title: Long-term Tolerability of Ticagrelor for the Secondary Prevention of Major Adverse Cardiovascular Events: A Secondary Analysis of the PEGASUS-TIMI 54 Trial.
abstract: In the PEGASUS-TIMI 54 trial, treatment with ticagrelor reduced the incidence of cardiovascular death, myocardial infarction, or stroke by 15% to 16% among stable patients compared with placebo. However, more patients prematurely discontinued treatment with ticagrelor than with placebo.
  
  
  
  To investigate the reasons and timing of discontinuation of treatment with ticagrelor among stable patients prior myocardial infarction.
  
  
  
  In the PEGASUS-TIMI 54 trial, 21 162 stable outpatients with prior myocardial infarction were randomly assigned to 90 mg of ticagrelor twice daily, 60 mg of ticagrelor twice daily, or placebo, with all of the patients receiving a low dose of aspirin. These participants were followed up for a median of 33 months (study start date: October 2010; completion date: December 2014). Discontinuation of treatment was evaluated by treatment arm, cause, and timing. This analysis was initiated in May 2015.
  
  
  
  Discontinuation of treatment.
  
  
  
  Over 33 months, 32%, 29%, and 21% of patients receiving 90 mg of ticagrelor, 60 mg of ticagrelor, and placebo, respectively, discontinued treatment (P < .001). Discontinuation of treatment due to an adverse event occurred in 19%, 16%, and 9% of patients, respectively (P < .001). The most frequent adverse events leading to discontinuation of treatment were bleeding (with Kaplan-Meier event rates of 7.8%, 6.2%, and 1.5% of patients, respectively; P < .001) and dyspnea (6.5%, 4.6%, and 0.8% of patients, respectively; P < .001). Eighty-six percent of bleeding events that led to the discontinuation of treatment with ticagrelor were nonmajor, and 86% of adverse events due to dyspnea that led to discontinuation of treatment with ticagrelor were mild or moderate in severity. The discontinuation rates are annualized for patients who received 90 mg of ticagrelor twice daily (hazard ratio [HR], 2.00 [95% CI, 1.84-2.16] for the first year; HR, 1.12 [95% CI, 1.00-1.26] for the second and third years) and patients who received 60 mg of ticagrelor twice daily (HR, 1.59 [95% CI, 1.46-1.73] for the first year; HR, 1.18 [95% CI, 1.06-1.32] for the second and third years) compared with patients who received placebo.
  
  
  
  When initiated among stable patients with prior myocardial infarction, discontinuation of treatment with ticagrelor was driven primarily by nonserious adverse events occurring primarily early after randomization. For patients completing 1 year of treatment, the subsequent discontinuation rate was low. These data demonstrate how adverse events considered "nonserious" by traditional trial criteria may have an effect on quality of life and, thus, may precipitate the discontinuation of treatments and underscore the need for patient education and counseling on the timing and nature of adverse effects with the aim of improving adherence when appropriate.
  
  
  
  clinicaltrials.gov Identifier: NCT01225562.
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: Department of Cardiology, CWZ Hospital, Nijmegen, the Netherlands.
authors.forename: Ton
authors.initials: T
authors.lastname: Oude Ophuis
authors.affiliation: Département Hospitalo Universitaire FIRE, AP-HP, Hôpital Bichat, Paris, France4Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: P Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, England.
authors.forename: Robert
authors.initials: R
authors.lastname: Storey
authors.affiliation: Cardiovascular Division, Newark Beth Israel Medical Center, Rutgers-New Jersey Medical School, Newark, New Jersey.
authors.forename: Marc
authors.initials: M
authors.lastname: Cohen
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts.
authors.forename: Julia
authors.initials: J
authors.lastname: Kuder
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts.
authors.forename: Kyungah
authors.initials: K
authors.lastname: Im
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts.
authors.forename: Giulia
authors.initials: G
authors.lastname: Magnani
authors.affiliation: Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Budaj
authors.affiliation: Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Theroux
authors.affiliation: Department of Cardiology, Kerckhoff Heart Center, Bad Nauheim, Germany10University of Giessen, Giessen, Hesse, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hamm
authors.affiliation: Internal Cardiology Department, University Hospital and Medical Faculty, Brno, Czech Republic.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Špinar
authors.affiliation: Department of Cardiology, Military Hospital, Budapest, Hungary.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kiss
authors.affiliation: South African Cardiology Clinical Trials Group, Milpark Hospital, Johannesburg, South Africa.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Dalby
authors.affiliation: Departamento de Clínicas Médicas, Hospital Nacional Cayetano Heredia, San Martin de Porres, Lima, Peru.
authors.forename: Felix A
authors.initials: FA
authors.lastname: Medina
authors.affiliation: Department of Cardiology, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Frederic
authors.initials: F
authors.lastname: Kontny
authors.affiliation: South Australian Health and Medical Research Institute, Flinders University, Adelaide, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.affiliation: AstraZeneca Research and Development, Mölndal, Sweden.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Jensen
authors.affiliation: AstraZeneca Research and Development, Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Held
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital Heart and Vascular Center, Boston, Massachusetts18Deputy Editor, JAMA Cardiology.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
mesh_terms: D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004417:Dyspnea / Q000139:chemically induced; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D009203:Myocardial Infarction / Q000517:prevention & control*; D058921:Purinergic P2Y Receptor Antagonists; D011788:Quality of Life; D055502:Secondary Prevention; D020521:Stroke / Q000517:prevention & control*; D000077486:Ticagrelor
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor; D000241:Adenosine