1. NOACs for ACS: Is there a Role?
Roxana Mehran MD, FACC, FSCAI, FAHA, FESC
Professor of Medicine (Cardiology), and
Population Health Science and Policy
The Icahn School of Medicine at Mount Sinai
CRT 2017
20th Anniversary
Washington, DC

2. Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
The Medicines Co., BMS, Astra Zeneca, Lilly/Daiichi Sankyo
Abbott Vascular, Boston Scientific, CSL Behring, Janssen (J+J), Claret
Advisory board for Janssen (J+J), Medscape, Osprey
Grant/Research Support
Consulting Fees/Honoraria

3. ACS: Pathophysiology
Ruptured plaque with thrombus; systemic inflammation with heightened platelet reactivity

4. Desai NR, Bhatt DL. JACC CV int. 2010;3:571-83
Antiplatelet Agents
Desai NR, Bhatt DL. JACC CV int. 2010;3:571-83

5. Master Treatment Algorithm for Duration of P2Y12 Inhibitor Therapy in Patients With CAD Treated With DAPT
Clopidogrel is the only currently-used P2Y12 inhibitor studied in patients with SIHD undergoing PCI. Aspirin therapy is almost always continued indefinitely in patients with CAD. Patients with a history of ACS more than one year prior who have since remained free of recurrent ACS are considered to have transitioned to SIHD. In patients treated with DAPT after DES implantation who develop a high risk of bleeding (e.g., treatment with oral anticoagulant therapy), are at high risk of severe bleeding complication (e.g., major intracranial surgery), or develop significant overt bleeding, discontinuation of P2Y12 inhibitor therapy after 3 months for SIHD or after 6 months for ACS may be reasonable. Arrows at the bottom of the figure denote that the optimal duration of prolonged DAPT is not established
ACS indicates acute coronary syndrome; BMS, bare metal stent; CABG, coronary artery bypass graft surgery; CAD coronary artery disease; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; lytic, fibrinolytic therapy; NSTE-ACS, non–ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; SIHD, stable ischemic heart disease; S/P, status post; and STEMI, ST-elevation myocardial infarction.

6. Thrombus: Made of Both Platelets & Fibrin
Courtesy of C. Michael Gibson, M.S., M.D.

7. Positive Feedback Loop: Thrombin Begets
Platelet Activation Which Begets Thrombin
Thrombin
Generation
Platelet
Activation
“Amplification”
“Burst”
“Activation”
Slide by C. Michael Gibson, M.S., M.D.

8. ACS: Platelet Resistance to Clopidogrel Declines Over Time
24 Hours
2 Hours
 Aggregation (%)
% of Patients 12 24
<= -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance = 63%
Resistance
Resistance = 31%
 Aggregation (%)
% of Patients 10 20
<= -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance
5 Days
30 Days
Resistance = 15%
 Aggregation (%)
% of Patients 14 28
<= -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance
 Aggregation (%)
% of Patients 11 22
<= -10
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance = 31%
Resistance
Gurbel et al. Circulation. 2003;107:

9. Novel Thienopyridines Do Not Block Activation by Thrombin
Ex vivo effects of single administration of CS-747 on washed platelet aggregation induced by ADP (A), collagen (B), and thrombin (C) in rats. CS-747 was orally administered once to rats at doses of 0.3 and 3 mg kg−1. The aggregation was measured 4 h after the dosing. Results are presented as the mean±s.e.mean (n=6). **P<0.01 vs control (vehicle-treated group).
“Treatment with CS-747 (Prasugrel) inhibited ex vivo washed platelet aggregation in response to ADP but not to thrombin. This is consistent with the hypothesis that the antiaggregative action of CS-747 (Prasugrel) is due to its specific inhibition of the Gi-linked P2T receptor rather than its interference with the fibrinogen receptors.”
Sugidachi A et al; Br J Pharmacol. Apr 2000; 129(7): 1439–1446.

10. Persistent Elevation of Thrombin Generation in Post-ACS Patients
F 1.2 nmol/L
Merlini et al. Circ 1994;90:61-68

11. TIMI PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke 51 Placebo
ATLAS ACS 2
PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke
TIMI 51
2 Yr KM Estimate
Placebo
10.7%
8.9%
HR ( )
mITT p = 0.008
ITT p = 0.002
ARR 1.8%
NNT = 56
Estimated Cumulative Incidence (%)
Rivaroxaban
(both doses)
Months After Randomization
No. at Risk
Placebo
5113
4307
3470
2664
1831
1079
421
Rivaroxaban
10229
8502
6753
5137
3554
2084
831
Gibson CM, AHA 2011

12. Estimated Cumulative incidence (%)
EFFICACY ENDPOINTS: Very Low Dose 2.5 mg BID Patients Treated with ASA + Thienopyridine
ATLAS ACS 2
TIMI 51
CV Death / MI / Stroke
Cardiovascular Death
All Cause Death 5% 5%
HR 0.85
mITT
p=0.039
ITT
p=0.011
12%
Placebo
HR 0.62
mITT
p<0.001
ITT
Placebo
HR 0.64
mITT
p<0.001
ITT
Placebo
10.4%
4.5%
4.2%
9.0%
2.7%
Estimated Cumulative incidence (%)
2.5%
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
NNT = 71
NNT = 59
NNT = 56 12 12 12 24 24 24
Months
Months
Months
Gibson CM, AHA 2011

13. TIMI STENT THROMBOSIS 51 ARC Definite / Probable / Possible
ATLAS ACS 2
STENT THROMBOSIS
ARC Definite / Probable / Possible
TIMI 51
2 Yr KM Estimate
2.9%
Placebo
2.3%
Estimated Cumulative Incidence (%)
HR ( )
mITT p = 0.016
ITT p = 0.008
Rivaroxaban
(both doses)
ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012
Months After Randomization
Gibson et al, J Am Coll Cardiol. 2013;62(4):286-90

14. TIMI CV Mortality Among Stented Patients (mITT) 51 2.27%
ATLAS ACS 2
CV Mortality Among Stented Patients (mITT)
Results in Patients Treated with ASA + Thienopyridine (Stratum 2)
TIMI 51
2 Yr KM Estimate
2.5
Placebo
2.27%
2.0
CV Mortality (%)
1.5
1.35%
1.0
HR ( )
mITT p = 0.014
ITT p = 0.039
0.5
Rivaroxaban
2.5 mg BID
0.0 90
180
270
360
450
540
630
720
Gibson et al, J Am Coll Cardiol. 2013;62(4):286-90

15. What is The Excess Rate of TIMI Major Non-CABG Bleeding for Novel Agents?
Rivaroxaban: 1.8% vs 0.6% over two years =
0.6% annually1
Ticagrelor: 2.8% vs 2.2% over one year =
0.6% annually2
Prasugrel: 2.4% vs 1.8% over one year =
0.6% annually3
0.6% per year for all 3 agents (rivaroxaban, ticagrelor, prasugrel)
NEJM 2011; Nov 13th
NEJM 2009;361:
NEJM 2007;357:

16. Stratify by MD decision to either Clopidogrel or Ticagrelor
G w_script.ppt
9/3/2018 9:31:32 PM
Recent ACS
Stabilized >48 hours & <10 days post-index event
Exclusions: Bleeding risk, anticoagulant use, prior stroke/TIA
ASA 100 mg qd
Screening
Phase
Stratify by MD decision to either Clopidogrel or Ticagrelor
> 48 hrs
< 10 days
Clopidogrel 75 mg qd
(n=1500)
Ticagrelor 90 mg bid
(n=1500) R R
Clopidogrel 75 mg qd +
ASA
100 mg qd
Clopidogrel 75 mg qd +
Rivaroxaban 2.5 mg bid
Ticagrelor
90 mg bid +
ASA
100 mg qd
Ticagrelor
90 mg bid +
Rivaroxaban 2.5 mg bid
Minimum 180; Maximum 360 Day F/U
PRIMARY SAFETY ENDPOINT: TIMI significant bleeding
EXPLORATORY EFFICACY ENDPOINT: Composite of CV death, MI, ischemic stroke, and stent thrombosis 17

17. Can Long-term Outcomes in ACS be Improved Beyond DAPT?
Or have we reached the point of declining returns in the ischemia-bleeding equation?
Primary Outcome: CV Death, MI, Ischemic Stroke
Safety: TIMI Major Bleeding
Randomize 1:1
Double-blind
Factor Xa inhibitor
Apixaban 5 mg BID
CrCl<40 ml/min 2.5 mg BID
Placebo
Recent (≤7days) acute coronary syndrome (STEMI or NSTE-ACS) + ≥2 additional risk factors
N=10,800
Alexander JH et al. NEJM 2011;365:

18. Trial Stopped Prematurely
On November 15, 2010 the Data Monitoring Committee recommended that the trial be stopped after enrollment of 7,048 pts with median follow-up 3.5 months due to an excess of clinically important bleeding in the apixaban arm without a counterbalancing reduction in ischemic events.

19. Primary Efficacy and Safety
Placebo (n=3705)
Apixaban (n=3687)
Median FU 241 days
TIMI Major Bleed
CV death, MI or ischemic stroke
Apixaban 48 (1.3%)
Placebo 18 (0.5%)
HR (95%CI)=
2.59 (1.50–4.46)
P=0.001
Apixaban 279 (7.5%)
Placebo 293 (7.9%)
0.95 (0.80–1.11)
P=0.51
Alexander JH et al. NEJM 2011;365:

20. Primary Endpoint CV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization
Placebo
Vorapaxar
2-year KM rate
 19.9%
 18.5%
HR (95% CI): 0.92 (0.85, 1.01)
P-value= 0.072
No. at risk Placebo Vorapaxar
Tricoci NEJM 2011

21. GUSTO Moderate/Severe
Bleeding Outcomes
GUSTO Moderate/Severe
ICH
Placebo
Vorapaxar
2-year KM rate
 5.2%
 7.2%
Placebo
Vorapaxar
2-year KM rate
 0.24%
 1.07%
No. at risk
HR (95% CI): 3.39 (1.78, 6.45)
P-value <0.001
HR (95% CI): 1.35 (1.16, 1.58)
P-value <0.001
No. at risk
Tricoci NEJM 2011

22. Morrow et al. ACC 2012, Chicago, March 24, 2012

23. Morrow et al. ACC 2012, Chicago, March 24, 2012

24. Stacking: An Unappreciated Enemy
Chronic oral anticoagulation
Routine post-PCI LMWH
GPIIb/IIIa inhibitors
UFH → Bivalirudin
Clopidogrel → Prasugrel / Ticagrelor
Aspirin (81 mg – 325 mg)
Courtesy: Gregg W. Stone