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Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial
Abstract
Background—: In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region ( P =0.045), with less effect of ticagrelor in North America than in the rest of the world. Methods and Results—: Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose ≥300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. Conclusions—: The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin. Clinical Trial Registration—: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00391872.
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“International trials of various pharmacotherapies have sometimes found discordant results in patients enrolled in the United States than seen in overall trial results.19–32”
From REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States (2020) · cites this paper as [20]
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“The reasons range from low numbers of patients enrolled in the United States to potential differences in background medical management or in patient risk profiles.”
From REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States (2020) · cites this paper as [20]
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Ticagrelor versus clopidogrel in patients with acute coronary syndromes
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- Wallentin L Becker RC Budaj A Cannon CP Emanuelsson H Held C Horrow J Husted S James S Katus H Mahaffey KW Scirica BM Skene A Steg PG Storey RF Harrington RA; PLATO Investigators Freij A Thorsén M . Ticagrelor versus clopidogrel in patients with acute coronary syndromes [supplement]. N Engl J Med. 2009;361:1045–1057 e1–e34. http://www.nejm.org/doi/suppl/10.1056/NEJMoa0904327/suppl_file/nejm_wallentin_1045sa1.pdf. Accessed June 10 2011. · DOI · Paper page
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Metadata
- Authors
- Mahaffey, K. W., Wojdyla, D. M., Carroll, K., Becker, R. C., Storey, R. F., Angiolillo, D. J., Held, C., Cannon, C. P., James, S., Pieper, K. S., Horrow, J., Harrington, R. A., & Wallentin, L.
- Affiliations
- Uppsala University (SE)
- ORCID
- Venue
- Circulation
- Published
- 2011-08-02
- Volume
- 124
- Issue
- 5
- Pages
- 544-554
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2085260510
- Cited by
- 434
- References
- 20
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 10 · 2023: 13 · 2022: 19 · 2021: 19 · 2020: 16 · 2019: 29 · 2018: 20 · 2017: 32 · 2016: 37 · 2015: 38 · 2014: 52 · 2013: 55 · 2012: 68
- FWCI
- 40.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Duke Clinical Research Institute
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Coronary Interventions and Diagnostics
- Keywords
- ticagrelor, clopidogrel, PLATO trial, regional interaction, platelet aggregation inhibition, antiplatelet therapy, cardiovascular mortality, myocardial infarction, stroke, subgroup analysis
- MeSH terms
- Clopidogrel, Ticagrelor, Adenosine, Aged, Aspirin, Combined Modality Therapy, Female, Humans, Male, Middle Aged, Myocardial Infarction, Platelet Aggregation Inhibitors, Risk Factors, Ticlopidine, United States, Global Health, Proportional Hazards Models, Stroke, Purinergic P2Y Receptor Antagonists
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