ACCP Cardiology PRN Journal Club

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The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction (PEGASUS-TIMI 54) Sheena Mathew, Pharm.D. May 29, 2015

Disclosure Statement: Presenters have no conflicts to report related to financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation

Background Patients with myocardial infarction (MI) have higher risk for recurrent ischemic events Activated platelets responsible for cardiovascular (CV) ischemic risk Use of dual-antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor can help reduce the risk of ischemic events in the first year after acute coronary syndrome (ACS) Bonaca MP., et al. NEJM. 2015;372(19):

Background: PLATO Trial Multi-center randomized double-blind trial Compared clopidogrel (loading dose mg, maintenance dose 75 mg daily) to ticagrelor (loading dose 180 mg, maintenance dose 90 mg twice daily) – In addition to aspirin mg Patient Population: All ACS patients, with or without ST- segment elevation with an onset of symptoms in the previous 24 hours Primary endpoint: composite of death from vascular causes, MI, or stroke Wallent L, et al. NEJM. 2009; 361 (11):

Background: PLATO Trial OutcomeTicagrelor vs. Clopidogrel, Hazard Ratio (95% CI) P-Value Primary outcome:9.8 % vs 11.7, 0.84 ( )<0.001 Secondary Endpoints: Death from any cause, MI, or stroke10.2% vs. 12.3%, 085 ( )<0.001 Death from vascular causes, MI, stroke, severe recurrent ischemia, TIA or other arterial thrombotic event 14.6% vs. 16.7%, 0.88 ( )<0.001 MI5.8% vs. 6.9%, 0.84 ( )0.005 Death from any cause4.5% vs. 5.9%, 0.78 ( )<0.001 Stent thrombosis-definite1.3% vs. 1.9%, 0.67 ( )0.009 Adverse Events TIMI Major Non-CABG Bleeding2.8% vs. 2.2%, 1.25 ( )0.03 PLATO Major Non-CABG Bleeding4.5% vs. 3.8%, 1.19 ( )0.03 Dyspnea-Any13.8% v.s 7.8%, 1.84 ( )<0.001 Wallent L, et al. NEJM. 2009; 361 (11):

Background TrialOutcomes DAPT Trial Compared continued thienopyridine vs aspirin alone for 30 months Statistically significant difference in the decrease of the primary outcome in the continued thienopyridine group: Stent-thrombosis MACCE: Death, MI Statistically significant increase in bleeding in the continued thienopyridine group (based on the GUSTO criteria and the BARC criteria) Trilogy-ACS Trial Compared the use of 30 months of DAPT with prasugrel vs. clopidogrel for 30 months in patients with unstable angina or MI without ST-segment elevation and did not undergo revascularization Prasugrel did not significantly reduce the primary endpoint of death from CV causes, MI, or stroke The incidence of bleeding occurred with similar frequency in both groups (based on the GUSTO criteria) in both age <75 years and overall population Slight increase in the prasugrel group in the TIMI criteria for major or minor bleed in patients <75 years of age Treatment with DAPT Beyond 12 Months Maur L, et al. NEJM. 2014; 371(23): Roe mT, et al. NEJM. 2012; 367 (14):

Background Treatment with DAPT Beyond 12 Months TrialOutcomes CHARISMA Trial DAPT with clopidogrel + low-dose aspirin vs. aspirin alone in patients with high-risk atherthrombotic events There was no difference between the two groups in the primary efficacy end point of first occurrence of MI, stroke, or death from CV causes Statistically significant increase in moderate bleeding based on the GUSTO definition in the clopidogrel group vs. the placebo group Bhatt DL, et al. NEJM. 354(16):

Background Minimum Duration of DAPT Drug-Eluting Stent (DES) ACCF/AHA/SCAI (2011) 12 months ESC (2014) 6 months in stable coronary artery disease (CAD) 12 months for ACS indications Bare Metal Stent (BMS) ACCF/AHA/SCAl (2011) 1 month in non-ACS indication 12 months for ACS indication ESC (2014) 1 month in stable CAD 12 months for ACS indication Levine G, et al. Circulation. 2011; 124(23): e574-e651 Windecker S, et al. Eur Heart J. 2014; 35:

Background & Purpose Randomized, Double-Blind, placebo-controlled clinical trial Purpose: – To test whether long-term therapy with ticagrelor added to low-dose aspirin reduces the risk of major CV events among stable patients with a history of MI. Bonaca MP., et al. NEJM. 2015;372(19):

Study-Design Inclusion CriteriaExclusion Criteria Spontaneous MI 1-3 years before enrollment Age ≥ 50 years One of the following additional high-risk features: Age of 65 years or older Diabetes mellitus requiring medications A second prior spontaneous MI Multivessel CAD Chronic renal dysfunction (CrCl<60 ml/min) Planned use of a P2Y 12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period Bleeding disorder history History of ischemic stroke History of intracranial bleed Central nervous system tumor Intravascular abnormality Gastrointestinal (GI) bleed within the previous 6 months Major surgery within the previous 30 days Renal failure requiring dialysis Concomitant use of potent inducer/inhibitor/substrate of CYP3A4 Bonaca MP., et al. NEJM. 2015;372(19):

Study-Design Arm 1 (n=7050) Aspirin mg daily Ticagrelor 90 mg twice daily Arm 2 (n=7045) Aspirin mg daily Ticagrelor 60 mg twice daily Arm 3 (n=7067) Aspirin mg daily Placebo Treatment Arms: Study Duration-3 years Bonaca MP., et al. NEJM. 2015;372(19):

Statistical Analysis Power: – 90-mg dose vs. placebo for the primary endpoint: 1360 events for 90% power to detect a 20% reduction – 60-mg dose vs. placebo for the primary endpoint:1360 events to provide 83% power to detect a 19% reduction Event probabilities: – Kaplan-Meier estimates of cumulative incidence at 36 months Hazard ratios: – Generated using Cox proportional hazard model Bonaca MP., et al. NEJM. 2015;372(19):

Study-Design Primary Endpoint Composite of CV death, MI, or stroke Secondary Endpoint CV death and death from any cause Composite endpoint of death from coronary heart disease, MI, or stroke Individual components of the composite endpoints Urgent coronary revascularization Hospitalization for unstable angina Transient ischemic attack (TIA) Safety Endpoint Major Bleeding based on the thrombolysis of myocardial infarction (TIMI) definition Intracranial hemorrhage Fatal bleeding Bonaca MP., et al. NEJM. 2015;372(19):

Patient Demographics CharacteristicTicagrelor, 90 mg (N=7050) Ticagrelor, 60 mg (N=7045) Placebo (N=7067) Age65.4± ± ±8.3 Multivessel CAD 1- no/total no. (%) 4155/7049 (58.9)4190/7042 (59.5)4213/7067 (59.6) History of PCI-no. /total no. (%) 5852/7049 (83.0)5879/7044 (83.5)5837/7066 (82.6) >1 Prior MI –no. (%)1143 (16.2)1168 (16.6)1188 (16.8) Years since MI-Median (IQR) 1.7 ( )1.7 ( ) Type of MI-no. (%) STEMI3753/7043 (53.4)3757/7035 (53.4)3809/7057 (54.0) NSTEMI2898/7043 (41.1)2842/7035 (40.4)2843/7057 (40.3) Unknown382/7043 (5.4)436/7035 (6.2)405/7057 (5.7) Aspirin at any dose-no. (%) 7039 (99.8)7036 (99.9)7057 (99.9 Bonaca MP., et al. NEJM. 2015;372(19):

Results EndpointTicagrelor 90 mg vs. Placebo; % (HR, 95% CI; P-value) Ticagrelor 60 mg. vs. Placebo; % (HR, 95% CI; P-value) CV Death, MI, or Stroke 7.85 vs (0.85, , p=0.008) 7.77 vs (0.84, , p=0.004) Death from CHD 1, MI, or stroke 6.99 vs (0.82, , p=0.002) 7.09 vs (0.83, , p=0.003) CV death or MI6.79 vs (0.85, , p=0.01) 6.77 vs (0.85, , p=0.01) Death from CHD, or MI 5.59 vs (0.81, , p=0.004) 5.75 vs (0.84, , p=0.01) CV death2.94 vs (0.87, , p=0.15) 2.86 vs (0.83, , p=0.07) 1 Coronary heart disease Bonaca MP., et al. NEJM. 2015;372(19):

Results OutcomeTicagrelor 90 mg vs. Placebo; % (HR, 95% CI; P-value) Ticagrelor 60 mg. vs. Placebo; % (HR, 95% CI; P-value) Death from CHD1.53 vs (0.73, , p=0.02) 1.72 vs (0.80, , 0.09) MI4.40 vs (0.81, , p=0.01) 4.53 vs (0.84, , p=0.03) Stroke- Any1.61 vs (0.82, , 0.14) 1.47 vs (0.75, , p=0.03) Death from any cause 5.15 vs (1.00, , p=0.99) 4.69 vs (0.89, , p=0.14) Bonaca MP., et al. NEJM. 2015;372(19):

Results Bonaca MP., et al. NEJM. 2015;372(19):

Results Bonaca MP., et al. NEJM. 2015;372(19):

Results Bonaca MP., et al. NEJM. 2015;372(19):

Author’s Conclusion Addition of ticagrelor at a dose of 90-mg twice daily or 60-mg twice daily, to low-dose aspirin reduced the risk of CV death, MI, or stroke and increased the risk of TIMI major bleeding among patients who had an MI 1-3 years later Bonaca MP., et al. NEJM. 2015;372(19):

Discussion Use of ticagrelor with low-dose aspirin in patients 1- 3 years after MI significantly reduced the risk of CV death, MI, or stroke Rates of discontinuation due to dyspnea of ticagrelor in the 90-mg group vs. the 60-mg was higher – displaying a more attractive benefit-risk profile in the 60-mg group Longer duration of ticagrelor treatment was associated with an increased risk of bleeding Bonaca MP., et al. NEJM. 2015;372(19):

Discussion PEGASUS-TIMI 54 compared to other long-term studies DAPT, Trilogy-ACS, and CHARISMA – varying data on extended-use of DAPT – mixed patient population Vorapaxar has been recently approved: – Reduction of thrombotic events in MI and peripheral arterial disease – Possible benefit for extended-use of DAPT Usage of these agents will come with risk of bleed Bonaca MP., et al. NEJM. 2015;372(19): Morrow DA., et al. NEJM. 2012;366:

Discussion Bonaca MP., et al. NEJM. 2015;372(19):

Critique Strengths Study Design Studied a lower-dose of ticagrelor (i.e. 60 mg twice daily) Endpoints appropriately powered Limitations Excluded other antiplatelet agents and anticoagulants Rates of discontinuation due to bleeding and dyspnea down-played Did not disclose patient population bleeding history

Practical Implications Displays the benefit and effect of DAPT with ticagrelor and aspirin in patients who had an MI in the previous 1-3 years Must assess the risk of bleed vs. the benefit in utilization of extended use of dual antiplatelet therapy – NNT: 90 mg: 84, 60 mg: 79 – NNH: 90 mg: 64, 60 mg: mg tablet strength not available – FDA recently accepted priority review of ticagrelor 60 mg tablet – If approved potential benefit of using 60-mg twice daily dose instead of the 90-mg twice daily dose

Acknowledgements Journal Club Mentor: – Carrie Oliphant, Pharm.D., BCPS-AQ Cardiology Program Directors: – ACCP Cardiology PRN Journal Club Coordinator: Craig Beavers, Pharm.D., FAHA, AACC, BCPS-AQ Cardiology, CACP – Elizabeth McNeely, Pharm.D., BCPS-AQ Cardiology

The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction (PEGASUS-TIMI 54) Sheena Mathew, Pharm.D. May 29, 2015

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