1. Ticagrelor for the prevention of thrombotic events in patients with Acute Coronary Syndrome Hannah Allegretto PharmD Candidate 2013 October 8, 2012

2. Learning Objectives List common causes and treatments of acute coronary syndrome (ACS) Identify risk factors for the development of ACS Describe key findings from a clinical trial of ticagrelor Define the placement of ticagrelor in ACS treatment

3. ACS Impact Approximately 785,000 Americans will have a new coronary attack annually – ~470,000 Americans will have a recurrent attack Every 25 seconds, an American will have a coronary event, and every minute, someone will die of one. Annually, 795,000 people experience a new or recurrent stroke. – In 2008, stroke accounted for 1 of every 18 deaths in the US. Circulation. 2012; 125: 188-97.

4. Acute Coronary Syndrome “Umbrella term” for signs and symptoms of myocardial ischemia 3 Types: – ST-Elevation Myocardial Infarction (STEMI) Fully occluded artery – Non-ST Elevation Myocardial Infarction (NSTEMI) and Unstable Angina (UA) Partially occluded artery Am J Nurs. 2009; 109: 42-52.

5. Risk Factors Smoking Male gender Hypertension Diabetes mellitus Obesity Dyslipidemia Family History Race http://www.mayoclinic.com/health/ acute-coronary-syndrome/DS01061/DSECTION=risk-factors.

6. Presentation Chest pain is major presenting symptom Patients may also feel: – Radiating pain into arm, neck, or back – Shortness of breath – Nausea In women: – Pain in the back reported as a numb, tingling, burning or stabbing sensation Am J Nurs. 2009; 109: 42-52.

7. Diagnosis Electrocardiogram Cardiac biomarkers – Troponins I and T increase within 4-6 hrs of MI – CK-MB enzyme released within 4-6 hours of injury Myoglobin – Heme protein, not cardiac specific – First to rise after myocardial damage Am J Nurs. 2009; 109: 42-52. Am Fam Physician. 2005; 72: 119-26.

8. ECG Findings www.thrombosisadviser. com/en/ image.php?image=stemi-and-nstemi-ecg-illustration &category=atherothrombosis

9. Current Treatment Options Antiplatelets Anticoagulants ACE Inhibitors Beta Blockers Nitroglycerine Calcium Channel Blockers Diuretics Thrombolytic agents J Am Coll Cardiol. 2009; 54: 2205-41. J Am Coll Cardiol. 2011; 57: 1920-59.

10. Ticagrelor (Brilinta®)

11. Mechanism of Action First oral agent of a new class termed “cyclopentyltriazolo-pyrimidines” Reversibly interacts with the platelet P2Y 12 adenosine diphosphate (ADP) receptor – Prevents signal transduction and platelet activation – Partial recovery of platelet aggregation within 12 hours after discontinuation Vasc Health Risk Manag. 2010; 6: 963-77. Am Heart J. 2011; 161: 450-61.

12. Pharmacokinetics/ Pharmacodynamics Absorption – T max : 1.5 hours – Mean absolute bioavailability: 36% Distribution: – Extensively bound to plasma proteins (>99%) Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

13. Pharmacokinetics/ Pharmacodynamics Metabolism: – Major: CYP3A4 – Forms an active metabolite Excretion: – Primarily excreted by hepatic metabolism – Metabolite primarily excreted by biliary secretion – T 1/2 approximately 7 hours Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

14. FDA Approved Indications Acute Coronary Syndrome – Indicated to reduce the rate of thrombotic CV events in patients with UA, NSTEMI, and STEMI Approved July 2011 Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

15. Contraindications History of Intracranial Hemorrhage (IH) – High risk of recurrance Active Pathological Bleeding – Ex. Peptic ulcer, IH Severe Hepatic Impairment – Increased risk of bleeding – Probable exposure increase – Not studied in this population Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

16. Adverse Reactions Dyspnea – Most common Bleeding Others – Headache – Dizziness – Cough Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

17. Drug Interactions Strong CYP 3A4 Inhibitors – Ex. Ketoconazole, clarithromycin, atazanavir Potent CYP 3A4 Inducers – Ex. Rifampin, dexamethasone, carbamazepine, phenytoin, phenobarbital Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

18. Black Box Warning Ticagrelor can cause significant, sometimes fatal, bleeding. Do not use in patients : – With active pathological bleeding/history of IH – Planned to undergo urgent CABG – With suspected bleeding, or in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG or other surgical procedures. Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

19. Black Box Warning If possible, manage bleeding without discontinuation of ticagrelor. Discontinuation increases risk of subsequent CV events. Warning: – Maintenance doses of aspirin > 100 mg decreased effectiveness of ticagrelor and should be avoided. Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

20. Availability and Dosing 90 mg tablets Loading dose: – 180 mg by mouth Maintenance Dose: – 90 mg by mouth twice daily with or without food Missed Dose: – Patient should take their next dose at its regularly scheduled time Brilinta package insert. Wilmington, DE: AstraZeneca LP; 2011 July.

21. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes Wallentin L, Becker RC, Budaj A et al. N Engl J Med. 2009; 361: 1045-57.

22. Study Design Phase III multicenter randomized, double- blind, double-dummy, parallel-group, event driven trial N Engl J Med.2009; 361: 1045-57

23. Study Objectives The primary objective is to test the hypothesis that ticagrelor is superior to clopidogrel for the prevention of vascular events in patients with non-ST-elevation ACS or ST-elevation ACS N Engl J Med.2009; 361: 1045-57

24. Inclusion Criteria Must be > 18 years old Hospitalized with documented evidence of non-ST elevation or ST-elevation ACS in the 24 hours before randomization Must have informed consent Persistent ST-segment elevation > 1 mm in > 2 contiguous leads or new LBBB plus primary PCI planned OR > 2 of the following: N Engl J Med.2009; 361: 1045-57

25. Inclusion Criteria ST-segment changes on ECG indicating ischemia. ST-segment depression or transient elevation > 2 mm in 2 or more contiguous leads Positive biomarker indicating myocardial necrosis One of the following: N Engl J Med.2009; 361: 1045-57

26. Inclusion Criteria One of the following: – >60yo – Previous MI/CABG – CAD with >50% stenosis in >2 vessels – Previous ischemic stroke, TIA, carotid stenosis, or cerebral revascularization – DM – Peripheral artery disease – Chronic renal dysfunction N Engl J Med.2009; 361: 1045-57

27. Exclusion Criteria CI to clopidogrel Oral anticoagulation therapy that cannot be stopped Fibrinolytic therapy planned or within previous 24 hours Concomitant oral or IV therapy with strong CYP3A inhibitors, CYP3A4 substrates with narrow therapeutic indices, or strong CYP3A inducers N Engl J Med.2009; 361: 1045-57

28. Exclusion Criteria Increased risk of bradycardia Dialysis required History of anemia or thrombocytopenia Pregnancy/lactation Involvement in planning/conducting the study N Engl J Med.2009; 361: 1045-57

29. Patient Enrollment Must be > 18 years old and hospitalized with documented evidence of non-ST elevation or ST-elevation ACS in the 24 hours before randomization Study involved >18,000 patients recruited from 800 sites in 43 countries N Engl J Med.2009; 361: 1045-57

30. Primary Outcome Time to the first occurrence of composite of death from vascular causes, myocardial infarction, or stroke N Engl J Med.2009; 361: 1045-57

31. Secondary End Points Time to first occurrence of composite of death from vascular diseases, myocardial infarction, or stroke in patients for whom invasive management was planned at randomization. Composite of death from any cause, myocardial infarction, or stroke Composite of death from vascular causes, MI, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, transient ischemic attack, or other arterial thrombotic events N Engl J Med.2009; 361: 1045-57

32. Secondary Endpoints MI alone Death from CV causes alone Stroke alone Death from any cause N Engl J Med.2009; 361: 1045-57

33. Primary Safety Endpoint Time to PLATO-defined and adjudicated first major bleeding event – Major bleed, life threatening: associated with >50 g/L decrease in hemoglobin – Major bleed, other: associated with 30-50 g/L decrease in hemoglobin – Minor bleed: requires medical intervention – Minimal bleed: all others not requiring intervention N Engl J Med.2009; 361: 1045-57

34. Treatment Protocol Patients randomly assigned to ticagrelor 90mg twice daily plus placebo or clopidogrel 75mg once daily plus placebo Patients in the ticagrelor group receive a 180mg loading dose Patients in clopidogrel group received a 300mg loading dose – If undergoing PCI >24 hours postrandomization, additional loading doses of 90mg ticagrelor or 300mg clopidogrel should be administered N Engl J Med.2009; 361: 1045-57

35. Treatment Protocol All patients receive 75-100mg aspirin daily – After stent placement, ASA up to 325mg allowed Randomization blocked by site Outpatient visits scheduled at 1, 3, 6, 9, and 12 months, with safety follow-up visit 1 month after the end of treatment – Randomized treatment scheduled for 12 months, but patients left study at their 6 or 9 month visit if the targeted number of primary end-point events occurred N Engl J Med.2009; 361: 1045-57

36. Statistics: Primary/Secondary Endpoints Approximately 1780 clinical events needed to achieve 90% power to detect a relative risk reduction of 13.5% for ticagrelor – Sample size needed: 18,000 Intention-to-treat analysis Cox proportional hazards model Kaplan-Meier analysis N Engl J Med.2009; 361: 1045-57 Kidney Int. 2008; 74: 560-65. J Eval Clin Pract. 2008; 14: 83-93.

37. Results: Demographics 18,624 patients enrolled in study – Ticagrelor Group: N = 9333 – Clopidogrel group: N = 9291 All patients included in intent-to-treat analysis No significant differences between groups – Age, gender, race, medical history, risk factors N Engl J Med.2009; 361: 1045-57

38. Results: Primary Outcome At 12 months: – Ticagrelor group: 864/9333 (9.8%) – Clopidogrel group: 1014/9291 (11.7%) – Hazard ratio for Ticagrelor group (95% CI) 0.84 (0.77-0.92) – P Value: <0.001 N Engl J Med.2009; 361: 1045-57

39. Results: Secondary Endpoints Secondary End PointTicagrelor Group Clopidogrel group Hazard Ratio for Ticagrelor Group (95% CI) P Value Death from any cause, MI, or stroke 901/9333 (10.2%) 1065/9291 (12.3%) 0.84 (0.77-0.92)<0.001 Death from vascular cause, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event 1290/9333 (14.6%) 1456/9291 (16.7%) 0.88 (0.81-0.95)<0.001 MI504/9333 (5.8%) 593/9291 (6.9%) 0.83 (0.75-0.95)<0.005 Death from vascular causes353/9333 (4.0%) 442/9291 (5.1%) 0.79 (0.69-0.91)<0.001 Death from any cause399/9333 (4.5%) 506/9291 (5.9%) 0.78 (0.69-0.89)<0.001 N Engl J Med.2009; 361: 1045-57

40. Results: Secondary Endpoints Stroke rate did not differ significantly between groups – More hemorrhagic strokes in ticagrelor group than clopidogrel group (0.2% vs 0.1%) Bleeding – No significant differences for rates of major bleeding between groups (11.6% vs 11.2%) – Fatal or life-threatening bleeding: 5.8% in both groups N Engl J Med.2009; 361: 1045-57

41. Results: Secondary Endpoints Non-CABG related major bleeding – Ticagrelor had a higher rate than clopidogrel (4.5% vs 3.8%) – P = 0.03 Intracranial bleeding – Ticagrelor had a higher rate than clopidogrel 26 (0.3%) vs 14 (0.2%) – P = 0.06 N Engl J Med.2009; 361: 1045-57

42. Adverse Events: Ticagrelor Dyspnea most common – 1270/9235 (13.8%) vs. 721/9186 (7.8%) with clopidogrel P value: <0.001 – Patients discontinuing study treatment 79/9235 (0.9%) vs 13/9186 (0.1%) with clopidogrel P value: <0.001 No significant differences with other ADEs – bradycardia, neoplasms arising during treatment, ventricular pauses N Engl J Med.2009; 361: 1045-57

43. Ticagrelor: Conflicting Results Effect across geographic region North America: – Total patients: 1814 – 102 events with ticagrelor vs 82 events with clopidogrel – Hazard Ratio: 1.25 N Engl J Med.2009; 361: 1045-57

44. Authors’ Conclusions Ticagrelor significantly reduced rate of death from vascular causes, myocardial infarction or stroke without an increase in overall major bleeding Similar benefit was seen for individual components of death from vascular causes and MI, but not stroke Ticagrelor was associated with an increase in the rate of non-procedure-related bleeding

45. Authors’ Conclusions Ticagrelor led to significantly higher rates of dyspnea, which caused several patients to discontinue the study Less procedure related bleeding may be expected due to the reversible antiplatelet effect of ticagrelor

46. Trial Critique: Strengths Randomized, double-blind, double-dummy, multi-center, active control trial Comparison to current standard of care International trial Large Sample Size

47. Trial Critique: Weaknesses 91% of patients were Caucasian No details about randomization, blinding, or allocation concealment were discussed Blinding of assessors is not discussed, possible bias exists Patients permitted to leave study once primary endpoints were reached by a certain number of patients AstraZeneca provided consulting fees for study and two authors are employed with AstraZeneca

48. Ticagrelor: Place in Therapy Recently added in to the UA/NSTEMI 2012 updated guidelines as equivalent to clopidogrel or prasugrel Further studies needed to investigate the discrepency in effectiveness seen in North America in the PLATO trial No current trials comparing ticagrelor vs prasugrel

49. Ticagrelor: Place in Therapy First line in patients with ACS expected to undergo future procedures Second line after clopidogrel for patients not expected to undergo procedures – Cost – Insurance Availability – Twice daily dosing – Dyspnea side effect

50. Questions?

51. Price Comparison CVS Pharmacy Cash Prices: – Brilinta 90mg: 180 tablets = $864.99 – Clopidogrel 75mg: 90 tablets = $499.99 – Effient 10mg: 90 tablets = $850.99

52. Formulary Coverage UPMC for Life – Tier 3, with limited quantity UPMC for You – Non-formulary BCBS Federal Employee – Tier 3 CVS Caremark – Non-formulary UPMC Commercial Plans – Tier 3 with limited quantity or non-formulary Gateway- Non-formulary