Elsevier

International Journal of Cardiology

Volume 324, 1 February 2021, Pages 30-37
International Journal of Cardiology

Regional variation in patients and outcomes in the GLOBAL LEADERS trial

https://doi.org/10.1016/j.ijcard.2020.09.039Get rights and content

Highlights

  • A geographic heterogeneity in the primary outcome of the GLOBAL-LEADERS trial was observed.

  • Variances in the complexity of PCI between countries might be the leading cause of the geographic heterogeneity.

  • Stratifying enrollment per country will strengthen the internal validity of the trial results.

Abstract

Background

Despite the overall neutral results of the GLOBAL-LEADERS trial, results from a prespecified subgroup analysis showed that patients from Western Europe had a significantly lower rate of the primary endpoint when treated with ticagrelor monotherapy. Therefore, we aimed to examine the regional disparities in patients' baseline characteristics and their response to ticagrelor monotherapy.

Methods

Patients' baseline characteristics and the treatment effects of ticagrelor combined with aspirin for 1 month, followed by ticagrelor monotherapy for 23-months versus 12-months of standard dual antiplatelet therapy (DAPT) were compared according to participating countries. The primary endpoint was a composite endpoint of all-cause death or new Q-wave myocardial infarction at two years.

Results

Significant variances in patients' baseline characteristics were found between participating countries. The primary endpoint varied significantly according to the country (Pinteraction = 0.027). Patients from France (1.6% versus 5.2%, HR: 0.31, 95%CI: 0.13–0.73) and The Netherlands (2.4% versus 4.8%, HR, 0.50, 95%CI: 0.26–0.94) had lower rates of the primary endpoint when allocated to ticagrelor monotherapy, compared with the standard DAPT regimen. Of the 26 baseline and post-randomization factors explored, variance in the rate of complex PCI between countries was identified as the top contributor to this regional interaction.

Conclusions

Patients' baseline characteristics varied between participating countries in the GLOBAL-LEADERS trial. There is a significant regional variance in the treatment effect of ticagrelor monotherapy, which could partly be explained by the differences in complex PCI being performed.

Clinical Trial Registration: ClinicalTrials.gov (NCT01813435).

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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