Νέα αληηζξνκβσηηθά θάξκαθα. Θσκάο Κ. Μαθξήο, MD FACC, FESC Σπληνληζηήο Γηεπζπληήο Καξδηνινγηθνύ Τκήκαηνο ΓΝΜ ΔΛΔΝΑ ΒΔΝΗΕΔΛΟΥ

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1 Νέα αληηζξνκβσηηθά θάξκαθα Θσκάο Κ. Μαθξήο, MD FACC, FESC Σπληνληζηήο Γηεπζπληήο Καξδηνινγηθνύ Τκήκαηνο ΓΝΜ ΔΛΔΝΑ ΒΔΝΗΕΔΛΟΥ

2 AF is the Most Common Cardiac Arrhythmia Ø AF affects Ø 1 in 25 adults >60 years 1 Ø 1 in 10 adults >80 years 1 Ø 6.8 million patients with AF in EU and US* 1,2 EU 4.5 million US 2.3 million * EU 2001, US 2006, both cited in 2006 guidelines 1. Go AS et al. JAMA 2001;285: Fuster V et al. J Am Coll Cardiol 2006;38:

3 Patients with hypertension, % Δπίπησζε αξηεξηαθήο ππέξηαζεο ζε κειέηεο αζζελώλ κε θνιπηθή καξκαξπγή 90 AF populations

4 Κιηληθά ζπκβάκαηα ζρεηηδόκελα ηελ θνιπηθή καξκαξπγή 1. Θάλαηνο 2. ΑΔΔ 3. Ννζειείεο 4. Αξλεηηθή επίδξαζε ζηελ πνηόηεηα δσήο θαη ηελ ηθαλόηεηα γηα άζθεζε 5. Γπζιεηηνπξγία αξηζηεξάο θνηιίαο Αξηεξηαθή ππέξηαζε Κνιπηθή καξκαξπγή Αγγεηαθά εγθεθαιηθά Καξδηαθή αλεπάξθεηα Σηεθαληαηα λνζνο European Heart Journal 2010; 31:

5 AF is an Independent Risk Factor for Stroke AF patients have a near 5-fold increased risk of stroke 1 1 in every 6 strokes occurs in a patient with AF 2 Ischemic stroke associated with AF is typically more severe than stroke due to other etiologies 3 Stroke risk persists even in asymptomatic AF 4 1. Wolf et al. Stroke 1991;22: Fuster V et al. Circulation 2006;114:e257-e Dulli DA et al. Neuroepidemiology 2003;22: Page RL et al. Circulation 2003;107:

6 Current Treatment Strategies for AF Prevention of thrombo-embolism Rate control Rhythm control ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:

7 Antithrombotic Drug Choices for Stroke Prevention Antiplatelet agents ASA Clopidogrel Anticoagulant Vitamin K antagonists (Warfarin)

8 Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention Warfarin Better Control Better AFASAK SPAF BAATAF Unblinded Unblinded Unblinded CAFA Terminated early SPINAF EAFT Double-blind; Men only 2 o prevention; Unblinded Aggregate 100% 50% 0-50% -100% Total risk reduction for all 5 studies combined is 68% Hart R, et al. Ann Intern Med 2007;146:857.

9 Aspirin for Atrial FibrillationStroke Risk Reductions AFASAK I SPAF I EAFT ESPS II LASAF UK-TIA Aggregate Total risk reduction for all 6 studies combined is 21% 100% 50% 0-50% -100% Aspirin Better Aspirin Worse Hart RG, et al. Ann Intern Med 2007; 147:590.

10 Warfarin compared with Aspirin for stroke prevention in AF Warfarin better Aspirin better AFASAK I AFASAK II Chinese ATAFS EAFT PATAF SPAF II Age 75 yrs Age >75 yrs All trials RRR 38% (95% CI: 18 52%) RRR (%)* 100 Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Hart RG et al. Ann Intern Med 2007;146:857 67

11 Cumulative Incidence ACTIVE-A Total Stroke Rates (3.3%/year) Aspirin 28% RRR HR 0.72 (95% CI, ) p < (2.4%/year) Clopidogrel + Aspirin Years Connolly SJ, et al. N Engl J Med 2009; 360:

12 Recommendation for Combining Anticoagulant With Antiplatelet Therapy ACC/AHA/HRS 2011 Focused Update The addition of clopidogrel to aspirin (ASA) to reduce the risk of major vascular events, including stroke, might be considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient preference or the physician's assessment of the patient's ability to safely sustain anticoagulation. (Level of Evidence: B) Circulation 2011; 123:

13 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions Warfarin Better Antiplatelet Rx Better ACTIVE-W Anticoagulation vs. Aspirin + Clopidogrel n = 6,706 Anticoagulation vs. Antiplatelet drugs 7 Trials n = 4, % 50% 0-50% Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857.

14 Stroke Prevention in Atrial Fibrillation Adjusted dose warfarin and antiplatelet agents have been shown to reduce the risk of stroke compared with control by 64% and 22%, respectively, with an increase in bleeding Warfarin has been shown to be more effective than aspirin, in reducing stroke by 45%, but increasing the risk of bleeding Based on these results, warfarin and other oral anticoagulants (OAC) are recommended for patients at increased risk of stroke; and aspirin is recommended for patients at lower risk Risk Reduction in Stroke (%) % -22 % Warfarin Antiplatelets Safety Outcomes (n) Ann Intern Med 2007; 146: W ICH A W A Major ECH

15 The CHADS 2 Index Stroke Risk Score for Atrial Fibrillation Score (points) Prevalence (%)* Congestive Heart failure 1 32 Hypertension 1 65 Age >75 years 1 28 Diabetes mellitus 1 18 Stroke or TIA 2 10 Moderate-High risk > Low risk VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

16 Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 Risk Category No risk factors CHADS 2 = 0 One moderate risk factor CHADS 2 = 1 Recommended Therapy Aspirin, mg qd Aspirin, mg/d or Warfarin (INR , target 2.5) Any high risk factor or >1 moderate risk factor CHADS 2 >2 or Mitral stenosis Prosthetic valve Warfarin (INR , target 2.5) Warfarin (INR , target 3.0) Fuster V, et al. Eur Heart J 2006;27:1979.

17 AF-related stroke is preventable Effect of VKA compared to placebo Anticoagulation with a vitamin-k-antagonist (VKA) is recommended for patients with more than 1 moderate risk factor (age,hbp, CHF or LVD, Diabetes) Stroke Death 2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-k-antagonist (INR 2-3) 1 67% 26% A meta-analysis of 29 trials in 28,044 patients showed that adjusted-dose warfarin results in a reduction in ischaemic stroke and in all-cause mortality 1 1. Hart RG et al. Ann Intern Med. 2007;146: Fuster V, et al. JACC. 2006; 48:

18 Odds Ratio Therapeutic Range for Warfarin INR Values at Stroke or ICH 15.0 Stroke Intracranial Hemorrhage INR Fuster et al. J Am Coll Cardiol. 2001;38:

19 Δλδνεγθεθαιηθή αηκνξξαγία : Ζ πιένλ επηθίλδπλε επηπινθή ηεο αληηζξνκβσηηθήο ζεξαπείαο >10% ηων ενδοεγκεθαλικών αιμοππαγιών αθοπά αζθενείρ πος λαμβάνοςν ανηιθπομβωηική θεπαπεία. Οι ενδοεγκεθαλικέρ αιμοππαγίερ καηά ηην διάπκεια ανηιπηκηικήρ αγωγήρ μποπεί να είναι θαναηηθόπερ. Σπγθξηηηθά κε placebo, η ανηιθπομβωηική θεπαπεία αςξάνει ηον κίνδςνο ελδνεγθεθαιηθήο αηκνξξαγίαο ~ 40% κε Aspirin ~ 200% κε warfarin (INR ; Αύμεζε %/year) INR = international normalized ratio Hart RG et al. Stroke 2005;36:

20 The HAS-BLED Score Risk Score for Predicting Bleeding in Anticoagulated Patients with Atrial Fibrillation Weight (points) H ypertension (>160 mmhg systolic) 1 A bnormal renal or hepatic function 1-2 S troke 1 B leeding history or anemia 1 L abile INR (TTR <60%) 1 E lderly (age >75 years) 1 D rugs (antiplatelet, NSAID) or alcohol 1-2 High risk (>4%/year) > 4 Moderate risk (2-4%/year) 2-3 Low risk (<2%.year) 0-1 Pisters R, et al Chest 2010 (online)

21 Time in therapeutic range (%) Ansell J et al. J Thromb Thrombolysis 2007;23:83 91 The INR for VKAs is often outside the therapeutic range: international study of anticoagulation management INR <2.0 INR INR > USA Canada France Italy Spain The predominant vitamin K antagonist (VKA) in use was warfarin in the USA, Canada and Italy; acenocoumarol in Spain; and fluindione in France; INR = international normalized ratio

22 Underuse of oral anticoagulants in AF: A Systematic Review Underuse of oral anticoagulants for high-risk atrial fibrillation patients was found in most of the 54 studies ( ) reporting both patient stroke risk and patients treated. Over two thirds of studies of atrial fibrillation patients with prior stroke or transient ischemic attack reported treatment levels of under 60% of eligible patients. Most studies based on CHADS2 score reported oral anticoagulant treatment levels of high-risk subjects below 70%. Ogilvie I et al Am J Med 2010;123:638

23 Advantages and Diasadvantages of Current Antithrombotics Advantages Used for many years Well studied/experience Effective if INR kept in therapeutic range Well known drug and food interactions Low cost Antidote/easy to recover Disadvantages Erratic INR control / frequent monitoring Narrow therapeutic index Medications adjustments often required Drug and food interactions Risk of bleeding Patients reluctance Underuse in high risk patients

24 Anticoagulant Choices for Stroke Prevention Warfarin New oral anticoagulants Direct Inhibitors of Factor X or Thrombin 1. Dabigatran: An oral DTI twice daily (renal clearance) 2. Rivaroxaban: Direct factor Xa inhibitor (renal clearance) once or twice daily 3. Apixaban: Direct factor Xa inhibitor (hepatic clearance) twice daily 4. Edoxaban: Direct factor Xa inhibitor (hepatic clearance) once daily Circulation 2010; 121:

25 Comparison of Features of New Anticoagulants With Those of Warfarin Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Food effect Yes No Drug interactions Many Few Monitoring Yes No Half-life Long Short Antidote Yes No

26 Atrial Fibrillation Phase 3 Study Timelines Dabigatran RE-LY RELYABLE Rivaroxaban ROCKET AHA 11/10 Edoxaban ENGAGE-AF TIMI AVERROES estimated completion April 2010 Apixaban ARISTOTLE Estimated completion November 2010

27 Trial N Drug Dose Comparator Trial Design RE-LY 18,113 Dabigatran 110 mg and 150 mg twice daily Warfarin Open AVERROES 5599 Apixaban 5 mg bid Aspirin Double blind ROCKET AF 14,264 Rivaroxaban 15 and 20 mg once daily Warfarin Double blind ARISTOTLE 18,201 Apixaban 5 mg twice daily* warfarin Double blind patients!!!

28 RE-LY: A Non-inferiority Trial Atrial Fibrillation with 1 Risk Factor Absence of Contraindications Conducted in 951 centers in 44 countries Blinded Event Adjudication R Open Blinded Warfarin Adjusted INR N=6000 Dabigatran etexilate 110 mg BID N=6000 Dabigatran etexilate 150 mg BID N=6000

29 RE-LY: Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = 1.46 Connolly et al., NEJM, HR (95% CI) Dabigatran better Warfarin better

30 Stroke or Systemic Embolism Dabigatran110 vs warfarin. Dabigatran150 vs. warfarin Rate(% per year) Age <65 D D150WAR Age Age CrCl CrCl CrCl > Dabigatran better Warfarin better Dabigatran better Warfarin better Healey et al., JACC, 2010

31 Number of events RE-LY Study: Hemorrhagic stroke RR 0.31 (95% CI: ) 50 p<0.001 (sup) RR 0.26 (95% CI: ) p<0.001 (sup) 40 RRR 69% RRR 74% % % 0.10% D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly et al., NEJM, 2009

32 RE-LY: Results Dabigatran 110 mg (%/yr) Dabigatran 150 mg (%/yr) Warfarin (%/yr) Primary outcome Major bleeding Hemorrhagic stroke 0.12* 0.10* 0.38 Mortality Dabigatran 110 mg twice daily Similar rate of ischemic stroke and systemic embolism Lower rate of major hemorrhage * P <.001 vs warfarin Dabigatran 150 mg twice daily Lower rate of ischemic stroke and systemic embolism Similar rate of major hemorrhage Conolly SJ et al. N Engl J Med 2009;361:

33 Meta-analysis of Ischemic Stroke or Systemic Embolism W vs placebo W vs W low dose W vs ASA W vsasa + clopidogrel W vs dabigatran 150 Camm J.: Oral presentation at ESC on Aug 30th Favours warfarin Favours other treatment

34 Stroke Prevention in Atrial Fibrillation The Antithrombotic Therapy In Perspective Treatment Stroke Risk (/year) No Therapy 4.5 ASA 3.7 ASA + Clopidogrel 2.8 Warfarin 1.7 Dabigatran Dabigatran

35 Stroke Prevention in Atrial Fibrillation The Antithrombotic Therapy In Perspective Treatment Stroke Risk (/year) No Therapy 4.5 ASA 3.7 ASA + Clopidogrel 2.8 Warfarin 1.7 Dabigatran Dabigatran %

36 Stroke Prevention in Atrial Fibrillation The Antithrombotic Therapy In Perspective Treatment Stroke Risk (/year) No Therapy 4.5 ASA 3.7 ASA + Clopidogrel 2.8 Warfarin 1.7 Dabigatran Dabigatran %

37 Stroke Prevention in Atrial Fibrillation The Antithrombotic Therapy In Perspective Treatment Stroke Risk (/year) No Therapy 4.5 ASA 3.7 ASA + Clopidogrel 2.8 Warfarin 1.7 Dabigatran Dabigatran %

38 Πνηα δόζε γηα πνηνλ αζζελή? Χαμηλή δόζη Ηλικιωμένοι Νεφπική ανεπάπκεια Χαμηλόρ κίνδςνορ για ΑΕΕ (CHADS 2 score of 1) Υψηλή δόζη Αςξημένορ κίνδςνορ για ΑΕΕ (CHADS 2 score 2)

39 FDA Approves Dabigatran for SPAF Dabigatran Reduces Stroke Rate Compared to Warfarin October 19, 2010 Dose of 75 mg BID for CrCl ml/ min Dose of 150 mg BID for CrCl > 30 ml/ min Switching from Warfarin to Dabigatran Stop Warfarin - Start dabigatran when INR 2.0 Twice-daily dosing of dabigatran First thing in the morning Late in the evening or at night Switching from Intravenous Heparin to Dabigatran Begin dabigatran 2-3 hours after discontinuing intravenous heparin 6 hours after starting dabigatran, you will have maximal effect of the drug

40 Πνηνο αζζελήο δελ έρεη έλδεημε γηα ιήςε Dabigatran? Αζζελήο ξπζκηζκέλνο κε warfarin ; CrCl < 15 ml/min Σνβαξή επαηηθή δπζιεηηνπξγία Απμεκέλνο θίλδπλνο ΓΔ αηκνξξαγίαο ; Mεραληθή βαιβίδα

41 ROCKET AF Trial Rivaroxaban Atrial Fibrillation Randomize Double blind / Double Dummy (n ~ 14,000) Risk Factors CHF Hypertension At least 2 Age 75 required Diabetes OR Stroke, TIA, or Systemic embolus Warfarin 20 mg daily 15 mg for Cr Cl INR target ( inclusive) Monthly monitoring and adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns systemic embolism Statistics: non-inferiority, >95% power, 2.3% warfarin event rate

42 Cumulative event rate (%) Primary Efficacy Outcome Stroke and non-cns Embolism Event Rate Rivaroxaban Warfarin Warfarin 3 Rivaroxaban 2 HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: < Days from Randomization No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

43 Rivaroxaban (N=7111) ROCKET AF: Results Rates of bleeding events Warfarin (N=7125) Events Event Rate Events Event Rate Hazard Ratio Variable no. (%) no./100 patient-yr Major bleeding no. (%) no./100 patient-yr Any 395 (5.6) (5.4) ( ) Intracranial hemorrhage 55 (0.8) (1.2) ( ) (95% CI) P value Ο κνλαδηθόο εθπξόζσπνο ηεο λέαο γεληάο αληηπεθηηθώλ ν νπνίνο ρνξεγείηαη κηα θνξά ηελ εκέξα. Patel MR et al. N Engl J Med 2011;365:

44 Randomization APIXABAN Phase 3 Clinical Trial vs Warfarin to Prevent Stroke or Embolism in AF Pts Patient characteristics Aged 18 years Atrial fibrillation 1 additional risk factor for stroke ARISTOTLE N=15, years Apixaban 2.5 mg bid or 5 mg bid Warfarin 2 mg qd, target INR Primary outcome measures: Time to first occurrence of confirmed stroke or systemic embolism Time to major bleeding in treatment or follow-up AF = atrial fibrillation; INR = international normalized ratio.national Institutes of Health Clinical Trials.gov. Accessed January 16, 2008.

45 ARISTOTLE Main Trial Results Stroke or systemic embolism ISTH major bleeding 21% RRR 31% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P=0.011 Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, ); P<0.001 Median TTR 66%

46 ARISTOTLE: Apixaban versus Warfarin in patients with AF End point Apixaban Warfarin HR(95% CI) (%/year) (%/year) p Stroke or systemic embolism* Major bleeding <0.001 All-cause mortality Hemorrhagic stroke <0.001 Ischemic/uncert ain stroke *Primary end point Granger CB et al. N Eng J Med 2011, on line

47 ARISTOTLE: Conclusions Compared with warfarin, apixaban prevented: 6 Strokes 4 hemorrhagic 15 Major bleeds 2 ischemic / uncertain type 8 Deaths Per 1000 patients treated, over 1.8 years Granger CB et al. N Engl J Med 2011;, August 28

48 AVERROES: Results Apixaban (N=2808) Aspirin (N=2791) HR with Apixaban Outcome %/yr %/yr 95% CI P value Stroke or systemic embolism ( ) <.001 Bleeding event Major ( ) 0.57 Intracranial ( ) 0.69 Conolly SJ et al. N Engl J Med 2010;364:

49 Trials with new oral anticoagulants Trial RELY ROCKET-AF ARISTOTLE Drug used Dabigatran Vs Warfarin Rivaroxaban vs Warfarin Apixaban vs Warfarin Dose 150 or 110 mg BID vs Warfarin (INR 2-3) 20 or 15mg QD vs Warfarin (INR 2-3) 5mg BID vs Warfarin (INR 2-3) No. of Patients Mean age (yrs) Percentage of Hypertension 80% 90% 85% Mean CHADS 2 Score Conclusions: Dabigatran 110mg non-inferior to warfarin, with 20% less major bleedings Dabigatran 150 mg superior to warfarin with similar rate of major bleedings Rivaroxaban non-inferior to warfarin on intention to treat analysis but superior in on treatment analysis Similar rate of major bleedings Apixaban was superior to warfarin in the risk of stroke or systemic embolism, bleeding and all cause mortality Approval FDA FDA approved 9/11 Doses of 150 mg and 75mg EMA:positive opinion (if CI Cr ml/min0 EMA: positive opinion

50 Αλαπάληεηα εξσηήκαηα Ζ δπζπεςία είλαη αηηία δηαθνπήο ηεο αγσγήο; Πσο ζα ρεηξηζηνύκε αζζελείο κε ηζηνξηθό ΓΔ αηκνξξαγίαο; Ο κηθξόο ρξόλνο εκίζεηαο δσήο ηνπ θαξκάθνπ απαηηεί ηελ αλάγθε ύπαξμεο αληηδόηνπ;

51 Πποβλημαηιζμοί για ηα νέα από ηος ζηόμαηορ ανηιπηκηικά Υςειό θόζηνο = πνηνο πιεξώλεη; Πσο ζα εθηηκήζνπκε ηελ ζπκκόξθσζε; Πσο ζα ζεξαπεύνπκε ηηο αηκνξξαγίεο; Αληίδνην;

52 Σπκπεξάζκαηα Πιενλεθηήκαηα Δπηπξόζζεην όθεινο σο πξνο ηελ κείσζε ησλ ΑΔΔ Γελ απαηηείηαη παξαθνινύζεζε INR Γελ επεξεάδεηαη ε δξάζε ηνπο από ηξνθέο ε θάξκαθα Μεηνλεθηήκαηα Κόζηνο Γελ ππάξρεη αληίδνην Γελ ππάξρεη εκπεηξία ζηελ αληηκεηώπηζε ησλ αηκνξξαγηώλ Γελ ππάξρεη αθόκα κεγάιε εκπεηξία ζηελ θιηληθή πξάμε Φνξήγεζε ζε ζπγθεθξηκέλνπο αζζελείο ( εμαηνκίθεπζε )