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

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

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

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

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.

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

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.

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: 2908-2913

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.

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

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 0.84 (0.74-0.96) 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

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

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 0.69 (0.51- 0.93) 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

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 0.56 (0.35- 0.89) 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

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;361:1045-1057. NEJM 2007;357:2001-2015

Stratify by MD decision to either Clopidogrel or Ticagrelor G02-536 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

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;365:699-708

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.

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;365:699-708

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 6471 5844 5468 5121 3794 2291 795 Vorapaxar 6473 5897 5570 5199 3881 2318 832 Tricoci NEJM 2011

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 6441 5673 5281 4823 3511 2038 678 6446 5694 5272 4760 3411 1965 657 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 6441 5536 5137 4674 3393 1972 650 6446 5529 5108 4598 3278 1883 625 Tricoci NEJM 2011

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

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

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