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Prospects for improving thrombosis management in atrial fibrillation

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

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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 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

  3. Epidemiology of Atrial Fibrillation Prevalence and Incidence of AF Prevalence(%) Incidence/1000 person-years 17.8% 60 Framingham Study Mayo Clinic Study CHS Rotterdam Study Framingham Study (men) 15 CHS (men) Mayo Clinic (men) 40 10 1 to 1.5% 20 5 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;114:119-125 Heeringa et al, EHJ 2006;27:949-953

  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 General Men 20 90 50 60 70 80 Age (yrs) Miyasaka et al, European Heart J 2007;28:1962-1967

  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% 20 14% 0 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* Circulatorystasis Endothelial injury Thrombosis • *>90% of thrombus accumulation originates in the Left Atrial Appendage (LAA) Hypercoagulable state

  8. Risk Factors for Stroke in Pts with Afib Risk Factors for Stroke in Non-valvular AF: CHADS Criteria Fuster et al, Circulation 2006;114:257-354

  9. 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 0 0 1 2 3 4 5 6 CHADS2 score • Overall Yearly Risk of Stroke in Non-valvular AF is 5% Fuster et al, Circulation 2006;114:257-354

  10. 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) Fang et al, JACC 2008;51:810-5

  11. 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 1.1% (0.8-1.6) Zero burden Low burden <5.5hrs 1.1% (0.4-2.8) 0.98 0.97 High burden >5.5hrs 2.4% (1.2-4.5) 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

  12. 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

  13. 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 EAFT All Trials (6) 50% 0 -50% Warfarin Better Warfarin Worse Hart et al, Arch Intern Med 1999;131:492

  14. 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, 2006Lip: Thromb Res 118, 2006 • TEs prevented minus ICHs induced • (TE rate off warfarin – TE rate on warfarin) minus 1.5 (ICH rate off warfarin – ICH rate on warfarin)

  15. Antithrombotic Therapies in AF Net Clinical Benefit of Warfarin Anticoagulation in AF Singer et al Annals of Int Med 2009;151:298-305

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

  17. 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;114:257-354

  18. Antithrombotic Therapies in AF Warfarin Treatment in European Countries (Euro Heart Survey) % of Patients No antithrombotic 100 antiplatelet OAC+ antiplatelet 75 OAC 50 • Despite the Guidelines: • Over-utilisation (49%) • Under-utilisation (33%) 67% 49% 25 Non Eligible (N=517) Eligible (N=4736) Nieuwlaat et al, Eur Heart J 2005;26:2422 (Euro Heart Survey)

  19. Warfarin is cornerstone of therapy Anticoag at INR 2.0-3.0 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) Antithrombotic Therapies in AF Core Findings

  20. 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

  21. 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

  22. Antiplatelet Therapies in AF ACTIVE W and A Study n = 14.500 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 #patients with AF unable to receive VKAs

  23. Active W Study Warfarin vs ASA+clopidogrel Warfarin (INR 2.0–3.0) vs ASA (75–100 mg) + clopidogrel (75 mg) 10 RR 1.44p=0.0003 Clopidogrel/ASA (n=3,335) 8 Warfarin (n=3,371) 5.60 6 RR 1.10 p=0.53 Annual incidence (%) 3.93 4 2.42 2.21 2 0 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;367:1903-1912

  24. 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) 7.6 8 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 2.0 2 1.3 0 Primary endpoint‡ Major bleeding ‡Composite of stroke, non CNS embolism, MI and vascular death Connolly et al.N Engl J Med 2009

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

  26. 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 Antiplatelets vs Anticoagulants in AF Conclusion

  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. 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) 1996 61% 56% 1.9% 140 0.5% SPAF III 2003 66% 73% 1.9% 139 0.4% SPORTIF III 2005 68% 84% 1.1% 132 0.1% SPORTIF V 2006 64% 23% 1.0% 133 0.4% ACTIVE W Connolly et al, Circulation 2007;116:449-455

  29. Indirect Antithrombotic Therapies in AF Effect of BP lowering by ARB on Vascular Events (ACTIVE-I) n = 14.500 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

  30. 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 ARBsreduced 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??? Yusuf et al, ESC 2009

  31. 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

  32. 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 • 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

  33. Non Pharmacological Strategies Freedom of Stroke after percutaneous closure of the LAA WATCHMAN LAA Closure Device in situ PROTECT-AF, Lancet 2009;374:534-542

  34. Non Pharmacological Strategies Freedom of Stroke after percutaneous closure of the LAA PROTECT-AF, Lancet 2009;374:534-542

  35. 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

  36. New Oral Antithrombotic Therapies Many Targets for Novel Anticoagulants in The Coagulation Pathway TF/VIIa ORAL PARENTERAL X IX IXa VIIIa Va RivaroxabanApixabanEndoxaban “Direct Xa” Inhibitors AT FondaparinuxIdraparinux Xa “Indirect Xa” Inhibitors II XimelagatranDabigatran “Direct IIa” Inhibitors IIa (Thrombin) Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  37. NH HO 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 H O O N O NH2 H N N melagatran • Exantha (Astra Zeneca)

  38. 4-6%: raised transaminase levels Few cases of fulminant hepatic failure 11 Oct 2004…Ximelagatran failed to receive approval from the US Food and Drug Administration But novel anticoagulants work!! 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 3 2,3 1,8 1,3 1,6 2 2 1 1 Warfarin Ximelagatran Warfarin Ximelagatran SPORTIF III Investigators, Lancet 2003;362:1691-1698

  39. 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 12-17 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)

  40. 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 Dabigatran Etexilate 150 mg b.i.d. N=6000 Warfarin 1 mg, 3mg, 5 mg (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 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

  41. 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 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

  42. 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 0,3 0 D110 mg BID D150 mg BID Warfarin 182 / 6,015 134 / 6,076 199 / 6,022

  43. Hemorrhagic stroke 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 74% RRR 69% 30 20 14 10 12 0.12% 0.10% 0 D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022

  44. 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) Gage et al. NEJM 2009

  45. New Antithrombotic Therapies in AF Many Targets for Novel Anticoagulants in The Coagulation Pathway TF/VIIa ORAL PARENTERAL X IX IXa VIIIa Va RivaroxabanApixaban Endoxaban “Direct Xa” Inhibitors AT FondaparinuxIdraparinux Xa “Indirect Xa” Inhibitors II XimelagatranDabigatran “Direct IIa” Inhibitors IIa (Thrombin) Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005

  46. 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

  47. 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)

  48. Risk Factors • CHF • Hypertension • Age  75 • Diabetes • OR • Stroke, TIA or Systemic embolus At least 2 required Direct Oral FXa Inhibitor: Rivaroxaban Stroke Prevention in AF: ROCKET AF 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 (2.0-3.0 inclusive) 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

  49. Prospects for improving thrombosis management in atrial fibrillation Meta-analysis of ischaemic strokeor systemic embolism W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs ximelagatran W vs dabigatran 150 0 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.

  50. 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)

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