title: Missed bleeding events after ticagrelor in PEGASUS trial: Massive non-compliance, information censoring, or both?
abstract: PEGASUS trial reported reduction of composite primary endpoint after conventional 180mg/daily ticagrelor (CT), and lower 120mg/daily dose ticagrelor (LT) at expense of extra bleeding. Following approval of CT and LT for long-term secondary prevention indication, recent FDA review verified some bleeding outcomes in PEGASUS. To compare the risks after CT and LT against placebo by seven TIMI scale variables, and 9 bleeding categories considered as serious adverse events (SAE) in light of PEGASUS drug discontinuation rates (DDR). The DDR in all PEGASUS arms was high reaching astronomical 32% for CT. The distribution of some outcomes (TIMI major, trauma, epistaxis, iron deficiency, hemoptysis, and anemia) was reasonable. However, the TIMI minor events were heavily underreported when compared to similar trials. Other bleedings (intracranial, spontaneous, hematuria, and gastrointestinal) appear sporadic, lacking expected dose-dependent impact of CT and LT. Few SAE outcomes (fatal, ecchymosis, hematoma, bruises, bleeding) paradoxically reported more bleeding after LT than after CT. Many bleeding outcomes were probably missed in PEGASUS potentially due to massive non-compliance, information censoring, or both. The FDA must improve reporting of trial outcomes especially in the sponsor-controlled environment when DDR and incomplete follow-up rates are high.
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA. Electronic address: vserebr1@jhmi.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Serebruany
authors.affiliation: Charles University, Prague, Czech Republic; Motol University Hospital, Prague, Czech Republic.
authors.forename: Ales
authors.initials: A
authors.lastname: Tomek
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000068597:Censorship, Research; D004334:Drug Administration Schedule; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D000077486:Ticagrelor
chemical_list: D000077486:Ticagrelor; D000241:Adenosine
keywords: Adverse events; Aspirin; Bleeding; Clinical trial; Non-compliance; Ticagrelor; Trial conduct