Long-term Tolerability of Ticagrelor for the Secondary Prevention of Major Adverse Cardiovascular Events: A Secondary Analysis of the PEGASUS-TIMI 54 Trial | Acute Coronary Syndromes | JAMA Network
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Original Investigation
July 2016

Long-term Tolerability of Ticagrelor for the Secondary Prevention of Major Adverse Cardiovascular Events: A Secondary Analysis of the PEGASUS-TIMI 54 Trial

Author Affiliations
  • 1TIMI Study Group, Brigham and Women’s Hospital Heart and Vascular Center, Boston, Massachusetts
  • 2Department of Cardiology, CWZ Hospital, Nijmegen, the Netherlands
  • 3Département Hospitalo Universitaire FIRE, AP-HP, Hôpital Bichat, Paris, France
  • 4Université Paris–Diderot, Sorbonne Paris Cité, Paris, France
  • 5Department of Cardiovascular Science, University of Sheffield, Sheffield, England
  • 6Cardiovascular Division, Newark Beth Israel Medical Center, Rutgers–New Jersey Medical School, Newark, New Jersey
  • 7Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland
  • 8Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
  • 9Department of Cardiology, Kerckhoff Heart Center, Bad Nauheim, Germany
  • 10University of Giessen, Giessen, Hesse, Germany
  • 11Internal Cardiology Department, University Hospital and Medical Faculty, Brno, Czech Republic
  • 12Department of Cardiology, Military Hospital, Budapest, Hungary
  • 13South African Cardiology Clinical Trials Group, Milpark Hospital, Johannesburg, South Africa
  • 14Departamento de Clínicas Médicas, Hospital Nacional Cayetano Heredia, San Martin de Porres, Lima, Peru
  • 15Department of Cardiology, Stavanger University Hospital, Stavanger, Norway
  • 16South Australian Health and Medical Research Institute, Flinders University, Adelaide, Australia
  • 17AstraZeneca Research and Development, Mölndal, Sweden
  • 18Deputy Editor, JAMA Cardiology
JAMA Cardiol. 2016;1(4):425-432. doi:10.1001/jamacardio.2016.1017
Abstract

Importance  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.

Objective  To investigate the reasons and timing of discontinuation of treatment with ticagrelor among stable patients prior myocardial infarction.

Design, Setting, and Participants  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.

Main Outcome and Measure  Discontinuation of treatment.

Results  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.

Conclusions and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01225562

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