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Prospects for improving thrombosis management in atrial fibrillation M. Duytschaever, P. Debonnaire, Y.Vandekerckhove and R. Tavernier St Jan Hospital,

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Presentation on theme: "Prospects for improving thrombosis management in atrial fibrillation M. Duytschaever, P. Debonnaire, Y.Vandekerckhove and R. Tavernier St Jan Hospital,"— Presentation transcript:

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

2 Presenter Disclosure Information of Mattias Duytschaever Biosense WebsterConsultant MedtronicConsultant SanofiAdvisory Board

3 Age (yrs) Prevalence (%) Framingham Study Mayo Clinic Study CHS Rotterdam Study Prevalence and Incidence of AF Epidemiology of Atrial Fibrillation Age (yrs) Incidence/1000 person-years Miyasaka et al, Circ 2006;114: Framingham Study (men) CHS (men) Mayo Clinic (men) 9090 At 55y Life time risk for AF = 23.8% Heeringa et al, EHJ 2006;27: % 1 to 1.5%

4 Impact of Atrial Fibrillation on Stroke Yearly Risk of Stroke in Non- valvular AF is 5%Yearly Risk of Stroke in Non- valvular AF is 5% AF is Associated with a 6-fold Increased Risk for StrokeAF is Associated with a 6-fold Increased Risk for Stroke Over 87% of strokes are ThromboembolicOver 87% of strokes are Thromboembolic 40% of Patients with AF have Silent Brain Infarction40% of Patients with AF have Silent Brain Infarction In Patients with AF there is Twice as much Cognitive Dysfunction or DementiaIn 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 causesStrokes by AF are Twice as Fatal or Disabling, and are more Likely to Recur compared to other causes Miyasaka et al, European Heart J 2007;28: Age (yrs) Incidence of Dementia/1000 person-years General Men Men with AF Stroke Prevention in AF is a Pressing Health Concern

5 Impact of Atrial Fibrillation on Stroke Marini et al, Stroke 2005 Stroke due to AF is more Severe Mortality after Stroke (%) % 30 daysAfter 1 year 14% 63% 34% Stroke due to AF Other Stroke 40 20

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

7 Endothelial injury Hypercoagulable state Circulatory stasis Virchow’s Triad* Atrial Fibrillation on Stroke Thrombosis *>90% of thrombus accumulation originates in the Left Atrial Appendage (LAA)

8 Jahangir et al, Circulation 2007;115: Survival Free of Death (%) Years observed expected % 68% 86% 57% Survival Free of Stroke/TIA (%) Years observed expected % 88% 96% 89% 72%* 85% Long-Term Outcome in Pts with Lone AF: a 30-year Follow-Up Study Risk Factors for Stroke in Pts with Afib

9 Stroke rate(% year) Wolf et al. Jacc 2001 and Arch Intern Med 1987 Age (yrs) AF and Stroke: Framingham Study, 30-year FU Risk Factors for Stroke in Pts with Afib % Age Prev AF % % Strokes per 1000PY ctrl Strokes per 1000PY AF RR The risk of Stroke increases Exponential with Age In general AF is Associated with a 6-fold Increased Risk for Stroke

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

11 C—CHF1 H—Hypertension1 A—Age >751 D—Diabetes mellitus1 S 2 —TIA/stroke2 Stroke rate (% per year) n=120n=463n=523n=337n=220n=65n=5 CHADS 2 score Risk Factors for Stroke in Non-valvular AF: CHADS 2 Score Risk Factors for Stroke in Pts with Afib Overall Yearly Risk of Stroke in Non-valvular AF is 5%Overall Yearly Risk of Stroke in Non-valvular AF is 5% Fuster et al, Circulation 2006;114:

12 How to Improve Risk Stratification? Fang et al, JACC 2008;51:810-5 Risk Factors for Stroke in Pts with Afib CHADS 2 criteria and other mild risk factors (female, diastolic dysfunction, LA dilatation, mild VHD, PAOD, CAD, renal failure)

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

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

15 50% AFASAK SPAF BAATAF CAFA SPINAF Warfarin Better Warfarin Worse EAFT All Trials (6) 0-50% RR Reduction (95% CI) Hart et al, Arch Intern Med 1999;131:492 Warfarin in Non-valvular AF Risk Patients (Pooled 1° RCT) Antithrombotic Therapies in AF 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%

16 Antithrombotic Therapies in AF Cooper: Arch Int Med 166, 2006 Lip: Thromb Res 118, 2006 Assuming 51 ischemic strokes/1000 pt-yr Assuming 51 ischemic strokes/1000 pt-yr Adjusted standard dose warfarin prevented 28 strokes at expense of 11 fatal bleeds Adjusted standard dose warfarin prevented 28 strokes at expense of 11 fatal bleeds Net Clinical Benefit of Warfarin Anticoagulation in AF TEs prevented minus ICHs induced TEs prevented minus ICHs induced (TE rate off warfarin – TE rate on warfarin) minus 1.5 (ICH rate off warfarin – ICH rate on warfarin) (TE rate off warfarin – TE rate on warfarin) minus 1.5 (ICH rate off warfarin – ICH rate on warfarin)

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

18 50% AFASAK (75mg) SPAF I (325mg) EAFT (300mg) ESPS II LASAF Aspirin Better Aspirin Worse UK-TIA All Trials (6) 0-50% RR Reduction (95% CI) Antithrombotic Therapies in AF JACC 2001;38(4):1-70 Aspirin in Non-valvular AF Risk Patients Relative Risk Reduction 21% (to placebo) Aspirin prevented 16 strokes at expense of 6 fatal bleeds Warfarin vs ASA: Relative Risk Reduction 41%

19 Warfarin vs Aspirin in the Elderly (BAFTA Study) Mant et al, Lancet 2007;370: Annual Rate of Primary Event 3.8% Aspirin 2.0% 1.8% Warfarin 1.9% N=973 >75y (Mean Age 81y) Controlled Randomised Trial Aspririn 75mg vs Warfarin INR % Warfarin at entry Primary Event: stroke, IC hemorraghe, arterial embolism Annual Rate of Major Bleeding Antithrombotic Therapies in AF NTT = 50

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

21 CHADS 2 criteria and other mild risk factors (female, diastolic dysfunction, LA dilatation, mild VHD, PAOD, CAD, renal failure) Antithrombotic Therapies in AF ACC/AHA/ESC Practice Guidelines for the management of AF (“not tabloids from the mountains”) CHADS CHADS CHADS CHADS nothing Aspirin 81mg to 325mg daily Warfarin (INR 2.0 to 3.0)

22 Warfarin Treatment in European Countries (Euro Heart Survey) Despite the Guidelines: Over-utilisation (49%) Under-utilisation (33%) Antithrombotic Therapies in AF % of Patients Non Eligible (N=517) Eligible (N=4736) % 49% OAC Nieuwlaat et al, Eur Heart J 2005;26:2422 (Euro Heart Survey) OAC+ antiplatelet antiplatelet No antithrombotic

23 JACC 2001;38(4):1-70Sportif II Trial Odds Ratio Bleeding Stroke International Normalised Ratio Patients with INR 2-3 (%) Weeks on Treatment Dose-Adjusted Warfarin (INR 2-3) Antithrombotic Therapies in AF The importance of TTR is proven in the SPORTIF III and V trial

24 Hylek et al, Circulation 2007;115:2689 Major Hemorrhage in the 1st Year of Warfarin R/ Among AF>65y AFI (1994) 1.3 Trial Annual Rate of Major Hemorr SPORTIF V (2005) 3.4 SPAF II >75 (1994) 4.2 N.R. Warfarin at entry 85% 0% Mean Age SPORTIF III (2003) 2.273% Hylek (2007) 7.20% 69y 72y 80y 70y 77y Antithrombotic Therapies in AF Cumulative Proportion with Major Hemorraghe Days on Warfarin >80y <80y

25 Warfarin is cornerstone of therapyWarfarin 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) Core Findings Antithrombotic Therapies in AF

26 Vit K Antagonists or Coumadin Antithrombotic Therapies in AF Sintrom1-4mg Acenocumarol (8u) Marevan 5mg Warfarin (20-60u) Marcoumar 3mgFenprocoumon ( u)

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

28 Rationale for dual antiplatelet therapy Antiplatelet Therapies in AF 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 Dose-adjusted OAC (INR 2.0–3.0) Clopidogrel (75 mg/d) + ASA (75–100 mg/day) Clopidogrel (75 mg/day) + ASA (75–100 mg/day) Placebo + ASA (75–100 mg/day) Placebo n = ACTIVE W ACTIVE A # ACTIVE I R R R Patients with documented AF Irbesartan (150–300 mg/day) Re-randomisation (if RRs >=110mmHg) with  1: EF<45% AHT >75yrs Diabetes Stroke/TIA/emboli CAD PAOD Yusuf et al, ESC 2009 ACTIVE W and A Study Antiplatelet Therapies in AF # patients with AF unable to receive VKAs

30 # Stopped after complete enrolment because of warfarin superiority; ‡ Composite of stroke, non CNS embolism, MI and vascular death Warfarin (INR 2.0–3.0) vs ASA (75–100 mg) + clopidogrel (75 mg) Annual incidence (%) RR 1.44 p= RR 1.10 p= Primary endpoint ‡ Major bleeding Clopidogrel/ASA (n=3,335) Warfarin (n=3,371) Warfarin vs ASA+clopidogrel Active W Study ACTIVE Investigators, Lancet 2006;367:

31 ‡ Composite of stroke, non CNS embolism, MI and vascular death Annual incidence (%) RR 0.89 p=0.01 RR 1.57 p< Connolly et al. N Engl J Med 2009 Primary endpoint ‡ Major bleeding Clopidogrel/ASA (n=3,772) ASA (n=3,782) ASA vs ASA+clopidogrel Active A Study ASA (75-100mg) vs ASA (75–100 mg) + clopidogrel (75 mg) Apsirine and clopidogrel: 1000pts treated for 3 years will prevent 28 strokes at a cost of 20 major bleeds

32 ACTIVE W and A Study: Stroke Rates Antiplatelets vs Anticoagulants in AF Active W (rate per year) 1.4% TreatmentVKA Active A (rate per year) - 2.4% A+C 2.4% - A 3.3% ACTIVE W and A Study: Major Bleeding Rates Active W (rate per year) 2.2% Active A (rate per year) - 2.4% 2.0% - 1.3%

33 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 Conclusion Antiplatelets vs Anticoagulants in AF

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

35 Decreasing Stroke Rates on Warfarin in Large AF Trials in High Risk Patients Connolly et al, Circulation 2007;116: SPAF III 1996 ACTIVE W 2006 TrialYear SPORTIF V 2005 SPORTIF III % 64% Therapeutic INR 68% 66% 56% 23% Warfarin at entry 84% 73% 1.9% 1.0% Annual Ischemic Stroke Rate 1.1% 1.9% 0.5% 0.4% Annual Hemorrh Stroke Rate 0.1% 0.4% Syst BP (mmHg) Indirect Antithrombotic Therapies in AF

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

37 Irbesartan in Atrial Fibrillation Yusuf et al, ESC 2009 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??? Effect of ARB and BP Lowering on Vascular Events (ACTIVE-I)

38 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) Hohnloser et al, N Engl J Med. 2009; 360: ATHENA Effect of dronedarone on cardiovascular events in AF Indirect Antithrombotic Therapies in AF

39 Patients at risk Placebo Dronedarone ATHENA: Primary Outcome Hohnloser et al, N Engl J Med. 2009; 360: Months % reduction in risk Time to first cardiovascular hospitalization or death Cumulative Incidence (%) HR for the primary outcome=0.76 P<.001 Placebo (39.4%) Dronedarone (31.9%) FU 21+/-5m Indirect Antithrombotic Therapies in AF

40 ATHENA: Post Hoc Analysis Outcome for Stroke Connolly et al, Circulation 2009;120: Indirect Antithrombotic Therapies in AF

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

42 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% Non Pharmacological Strategies

43 Oral et al Circulation 2006;114:759 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. 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 Freedom of Stroke after Catheter Ablation for AF (PVI)

44 Freedom of Stroke after percutaneous closure of the LAA WATCHMAN LAA Closure Device in situ Non Pharmacological Strategies PROTECT-AF, Lancet 2009;374:

45 Freedom of Stroke after percutaneous closure of the LAA Non Pharmacological Strategies

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

47 Fondaparinux Idraparinux Rivaroxaban Apixaban Endoxaban Ximelagatran Dabigatran ORALPARENTERAL IIa (Thrombin) TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT Adapted from Weitz & Bates, J Thromb Haemost 2005 New Oral Antithrombotic Therapies Many Targets for Novel Anticoagulants in The Coagulation Pathway “Direct IIa” Inhibitors “Direct Xa” Inhibitors “Indirect Xa” Inhibitors XaXa

48 HO NH N N H O O N H O NH 2 melagatran  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 Direct Oral FIIa Inhibitors Ximelagatran: Key Characteristics Exantha (Astra Zeneca)

49 Annual Event Rate (%) WarfarinXimelagatran Stroke and Systemic Embolism 2,3 1,6 Annual Event Rate (%) WarfarinXimelagatran Major Bleeding 1,81,3 SPORTIF III Investigators, Lancet 2003;362: AF and >=1 RF Warfarin INR 2-3 vs Ximelagatran 2*36mg Open Label phase III N=3407 (non-inferiority) Stroke Prevention in AF: SPORTIF III Direct Oral FIIa Inhibitor: Ximelagatran 11 Oct 2004 … 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

50 Event rate (%) ALT >3x ULN p < % 0.8 % Other Adverse Events – SP III Liver Enzyme Elevation Treatment Duration (months) Incidence (n) Ximelagatran Warfarin NOT APPROVED Direct Oral FIIa Inhibitors Ximelagatran (Exanta)

51 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 PK/PD = pharmacokinetics and pharmacodynamics Pradaxa (Boehringer Ingelheim) Direct Oral FIIa Inhibitors Dabigatran Etexilate: Key Characteristics

52 Secondary Prevention of Cardiac Events in Patients with ACS* Stroke Prevention in Patients with Atrial Fibrillation Acute VTE Treatment Secondary VTE Prevention Primary VTE Prevention (completed) *Phase II Direct Oral FIIa Inhibitor: Dabigatran Clinical Program enrolled pts in REVOLUTION program

53 EMEA Approved Direct Oral FIIa Inhibitor: Dabigatran 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 *rivaroxaban is superior

54 Non-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism (at least one high risk factor) 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 Stroke Prevention in AF: RELY Study (St Jan Bruges) Direct Oral FIIa Inhibitor: Dabigatran Connolly et al. NEJM 2009

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

56 RR 0.66 (95% CI: 0.53–0.82) p<0.001 (sup) 1,53 1,11 1,69 0 0,3 0,6 0,9 1,2 1,5 1,8 D110 mg BIDD150 mg BIDWarfarin RR 0.91 (95% CI: 0.74–1.11) p<0.001 (NI) % per year 182 / 6, / 6, / 6,022 RRR 34% Stroke or systemic embolism (SSE)

57 Dabigatran 110 mg vs. warfarin Dabigatran 150 mg vs. warfarin Noninferiority p-value <0.001 Superiority p-value 0.34 <0.001 Margin = 1.46 HR (95% CI) Connolly et al. NEJM 2009

58 RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) Hemorrhagic stroke RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) Number of events 6,0156,0766, D110 mg BIDD150 mg BIDWarfarin 0.10% 0.38% RRR 69% RRR 74% 0.12%

59 3,75 3,64 4,13 0,00 1,00 2,00 3,00 4,00 D110 mg BIDD150 mg BIDWarfarin RR 0.88 (95% CI: 0.77–1.00) p=0.051 (sup) All cause mortality RR 0.91 (95% CI: 0.80–1.03) p=0.13 (sup) 446 / 6, / 6, / 6,022 % per year

60 Still Room for Improvement? Direct Oral FIIa Inhibitor: Dabigatran Gage et al. NEJM 2009 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)

61 Fondaparinux Idraparinux Rivaroxaban Apixaban Endoxaban Ximelagatran Dabigatran ORALPARENTERAL IIa (Thrombin) TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT Adapted from Weitz & Bates, J Thromb Haemost 2005 New Antithrombotic Therapies in AF “Direct IIa” Inhibitors “Direct Xa” Inhibitors “Indirect Xa” Inhibitors XaXa Many Targets for Novel Anticoagulants in The Coagulation Pathway

62 Position of FXa in the coagulation Pathway Arixtra > LMWH > UFH Inhibition of thrombin might have deleterious consequences Larger therapeutic window with Xa inhibition New Antithrombotic Therapies in AF Rationale for FXa Inhibitors

63 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 Direct Oral FXa Inhibitors Rivaroxaban: Key Characteristics Xarelto (Bayer)

64 Clinical Program: pts to be enrolled Phase IIPhase 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 treatmentODIXa-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 ATLAS MAGELLAN Direct Oral FXa Inhibitor: Rivaroxaban

65 Incidence (%) 0.1% 0.3% 3.7% 1.1% 2.0% 0.2% 0.5% 0.3% Total VTE RRR 70% Major VTE RRR 88% Symptomatic VTE Major bleeding Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily p<0.001 p=0.222p=0.178 Extended Thrombo-prophylaxis after THR: RECORD 1 Direct Oral FXa Inhibitor: Rivaroxaban

66 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) A good safety profile similar incidence of major bleeding Direct Oral FXa Inhibitor: Rivaroxaban EMEA Approved

67 Rivaroxaban Warfarin 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 INR target ( inclusive) 20 mg once daily 15 mg for Cr Cl Atrial Fibrillation Randomize Double blind / Double Dummy (n ~ 14,000) Risk Factors CHFCHF HypertensionHypertension Age  75Age  75 DiabetesDiabetesOR Stroke, TIA or Systemic embolusStroke, TIA or Systemic embolus At least 2 required Direct Oral FXa Inhibitor: Rivaroxaban Stroke Prevention in AF: ROCKET AF Finished recruitment N=15.000

68 Camm J.: Oral presentation at ESC on Aug 30th 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 Favours warfarinFavours other treatment Prospects for improving thrombosis management in atrial fibrillation

69 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) Prospects for improving thrombosis management in atrial fibrillation

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71 Atrial Fibrillation and StrokeAtrial Fibrillation and Stroke –Epidemiology –Warfarin –Antiplatelet Strategy Novel Antithrombotic StrategiesNovel Antithrombotic Strategies –Indirect Antithrombotic Drugs –New Antithrombotic Drugs –Non-pharmacological Strategies Atrial Fibrillation and Stroke

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

73 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] RR (fixed) [95% Cl] Favours adjusted warfarin Favours other treatment 13 trials reviewed (n=14,423) AF, atrial fibrillation; ASA, acetylsalicylic acid; CI, confidence interval; FLD, fixed low dose Lip et al. Thromb Res 2006 Comparison Meta-analysis of ischaemic stroke/systemic embolism with adjusted-dose oral anticoagulants in AF Challenges of Antithrombotic AF Therapies

74 AF ++ ACS +++ Endothelial injury Hypercoagulable state Circulatory stasis +++ = Strong association ++ = Possible association, due to ischaemia or underlying inflammation state + = Weak association, if at all AF ++ ACS ++ AF +++ ACS + Virchow’s Triad* Atrial Fibrillation on Stroke Thrombosis *Greater than 90% of thrombus accumulation originates in the Left Atrial Appendage (LAA)

75 Time under Therapautic INR (TTR) Antithrombotic Therapies in AF White et al, Arch Int Med 2007;167:239 Do the right ting, do the right thing right

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77 Factor Xa–Factor Va complex is resistant to inhibition by antithrombin Factor Xa sensitive to AT inhibition Factor Xa–Factor Va resistant to AT inhibition Esmon Thromb Haemost 2008

78 Maintaining Sinus Rhythm and Stroke Conventional Antiarrhythmic Drugs for AF Wyse et al. NEJM 2002  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

79 ACTIVE Investigators, Lancet 2006;367: 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 Antiplatelet Therapies in AF

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

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82 Glotzer et al, Circulation, 2003;107:1614 Proportion of Patients with AF AHRE No AHRE AF Relation Between AF Burden and Stroke

83 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 Atrial Fibrillation begets Trouble


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