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Article Title/Citation, Journal, Authors, Affiliation BACKGROUND AND OVERVIEW Article Title: “Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction.” (PEGASUS-TIMI54) Journal: The New England Journal of Medicine (NEJM) Published: May 7, 2015 Authors: Bonaca M, Bhatt D, Cohen M, et al. Affiliations: The Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston; the Cardiovascular Division, Department of Medicine, Newark Beth Israel Medical Center, Rutgers–New Jersey Medical School, Newark; French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire Fibrosis, Inflammation, Remodeling, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, INSERM Unité 1148, and Université Paris– Diderot, Sorbonne Paris Cité — all in Paris; National Heart and Lung Institute, Royal Brompton Hospital, Imperial College, London, and Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom; AstraZeneca, Mölndal, Sweden; Icahn School of Medicine at Mount Sinai, New York; Canisius– Wilhelmina Hospital, Nijmegen, the Netherlands; Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland; Montreal Heart Institute, Université de Montréal, Montreal; Cardiology Research Center, Moscow; Kerckhoff Heart Center, Bad Nauheim, and University of Giessen, Giessen — both in Germany; Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan; University Hospital, Jihlavska, Brno, Czech Republic; Heart Institute (InCor)–University of São Paulo Medical School, São Paulo; and the Department of Cardiology, Military Hospital, Budapest, Hungary. Study objectives/purpose Brief background Funding sources and disclosures Study design and methodology To determine if the addition of Ticagrelor, a P2Y12 receptor antagonist, to standard therapy would be beneficial long-term in patients who have previously experienced a myocardial infarction. Current ACS guidelines recommend the use of dual anti-platelet therapy (DAPT) in patients who have experienced a myocardial infarction (MI) for up to one year. These recommendations include Aspirin (Class I,LOE-A) and a P2Y12 receptor antagonist (Class I, LOE-B). It is important to note that the guidelines do mention that DAPT therapy >12 months can be considered in patients undergoing stent treatment (Class IIb, LOE-C). In a post hoc analysis of CHARISMA, it was determined that longer treatment with dual antiplatelet therapy reduced ischemic events in patients with prior MI. Also, notably in the PLATO trial, Ticagreor was compared against Clopidogrel in the reduction of combined primary end point of cardiovascular (CV) death, myocardial infarction (MI), or stroke, and showed to have a significant reduction vs Clopidogrel, while not having any significant increase in major bleeding. Funding/Source(s): AstraZeneca METHODS Randomized, double-blind, placebo-controlled clinical trial. Randomization took place in 31 countries at 1,160 sites Patient selection & enrollment [ Medium follow-up time was 33 months Inclusion Criteria: o Spontaneous Myocardial Infarction 1-3 years prior o At least 50 years old o Including one additional high risk factor: ≥ 65 years old Diabetes Mellitus requiring medication Second prior spontaneous Myocardial Infarction Chronic Renal Dysfunction- CrCl < 60 mL/min Multivessel Coronary Artery Disease o Able to tolerate Aspirin Study interventions Outcome measures/ endpoints Exclusion Criteria: o Planned use of: P2Y12 Receptor Antagonist Dipyridamole Cilostazol Anticoagulant therapy during study period o Bleeding disorders or coagulation disorder o History of an Ischemic Stroke or Intracranial Bleed o CNS Tumor o Intracranial Vascular Abnormality o GI Bleeding Disorder within 6 months o Major Surgery with 30 days o Dialysis patients o Eligible patients were assigned in a 1:1:1 Ticagrelor 90mg BID, 60mg BID, or Placebo. o All patients received Aspirin, between 75-150 mg. o Patients undergoing elective, major non-cardiovascular procedures were required to stop study drug treatment 5 days prior and advised by physician when to restart. Primary Efficacy End Point: o Composite of cardiovascular death, myocardial infarction, or stroke. Secondary Efficacy End Points: o Cardiovascular death o Death from any cause Exploratory Efficacy End Points: o Myocardial infarction o Stroke o Death from coronary heart disease o Composite of death from coronary heart disease, myocardial infarction, or stroke Primary Safety End Point: o Thrombolysis in Myocardial Infarction (TIMI) major bleeding Statistical analyses including power and sample size calculations Enrollment & baseline characteristics Safety End points (Other): o Intracranial hemorrhage o Fatal bleeding o Adverse Events o A 90% power to detect a 20% reduction in relative risk with the 90 mg dose of Ticagrelor o 83% power was needed to detect a19% reduction in relative risk in the 60 mg dose o Primary efficacy analysis was done on an intent-to-treat basis o Safety analysis included all patients randomized and received at least one dose o A P value of P = 0.05 is considered statistically significant. o Kaplan-Meier estimates were used to express event probabilities at a cumulative incidences of 36 months o Cox proportional-hazards model was used to generate hazard ratios and 95% CI RESULTS o o o o o o o o o o o o 21,162 patients were initially randomized to the study Randomization took place between October 2010 through May 2013 20,942 patients received at least one dose of study drug or placebo Median age was 70 years old Median time from qualifying MI was 1.7 years 53% of qualifying events were STEMI 40% of qualifying events were NSTEMI 83% of patients had history of PCI 59.4% of patients had multi-vessel coronary artery disease 32% of patients are diabetic mellitus 16% of patients had >1 myocardial infarction 23.2% of patients had a GFR < 60 mL/min o Median duration of follow-up was 33 months o Medication at enrollment: 99.8% Aspirin 92.6% Statin 82.6% Beta-blocker 80.4% ACE inhibitor (or ARB) Summary of primary and secondary outcomes Ticagrelor, 90 mg (N=7050) Outcomes CV death, MI, Stroke Death CHD, MI, Stroke CV death or MI Death CHD or MI CV death Death from CHD MI Brief summary of authors’ main discussion points Author’s conclusions 493 (7.85) Ticagrelor Placebo 60 mg (N=7067) (N=7045) number (percent) 487 (7.77) 578 (9.04) NNT =84 438 (6.99) NNT = 78 445 (7.09) 535 (8.33) 424 (6.79) 422 (6.77) 497 (7.81) 350 (5.59) 360 (5.75) 429 (6.68) 182 (2.94) 174 (2.86) 210 (3.39) 97 (1.53) 106 (1.72) 132 (2.08) 275 (4.40) 285 (4.53) 338 (5.25) Ticagrelor, 90 mg vs Placebo 95% ci HR = 0.85 P= 0.008 Ticagrelor, 60 mg vs Plavebo HR= 0.82 P= 0.002 HR= 0.85 P= 0.01 HR= 0.81 P= 0.004 HR= 0.87 P= 0.15 HR= 0.73 P= 0.02 HR= 0.81 P= 0.01 HR= 1.00 P= 0.99 HR= 0.83 P= 0.003 HR= 0.85 P= 0.01 HR= 0.84 P= 0.01 HR= 0.83 P= 0.07 HR= 0.80 P= 0.09 HR= 0.84 P= 0.03 HR= P= 0.14 HR= 0.84 P= 0.004 Death from 326 (5.15) 289 (4.69) 326 (5.16) any cause Safety End Points TIMI major 127 (2.60) 115 (2.30) 54 (1.06) HR= 2.69 HR= 2.32 P <0.001 P <0.001 Bleeding NNH = 65 NNH = 81 TIMI minor 66 (1.31) 55 (1.80) 18 (0.36) HR= 4.15 HR= 3.31 P <0.001 P <0.001 Bleeding Bleeding 122 (2.43) 105 (2.09) 37 (0.72) HR= 3.75 HR= 3.08 P <0.001 P <0.001 Transfusion Bleeding 453 (7.81) 354 (6.15) 86 (1.50) HR= 5.79 HR= 4.40 P <0.001 P <0.001 D/C Fatal/ 32 (0.63) 33 (0.71) 30 (0.60) HR= 1.22 HR= 1.20 Nonfatal P= 0.43 P= 0.47 ICH Adverse Events Dyspnea 1205 987 (15.84) 383 (6.38) HR= 3.55 HR= 2.81 P <0.001 P <0.001 (18.93) Dyspnea 430 (6.50) 297 (4.55) 51 (0.79) HR= 8.89 HR= 6.06 P <0.001 P <0.001 D/C AUTHORS’ DISCUSSION & CONCLUSIONS Ticagrelor plus low-dose aspirin showed significance in both dosing regimens in reducing the risk of CV death, MI, or stroke, while increasing TIMI major bleeding, TIMI minor bleeding, bleeding requiring transfusion, d/c of therapy due to bleeding. There was no significance observed in fatal bleeding or nonfatal Intracranial hemorrhage between study drugs and control. In addition, both doses of Ticagrelor lead to increased dyspnea. In the DAPT trial, which compared either Clopidogrel or Prasugrel for long-term use greater than a year, up to 30 months, also showed a significant reduction in stent thrombosis and adverse CV and cerebrovascular events in patients who received a stent post-MI. Although these two study’s differed in the populations studied, they showed that there is a benefit in using a P2Y12 receptor antagonist for greater than one year. The addition of Ticagrelor to low-dose aspirin, for dual antiplatelet therapy should be considered in patients whom have previously experienced a MI greater than a year. The 60 mg dose may be more favorable of a choice since it had lower rates of bleeding and Study strengths Study limitations Applicability to patient care and impact on pharmacists and/or healthcare providers dyspnea which lead to a lower rate of d/c of drug. STUDENT’S DISCUSSION & CONCLUSIONS Strengths: 1. Studied in a large population 2. The population was diverse, including people from 31 countries 3. Baseline characteristics were similar among all three groups 4. Showed a comparison between two different doses vs placebo 5. Enrolled patients that are at a higher bleeding risk compared to DAPT trial, therefore broadening the population that may benefit from this data Limitations: 1. Excluded patients with a need for an oral ATc 2. Enrollment was preceded with a break in treatment prior to initiation of therapy, with a mean start time of 1.7 years from MI. a. This break in treatment excluded a period of time which could have been more beneficial to patients 3. The trial did not report statistical difference between the two dose forms 4. Manufacture funded Based on the results of this study (PEGASUS-TIMI54) and similar study’s (DAPT), P2Y12 receptor antagonists definitely have a place in therapy for long-term usage post-MI. They may not be beneficial in patients who did not tolerate the drug well during the initial 12 months of treatment, but could be recommended in patients who tolerated the drug well and experienced no bleeding events. TIMI Bleeding Classification Major: 1) Any intracranial* bleeding, OR 2) Clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥5 g/dL (or, when hemoglobin is not available, a fall in hematocrit of ≥15%), OR 3) Fatal bleeding (a bleeding event that directly led to death within 7 days) Minor: Any clinically overt sign of hemorrhage (including imaging) that is associated with a fall in Hgb of 3 to < 5 g/dL (or, when hemoglobin is not available, a fall in hematocrit of 9 to < 15%)