Lessons from recent antithrombotic studies and trials in atrial fibrillation

Transcription

1 Lessons from recent antithrombotic studies and trials in atrial fibrillation Thromboembolism cause of stroke in AF Lars Wallentin Uppsala Clinical Research Centre (UCR) Uppsala

2 Disclosures for Lars Wallentin Bristol-Myers Squibb Boehringer Ingelheim AstraZeneca GlaxoSmithKline Schering-Plough Eli Lilly & Co. Research grant Research grant Research grant Research grant Research grant Research grant Regado Biosciences Athera Biotechnologies Evolva Consultancy Consultancy Consultancy

3 Atrial fibrillation Most common arrhythmia 1.5% of the population Increases with age Stroke risk Five fold increase at AF Risk related to risk factors Congestive heart failure Hypertension Age > 75 Diabetes S 2 troke Reduced with antithrombotics Aspirin ( 19%) Warfarin ( 64%) Thromboembolism cause of stroke in AF

4 Targets for long-term antithrombotic treatment Warfarin* Rivaroxaban Apixaban Edoxaban Betrixaban Fondaparinux Idraparinux LMWH AT AT Dabigatran Tissue factor Plasma clotting cascade * Prothrombin * Factor Xa * Thrombin * Fibrinogen Aspirin Collagen Thrombin Conformational activation of GPIIb/IIIa Platelet aggregation Fibrin Tx A 2 ADP PAR1 PAR1-inhib Clopidogrel Prasugrel Ticagrelor GPIIb/IIIa inhibitors Thrombus

5 Lessions learnt from recent trials of antithrombotic treatment in AF Suitable trial design Overall benefits and risks with new treatments - New platelet inhibitor treatment - New anticoagulant treatment Importance of comparator - No anticoagulant - Anticoagulant naive - INR control Risk stratification

6 Trial design comparing new agents with warfarin in AF Single, large trial ( ) Event driven 450 primary events Randomized vs Warfarin Double blind, double dummy Non-inferiority (& superiority) Warfarin switchers and starters CHADS-score >=1 or >=2 TTR for warfarin arm 2-3 > 65%

7 Trial design comparing new agents with aspirin in AF Single, large trial (6000) Event driven 225 primary events Randomized vs Aspirin Double blind, placebo controlled Superiority CHADS-score >=1 Warfarin unsuitable, intolerant, bleeding

8 Lessions learnt from recent trials of antithrombotic treatment in AF Suitable trial design Overall benefits and risks with new treatments - New platelet inhibitor treatment - New anticoagulant treatment Importance of comparator - No anticoagulant - Anticoagulant naive - INR control Risk stratification

9 Phase III trial evaluating platelet inhibition in AF Versus warfarin - Clopidogrel + Aspirin (Active-W) Versus aspirin - Clopidogrel + Aspirin (Active-A) 2009

10 ACTIVE Program: Three Trials Documented AF + 1 risk factor: Age 75, Hypertension, Prior stroke/tia, LVEF<45, PAD, Age CAD or diabetes Contra-indications to OAC or Unwilling ACTIVE W ACTIVE A 6500 patients 7500 patients Clopidogrel+ASA vs. OAC Clopidogrel+ASA vs. ASA No Exclusion criteria for ACTIVE I ACTIVE I ~9000 patients Irbesartan vs placebo Partial Factorial Design ACTIVE W Results AHA Meeting: November 14, 1350g

11 Cumulative Hazard Rates Stroke, Non-CNS Systemic Embolism, MI & Vascular Death RR = 1.45 P = Clopidogrel+ASA 5.64 %/year 3.93 %/year OAC # at Risk C+A OAC Years ACTIVE W Results AHA Meeting: November 14, 1350g

12 Cumulative Hazard Rates Major Bleeding 2.4 %/year RR = 1.06 P = %/year OAC Clopidogrel+ASA # at Risk C+A OAC Years ACTIVE W Results AHA Meeting: November 14, 1350g

13 Cumulative Hazard Rates ACTIVE Primary Outcome (Stroke, MI, non-cns Systemic Embolism, Vascular Death) HR=0.89 ( ) p=0.014 Placebo+Aspirin Clopidogrel+Aspirin No. at Risk C+A ASA Years

14 Cumulative Hazard Rates ACTIVE Stroke HR=0.72 ( ) p= Placebo+Aspirin Clopidogrel+Aspirin No. at Risk C+A ASA Years

15 ACTIVE A and W: ACTIVE Stroke Rates and Risk Reductions Treatment VKA C+A Aspirin ACTIVE W (Rate per year) ACTIVE A (Rate per year) RRR versus Aspirin -58% -28% -- RRR versus C+A -42% -- --

16 Phase III trials comparing new anticoagulants in AF Versus Warfarin Direct thrombin inhibition - Ximelagatran (Sportif III & V) 2003, Dabigatran (RELY) 2009 Direct factor Xa inhibition - Rivaroxaban (ROCKET) Nov Apixaban (ARISTOTLE) Aug Edoxaban (ENGAGE-AF TIMI48) 2012? - Betrixaban (start phase III 2011?) 2014? Versus Aspirin - Apixaban (AVERROES) Aug 29, 2010

17 Thrombin Factor Xa Dabigatran Apixaban Pinto et.al Amer Chem Soc 2005 Dabigatran Specific selective competitive direct fiia inhibitor Inhibits free and fibrin-bound fiia activity Oral prodrug with poor oral bioavailability 6.5% T ½ : Dabigatran h (80% renal excretion) Twice a day dosing 1-4 h post-dose for max inhibition of Factor IIa No direct effect on platelet aggregation Apixaban & Rivaroxaban Specific selective competitive direct fxa inhibitor Inhibits free and fibrin-bound fxa & prothrombinase Good oral bioavailability T ½ : Apixaban 12 h, Rivaroxaban 6-9 h Once twice a day dosing 1-4 h post-dose for max inhibition of Factor Xa No direct effect on platelet aggregation

18 RE-LY study design Atrial fibrillation with 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR ) N=6022 Dabigatran etexilate 110 mg bid N=6015 Dabigatran etexilate 150 mg bid N=6076 Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up Ezekowitz MD, et al. Am Heart J 2009;157: Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

19 Cumulative hazard rates Time to first stroke / SSE Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RR 0.90 (95% CI: ) p<0.001 (NI) p=0.29 (Sup) RRR 35% RR 0.65 (95% CI: ) p<0.001 (NI) p<0.001 (Sup) Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

20 % per year Vascular mortality 3.00 RR 0.90 (95% CI: ) p=0.21 (sup) RR 0.85 (95% CI: ) p=0.04 (sup) RRR 15% D110 mg BID D150 mg BID Warfarin 289/ 6,015 Connolly SJ., et al. N Engl J Med 2009; 361: / 6, / 6,022 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

21 % per year Major bleeding rates RR 0.80 (95% CI: ) 2.87 p=0.003 (sup) RRR 20% RR 0.93 (95% CI: ) p=0.31 (sup) D110 mg BID D150 mg BID Warfarin 342 / 6, / 6, / 6,022 Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

22 Number of events 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 D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

23 Lessions learnt from recent trials of antithrombotic treatment in AF Suitable trial design Overall benefits and risks with new treatments - New platelet inhibitor treatment - New anticoagulant treatment Importance of comparator - No anticoagulant - Anticoagulant naive - INR control Risk stratification

24 Control group No anticoagulant AVERROES 36 countries, 522 centres AF and 1 risk factor, and demonstrated or expected unsuitable for VKA Apixaban 5 mg BID 2.5 mg BID in selected patients R 5,600 patients Double-Blind ASA ( mg/d) Primary Outcome: Stroke or Systemic Embolic Event (SEE) June 10, 2010 stopped interim analysis shows clear evidence of a clinically important reduction in stroke and systemic embolism and an acceptable safety profile compared to aspirin.

25 Cumulative Hazard Rates Interaction Entry vs No Entry OAC on Primary Outcome +Major Bleeding Entry OAC Interaction P = 0.17 No Entry OAC RR = 1.51 P < RR = 1.14 P = 0.45 C+A OAC OAC C+A Years ACTIVE W Results AHA Meeting: November 14, 1350g

26 Interaction VKA experienced vs naive on Primary Outcome (stroke or SE) Non-inferiority p-value Superiority p-value Interaction p-value Dabigatran 110 vs. Warfarin VKA Experience < VKA Naive Dabigatran 150 vs. Warfarin <0.001 < VKA Experience VKA Naive Hazard Ratio's (95% CI)

27 Mean TTR by country

28 Cumulative Hazard Rates Interaction Centre INR Control on Primary Outcome +Major Bleeding % INR in Range Interaction P = <65% INR in Range RR = 1.80 P < RR = 1.06 P = 0.66 C+A OAC OAC C+A Years ACTIVE W Results AHA Meeting: November 14, 1350g

29 % per year Stroke / SSE According to center based time in therapeutic range (cttr) Q1: cttr < 57.1% Q2: cttr % Q3: cttr % Q4: cttr > 72.6% 2,4 1,8 * Interaction p-value (D 110mg BID vs W.) = 0.90 Interaction p-value (D 150mg BID vs W.) = 0.20 *Interaction p evaluated by a multivariable approach with center based TTR as a continuous variable. 1,2 0,6 W D* D W D* D W D* D W D* D Wallentin L., et al. Lancet 2010; in press. Q1 Q2 Q3 Q4 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

30 % per year Intracranial bleeding According to center based time in therapeutic range (cttr) Q1: cttr < 57.1% Q2: cttr % Q3: cttr % Q4: cttr > 72.6% 1 * Interaction p-value (D 110mg BID vs W.) = 0.71 Interaction p-value (D 150mg BID vs W.) = 0.89 *Interaction p evaluated by a multivariable approach with center based TTR as a continuous variable. 0,75 0,5 0,25 0 W D* D Wallentin L., et al. Lancet 2010; in press. W D* D W D* D W D* D Q1 Q2 Q3 Q Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

31 % per year Total death According to center based time in therapeutic range (cttr) Q1: cttr < 57.1% Q2: cttr % Q3: cttr % Q4: cttr > 72.6% * Interaction p-value (D 110mg BID vs W.) = 0.07 Interaction p-value (D 150mg BID vs W.) = *Interaction p evaluated by a multivariable approach with center based TTR as a continuous variable W D* D W D* D W D* D W D* D Wallentin L., et al. Lancet 2010; in press. Q1 Q2 Q3 Q4 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

32 Lessions learnt from recent trials of antithrombotic treatment in AF Suitable trial design Overall benefits and risks with new treatments - New platelet inhibitor treatment - New anticoagulant treatment Importance of comparator - No anticoagulant - Anticoagulant naive - INR control Risk stratification

33 CHADS 2 score overall event rates %/year Stroke and systemic embolism 1 0 CHADS 2 No of pts Major bleeding CHADS

34 CHADS-VASC score Lip GYH Thrombosis Haemostasis 2010

35 Stroke and systemic embolism (SE) D110 BID vs. warfarin D150 BID vs. warfarin CHADS2 Annual rate, % D110 D150 WARFARIN P = 0.37 P = Dabigatran Warfarin better better Dabigatran better Warfarin better Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

36 Intracranial bleeding D110 BID vs. warfarin D150 BID vs. warfarin CHADS2 Annual rate, % D110 D150 WARFARIN P = 0.7 P = Dabigatran Warfarin better better Dabigatran better Warfarin better Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

37 Lessions learnt from recent trials of antithrombotic treatment in AF Optimal trial designs well established Overall benefits and risks with new treatments - New plt inhibitors add to ASA, inferior to OAC - New OAC advantages compared to warfarin Importance of comparator - No anticoagulant - high event rates, not to be used - VKA naïve no importance after 3 months - INR control modulates effects on outcomes Risk stratification - Related to event rates even with OAC treatment - Relative benefits of new OAC consistent over risk strata

38 Future trials of antithrombotic treatment in AF Overall benefits and risks with new treatments - Incremental benefit vs New OAC - Specific benefits vs New OAC - Personalization of treatment with New OAC Importance of comparator - New comparator will be New OAC Risk stratification - Based on clinical and biochemical markers - Personalization of treatment - Importance of genetics should be explored

39 Which flower should I choose? Which is the ideal type for this environment and occasion? Thanks for your attention