Clinical trial NCT03231059: GLOBAL LEADERS Adjudication Sub-Study
Official title: GLOBAL LEADERS Adjudication Sub-Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Coronary Artery Disease
Platelet-aggregation Inhibitors
Keywords: Coronary artery disease
Percutaneous coronary intervention
Drug-eluting stent
Antiplatelet drugs
Clinical event committee
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: European Cardiovascular Research Center
First posted: 2017-07-27
Enrollment: 7365
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients included in the GLOBAL LEADERS Trial, e.g. "All comers" with coronary artery disease requiring percutaneous coronary intervention (PCI)

Brief summary: The GLOBAL LEADERS Adjudication Sub-StudY, GLASSY, is based on a re-assessment of all the events reported in the dataset of the parent trial (COMPARATIVE EFFECTIVENESS OF 1 MONTH OF TICAGRELOR PLUS ASPIRIN FOLLOWED BY TICAGRELOR MONOTHERAPY VERSUS A CURRENT-DAY INTENSIVE DUAL ANTIPLATELET THERAPY IN ALL-COMERS PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION WITH BIVALIRUDIN AND BIOMATRIX FAMILY DRUG-ELUTING STENT USE) by an independent Clinical Event Committee (CEC), composed of three physicians not involved in the main trial. The substudy include the first 19 top-enrolling sites of the GLOBAL LEADERS to reach the estimated sample size of 7,186 patients for the two co-primary outcomes of death, any non-fatal myocardial infarction, any non-fatal stroke or urgent target vessel revascularization and bleeding events classified as 3 or 5 according to the Bleeding Academic Research Consortium (BARC) criteria. To ensure a comprehensive assessment of clinical events, a triggers logic is adopted to identify other potential events qualifying for study endpoints but not reported as such by local investigators.

Detailed description: The GLOBAL LEADERS trial was designed to determine the benefits and risks of an antithrombotic regimen using ticagrelor 90 mg BID combined with low-dose (75 mg OD) acetylsalicylic acid (ASA) for one month followed by ticagrelor 90 mg BID alone for 23 months, compared to conventional dual antiplatelet therapy (DAPT) in all-comers patients with coronary artery disease undergoing biolimus-eluting stent implantation on bivalirudin. It was intended as a pragmatic clinical trial and, by design, endpoints included in primary and secondary analyses are only investigator-reported (IR) and will not undergo independent adjudication by a CEC. It is well known that in the absence of blinding of randomized treatment (i.e. in an open-label design such as GLOBAL LEADERS) the use of IR outcome may introduce detection and/or reporting bias. There are multiple lines of evidence indicating that central and independent adjudication of events may affect the results of a randomized trial by minimizing variability and heterogeneity inherently present when several different clinicians and data managers apply definitions of endpoints which are complex and sometimes not well known.Moreover, independent adjudication of ischaemic and bleeding endpoints may provide important mechanistic information that may deepen understanding of the primary endpoint result of the study by better characterizing component of such endpoints including, but not limited to, precise cause of death, sub-type of myocardial infarction (MI), and bleeding location. The objectives of this substudy are: to assess the impact of CEC-adjudication process on the results of the study; to quantify the added value of CEC adjudication process for endpoint reporting by evaluating the concordance between IR-reported and CEC-adjudicated events; to gather mechanistic information to aid in the interpretation of the effect of the experimental treatment in the parent trial and to identify specific subgroups of patients that could particularly benefit from the experimental therapy in terms of ischemic and bleeding events.

Eligibility criteria: Inclusion Criteria:

"All comer" patients

1. Age ≥18 years;
2. Presence of one or more coronary artery stenoses of 50% or more in a native coronary artery or in a saphenous venous or arterial bypass conduit suitable for coronary stent implantation. The vessel should have a reference vessel diameter of at least 2.25 mm (no limitation on the number of treated lesions, vessels, or lesion length);
3. Able to provide informed consent and willing to participate in 2 year follow- up period.

Exclusion Criteria:

1. Known intolerance to aspirin, P2Y12 inhibitors, bivalirudin, stainless steel or biolimus;
2. Known intake of a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir), as co-administration may lead to a substantial increase in exposure to ticagrelor;
3. Known moderate to severe hepatic impairment (alanine-aminotransferase ≥ 3 x ULN);
4. Planned surgery, including CABG as a staged procedure (hybrid) within 12 months of the index procedure, unless dual antiplatelet therapy is maintained throughout the peri-surgical period;
5. Need for chronic oral anti-coagulation therapy;
6. Active major bleeding or major surgery within the last 30 days;
7. Known history of intracranial haemorrhagic stroke or intra-cranial aneurysm;
8. Known stroke (any type) within the last 30 days;
9. Known pregnancy at time of randomisation;
10. Female who is breastfeeding at time of randomisation;
11. Currently participating in another trial and not yet at its primary endpoint

Primary outcomes:
measure: Composite of death, stroke, cardiac and bleeding events
timeFrame: 24 months
Secondary outcomes:
measure: Death
timeFrame: 24 months or at earlier time point
measure: Non-fatal MI
timeFrame: 24 months or at earlier time point
measure: Non-fatal stroke
timeFrame: 24 months or at earlier time point
measure: Rates of urgent revascularization of the target vessel (Urgent TVR)
timeFrame: 24 months or at earlier time point
measure: Definite, probable or possible Stent thrombosis
timeFrame: 24 months or at earlier time point
measure: Bleeding events
timeFrame: 24 months or at earlier time point
measure: Differences between the rates of outcomes reported by the investigators and the rates of outcomes as adjudicated by an independent clinical event committee
timeFrame: 24 months or at earlier time point
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Wilhelminenspital 1160
city: Bonheiden
country: Belgium
facility: Research centre Bonheiden 3204
city: Charleroi
country: Belgium
facility: Research centre Charleroi 3202
city: Genk
country: Belgium
facility: Research centre Genk 3205
city: Hasselt
country: Belgium
facility: Research centre Hasselt 3203
city: Sofia
country: Bulgaria
facility: Research centre Sofia, 9901
city: Bad Nauheim
country: Germany
facility: Research centre Bad Nauheim 4902
city: Essen
country: Germany
facility: Research centre Essen 4903
city: Arezzo
country: Italy
facility: Research centre Arezzo 3902
city: Ferrara
country: Italy
facility: Research centre Ferrara 3905
city: Pavia
country: Italy
facility: Research centre Pavia 3903
city: Terni
country: Italy
facility: Research centre Terni 3909
city: Amsterdam
country: Netherlands
facility: Research centre Amsterdam 3104
city: Rotterdam
country: Netherlands
facility: Research centre Rotterdam 3101
city: Chrzanów
country: Poland
facility: Research centre Chrzanow 4802
city: Dąbrowa Górnicza
country: Poland
facility: Research centre Dabrowa Gornicza 4801
city: Kraków
country: Poland
facility: Research centre Krakov 4807
city: Bern
country: Switzerland
facility: Inselspital Bern University Hospital
city: Blackburn
country: United Kingdom
facility: Research centre Blackburn 4404
Study officials:
affiliation: Inselspital Bern University Hospital
name: Stephan Windecker, MD
role: STUDY_CHAIR
affiliation: Inselspital Bern University Hospital
name: Marco Valgimigli, MD
role: PRINCIPAL_INVESTIGATOR
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