title: The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial: results of the continuous electrocardiographic assessment substudy.
abstract: OBJECTIVE
  The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes.
  
  
  BACKGROUND
  Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes.
  
  
  METHODS
  Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days).
  
  
  RESULTS
  A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses ≥3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest.
  
  
  CONCLUSIONS
  In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).
authors.affiliation: TIMI Study Group, Brigham and Women's Hospital, Cardiovascular Division, 350 Longwood Avenue, Boston, MA 02215, USA. bscirica@partners.org
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.forename: Håkan
authors.initials: H
authors.lastname: Emanuelsson
authors.forename: Eric L
authors.initials: EL
authors.lastname: Michelson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.forename: Steen
authors.initials: S
authors.lastname: Husted
authors.forename: Stefan
authors.initials: S
authors.lastname: James
authors.forename: Hugo
authors.initials: H
authors.lastname: Katus
authors.forename: Prem
authors.initials: P
authors.lastname: Pais
authors.forename: Dimitar
authors.initials: D
authors.lastname: Raev
authors.forename: Jindrich
authors.initials: J
authors.lastname: Spinar
authors.forename: Ph Gabriel
authors.initials: PG
authors.lastname: Steg
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000368:Aged; D001919:Bradycardia / Q000139:chemically induced / Q000453:epidemiology*; D000077144:Clopidogrel; D004562:Electrocardiography / Q000379:methods*; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects*; D000077486:Ticagrelor; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine