4mg Acenocumarol (8u) Marevan 5mg Warfarin (20-60u) Marcoumar 3mg Fenprocoumon ( u) At INR >2 prevention of stroke but also clear reduction of sevrity of stroke Het is de Belgische producent Therabel die zelf Marevan uit de terugbetaling gehaald heeft. Daarmee wil de firma de prijs van het geneesmiddel kunnen verhogen. Terugbetaalde geneesmiddelen zijn immers aan een veel strengere prijscontrole onderworpen dan niet terugbetaalde. Marevan is een relatief oud geneesmiddel en daarom goedkoop. Marevan kostte tot voor kort 2,16 euro en is nu verhoogd tot 2,86 euro voor een doosje. A Recent Meta-analysis demonstrated that Treating 1000 Patients with AF for 1 year With Warfarin vs Aspirin Prevented 23 Ischemic Strokes but Caused 9 Additional Major Bleeds

27 Prospects for improving thrombosis management in atrial fibrillation
Atrial Fibrillation and Stroke Clinical Relevance of AF and Stroke Warfarin and Aspirin Dual Antiplatelet Strategy Novel Antithrombotic Strategies Control of Risk Factors Non-pharmacological Strategies New Oral Anti-thrombotic Drugs

28 Antiplatelet Therapies in AF
Rationale for dual antiplatelet therapy Increased platelet activation in AF Aspirin reduces stroke in AF by 22% Addition of clopidogrel to aspirin achieves greater suppression of platelet activity Addition of clopidogrel to aspirin reduces vascuclar events in ACS with acceptable risk of bleeding

29 Antiplatelet Therapies in AF
ACTIVE W and A Study n = Dose-adjusted OAC (INR 2.0–3.0) Patients with documented AF ACTIVE W R Irbesartan (150–300 mg/day) Clopidogrel (75 mg/d) + ASA (75–100 mg/day) with 1: EF<45% AHT >75yrs Diabetes Stroke/TIA/emboli CAD PAOD R ACTIVE I Clopidogrel (75 mg/day) + ASA (75–100 mg/day) SANOFI Inclusion for ACTIVE W or A study: I.e atrial fibrillation at enrollment or had had at least two episodes of intermittent atrial fibrillation in the previous 6 months. As reported by heartwire, the ACTIVE program included two studies of patients with atrial fibrillation and one or more additional risk factors for stroke. If they were considered suitable candidates for warfarin therapy, they were enrolled in ACTIVE-W, a comparison of warfarin with the combination of clopidogrel and aspirin. The results of ACTIVE-W were reported previously and showed that use of warfarin reduced the risk for stroke by 42% over clopidogrel and aspirin. In the ACTIVE-A study, which included patients unsuitable for warfarin, clopidogrel plus aspirin reduced the risk of major vascular events or death from vascular causes by 11% when compared with aspirin plus placebo Placebo R ACTIVE A # Re-randomisation (if RRs >=110mmHg) Placebo + ASA (75–100 mg/day) Yusuf et al, ESC 2009 #patients with AF unable to receive VKAs

30 Warfarin vs ASA+clopidogrel
Active W Study Warfarin vs ASA+clopidogrel Warfarin (INR 2.0–3.0) vs ASA (75–100 mg) + clopidogrel (75 mg) 10 RR 1.44 p=0.0003 Clopidogrel/ASA (n=3,335) 8 Warfarin (n=3,371) 6 5.60 RR 1.10 p=0.53 Annual incidence (%) 4 3.93 Wat wisten we al: Aspirine geeft bijna evenveel bloedingen als warfarine (cfr BAFTA, andere data suggerere iets minder bloedingen cfr fatal bleeds 6vs 11, cfr active A arm). So more bleeding in A+C group vs W is not os surprsing Interessant: qua prevention of strokes was A+C better than A alone (logical) but nout enought to compete with Warfarin (this is new infromation from the study) Studie werd gestopt Bleeding definitions in ACTIVE trials ACTIVE-W: Major bleeding was defined as any bleeding requiring transfusion of at least two units of red blood cells or equivalent of whole blood, or which was severe. Severe bleeding was bleeding associated with any of the following: death, drop in haemoglobin of at least 50 g/L, substantial hypotension with the need for inotropic agents, intraocular bleeding leading to substantial loss of vision, bleeding requiring surgical intervention (other than vascular site repair), symptomatic intracranial haemorrhage, or requirement for a transfusion of a least four units of blood. Minor bleeding was any other bleeding requiring modification of the study drug regimen. ACTIVE-W had the following bleeding definitions: Major bleeding: Bleeding requiring transfusion of at least two units of red blood cells or equivalent of whole blood, or which was severe. Severe bleeding: Bleeding associated with any of the following: death, drop in haemoglobin of at least 50 g/L, substantial hypotension with the need for inotropic agents, intraocular bleeding leading to substantial loss of vision, bleeding requiring surgical intervention (other than vascular site repair), symptomatic intracranial haemorrhage, or requirement for a transfusion of a least four units of blood.  Minor bleeding was any other bleeding requiring modification of the study drug regimen. ACTIVE-A had the following bleeding definitions: Major hemorrhage: Major hemorrhage was defined as any overt bleeding requiring transfusion of at least two units of blood or any overt bleeding meeting the criteria for severe hemorrhage Severe hemorrhage Severe hemorrhage included any of the following: fatal hemorrhage, a drop in the hemoglobin level of 5.0 g per deciliter or more, hypotension requiring inotropic agents intraocular bleeding leading to substantial loss of vision requirement for surgical intervention symptomatic intracranial hemorrhage, or requirement for transfusion off our units or more of blood. Minor bleeding was defined as any nonmajor bleeding associated with modification of the study-drug regimen. Abbreviations ACTIVE, Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events; AF, atrial fibrillation; ASA, acetylsalicylic acid; CHD, coronary heart disease; CNS, central nervous system; INR, international normalized ratio; LVEF; left ventricular ejection fraction; MI, myocardial infarction; NS, non-significant; PAD, peripheral arterial disease; RR, relative risk; TIA, transient ischaemic attack Reference ACTIVE Writing Group of the ACTIVE Investigators, Connolly SJ et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of vascular events (ACTIVE W): a randomised controlled trial. Lancet 2006;376:1903–1912 2.42 2.21 2 Primary endpoint‡ Major bleeding #Stopped after complete enrolment because of warfarin superiority; ‡Composite of stroke, non CNS embolism, MI and vascular death ACTIVE Investigators, Lancet 2006;367: 30

31 ASA vs ASA+clopidogrel
Active A Study ASA vs ASA+clopidogrel ASA (75-100mg) vs ASA (75–100 mg) + clopidogrel (75 mg) RR 0.89 p=0.01 10 Clopidogrel/ASA (n=3,772) 8 7.6 ASA (n=3,782) 6.8 6 Annual incidence (%) Apsirine and clopidogrel: 1000pts treated for 3 years will prevent 28 strokes at a cost of 20 major bleeds RR 1.57 p<0.001 4 can not take warfarin (low compliance, active bleeding, IC hemoorgahe) Wat wisten we al: A+C geeft meer bleoding dan aspirine alleen (dat is toch geen verrassing) What is new: A+C minder stroke dan A. What is new: the net clinical benefit met name de gap between 28 an 20 becomes small Wat zeggen eigl de guidelines in ptn die geen A/C kunnen krijgen? A of A+C Abbreviations ACTIVE, Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events; AF, atrial fibrillation; ASA, acetylsalicylic acid; CHD, coronary heart disease; CNS, central nervous system; INR, international normalized ratio; LVEF; left ventricular ejection fraction; MI, myocardial infarction; PAD, peripheral arterial disease; RR, relative risk; TIA, transient ischaemic attack Reference Connolly SJ, Yusuf S, Camm J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066–2078 2.0 2 1.3 Primary endpoint‡ Major bleeding ‡Composite of stroke, non CNS embolism, MI and vascular death Connolly et al. N Engl J Med 2009 31

32 Antiplatelets vs Anticoagulants in AF
ACTIVE W and A Study: Stroke Rates Treatment VKA A+C A Active W (rate per year) 1.4% 2.4% - Active A (rate per year) - 2.4% 3.3% ACTIVE W and A Study: Major Bleeding Rates Duidelijk Total No events in A+C = 4.4 Total No events in A = 4.4 Dus met asirine minder bloedingen tav Warfarine blijkt uit bovenstaande data; komt ook overeen met feit dat Warfarin tav aspirine tweemaal zoveel ICH geeft Active W (rate per year) 2.2% 2.4% - Active A (rate per year) - 2.0% 1.3%

33 Antiplatelets vs Anticoagulants in AF
Conclusion Warfarin is the treatment of choice for pts with AF at higher risk In pts unsuited for warfarin, addition of clopidogrel to ASA reduces stroke by 28% there is a risk of major haemorrhage Anticoagulation is the preferred mechanism to prevent stroke There is a price to pay Mij iet duidelijk wta de guidelines zullen zeggen in pts not eligible for warfarin: Aspirine alleen Of aspriine + clopidogrel ((the gap between 28 an 20 becomes small) 33

34 Prospects for improving thrombosis management in atrial fibrillation
Atrial Fibrillation and Stroke Clinical Relevance of AF and Stroke Warfarin and Aspirin Dual Antiplatelet Strategy Novel Antithrombotic Strategies Control of Risk Factors Non-pharmacological Strategies New Oral Anti-thrombotic Drugs

35 Indirect Antithrombotic Therapies in AF
Decreasing Stroke Rates on Warfarin in Large AF Trials in High Risk Patients Annual Ischemic Stroke Rate Annual Hemorrh Stroke Rate Trial Year Therapeutic INR Warfarin at entry Syst BP (mmHg) SPAF III 1996 61% 56% 1.9% 140 0.5% SPORTIF III 2003 66% 73% 1.9% 139 0.4% Rates of strokes in AF trials appear to be declining over time Column 1. Before 1995 trials did not select high-risk patients. In fact 35% were <65 and had no risk factors.Since 1996, SPAF3 only risk patients Column 2. Progressive years Column 3. Good news more therpautic INRs are reached (however plateaued at 60%) Column 4. Warafrine at entry : warfarin tolerant = self selected responders (iit warfarin naieve pats) Column 5: Each year decline in stroke rates, despite selecting high-risk patients and equivalent INR Colmun 6: Reason: miore effective concomittant therapies (systemic hypertension, statin, ACE-I) Colmun 7: On the other hand data on hemorraghic stroke may be to low (however warfarin at entry) SPORTIF V 2005 68% 84% 1.1% 132 0.1% ACTIVE W 2006 64% 23% 1.0% 133 0.4% Connolly et al, Circulation 2007;116:

36 Indirect Antithrombotic Therapies in AF
Effect of BP lowering by ARB on Vascular Events (ACTIVE-I) n = Dose-adjusted OAC (INR 2.0–3.0) Patients with documented AF ACTIVE W R Irbesartan (150–300 mg/day) Clopidogrel (75 mg/d) + ASA (75–100 mg/day) with 1: EF<45% AHT >75yrs Diabetes Stroke/TIA/emboli CAD PAOD R ACTIVE I Clopidogrel (75 mg/day) + ASA (75–100 mg/day) Placebo R ACTIVE A Re-randomisation (if RRs >=110mmHg) Placebo + ASA (75–100 mg/day) Yusuf et al, ESC 2009

37 Irbesartan in Atrial Fibrillation
Effect of ARB and BP Lowering on Vascular Events (ACTIVE-I) Primary composite end point of stroke, MI, and cardiovascular death Treatment with ARBs reduced systolic and diastolic blood pressure 6.84 mm Hg and 4.51 mm Hg (vs 3.93 mm Hg and 2.63 mm Hg). No overall benefit in primary endpoint 14% reduction in heart-failure hospitalizations alone (secondary end point) More aggressive BP lowering??? Documented AF (66% permanent AF) SBP 138/83mmHg (normotensive population) There is a true clinical relevance of this study. A patient popluation that normally would not take sartane per se. Only either rhythm control/rate control and A/C and treatment of risk factors. Vascular events: stroel, infarction, vascular death Would have had relevance but turns out negative..... Yusuf et al, ESC 2009

38 Indirect Antithrombotic Therapies in AF
Template _1 4/14/2017 9:23 PM ATHENA Effect of dronedarone on cardiovascular events in AF Phase III MCRCT with a Minimum follow-up 12 months Dronedarone 400mg BID vs Placebo N=4628 patients with a history of paroxysmal or persistent AF (within the prior 6 months) with: Age ≥ 75 years with or without additional risk factors for stroke or death Age ≥ 70 years and ≥ 1 risk factor (hypertension, diabetes, prior stroke/TIA, LA ≥ 50 mm, LVEF ≤ .40) Primary EP: time to Cardiovascular Hospitalisation or Death (Safety study) Patients with permanent AF, defined as a duration of at least 12 months, were also excluded, pts with conventional AADS were excluded (basically these are known pts on “rate controlling” drugs, a new ptwith AF with not be randomised to placebo, therefore it is “on top of rate control” study. Ptn populatie behandeld met rate control (asymptomatisch) vermits ptn met AAR werden ge-excludeerd (lijkt dus sterk op AFFIRM trial rate control arm). Largest safety trial on AADS so far. Exclusion: a requirement for concomitant medication that was prohibited (i.e., other class I or III antiarrhythmic drugs) Exclusion: advanced herat failure with recent decompensation (NYHA IV) Pts younger then 70 years of ae were no longer eligible (in the beginiing it was... Either >70, either hypetrension, either iabetes, ...) Eg a diabetes of 50yrs was OK Hohnloser et al, N Engl J Med. 2009; 360:668-78 38

39 Indirect Antithrombotic Therapies in AF
Template _1 4/14/2017 9:23 PM ATHENA: Primary Outcome Time to first cardiovascular hospitalization or death Cumulative Incidence (%) 50 HR for the primary outcome=0.76 P<.001 24% reduction in risk 40 30 Placebo (39.4%) 20 Dronedarone (31.9%) 10 There is and Effect on hypertension in the Athean trial (Connoly mentions this in Stroke psot hoc study) Dronedarone significantly decreased the risk of cardiovascular hospitalisations or death from any cause by 24% (p<0.001), meeting the primary study endpoint. So far after 21 months no toxic effects (too short FU for complications ush as pulmonary toxic effects). Why no incremental mortality in Atehena in contrats to Andromeda? andromeda recent unstable heart failure Andromeda no AF as mandatory enrollment Months 6 12 18 24 30 Patients at risk Placebo Dronedarone FU 21+/-5m Hohnloser et al, N Engl J Med. 2009; 360:668-78 39

40 Indirect Antithrombotic Therapies in AF
Template _1 4/14/2017 9:23 PM ATHENA: Post Hoc Analysis Outcome for Stroke On top of reasonable anticoagulation (60% A/C) Re-opening the possibility that either pharmacological or nonpharmacological suppression of AF could have a beneficial effect on stroke. This post hoc study is hypothesis generating and must be confirmed Limitation: this was not a pre-specified endpoint nor centrally adjucated (only collected carefully) Therfeore some strokes were possibly not included...(underreporting of events) On the other hand there shoudl be o bias because the stduy was blinded Why effect on stroke? AF suppression (-25% in Euridis and Adonis, less AF hospitalisation in ATHENA) most likely Small Anti-hypertensive Effect in ATHENA (w or w/o AF interplay) small changes in RR have been rported to have a major impact on stroke Rate control : Anti-hypotensive Effect during AF: Rate control during Afib (Errato) might prevent hypotension Direct Vascular remodeling? My idea Direct Anti-thrombotic effect? My idea Background—Many patients with atrial fibrillation are at high risk for stroke and require antithrombotic therapy. Antiarrhythmic drugs have not previously been shown to reduce the risk of stroke in atrial fibrillation. The effect of dronedarone, a new multichannel-blocking antiarrhythmic drug, on stroke has been evaluated in a randomized, double-blind clinical trial, ATHENA (A placebo-controlled, double-blind, parallel-arm Trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter). Methods and Results—Patients with persistent or paroxysmal atrial fibrillation and at least 1 risk factor for cardiovascular hospitalization were randomized to receive dronedarone (400 mg BID) or double-blind matching placebo and followed up for a minimum of 1 year to a common termination at 30 months. All strokes that occurred during the study were included in the present post hoc analysis. There were 4628 patients randomized to placebo or dronedarone. The baseline risk factors for stroke were well balanced between the 2 groups, and the baseline mean CHADS2 score was 2. The baseline use of either oral anticoagulant therapy or antiplatelet agent alone was 60%. Dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (hazard ratio 0.66, 95% confidence interval 0.46 to 0.96, P0.027). The effect of dronedarone was similar whether or not patients were receiving oral anticoagulant therapy, and there was a significantly greater effect of dronedarone in patients with higher CHADS2 scores. Conclusions—In this post hoc analysis, a reduction in stroke was observed in patients with atrial fibrillation who were receiving usual care, which included antithrombotic therapy and heart rate control, who were randomized to dronedarone. Further studies to investigate the effect of dronedarone and other antiarrhythmic agents on stroke are indicated. (Circulation. 2009;120: Connolly et al, Circulation 2009;120: 40

41 Prospects for improving thrombosis management in atrial fibrillation
Atrial Fibrillation and Stroke Clinical Relevance of AF and Stroke Warfarin and Aspirin Dual Antiplatelet Strategy Novel Antithrombotic Strategies Control of Risk Factors Non-pharmacological Strategies New Oral Anti-thrombotic Drugs

42 Non Pharmacological Strategies
Freedom of Stroke after Cox-Maze Procedure (AF and LAA) Damiano (Cox Lab): In over 1200 patient-years of FU there was only one late stroke 90% were off coumadin at last follow-up Pet et al HRS CHADS 0 or 1 off warfarin: yearly stroke risk 0.1% CHADS >=2: yearly stroke risk 0.3%

43 Non Pharmacological Strategies
Freedom of Stroke after Catheter Ablation for AF (PVI) Observational Cohort Study in 755 patients, 2 y FU, Stop A/C In 256 pts with successful ablation and no RF for stroke: no T.E. In 180 pts with successful ablation and >1 RF for stroke: no T.E. Oral et al Circulation 2006;114:759 Ablation in CHADS positive pts Observational Multic Study in 2436 patients, 31 m FU, Stop A/C In 1508 pts with successful ablation and no RF for stroke: 1 T.E. In 928 pts with successful ablation and >1 RF for stroke: no T.E. Corrado et al Heart Rhythm 2007;abstract

44 Non Pharmacological Strategies
Freedom of Stroke after percutaneous closure of the LAA WATCHMAN LAA Closure Device in situ Background In patients with non-valvular atrial fi brillation, embolic stroke is thought to be associated with left atrial appendage (LAA) thrombi. We assessed the effi cacy and safety of percutaneous closure of the LAA for prevention of stroke compared with warfarin treatment in patients with atrial fi brillation. Methods Adult patients with non-valvular atrial fibrillation were eligible for inclusion in this multicentre, randomised non-inferiority trial if they had at least one of the following: previous stroke or transient ischaemic attack, congestive heart failure, diabetes, hypertension, or were 75 years or older. 707 eligible patients were randomly assigned in a 2:1 ratio by computer-generated randomisation sequence to percutaneous closure of the LAA and subsequent discontinuation of warfarin (intervention; n=463) or to warfarin treatment with a target international normalised ratio between 2·0 and 3·0 (control; n=244). Effi cacy was assessed by a primary composite endpoint of stroke, cardiovascular death, and systemic embolism. We selected a one-sided probability criterion of non-inferiority for the intervention of at least 97·5%, by use of a two-fold non-inferiority margin. Serious adverse events that constituted the primary endpoint for safety included major bleeding, pericardial eff usion, and device embolisation. Analysis was by intention to treat. This study is registered with Clinicaltrials.gov, number NCT Findings At 1065 patient-years of follow-up, the primary effi cacy event rate was 3·0 per 100 patient-years (95% credible interval [CrI] 1·9–4·5) in the intervention group and 4·9 per 100 patient-years (2·8–7·1) in the control group (rate ratio [RR] 0·62, 95% CrI 0·35–1·25). The probability of non-inferiority of the intervention was more than 99·9%. Primary safety events were more frequent in the intervention group than in the control group (7·4 per 100 patientyears, 95% CrI 5·5–9·7, vs 4·4 per 100 patient-years, 95% CrI 2·5–6·7; RR 1·69, 1·01–3·19). Interpretation The effi cacy of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of periprocedural complications. Closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with non-valvular atrial fi brillation. PROTECT-AF, Lancet 2009;374:

45 Non Pharmacological Strategies
Freedom of Stroke after percutaneous closure of the LAA Vergeleken met warfarine wat als tav D 150 Wta als geen warfarin non compliante ptn meer Niche: onder A/C stroke, cocnomittante procedures (AF ablatie) Background In patients with non-valvular atrial fi brillation, embolic stroke is thought to be associated with left atrial appendage (LAA) thrombi. We assessed the effi cacy and safety of percutaneous closure of the LAA for prevention of stroke compared with warfarin treatment in patients with atrial fi brillation. Methods Adult patients with non-valvular atrial fibrillation were eligible for inclusion in this multicentre, randomised non-inferiority trial if they had at least one of the following: previous stroke or transient ischaemic attack, congestive heart failure, diabetes, hypertension, or were 75 years or older. 707 eligible patients were randomly assigned in a 2:1 ratio by computer-generated randomisation sequence to percutaneous closure of the LAA and subsequent discontinuation of warfarin (intervention; n=463) or to warfarin treatment with a target international normalised ratio between 2·0 and 3·0 (control; n=244). Effi cacy was assessed by a primary composite endpoint of stroke, cardiovascular death, and systemic embolism. We selected a one-sided probability criterion of non-inferiority for the intervention of at least 97·5%, by use of a two-fold non-inferiority margin. Serious adverse events that constituted the primary endpoint for safety included major bleeding, pericardial eff usion, and device embolisation. Analysis was by intention to treat. This study is registered with Clinicaltrials.gov, number NCT Findings At 1065 patient-years of follow-up, the primary effi cacy event rate was 3·0 per 100 patient-years (95% credible interval [CrI] 1·9–4·5) in the intervention group and 4·9 per 100 patient-years (2·8–7·1) in the control group (rate ratio [RR] 0·62, 95% CrI 0·35–1·25). The probability of non-inferiority of the intervention was more than 99·9%. Primary safety events were more frequent in the intervention group than in the control group (7·4 per 100 patientyears, 95% CrI 5·5–9·7, vs 4·4 per 100 patient-years, 95% CrI 2·5–6·7; RR 1·69, 1·01–3·19). Interpretation The effi cacy of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of periprocedural complications. Closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with non-valvular atrial fi brillation. PROTECT-AF, Lancet 2009;374:

46 Prospects for improving thrombosis management in atrial fibrillation
Atrial Fibrillation and Stroke Clinical Relevance of AF and Stroke Warfarin and Aspirin Dual Antiplatelet Strategy Novel Antithrombotic Strategies Control of Risk Factors Non-pharmacological Strategies New Oral Anti-thrombotic Drugs From Lone AF to Heart Failure New Dta

47 New Oral Antithrombotic Therapies
Many Targets for Novel Anticoagulants in The Coagulation Pathway TF/VIIa ORAL PARENTERAL X IX IXa VIIIa Va Rivaroxaban Apixaban Endoxaban “Direct Xa” Inhibitors AT Fondaparinux Idraparinux Xa Warfarin broadly inhibits coagulation (inhibiting factors II (indirect by working on precusors) , Xa (indirect via AT), VII, IX, and protein C and S. By selectively inhibiting II or X drugs may have anticoagulant effect while preserving other hemostatic mechanisms in the coagulation pathway and thus potentially mitigating the risk of bleeding UFH: FX, Fxa = IIa (3) LMWH: FX, Fxa > IIa (2) Fondaparinux (Arixtra): Fxa (via antitrombine III), geen IIa, geen X (1) Rivaroxaban: direct Fxa (geen AT III nodig), geen IIa, geen X Factor Xa inhibitors a.Fondaparinux: anti Xa LMWH anti-Fxa > anti IIa UFH: anti Fxa = anti IIa Factor X inhibitors Heparin IV, LMWH Idra-parinux SC once weekly (AMADEUS trial) SC once weekly vs INR Warfarin trial terminated early because of safety There are many targets for novel anticoagulants in the coagulation pathway (cfr pipeline slide of Prof Hermans): Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 59­7939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853 “Indirect Xa” Inhibitors II “Direct IIa” Inhibitors Ximelagatran Dabigatran IIa (Thrombin) Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005 47

48 Direct Oral FIIa Inhibitors
Ximelagatran: Key Characteristics Oral precursor of Melagatran Effective Direct Thrombin Inhibitor No coagulation monitoring required Fixed dosing and predictable response Does not involve CYP450 system Renal excretion Dosing is fixed HO NH O H O O N NH2 Direct means no activatio of cofactors needed Ximelagatran is the oral precursor of melagatran, the active metabolite. It is very well absorbed without interference by food intake and bioconverted to melagatran. This bioconversion does NOT involve the CYP450 system. Excretion is renally dependent and therefore current studies have excluded patients with low creatinine clearance (<30 mL/min). Melagatran has a short half-life, but clinical studies demonstrate efficacy with bid dosing. Importantly, no coagulation monitoring is required and the dosing is fixed irrespective of body weight. H N N melagatran Exantha (Astra Zeneca) 48

49 Direct Oral FIIa Inhibitor: Ximelagatran
Stroke Prevention in AF: SPORTIF III Stroke and Systemic Embolism Major Bleeding AF and >=1 RF Warfarin INR 2-3 vs Ximelagatran 2*36mg Open Label phase III N=3407 (non-inferiority) Annual Event Rate (%) Annual Event Rate (%) 3 2,3 3 1,8 1,3 1,6 2 2 11 Oct … Ximelagatran failed to receive approval from the US Food and Drug Administration But novel anticoagulants work!! 4-6%: raised transaminase levels Few cases of fulminant hepatic failure 1 1 This was the test case but dabigatran is the only show in town Factor II Inhibitor = Oral direct thrombin inhibitor = ximelagatran, a prodrug of melagatran Ximelagatran BD 2*36mg vs INR titrated Warfarine Of course placebo control studies are not possible (non-inferiorty endpoint) Warfarin Ximelagatran Warfarin Ximelagatran SPORTIF III Investigators, Lancet 2003;362:

50 Other Adverse Events – SP III Liver Enzyme Elevation
Direct Oral FIIa Inhibitors Ximelagatran (Exanta) Other Adverse Events – SP III Liver Enzyme Elevation Event rate (%) ALT >3x ULN p <0.001 6.3% 0.8% 10 20 30 40 50 1 2 3 4 5 6 7 8 9 11 12 13 14 15 16 17 18 19 21 Treatment Duration (months) Incidence (n) Ximelagatran Warfarin NOT APPROVED 50

51 Direct Oral FIIa Inhibitors
Dabigatran Etexilate: Key Characteristics Is an oral pro-drug, rapidly converted to dabigatran Inhibits both clot-bound and free thrombin Fast onset and offset of action Weak bioavailability ~6.5 % Predictable and reproducible PK/PD* No Need for Monitoring – Fixed dose Half life hours (twice daily) Renal excretion ~80% Is not metabolized by CYP450 and does not induce nor inhibit CYP450 leading to a low potential for drug interactions Dabigatran etexilate inhibits both clot bound and free thrombin, which enables it to prevent thrombus formation in addition to lysing a thrombus which may have formed earlier. This could be very important in situations where thrombin already exists. Only small amounts of thrombin are required to initiate the upregulation of those factors responsible for additional thrombin production. The maximal effect of dabigatran etexilate on clotting parameters occurs simultaneously to maximal dabigatran etexilate plasma concentrations, both with a rapid onset of action (Stangier J et al. Clin Pharmacokinet 2008; in press). Offset of action of dabigatran etexilate also occurs in parallel with its elimination With a bioavailability of 6.5%, dabigatran etexilate has demonstrated predictable pharmacokinetics and a dose-proportional increase in plasma concentration over a wide concentration range, with no first-pass elimination effects (Belch S et al. DMB 2007; doi: /dmb Stangier J et al. Clin Pharmacokinet 2008; in press). In addition there is no drug-food interactions (Stangier J et al. J Clin Pharmacol 2005; 45: ) and a low potential for drug-drug interactions. Dabigatran etexilate and it’s metabolites are not metabolized by and do not influence cytochrome P450 enzymes (Ieko MDrug evaluation: dabigatran etexilate, a thrombin inhibitor for the prevention of venous thromboembolism and stroke. Curr Opin Invest Drugs 2007; 8 (9): ). The low bioavailability is the reason for the relatively high dosages of prodrug in the dabigatran etexilate capsule. As 6.5% of this prodrug is absorbed and changed to it’s active form dabigatran, this reversible direct thrombin inhibitor has a potent anticoagulant activity. The pharmacokinetics of dabigatran etexilate were not significantly influenced by, weight, gender smoking or alcohol consumption (Troconiz, IF et al.  J Am Coll Cardiol 2003; 42: ). Dabigatran etexilate administration results in a dose-proportional increase in plasma concentrations, with rapid onset and low intra-and inter-individual variation (Stangier J et al. Clin Pharmacokinet 2008; in press). The clinical phase III studies showed a well balanced efficacy and safety of dabigatran etexilate comparable with enoxaparin. It is important to note that dabigatran etexilate is not metabolized by CYP450 nor does it induce or inhibit this cytochrome. Dabigatran etexilate has low potential for drug and food interactions and has a fast onset and offset of action. This is unlike warfarin which has a narrow therapeutic window, requires frequent coagulation monitoring and can take up to 4-5 days to be effective. As a direct thrombin inhibitor dabigatran effectively binds to both free and clot-bound thrombin and provides immediate inhibition of thrombin. References: 1. Stangier J et al. The Pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. British Journal of Clinical Pharmacology 2007, DOI: /j 2. Sorbera LA et al Dabigatran/Dabigatran Etexilate Drugs of the Future 2005; 30 (9): Dabigatran etexilate is a novel oral direct thrombin inhibitor currently in clinical development. Dabigatran etexilate is not approved for clinical use. The following information is provided to inform on the background characteristics of dabigatran etexilate. 1. Eriksson BI et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate in patients undergoing total hip replacement. Journal of Thrombosis and Haemostasis 2004; 2: 1573–1580 2. Eriksson BI et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. Journal of Thrombosis and Haemostasis 2005; 3: 103–111 3. Wallentin L et al; PETRO-investigators. Safety and efficacy of a new oral direct thrombin inhibitor dabigatran in atrial fibrillation: a dose finding trial with comparison to warfarin. European Heart Journal 2005; 26(suppl): 482. 4. Stassen JM, Hauel NH, Nar H et al. Identification and in vitro characterisation of BIBR 953 ZW, a novel synthetic low molecular weight direct thrombin inhibitor. 28th Congress of the International Society on Thrombosis and Haemostasis; Paris July 6-12, 2001 5. Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors J Med Chem 2002; 45: PK/PD = pharmacokinetics and pharmacodynamics Pradaxa (Boehringer Ingelheim) 51

52 Direct Oral FIIa Inhibitor: Dabigatran
Clinical Program enrolled pts in REVOLUTION program Primary VTE Prevention (completed) Secondary Prevention of Cardiac Events in Patients with ACS* *Phase II Acute VTE Treatment Secondary VTE Prevention Stroke Prevention in Patients with Atrial Fibrillation Dabigatran etexilate is being extensively studied across a range of indications. More than patients are involved in the RE-VOLUTION Phase III clinical trial program. Primary VTE Prevention RE-NOVATE has been published in the Lancet. It involved 3494 patients undergoing elective total hip replacement RE-MODEL has been published in The Journal of Thrombosis and Haemostasis. It involved 2076 patients undergoing elective total knee replacement RE-MOBILIZE has completed and was presented at ISTH It involved 2610 patients undergoing elective total knee replacement VTE Treatment RE-COVER is ongoing and plans to randomize 2600 patients with Acute VTE VTE Secondary Prevention RE-MEDY is ongoing and plans to randomize 2000 patients with symptomatic acute VTE who have been treated for a duration of 3–6 months at the time of entry RE-SONATE is ongoing and plans to randomize 1800 patients with symptomatic VTE who have been treated with a vitamin K antagonist for months at time of entry RE-LY Ongoing; recruitment completed December 2007; 18,114 patients enrolled. RE-LY is the largest atrial fibrillation outcomes trial to date and will compare two blinded doses of dabigatran versus warfarin (INR 2.0 – 3.0). Median treatment duration will be approximately 24 months. Efficacy outcomes are composite of stroke and systemic embolism. Safety outcome is occurrence of bleeding events during treatment period. RE-DEEM Ongoing; Phase II dose finding safety and tolerability study with 1800 planned patients post-index myocardial infarction. 52

53 Direct Oral FIIa Inhibitor: Dabigatran
EMEA Approved As effective as enoxaparin for the prevention of VTE Similar safety profile with low risk of bleeding No liver enzyme elevation Fixed oral dosing without coagulation monitoring Not approved for clinical use yet but EMEA approved Dabigatran etexilate is a novel oral direct thrombin inhibitor currently in clinical development. Dabigatran etexilate is not approved for clinical use. The following information is provided to inform on the background characteristics of dabigatran etexilate. *rivaroxaban is superior 53

54 Direct Oral FIIa Inhibitor: Dabigatran
Stroke Prevention in AF: RELY Study (St Jan Bruges) Non-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism (at least one high risk factor) 18.113 R Warfarin 1 mg, 3mg, 5 mg (INR ) N=6000 Dabigatran Etexilate 110 mg b.i.d. N=6000 Dabigatran Etexilate 150 mg b.i.d. N=6000 Primary objective: Noninferiority to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up. Primary end point: Stroke + systemic embolism Connolly et al. NEJM 2009 54

55 Time to first stroke / SSE
RR 0.91 (95% CI: 0.74–1.11) p<0.001 (NI) p=0.34 (Sup) 0.05 0.04 RRR 34% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.03 Cumulative hazard rates RR 0.66 (95% CI: 0.53–0.82) p<0.001 (NI) p<0.001 (Sup) 0.02 0.01 0.0 0.5 1.0 1.5 2.0 2.5 Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Warfarin (TTR 64%) Connolly et al. NEJM 2009

56 Stroke or systemic embolism (SSE)
RR 0.91 (95% CI: 0.74–1.11) p<0.001 (NI) RR 0.66 (95% CI: 0.53–0.82) p<0.001 (sup) 1,8 % per year 1,69 1,5 1,53 RRR 34% 1,2 1,11 0,9 0,6 D110: 20% minder majeure bleoingen D: vergelijkbaar bleodings risico 0,3 D110 mg BID D150 mg BID Warfarin 182 / 6,015 134 / 6,076 199 / 6,022

57 Stroke or systemic embolism (SSE)
Noninferiority Superiority p-value p-value Dabigatran 110 mg vs. warfarin <0.001 0.34 Dabigatran 150 mg vs. warfarin <0.001 <0.001 Non-inferiority: minstens 72% van het beschermende effect van warfarine tegen TE moest bereikt worden In nirmal trial the line of identidity is important: if CI outside tis line then significant In non-inferiorty trials: the line of non-inferirority is the line of imprtance (CI should be outsdie) Both dosages of dabigatran etexilate met the non-inferiority criteria (p value < 0.001). The upper limit of the confidence intervals for dabigatran etexilate 110 mg BID was far below the non-inferiority margin of 1.46. Dabigatran 150 mg BID demonstrated superiority with the point of estimate and 95% CI well below the line of unity and a p-value of < (superiority). Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Connolly et al. NEJM 2009

58 Hemorrhagic stroke RRR RRR 69% 74% 50 45 40 30 20 14 10 12 D110 mg BID
RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) 50 Number of events 45 40 0.38% RRR 69% RRR 74% 30 20 Belangrijk want warfarine heeft preces 2* zoveel ICH als aspirine, dus hier mocht er wel verbetering zijn (welkome bevinding) Algemeen bloedingen lager in D 110 dan in W, en vergelijkbaar in D 150 tov W Intracraniele bloedingen evenwel nog beter nieuws: HS = ICB (intracraniele bloeding) Prognose van HS or ICB is slecht 1 aars mortalitiet 50% and 100% sekwellen In Rely wordt Netto klinisch benefit uigedrukt als aantal cumulatieve events (ipv uitgespaarde events) nl TE events + bloedingen). Gezien boventsaande dat ook hier: D % en D % lager dan Warfarine 7.64% Both dosages of dabigatran etexilate significantly reduced the incidence of hemorrhagic stroke (one element of the primary efficacy endpoint including stroke and systemic embolism) compared to warfarin: The relative risk reduction (RRR) for dabigatran etexilate 110mg BID compared to warfarin was 69%, RRR for dabigatran etexilate 150mg was 74%. 14 10 12 0.12% 0.10% D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022

59 All cause mortality RR 0.91 (95% CI: 0.80–1.03) p=0.13 (sup) RR 0.88 (95% CI: 0.77–1.00) p=0.051 (sup) 4,00 4,13 % per year 3,75 3,64 3,00 2,00 1,00 0,00 D110 mg BID D150 mg BID Warfarin 446 / 6,015 438 / 6,076 487 / 6,022

60 Direct Oral FIIa Inhibitor: Dabigatran
Still Room for Improvement? Unblinded warfarin administration NNT to prevent 1 NHS (1.2% to 0.9%): 357 Outcome with dabigatran  TTR 79% (unlikely even with self monitoring) Myocardial infarction (D 0.72% vs W 0.5%/yr) Dyspepsia and abdominal pain (D 11% vs W 6%) Hepatic risks after longer Follow-up? Drug interactions (verapamil, amiodarone, quinidine) About infarction: In RELY editiorial one can read: After DVT, Xim was associated with more infarction compared to warfarin After MI, Xim was associated with less infarction compared to???? Dyspepsie zou door coating zijn (ev PPI?) Drug interactions via P-glycoproteine-pathway Iinhibotren (verapamil, amiodarone, quinidine) (niet via CYP 450) Gage et al. NEJM 2009 60

61 New Antithrombotic Therapies in AF
Many Targets for Novel Anticoagulants in The Coagulation Pathway TF/VIIa ORAL PARENTERAL X IX IXa VIIIa Va “Direct Xa” Inhibitors Rivaroxaban Apixaban Endoxaban AT Fondaparinux Idraparinux Xa Warfarin broadly inhibits coagulation (inhibiting factors II (indirect by working on precusors) , Xa (indirect via AT), VII, IX, and protein C and S. By selectively inhibiting II or X drugs may have anticoagulant effect while preserving other hemostatic mechanisms in the coagulation pathway and thus potentially mitigating the risk of bleeding UFH: FX, Fxa = IIa (3) LMWH: FX, Fxa > IIa (2) Fondaparinux (Arixtra): Fxa (via antitrombine III), geen IIa, geen X (1) Rivaroxaban: direct Fxa (it does not require activation of co-factors, geen AT III nodig), geen IIa, geen X Factor Xa inhibitors a.Fondaparinux: anti Xa LMWH anti-Fxa > anti IIa UFH: anti Fxa = anti IIa Factor X inhibitors Heparin IV, LMWH Idra-parinux SC once weekly (AMADEUS trial) SC once weekly vs INR Warfarin trial terminated early because of safety Fxa inhibiotrs: AMADEUS: Idraparinux.. Is een SC Xa inhibiotr (efficenter maar reulteert in meer bloedingen. Studie gestopt. Directe Fxa inhibitors: Rivaroxa (Rocket AF) Bayer Apixa (ARISTOTLE trial) Endoxaban (Engage AF) There are many targets for novel anticoagulants in the coagulation pathway: Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 59­7939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853 “Indirect Xa” Inhibitors II “Direct IIa” Inhibitors Ximelagatran Dabigatran IIa (Thrombin) Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005 61

62 New Antithrombotic Therapies in AF
Rationale for FXa Inhibitors Position of FXa in the coagulation Pathway Arixtra > LMWH > UFH Inhibition of thrombin might have deleterious consequences Larger therapeutic window with Xa inhibition Xa is situtaed in the amplification proces Inhibition of 1 unit of Xa prevents generation of 1000 units of thrombin (amplification proces) Higher selctivity for Xa ihibtion by heparins is associated with a more potent anticoagulant effect: Fonadaparinix > LMWH > UFH Fondaparinux: anti Xa LMWH anti-Fxa > anti IIa UFH: anti Fxa = anti IIa 3. FIIa has many functions a; procoagulant (fibrin formation) b; anticoagulation (via portein C activation, prostacyclin formation) C; inflammation (cell adhesion) d. Cellular proliferrion Fxa has limited functions: d. Cellular proliferrion/inflammation

63 Direct Oral FXa Inhibitors
Rivaroxaban: Key Characteristics Direct, oral, specific, competitive FXa inhibitor Inhibits both clot-bound and free factor Xa Predictable and reproducible PK/PD* No coagulation monitoring required High oral bioavailability (80%) Half life 5-9 hours Renal and feces excretion Fixed dosing, irrespective of Age, gender, body weight,… Mild/moderate renal impairment Results of in vitro studies have shown that rivaroxaban is a direct, specific, competitive Factor Xa (FXa) inhibitor.1 Studies in healthy subjects demonstrated that it has no direct effect on thrombin and does not require a cofactor2 Rivaroxaban inhibits FXa generated via the intrinsic or extrinsic coagulation pathway in human plasma,3 and free and fibrin-bound FXa activity and prothrombinase activity1,4 Rivaroxaban is an effective anticoagulant, as demonstrated by its effects on global clotting tests (prothrombin time, activated partial thromboplastin time)2,5 Rivaroxaban inhibits thrombin generation6 Rivaroxaban does not directly affect platelet aggregation3,7,8 Recombinant Factor VIIa, given after the initiation of bleeding, partially reversed the anticoagulant effect of high-dose rivaroxaban9 Perzborn E et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Kubitza D et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Fareed J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3(S1):Abstract P0518 Depasse F et al. Effect of BAY – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005;3 (Suppl. 1):Abstract P1104 Kubitza D et al. Safety, pharmacodynamics and pharmacokinetics of BAY 59­7939 – an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873–880 Graff J et al. Effects of the oral, direct Factor Xa-inhibitor rivaroxaban (BAY ) on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; doi: / Perzborn E et al. Biochemical and pharmacologic properties of BAY , an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33(S2):Abstract PO079 Kubitza D et al. Rivaroxaban (BAY 59‑7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007;63:469–474 Tinel H, Huetter J, Perzborn E. Partial reversal of the anticoagulant effect of high-dose rivaroxaban – an oral, direct Factor Xa inhibitor – by recombinant Factor VIIa in rats. Blood 2006;108:Abstract 915 Xarelto (Bayer) 63

64 Direct Oral FXa Inhibitor: Rivaroxaban
Clinical Program: pts to be enrolled Phase II Phase III VTE prevention after major orthopaedic surgery ODIXa-HIP1 ODIXa-HIP2 ODIXa-KNEE ODIXa-OD-HIP RECORD1 RECORD2 RECORD3 RECORD4 VTE prevention in hospitalized medically ill patients VTE treatment ODIXa-DVT EINSTEIN-DVT EINSTEIN-PE EINSTEIN-EXT Stroke prevention in atrial fibrillation 3 Japanese dose-finding studies ROCKET-AF Secondary prevention of acute coronary syndromes MAGELLAN ATLAS 64

65 Direct Oral FXa Inhibitor: Rivaroxaban
Extended Thrombo-prophylaxis after THR: RECORD 1 4 3.7% 3 Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily Incidence (%) 2.0% 2 1.1% Rivaroxaban for extended thromboprophylaxis after THR (knee even better) compared with enoxaparin showed: Superior efficacy for the primary composite endpoint (DVT, PE, and all-cause mortality) Superior efficacy for major VTE Good safety profile Low and similar incidence of major bleeding Well tolerated No evidence of any liver safety issues attributable to rivaroxaban 1 0.5% 0.3% 0.3% 0.2% 0.1% Total VTE Major VTE Symptomatic VTE Major bleeding RRR 70% RRR 88% p<0.001 p<0.001 p=0.222 p=0.178 65

66 Direct Oral FXa Inhibitor: Rivaroxaban
EMEA Approved Rivaroxaban head-to-head comparison with enoxaparin in patients undergoing THR and TKR showed: Superior efficacy for the primary endpoint (total VTE) Superior efficacy major VTE (THR) and symptomatic VTE (THR and TKR) Results of in vitro studies have shown that rivaroxaban is a direct, specific, competitive Factor Xa (FXa) inhibitor.1 Studies in healthy subjects demonstrated that it has no direct effect on thrombin and does not require a cofactor2 Rivaroxaban inhibits FXa generated via the intrinsic or extrinsic coagulation pathway in human plasma,3 and free and fibrin-bound FXa activity and prothrombinase activity1,4 Rivaroxaban is an effective anticoagulant, as demonstrated by its effects on global clotting tests (prothrombin time, activated partial thromboplastin time)2,5 Rivaroxaban inhibits thrombin generation6 Rivaroxaban does not directly affect platelet aggregation3,7,8 Recombinant Factor VIIa, given after the initiation of bleeding, partially reversed the anticoagulant effect of high-dose rivaroxaban9 Perzborn E et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59­7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Kubitza D et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59­7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Fareed J et al. Antithrombotic mechanism of action of BAY 59­7939 – a novel, oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3(S1):Abstract P0518 Depasse F et al. Effect of BAY – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005;3 (Suppl. 1):Abstract P1104 Kubitza D et al. Safety, pharmacodynamics and pharmacokinetics of BAY 59­7939 – an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873–880 Graff J et al. Effects of the oral, direct Factor Xa-inhibitor rivaroxaban (BAY ) on platelet-induced thrombin generation and prothrombinase activity. J Clin Pharmacol 2007; doi: / Perzborn E et al. Biochemical and pharmacologic properties of BAY , an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33(S2):Abstract PO079 Kubitza D et al. Rivaroxaban (BAY 59‑7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007;63:469–474 Tinel H, Huetter J, Perzborn E. Partial reversal of the anticoagulant effect of high-dose rivaroxaban – an oral, direct Factor Xa inhibitor – by recombinant Factor VIIa in rats. Blood 2006;108:Abstract 915 A good safety profile similar incidence of major bleeding 66

67 Direct Oral FXa Inhibitor: Rivaroxaban
Stroke Prevention in AF: ROCKET AF Risk Factors CHF Hypertension Age  75 Diabetes OR Stroke, TIA or Systemic embolus At least 2 required Atrial Fibrillation Rivaroxaban Randomize Double blind / Double Dummy (n ~ 14,000) Warfarin 20 mg once daily 15 mg for Cr Cl 30-49 INR target - 2.5 ( inclusive) This slide shows the basic protocol design Title center aligned Primary Efficacy Endpoint: Stroke or non-CNS Systemic Embolism Primary Safety Endpoint: CE of Major Bleeding and Clinically Relevant Bleeding Statistics: non-inferiority, >95% power, 2.3% warfarin event rate Finished recruitment N=15.000 67

68 Meta-analysis of ischaemic stroke or systemic embolism
Prospects for improving thrombosis management in atrial fibrillation Meta-analysis of ischaemic stroke or systemic embolism W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs ximelagatran W vs dabigatran 150 Compared to line of UNITY!!!! The only show in town 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other treatment Camm J.: Oral presentation at ESC on Aug 30th 2009.

69 Prospects for improving thrombosis management in atrial fibrillation
AF is a Growing Public Health Problem which Has Reached Epidemic Proportions Stroke Prevention is a Pressing Health Concern, with Warfarin being the Single Most Effective Treatment Many AF Patienst at risk for Stroke Will Benefit from Novel Anticoagulants Goals in 2010 and Beyond: Breaking the Warfarin Barrier Head-to-head Comparisons of FIIa and FXa Inhibitors True cure for AF (Ablation, Maze)

70

71 Atrial Fibrillation and Stroke
Epidemiology Warfarin Antiplatelet Strategy Novel Antithrombotic Strategies Indirect Antithrombotic Drugs New Antithrombotic Drugs Non-pharmacological Strategies From Lone AF to Heart Failure New Dta

72 Antistollingsbeleid bij VKF
Innovatie door nieuwe orale antistollingsmiddelen bij VKF : nog wat geduld… Kwaliteitsbewaking van coumarines : een absolute prioriteit ! Alertheid peri-operatief mbt antitrombotica ! 72

73 Challenges of Antithrombotic AF Therapies
Meta-analysis of ischaemic stroke/systemic embolism with adjusted-dose oral anticoagulants in AF 13 trials reviewed (n=14,423) Comparison RR (fixed) [95% Cl] Warfarin vs placebo 0.33 [0.24, 0.45] Warfarin vs ASA 0.59 [0.40, 0.86] Warfarin vs all FLD warfarin 0.36 [0.23, 0.58] Warfarin vs ximelagatran 1.04 [0.77, 1.40] Reference Lip G, et al. Thromb Res. 2006;118: 0.01 0.1 1 10 100 Favours adjusted warfarin Favours other treatment AF, atrial fibrillation; ASA, acetylsalicylic acid; CI, confidence interval; FLD, fixed low dose Lip et al. Thromb Res 2006

74 Thrombosis Atrial Fibrillation on Stroke Virchow’s Triad*
Circulatory stasis Endothelial injury AF +++ ACS + AF ++ ACS +++ Thrombosis *Greater than 90% of thrombus accumulation originates in the Left Atrial Appendage (LAA) An adaptation of the relevance of Virchow’s triad to AF and ACS is shown in this slide Key message Virchow’s triad key pathogenic factors in the coagulation process are involved in arterial thrombosis associated with AF and ACS: BLOOD VESSEL STASIS Abbreviations ACS, acute coronary syndrome; AF, atrial fibrillation Hypercoagulable state AF ++ ACS ++ +++ = Strong association ++ = Possible association, due to ischaemia or underlying inflammation state + = Weak association, if at all 74

75 Antithrombotic Therapies in AF
Time under Therapautic INR (TTR) At INR >2 prevention of stroke but also clear reduction of sevrity of stroke A Recent Meta-analysis demonstrated that Treating 1000 Patients with AF for 1 year With Warfarin vs Aspirin Prevented 23 Ischemic Strokes but Caused 9 Additional Major Bleeds Do the right ting, do the right thing right White et al, Arch Int Med 2007;167:239

76 Key message Heparin interacts with antithrombin to catalyse inactivation of Factor Xa and thrombin. For heparin to catalyse inhibition of thrombin, it must bind to antithrombin and thrombin. To catalyse inhibition of Factor Xa, a heparin molecule must bind only to antithrombin Abbreviations AT, antithrombin; FXa, Factor Xa

77 Factor Xa–Factor Va complex is resistant to inhibition by antithrombin
Factor Xa–Factor Va resistant to AT inhibition Factor Xa sensitive to AT inhibition Factor Xa exists in two forms: free and in complex with activated Factor V (Factor Va) in the prothrombinase complex Free Factor Xa is sensitive to inhibition by antithrombin and heparin, whereas Factor Xa in the prothrombinase complex is not In the presence of sufficient antithrombin, unfractionated heparin, low molecular weight heparins and fondaparinux effectively catalyse inactivation of free Factor Xa but not Factor Xa contained in the prothrombinase complex Key message Factor Xa exists in two forms: free and in complex with Factor Va (prothrombinase complex). Heparins effectively catalyse inactivation of free Factor Xa, but not Factor Xa contained in the prothrombinase complex Abbreviations AT, antithrombin; Va, Factor Va; Xa, Factor Xa References Esmon CT. Molecular basis of anticoagulation with oral anticoagulants. Thromb Haemost 2008; Suppl: 4-9. Esmon Thromb Haemost 2008 77

78 Conventional Antiarrhythmic Drugs for AF
Maintaining Sinus Rhythm and Stroke 4060 patients, FU 5 year Paroxysmal or Recurrent Persistent Asymptomatic AF > 65 yr or Other RF for Stroke or Death Rhythm Control : cardioversion, antiarrhythmic drugs, Stop coumadin if SR Rate Control : heart rate from 80/’ en 110/’ ; continued coumadin EP: Cumulative Mortality Mortaiteit is het relavnt EP voorde patient want van de rest heeft ie geen last. Effect van beta-blocker of CV hospitalisatie? Wyse et al. NEJM 2002

79 Antiplatelet Therapies in AF
Challenges of New Antithrombotic Therapies in AF (ACTIVE W) Warfarin (INR 2-3) vs Asprin (75mg) +Clopidogrel (75mg) CRT (3371/3335) Primary Outcome - stroke, non CNS embols, myocardial infarction, vascular death Study was Stopped Early Challenges of new anti-thrombotic therapies: aoral antiocoaugulation is suiperio to aspirone + clopidogrel especially in those already taking oral anticoagulation treatment Patients with Warfarin at entry: primary outcome (Stroke, embolus, myocardial ifarction, vascular detah) 3.7% per year - less efficacy if lower than aspirine + clopidogrel - less efficay if new warfarin Major bleeding 2% per year - less safety if aspirin + clopidogrel - less safety if new warfarin ACTIVE Investigators, Lancet 2006;367:

80 Indirect Antithrombotic Therapies in AF
Prevalence of Arterial Hypertension Patients with Hypertension (%) Paroxysmal persistent 80 Recurrent persistent Recurrent persistent 70 Recurrent persistent Paroxysmal persistent Paroxysmal persistent 60 50 40 30 20 10 PIAF RACE STAF AFFIRM* HOT CAFE AFFIRM** * Hypertension as a predominant cardiac diagnosis ** Overall prevalence of hypertension Camm AJ et al. Dialog in Cardiov Med 2003

81

82 Relation Between AF Burden and Stroke
Proportion of Patients with AF 125 100 75 50 Background— Some current pacing systems can automatically detect and record atrial tachyarrhythmias that may be asymptomatic. We prospectively studied a 312-patient (pt) subgroup of MOST (MOde Selection Trial), a 2010-patient, 6-year randomized trial of DDDR versus VVIR pacing in sinus node dysfunction (SND). The purpose of the study was to correlate atrial high rate events (AHREs) detected by pacemaker diagnostics with clinical outcomes. Methods and Results— Pacemakers were programmed to log an AHRE when the atrial rate was >220 bpm for 10 consecutive beats. Analysis was confined to patients with at least 1 AHRE duration exceeding 5 minutes. The 312 patients were median age 74 years, 55% female, and 60% had a history of SVT. 160 of 312 (51.3%) patients enrolled had at least 1 AHRE >5 minutes duration over median follow-up of 27 months. Cox proportional hazards analysis assessed the relationship of AHREs with clinical events, adjusting for prognostic variables and baseline covariates. The presence of any AHRE was an independent predictor of the following: total mortality (hazard ratio AHRE versus no AHRE and 95% confidence intervals=2.48 [1.25, 4.91], P=0.0092); death or nonfatal stroke (2.79 [1.51, 5.15], P=0.0011); and atrial fibrillation (5.93 [2.88, 12.2], P=0.0001). There was no significant effect of pacing mode on the presence or absence of AHREs. Conclusions— AHRE detected by pacemakers in patients with SND identify patients that are more than twice as likely to die or have a stroke, and 6 times as likely to develop atrial fibrillation as similar patients without AHRE. AF 25 AHRE No AHRE Glotzer et al, Circulation, 2003;107:1614

83 Atrial Fibrillation begets Trouble
Half of all hospitalizations for Arrhythmias 2- to 3-fold increased risk for Hospitalizations 1.6-fold increased risk for developing HF 3-fold increased risk for worsening HF 5- to 7-fold increased risk for Stroke 10-fold increased risk for Stroke in hypertrophic CMP 1.8-fold increased risk for Mortality in population 4.2-fold increased risk for CV Mortality in lone AF 2.5-fold increased risk for Mortality in HF 4.5-fold increased risk for Mortality in ACS Stroke Heart Failure Death (in HF) Dementia


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