Balancing Efficacy and Safety of P2Y12 Inhibitors for ACS Patients

SYP.CLO-A.16.07.01 Balancing Efficacy and Safety of P2Y12 Inhibitors for ACS Patients dr. Hariadi Hariawan, Sp.PD, Sp.JP (K)

TOPICS Efficacy Safety Consideration from Currently Available Antiplatelet Agents Dual Antiplatelet Therapy (DAPT), How Long to Treat? Optimizing Risk-Benefit Ratio : Highlights of Recent Guidelines

Atherothrombosis: A Significant Cause of Major Ischemic Events Atherothrombosis is characterized by a sudden, unpredictable atherosclerotic plaque disruption leading to platelet activation and thrombus formation Plaque rupture 1 Plaque erosion 2 1. Falk E, et al. Circulation 1995; 92: 657 671. 2. Arbustini E, et al. Heart 1999; 82: 269 272. 3. Aronow WS, et al. Am J Cardiol 1994; 74(1): 64 65.

Atherothrombosis is the underlying condition that results in events leading to myocardial infarction (MI), ischemic stroke or vascular death An atherothrombotic manifestation in one vascular bed results in an increased risk of further events in all vascular beds 3

Major role of platelets in atherothrombosis Normal platelets in flowing blood Platelets adhering to damaged endothelium and undergoing activation Aggregation of platelets into a thrombus Platelets Platelets adhering to subendothelial space Platelet thrombus Endothelial cells Subendothelial space Adapted from Ferguson JJ. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz;2000:15 35.

Atherothrombosis is often found in more than one arterial bed * Cerebrovascular disease 24.7% 7.4% Cardiovascular disease 29.9% 3.3% 3.8% 11.8% 26.2% 19.2% A total of ~26% of patients had manifestations of PAD atherothrombosis in more than one arterial bed *Data from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study (n=19,185) Total does not add up because of rounding Coccheri S. Eur Heart J 1998;19(Suppl):227.

The rationale behind dual antiplatelet therapy 2 indications for DAPT after successful stenting : 1. the stented segment requires protection from stent thrombosis that occurs as a result of inflammation during healing. 2. the areas inside and outside the stented section require protection from the development of progressive atherosclerosis and plaque rupture of less concern with drug-eluting stents, especially second- and thirdgeneration drug-eluting stents. continues to be important Colombo A, et al.n Eng J Med.2014;371(23):2225-6.

Meta-Analysis: Late Thrombosis in First- Generation DES vs BMS Median Time of Late Stent Thrombosis (Mos) 20 P =.0003 P =.0052 P =.04 16 12 Either DES Sirolimus stent Paclitaxel stent BMS 8 4 0 DES vs BMS Sirolimus Stent vs BMS Paclitaxel Stent vs BMS Bavry AA, et al. Am J Med. 2006;119:1056-1661.

EXAMINATION: Incidence of Stent Thrombosis With EES vs BMS in Acute MI Cumulative Incidence of Events (%) 3.0 2.5 Definite stent thrombosis Cardiac death Target-vessel MI Target-vessel revascularization Probable stent thrombosis Cardiac death Target-vessel MI Target-vessel revascularization 2.0 1.5 Stent thrombosis HR: 2.75 (95% CI: 1.15-6.54); P =.0169 1.0 0.5 EES BMS 0 0 60 120 180 240 300 360 Days After Initial Procedure Sabate M, et al. Lancet. 2012;380:1482-1490.

Oral Antiplatelet Agents Antiplatelet Agent Class Binding Dosing Aspirin [1] Thromboxane inhibitor Irreversible QD Clopidogrel [2] ADP receptor antagonist Irreversible QD Prasugrel [3] Ticagrelor [4] ADP receptor antagonist (more potent than clopidogrel) ADP receptor antagonist (more potent than clopidogrel) Irreversible Reversible QD BID 1. Aspirin [package insert]. 2. Clopidogrel [package insert]. 3. Prasugrel [package insert]. 4. Ticagrelor [package insert].

Metabolic Pathway of P2Y 12 -receptor Inhibitors Levine GN, et al.nat Rev Cardiol.2014. doi: 10.1038/nrcardio.2014.104

Major studies of P2Y 12 inhibitors in patients with ACS or undergoing PCI Levine GN, et al.nat Rev Cardiol.2014. doi: 10.1038/nrcardio.2014.104

Major studies of P2Y 12 inhibitors in patients with ACS or undergoing PCI Prasugrel is currently not available in Indonesia Levine GN, et al.nat Rev Cardiol.2014. doi: 10.1038/nrcardio.2014.104

Cumulative HR* CURE: CV Death, MI, or Stroke With 12 Months of DAPT in NSTEMI Dual antiplatelet therapy resulted in 20% reduction in relative risk of MI, stroke, or CV-related death over aspirin alone 0.14 Placebo + ASA 20% RRR 0.12 (n = 6303) P =.00009 0.10 N = 12,562 0.08 0.06 0.04 0.02 0.00 0 3 6 9 12 *MI, stroke, CV death. For 3-12 mos. Clopidogrel + ASA (n = 6259) Mos of Follow-up Yusuf S, et al. N Engl J Med. 2001;345:494-502.

Primary Outcome Event Rate (%) CHARISMA: CV Death, MI, or Stroke in Pts With Prior MI, Stroke, or PAD Secondary endpoint of stroke also significantly lower with clopidogrel + ASA (3.0%) vs placebo + ASA (3.8%), P = 0.048 Post Hoc Analysis of CAPRIE-like Subgroup 10 of Pts in CHARISMA Trial 8.8% 8 Placebo + ASA (n = 4743) 7.3% 6 Clopidogrel + ASA (n = 4745) 4 2 0 17.1% RRR (95% CI: 4.4% to 28.1%; P =.01) 0 6 12 18 24 30 Mos Since Randomization Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Primary Outcome Event Rate (%) CHARISMA: CV Death, MI, or Stroke in Pts With Prior MI 10 8 6 N = 3846 Placebo + ASA Clopidogrel + ASA 8.3% 6.6% 4 2 0 HR: 0.774 (95% CI: 0.613-0.978; P =.031) 0 6 12 18 24 30 Mos Since Randomization Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Primary Outcome Event Rate (%) CHARISMA: CV Death, MI, or Stroke in CAD Pts Without Prior MI 10 N = 1989 8 6 4 Placebo + ASA Clopidogrel + ASA 6.3% 5.7% 2 0 HR: 1.103 (95% CI: 0.770-1.580; P =.593) 0 6 12 18 24 30 Mos Since Randomization Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Hazard Function/d CHARISMA: Timing of Severe or Moderate Bleeding* In pts tolerating clopidogrel plus ASA, reasonable to continue beyond 12 months if clinically indicated 0.00008 0.00006 Clopidogrel + ASA Placebo + ASA 0.00004 0.00002 0 015 60 135 270 450 Days Since Randomization 630 810 *By GUSTO (Global Utilization of Streptokinase and t-pa for Occluded Coronary Arteries) criteria, including fatal bleeding, primary intracranial hemorrhage, and bleeding causing hemodynamic compromise and requiring blood or fluid replacement, inotropic support, or surgical intervention. Bhatt DL, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial Steg PGB, Harrington RA, Emanuelsson H, et al.circulation.2013;128:1055-65 Method : multicenter, double-blind, randomized trial, comparing ticagrelor (180-mg LD 90 mg BID) and clopidogrel (300-to-600-mg LD 75 mg OD) for the prevention of cardiovascular events Results : n=18,624

Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial Steg PGB, Harrington RA, Emanuelsson H, et al.circulation.2013;128:1055 65 Efficacy Summary : Primary end point was better for ticagrelor Secondary end point was better for ticagrelor except stroke The rate of death from any cause was also reduced with ticagrelor

Cumulative incidence (%) K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 0 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 Clopidogrel 9,291 8,521 8,362 8,124 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval 6,743 6,743 Clopidogrel 5,161 5,096 Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 4,147 4,047 11.7 9.8

K-M estimated rate (% per year) Time to major bleeding primary safety event 15 10 Ticagrelor Clopidogrel 11.58 11.20 5 No. at risk Ticagrelor Clopidogrel 0 9,235 9,186 0 60 120 180 240 300 360 7,246 7,305 Days from first IP dose 6,826 6,930 HR 1.04 (95% CI 0.95 1.13), p=0.434 6,545 6,670 5,129 5,209 3,783 3,841 3,433 3,479

Balance between antiplatelet effect and bleeding risk Use of more potent P2Y12 inhibitors (ticagrelor or prasugrel) in place of clopidogrel also results in decreased ischemic risk and increased bleeding risk Levine GN, et al 2016 ACC/AHA Guideline

Randomized Trials Evaluating Duration of DAPT After Stent Implantation 1 month 3 months 48 months 6 months 30 months DAPT ARCTIC 12 months EXCELLENT ITALIC ISAR SAFE DAPT-STEMI *Biolimus A9-eluting stent. 24 months Capodanno D, et al. Circulation. 2013;128:2785-2798.

Extended-Duration DAPT After DES Meta-analysis of 31,666 pts with DES and DAPT for 6 mos vs 12 mos vs > 12 mos Treatment with DAPT for > 12 mos: Reduced MI and stent thrombosis 25% decrease in MI (P =.01) 41% decrease in stent thrombosis (P =.06) Palmerini T, et al. Lancet. 2015;385:2371-2382. Increased bleeding, overall mortality, and non-cardiac mortality 72% increase in bleeding (P <.0001) 49% increase in noncardiac mortality (P =.006) 22% increase in mortality (P =.02)

Optimal Duration of DAPT? Eisen A, et al. Nat Rev Cardiol. 2015;12:445-446..

2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease Levine GN, et al.circulation.2016;133:000-000

Factors Associated With Increased Ischemic and Bleeding Risk

DAPT Score A score of 2 is associated with a favorable benefit/risk ratio for prolonged DAPT; A score of < 2 is associated with an unfavorable benefit/risk ratio. CHF: congestive heart failure; DAPT: dual antiplatelet therapy; LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention.

2016 ACC/AHA DAPT guideline recommendations: SIHD and ACS

Treatment Algorithm for DAPT in Recent ACS (NSTE-ACS or STEMI) CURE CURE COMMIT CLARITY CURE COMMIT DAPT CHARISMA PEGASUS

Treatment Algorithm for DAPT in SIHD (Without ACS Within the Past Several Years) Patients with hx of ACS >1 year prior who have since remained free of recurrent ACS are considered to have transitioned to SIHD; Aspirin therapy is almost always continued indefinitely in patients with CHD.

Treatment Algorithm for Duration of P2Y12 Inhibitor Therapy in Patients Treated With PCI DAPT CHARISMA PEGASUS

Summary of the Guideline (1/2) Intensification of antiplatelet therapy, with P2Y12 inhibitor + aspirin, as well as prolongation of DAPT, necessitates a fundamental tradeoff between decreasing ischemic risk and increasing bleeding risk; Shorter-duration DAPT can be considered for patients at lower ischemic risk with high bleeding risk (DAPT score <2), whereas longer-duration DAPT may be reasonable for patients at higher ischemic risk with lower bleeding risk (DAPT score 2);

Summary of the Guideline (2/2) Clopidogrel is recommended for all ACS pts no matter receiving any treatment option (PCI, medical treatment, lytic or CABG), while ticagrelor is recommended for ACS pts receiving PCI, medical treatment or CABG, but not in lytic pts; Prasugrel is recommended only in PCI pts. Updated recommendations for duration of DAPT are now similar for patients with NSTE-ACS and STEMI, as both are part of the spectrum of acute coronary syndrome. A Class I recommendation ( should be given ) in most clinical settings is made for at least 6-12 months of DAPT (depending on the setting), and a Class IIb recommendation ( may be reasonable ) is made for prolonged DAPT beyond this initial 6- to 12-month period.

CONCLUSION Choice and duration of DAPT should be individualized to achieve optimum risk-benefit of the treatment. Evidence and guidelines are available to help the decision. Use of more potent P2Y12 inhibitors (ticagrelor or prasugrel) in place of clopidogrel also results in decreased ischemic risk and increased bleeding. Choice of antiplatelet should be based on careful review on the balance between antiplatelet efficacy and risk of bleeding. Tolerability, compliance to treatment, patient s preference and cost should also be considered