Regional variation in patients and outcomes in the GLOBAL LEADERS trial
Section snippets
Background
In order to expedite recruitment and reduce costs, large randomized controlled trials (RCT) are often designed to recruit participants from many different countries [1,2]. Such global recruitment also enhances the generalizability of a trial's findings to a broader international population. However, despite uniform enrollment criteria, variations are expected in trials in terms of patient population, background demographics and treatment preferences [3]. Consequently, minor and occasionally
Study design
The GLOBAL LEADERS trial [1] is a prospective, multi-center, randomized controlled trial (NCT01813435), which enrolled a total of 15,991 patients at 130 hospitals in 18 countries (Europe, Asia, Australasia, North America and South America) between July 2013 and November 2015, and aimed to evaluate two antiplatelet strategies after PCI using bivalirudin and biolimus A9-eluting stents (Biomatrix) in an all-comers population. Details of the study have been previously described [7]. In brief, the
Baseline characteristics
Of the 15,991 patients enrolled in the GLOBAL LEADERS trial, 23 patients subsequently withdrew consent and requested the deletion of their data from the database. Thus, there are 15,968 patients remained in the present analyses.
Baseline characteristics are presented in Table 1 (table with complete variables is shown in Supplemental Table 1). The risk profile of patients varied significantly among countries. Patients from Bulgaria had higher percentages of patients with hypertension,
Discussion
The main findings can be summarized as follows:
1) Substantial between-country disparities in patient's comorbidities, the rates of complex PCI, adherence to prescribed anti-platelet therapy, recruitment, and event rates were identified in the GLOBAL-LEADERS trial.
2) Geographic heterogeneity in the primary outcome was also observed. This result questioned the internal validity of the GLOBAL-LEADERS trial.
3) Effect modifier analysis indicated that patient selection -variances in the rates of
Limitations
1) The effect of treatment assignment across 3 global regions was a prespecified analysis for GLOBAL-LEADERS trial, which led to a more refined, but post hoc analysis per countries. The exploration of clinical patterns by countries provides a better insight into the trial results in investigating possible geographical heterogeneity [3].
2) Despite the large sample size in the GLOBAL-LEADERS trial, the current analyses were not adequately powered to produce reliable evidence for geographic
Conclusion
Significant differences in the patients' clinical profiles, recruitment, adherence, and event rates were observed between participating countries in the GLOBAL-LEADERS trial. There is a significant regional variance in the treatment effect of ticagrelor monotherapy, which could be in part explained by the disparities in the proportion of patients with complex PCI procedures among countries.
Disclosure
Dr. Steg received grants and personal fees from Bayer/Janssen, grants and personal fees from Merck, grants and personal fees from Sanofi, grants and personal fees from Amarin, personal fees from Amgen, personal fees from Bristol Myers Squibb, personal fees from Boehringer-Ingelheim, personal fees from Pfizer, personal fees from Novartis, personal fees from Regeneron, personal fees from Lilly, personal fees from AstraZeneca, grants, personal fees and non-financial support from Servier, outside
Funding
This work was supported by the European Clinical Research Institute, which received unrestricted grants from Biosensors International, AstraZeneca, and the Medicines Company.
Author statement
Please find below the description of each author's contribution to the submitted manuscript.
Chao Gao gathered and analyzed the data, drafted the manuscript.
Kuniaki Takahashi, Hironori Hara, Masafumi Ono, Hideyuki Kawashima, and Rutao Wang, gathered, cleaned data and contributed to the interpretation of the data.
Scot Garg, Gilles Montalescot, Michael Haude, Ton Slagboom, Christian Hamm, Philippe Gabriel Steg, and Robert-Jan van Geuns gathered and interpreted data, and helped in revising the
Declaration of Competing Interest
None.
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