Rivaroxaban has been studied as an addition to antiplatelet therapy in patients with coronary artery disease in several large trials. The ATLAS-ACS 2 trial found that low-dose rivaroxaban (2.5mg twice daily) added to dual antiplatelet therapy after acute coronary syndrome reduced the composite of death, heart attack, and stroke compared to placebo, but increased bleeding risk. The COMPASS trial showed that in stable coronary or peripheral artery disease patients, low-dose rivaroxaban (2.5mg twice daily) added to aspirin reduced the composite of death, heart attack, and stroke compared to aspirin alone, again with increased bleeding. The risk-

1. NOAC In Coronary Artery Disease
The Novel Shield ?
Ahmed ElBorae, MSc
Faculty of medicine, Cairo University
Aswan Heart Centre, Magdi Yacoub Heart Foundation

2. • Know your enemy
• Previous wars
• New targets
Agenda

5. Anticoagulation in CAD trials
2001
2002
OASIS-main
WARIS-2
2003ESTEEM
RE-DEEM
APPRAISE2
ATLAS-ACS2
GEMINI-ACS1
2011
2012
2017
ATACS1994
(Warfarin+ASA)
ACS
(NOAC+DAPT)
ACS
(NOAC+P2y12i)
ACS
(NOAC+ASA)
CCS
COMPASS2017
2018COMMANDER-HF
(NOAC+)
HF+CCS

7. Definitions

8. Warfarin + Aspirin after ACS
Old data (Before PPCI era)

10. The first used NOAC (ximelagatran) + ASA post ACS
Significant reduction in the composite of (death, myocardial infarction, CVS) at 6 months
withdrawn due to liver toxicity.
ESTEEM trial

11. RE-DEEM trial (1861 patients)
RCT (1:1) Dabigatran (50mg vs. 75mg vs. 110 mg vs. 150 mg) (b.i.d) vs. Placebo
with DAPT after ACS
Dose-related x 2-4 folds increased risk of bleeding
(Major+clinically relevant minor)
(ISTH)

12. APPRAISE-2 trial (7400 patients)
RCT (1:1) Apixaban 5mg (b.i.d) with Antiplatelet Therapy after ACS vs. Placebo
Apixaban group had a higher rate of TIMI major bleedingNo significant reduction in recurrent ischemic events

13. ATLAS ACS (Phase 2 trial)
(Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with ACS)
• Enrolled 3491 ACS patients
• Rivaroxaban total daily doses (5 to 20 mg) Vs. placebo
• Reduced the composite end point of (death, MI, stroke)
• Dose-dependent increase in bleeding events
• Lowest hazard ratio (2.5 mg b.i.d)

14. ATLAS ACS 2 (Phase 3 trial)
(Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with ACS)
Rivaroxaban 2.5mg B.I.D
Rivaroxaban 5mg B.I.D
Placebo
1
2
3
RCT (1:1:1)
• 15,526 patients
• 766 Centers
• 44 countries

15. ATLAS ACS 2 (Phase 3 trial)
(Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with ACS)
Rivaroxaban 2.5mg B.I.D
Rivaroxaban 5mg B.I.D
Placebo
1
2
3
> Inclusion criteria
• Recent ACS (1 week)
• If age < 55 , + (DM or old MI)
> Exclusion criteria
• Platelet < 90,000/ml
• Hemoglobin < 10 g/dl
• Significant GIT bleeding 12 months
• Intracranial hemorrhage
• Creatinine clearance <30 ml/min.
• CVS or TIA while on DAPT

16. (Risk profile)
• Mean age 62 years
• Male (75%)
• 26% (Old MI)
• 32% (DM)
• 67% (HTN)
Presentation
• 50% STEMI
• 25% NSTEMI
• 25% Unstable angina
Treatment strategy
• 60% (PCI/ CABG)
• 93% on DAPT

17. 9.1%
10.7%
Including hemorrhage-related deaths
10.7%
8.8%
4.1%
2.7%
4.1%
3.9%

18. One major bleeding / 67 patients treated with Rivaroxaban for 2 years
2.4%1.8%
0.6% 0.6%
P 0.009
P 0.66

19. Rivaroxaban 2.5mg B.I.D
Aspirin 100 mg
1
GEMINI-ACS 1 (Phase2)
(Low-dose Rivaroxaban vs. aspirin) + P2Y12 inhibition in ACS at 1 Year
Multi-centre international double blinded RCT
Ticagrelol
Or
Clopidogrel
RCT (1:1)
• 3037 ACS
• 321 Centers
• 21 countries

20. Rivaroxaban 2.5mg B.I.D
Aspirin 100 mg
1
GEMINI-ACS 1 (Phase2)
(Low-dose Rivaroxaban vs. aspirin) + P2Y12 inhibition in ACS at 1 Year
Multi-centre international double blinded RCT
Ticagrelol
Or
Clopidogrel
> Inclusion criteria
• Recent ACS (1 week)
• If age < 55 , + (DM or old MI)
> Exclusion criteria
• Active bleeding
• Significant GIT bleeding 12 months
• Intracranial hemorrhage
• Creatinine clearance <20 ml/min.
• Indication for full NOAC dose

21. (Risk profile)
• Mean age 63 years
• Male (75%)
• 23% (Old MI)
• 30% (DM)
• 75% (HTN)
Presentation
• 49% STEMI
• 40% NSTEMI
• 11% Unstable angina
Treatment strategy
• 87% (PCI)
• 56% on Ticagrelol

22. 5% 5%
No significant difference in bleeding or MACE (Not powered for MACE)
Multivariable analysis > Higher bleeding with Ticagrelol (7% vs. 3%)
N.B: Rivaroxaban arm > non-significantly higher ischemic events at 30 days

23. COMPASS
(Cardiovascular Outcomes for People Using Anticoagulation Strategies)
Multi-centre international double blinded RCT
2
RCT (1:1:1)
• 27395 patients
• 602 Centers
• 33 countries

24. COMPASS
(Cardiovascular Outcomes for People Using Anticoagulation Strategies)
Multi-centre international double blinded RCT
2
> Inclusion criteria
• CAD or PAD
• If age < 65 : + 2 RF (DM, smoker, GFR <60), HF, CVS> 1 month)
or Documented atherosclerosis in 2 vascular beds
> Exclusion criteria
• High bleeding risk
• Intracranial hemorrhage
• Creatinine clearance <15 ml/min.
• Advanced HF
• On DAPT therapy
• Indicated for full dose NOAC
• Other condition with poor prognosis

25. (Risk profile)
• Mean age 68 years
• Male (78%)
• 62% (Old MI)
• 38% (DM)
• 75% (HTN)
• 21% (HF)
Presentation
• 91% CAD
• 27% PAD
PPI
• 36% already on PPI
• Other randomized (1:1) for PPI

26. 5.4%
4.9%
4.1%
RRR 24%

27. P value for significance = 0.0025

29. + any bleeding that led to hospitalization with or without an overnight stay
Leads to 30 % increase in the bleeding endpoint

30. Net clinical benefit

33. COMMANDER HF trial (5022 patients)
RCT (1:1) Rivaroxaban 2.5mg (b.i.d) vs. Placebo
HFrEF+ CCS
Rivaroxaban group had a higher ISTH major bleeding
No significant reduction in MACE
• 93% on ASA
• 35% on DAPT

35. High ischemic risk
Diffuse multi-vessel CAD plus one of the following:
-DM
-Recurrent MI
-PAD
-CKD eGFR (15-59)
Intermediate ischemic risk
-Any of the above
-Heart failure
High bleeding risk
-Prior intracerebral hge or stroke
-Recent GIT bleeding or Anemia
-Intracerebral or GIT pathology
-Liver failure
-Coagulopathy
-Frailty
-eGFR < 15 or dialysis

36. Adding to DAPT from the start
(ATLAS-ACS)

37. Adding to ASA after 12 months of DAPT
(COMPASS)

40. Take home message
• Low dose Rivaroxaban plus DAPT post ACS reduced MACE, yet with
increased bleeding risk (ATLAS-ACS 2)
• Low dose Rivaroxaban plus ASA in CCS reduced MACE, again with
increased bleeding risk (COMPASS)
• Tailored patient approach should be adopted

41. Thank You