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Anticoagulants for Acute Coronary Syndromes
- 1. Anticoagulants in Acute Coronary Syndrome LHH Cardiology Grand Rounds March 11th 2014 Salaheldin Abusin Interventional Cardiology Fellow
- 2. Outline • Review the Historical Evidence for use of anticoagulants in secondary prevention after ACS (pre DAPT era) • Review the Evidence for the use of novel anticoagulants as third agent in addition to DAPT – Apixaban – APPRAISE trial – Dabigatran – REDEEM trial – Rivoraxaban – ATLAS ACS TIMI 58 trial
- 3. Vorapaxar
- 4. Clopidogrel CURE Clopidogrel CURE AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS Prasugrel TRITON TIMI 38 Prasugrel TRITON TIMI 38 Ticagrelor PLATO Ticagrelor PLATO Warfarin CHAMP trial Warfarin CHAMP trial Dabigatran RE-DEEM trial Dabigatran RE-DEEM trial Apixaban APPRAISE trial Apixaban APPRAISE trial Rivoroxaban ATLAS ACS TIMI 51 trial Rivoroxaban ATLAS ACS TIMI 51 trial Ximelagatran ESTEEM trial Ximelagatran ESTEEM trial Clopidogrel CREDO Clopidogrel CREDO
- 5. Warfarin
- 6. Aspirin + warfarin after ACS CHAMP trial • N= 5059 • Randomized, Open Label • Patient within 14 days of Acute MI • 2:3, STEMI/NSTEMI • 1st arm Warfarin (target INR 1.5-2.5) + ASA 81mg • 2nd arm ASA 325mg • Followed up for 2.7 years Fiori et al, Circulation 2002
- 7. CHAMP Trial Results • No difference in the 1° endpoint (mortality) • 17.3% vs 17.6%, P=0.76 • Major Bleeding significantly higher in the warfarin arm – 1.28 events / 100 person years vs – 0.72 events/ 100 person years – P <0.001
- 8. Xilmegatran
- 9. Xilmegatran • Direct Thrombin Inhibitor • Same family as – Dabigatran – Argatroban
- 10. Aspirin + Ximelagatran after ACS ESTEEM trial – Phase 2 trial • N=1883 • Within 14 days of STEMI/NSTEMI (2:1) • All patients were on aspirin 160mg • Dose finding trial • 24mg/36mg/48mg/60mg/Placebo • Primary Endpoint Death/MI/recurrent ischemia Wallentin et al, Lancet 2003
- 11. Aspirin + Ximelagatran after ACS ESTEEM trial – Phase 2 trial • Followed for 6 months • MACE Primary Endpoint – 12.7% vs 16.3% (P=0.036) at 6 months – ARR 3.6%, NNT = 27 – Not dose dependant • Major Bleeding – 1.8% vs 0.9% (not significant statistically) • Hepatotoxicity halted the further development of this agent
- 12. Clopidogrel CURE Clopidogrel CURE AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS Prasugrel TRITON TIMI 38 Prasugrel TRITON TIMI 38 Ticagrelor PLATO Ticagrelor PLATO Warfarin CHAMP trial Warfarin CHAMP trial Dabigatran RE-DEEM trial Dabigatran RE-DEEM trial Apixaban APPRAISE trial Apixaban APPRAISE trial Rivoroxaban ATLAS ACS TIMI 51 trial Rivoroxaban ATLAS ACS TIMI 51 trial Ximelagatran ESTEEM trial Ximelagatran ESTEEM trial Clopidogrel CREDO Clopidogrel CREDO
- 13. Things to consider • The need for a 3rd agent beyond DAPT for ACS • Risk of Ischemic Events – ~ 10% risk of ischemic events – ~3% risk of death from cardiovascular cause • Risk of Bleeding Events – ~2% risk of bleeding – 0.3% risk of fatal bleeding • Any 3rd agent needs to prove efficacy and safety
- 14. Dabigatran
- 15. Dabigatran (Pradaxa) • Direct Thrombin Inhibitor • Approved for – Stroke Prevention in non valvular A fib – First of the 3 FDA approved novel anticoagulants • RELY trial, NEJM, 2009 • 150mg BID for normal renal function • 75mg BID for impaired renal function • Although 110mg BID was the safer dose – Prevention of DVT in hip/knee surgery
- 16. DAPT + Dabigatran after ACS REDEEM trial – Phase 2 trial • Phase II Trial • Dose finding • Randomized, Double Blind Trial • N=1861 • Within 7days of STEMI/NSTEMI (60%/40%) Oldgren et al, EHJ 2011
- 17. DAPT + Dabigatran after ACS REDEEM trial – Phase 2 trial • All patients were on DAPT – Aspirin & Clopidogrel • Dabigatran (Dose Escalation Randomization) – 50mg BID, 75mg BID (first stage) – 110 mg BID (second stage) – 150mg BID (third stage) • Placebo • Followed for 6 months Oldgren et al, EHJ 2011
- 19. DAPT + Dabigatran after ACS REDEEM trial – Phase 2 trial • Safety Trial • Composite Endpoint of Primary Endpoint – Major Bleeding (ISTH definition) • Critical location (eyes, brain, joints, retroperitoneal, pericardial) • >= 2gm/dl drop in Hb • Transfusion 2 or more units – Clinically relevant minor bleeding • Overt bleeding less than major bleeding • Prompted a clinical response (hospital admission, additional medical/surgical treatment, change in ttt)
- 20. Clopidogrel CURE Clopidogrel CURE AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS Prasugrel TRITON TIMI 38 Prasugrel TRITON TIMI 38 Ticagrelor PLATO Ticagrelor PLATO Warfarin CHAMP trial Warfarin CHAMP trial Dabigatran RE-DEEM trial Dabigatran RE-DEEM trial Apixaban APPRAISE trial Apixaban APPRAISE trial Rivoroxaban ATLAS ACS TIMI 51 trial Rivoroxaban ATLAS ACS TIMI 51 trial Ximelagatran ESTEEM trial Ximelagatran ESTEEM trial Clopidogrel CREDO Clopidogrel CREDO
- 21. Apixaban
- 22. Apixaban(Eliquis) • Direct Factor Xa Inhibitor • Approved for – Stroke Prevention in non valvular A fib – 3rd agent to get approved from the novel anticoagulants • ARITSTOTLE trial, NEJM, 2011 • 5mg BID for normal renal function • 2.5mg BID for impaired renal function, low weight, >80
- 23. DAPT + Apixaban after ACS APPRAISE trial • Randomized, Double Blind Trial • N=7392 • Within 7days of STEMI/NSTEMI (40%/60%) • Additional 2 risk factors – Previous MI, Low EF, Impaired renal function – DM, CVA, PAD • Followed for ~ 8 months Alexander et al, NEJM 2011
- 24. DAPT + Apixaban after ACS APPRAISE trial • All patients were on DAPT (Aspirin & Clopidogrel) • Apixaban 5mg BID vs Placebo • Composite Primary Endpoint – MACCE (CV Death, MI, Ischemic Stroke) • Primary Safety Outcome – TIMI Bleeding definition – Major Bleeding (IC Bleeding, bleeding with > 5g/dl drop, fatal bleeding)
- 25. DAPT + Apixaban after ACS APPRAISE trial
- 26. DAPT + Apixaban after ACS APPRAISE trial
- 27. • Trial Stopped early • Primary Endpoint • 7.5% in Apixaban vs 7.9% in Placebo (not significant) • Primary Safety Endpoint • 1.3% Apixaban vs 0.5% with placebo • IC bleeding • 0.6% Apixaban, 0.2% placebo DAPT + Apixaban after ACS APPRAISE trial
- 28. Clopidogrel CURE Clopidogrel CURE AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS AHA.ACC 2007 Guidelines Establish DAPT as standard of care for ACS Prasugrel TRITON TIMI 38 Prasugrel TRITON TIMI 38 Ticagrelor PLATO Ticagrelor PLATO Warfarin CHAMP trial Warfarin CHAMP trial Dabigatran RE-DEEM trial Dabigatran RE-DEEM trial Apixaban APPRAISE trial Apixaban APPRAISE trial Rivoroxaban ATLAS ACS TIMI 51 trial Rivoroxaban ATLAS ACS TIMI 51 trial Ximelagatran ESTEEM trial Ximelagatran ESTEEM trial Clopidogrel CREDO Clopidogrel CREDO
- 29. Rivaroxaban
- 30. Rivoraxaban (Xarelto) • Direct Factor Xa Inhibitor • Stroke Prevention in non valvular A fib • 2nd agent to get approved from the novel anticoagulants • ROCKET AF trial, NEJM, 2011 (non inferior) • 20mg once daily for normal renal function • 15mg once daily for impaired renal function • prevention of DVT in knee/hip replacement • Treatment for DVT & PE & • Prevention of recurrence DVT/PE
- 31. DAPT + Rivaroxaban after ACS ATLAS ACS TIMI 51 trial
- 32. DAPT + Rivaroxaban after ACS ATLAS ACS TIMI 51 trial • Randomized, Double Blind Trial • N=15,526 • Within 5 days of ACS – STEMI 50% – NSTEMI 25% – USA 25% • >55 or • < 55 + DM or previous MI Mega et al, NEJM 2012
- 33. Excluded • Plat <90,000 • PH of ICH • PH of TIA/Stroke on DAPT • Significant GI bleeding in last 12 months • Hb < 10 • Cr Cl <30ml/min
- 34. • All patients were on DAPT (Aspirin & Clopidogrel) • 3 arms – Rivoraxaban 5mg BID – Rivoraxaban 2.5mg BID – Placebo • Followed for 13 months
- 35. Baseline Characteristics • Average patient was a 62 yo, 80 kg, white, male • Normal renal function • 1/3 DM, 2/3 HTN, ½ dyslipidemia, ¼ previous MI • Region – 40% Eastern Europe – 21% Asian – 13.7% Western Europe – 5% North America
- 36. Concomitant therapy • Aspirin 98% • Thienopyridine 92% • Beta blockers 66% • ACEI/ARB 40% • Statin 83% • CCB 15.8%
- 38. Efficacy • Primary Endpoint composite( CV Death, MI, Stroke) – 8.9% Rivaroxaban vs 10.7% placebo – ARR 1.8%, NNT 55 – P=0.008 • According to each dose – 2.5mg 9.1% (p=0.02) – 5mg 8.8% (p=0.03) – Placebo 10.7%
- 39. 2.5mg 5mg Placebo CV Death 2.7% 4.0% 4.1% Fatal Bleeding 0.1% 0.4% 0.2% Any Death 2.9% 4.4% 4.5% Death • NNT to save 1 life (from CV death) = 71 • NNT to save 1 life (any death) = 63
- 40. Ischemic Endpoints MI, Ischemic Stroke, ST • NNT to prevent 1 MI (5mg) = 59 • NNT to prevent 1 ST = 143 2.5mg 5mg Placebo Non fatal MI 6.1% 4.9% 6.6% Ischemic Stroke 1.0% 0.9% 1.0% Stent thrombosis 2.2% 2.3% 2.9%
- 41. Bleeding Endpoints • NNH to cause one major bleed (2.5mg) = 83 • NNH to cause one ICH bleeding (2.5mg) = 500 2.5mg 5mg Placebo Major Bleeding 1.8% 2.4% 0.6% ICH 0.4% 0.7% 0.2%
- 42. If you use 5mg BID Rivoraxaban as 3rd Agent • No significant reduction in death (whatever type) • Treat 59 patients to prevent 1 non fatal MI • Treat 167 patients to prevent 1 ST • Treat 55 patients to get 1 major bleed • Treat 200 patients to get 1 ICH • Not favorable
- 43. If you use 2.5mg BID Rivoraxaban as 3rd Agent • Treat 71 patients to prevent 1 death • Treat 143 patients to prevent 1 ST • Treat 88 patients to get 1 major bleed • Treat 590 patients to get 1 ICH • OK result
- 44. Finding the sweet spot • Subanalysis of patients with STEMI revealed a mortality benefit • 2.5mg BID 2.5% • Placebo 4.2% • ARR 1.7%, NNT 59 Mega et al, JACC 2013
- 45. Mega et al, JACC 2013
- 46. Finding the sweet spot • Subanalysis of patients who received stents for ACS revealed a reduction in Stent thrombosis • 2.5mg BID 1.9% • Placebo 1.5% • ARR 0.4%, NNT 250 Gibson et al, JACC 2013
- 47. Gibson et al, JACC 2013
- 48. What we learnt • Novel anticoagulants generally don’t work as 3rd agent add on to DAPT due to prohibitive bleeding risk • Unless you give it in patients with – Low risk of bleeding – At very low dose ( Rivaroxaban 2.5mg BID) – Especially after STEMI, and those who undergo PCI – Still have to deal with the risk of a major bleed
- 49. What Next?
- 51. Too little, too late • Low Bleeding Risk/High Ischemic Risk ACS patients – younger patient – STEMI – undergo PCI • Achieve benefit with Prasugrel/Ticagrelor • Instead of polypharmacy with 3 agents