PLATO Substudy: ‘Smoker’s Paradox’ Shows No Effect on Ticagrelor

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In patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), habitual cigarette smoking is associated with a greater risk of subsequent stent thrombosis, according to a substudy of the PLATO trial published online July 30, 2012, ahead of print in the American Heart Journal. However, regardless of smoking status, the reduction in vascular death, myocardial infarction (MI), stroke, and stent thrombosis is consistent with both ticagrelor and clopidogrel.

The multicenter PLATO trial, published in the New England Journal of Medicine in 2009, randomized 18,624 ACS patients to ticagrelor (180-mg loading dose then 90 mg twice daily) or clopidogrel (300- to 600-mg loading dose then 75 mg once daily). All patients also received aspirin. At 12-month follow-up, the primary efficacy endpoint (composite of cardiovascular death, MI, or stroke) was reduced with ticagrelor (9.8% vs. 11.7% with clopidogrel; P < 0.001).

For the subgroup analysis, Jan H. Cornel, MD, PhD, of Medisch Centrum Alkmaar (Alkmaar, The Netherlands), and colleagues analyzed the 18,610 patients with known smoking status (habitual smokers n = 6,678; ex- or nonsmokers n = 11,932).

Higher Definite Stent Thrombosis Rate for Smokers

While smokers had a lower incidence of most endpoints at 12-month follow up, they had a higher incidence of definite stent thrombosis and any stent thrombosis compared with ex- or nonsmokers. After adjustment for baseline characteristics, smoking was associated with a 44% higher incidence of definite stent thrombosis at 12 months and a 31% higher incidence within the first 10 days after PCI. However, smoking was not significantly associated with any other ischemic or bleeding endpoints (table 1).

Table 1. Twelve-Month Outcomes for Smokers


Adjusted HR (95% CI)

P Value

Cardiovascular Death, MI, or Stroke (primary efficacy endpoint)

1.08 (0.95-1.22)


All-Cause Death

1.08 (0.90-1.30)


Cardiovascular Death

1.01 (0.83-1.23)


Major Bleeding

0.96 (0.85-1.08)


Definite Stent Thrombosisa

1.44 (1.07-1.94)


Definite Stent Thrombosisa (First 10 Days)

1.31 (0.89-1.92)


a Of the 11,283 patient who received stents, 41.6% (n = 4,691) were smokers.

The effects of ticagrelor compared with clopidogrel were consistent for all outcomes regardless of smoking status (table 2).

Table 2. Treatment Group Outcomes




Adjusted HR

P for Interaction

Vascular Death, MI, or Stroke



0.83 (0.68-1.00)
0.89 (0.79-1.00)


Definite Stent Thrombosis



0.59 (0.39-0.91)
0.69 (0.45-1.07)


Major Bleeding



1.18 (0.98-1.43)
1.04 (0.92-1.18)




Smokers were more often younger, male, and presented with STEMI. They also were less likely to have hypertension, diabetes, chronic kidney disease, or a history of cardiovascular disease. Most were already on cardiovascular medication, although less frequently than in the ex- and nonsmoker group.


Ticagrelor Wins Overall


While several studies have suggested that smoking is associated with increased platelet reactivity and greater therapeutic response to antiplatelet interventions, differences in baseline risk between smokers and nonsmokers “likely account for the significantly lower event rate of the primary composite efficacy endpoint, previously described as the ‘smokers paradox,’” the authors write. “After correction for the differences in baseline characteristics, the risk for recurrence of cardiovascular events did not differ significantly between habitual and ex/nonsmokers, except for definite stent thrombosis, which was more common in smokers.”


They suggest that “genetic, metabolic, cellular, and clinical factors” are likely the cause of “a highly variable inter-patient response to clopidogrel. Furthermore, the subgroup analysis “supports the concept that a more potent and consistent antiplatelet therapy [ticagrelor] may have the same benefit both in smokers and ex/nonsmokers equally without any interaction between smoking status and treatment effects,” the study authors write.


Because no interaction was observed between smoking status and ticagrelor effectiveness compared with clopidogrel, Dr. Cornel and colleagues argue that “these results do not support that smoking might increase the efficacy of clopidogrel.”


Ultimately, the “hypothetical improvement in clopidogrel metabolism due to smoking does not translate into reduced benefit of ticagrelor over clopidogrel among smokers,” they conclude. “Therefore a potential enhanced efficacy of clopidogrel in smokers appears to be a less favorable management approach when compared with the superior effects of ticagrelor both in smokers and nonsmokers.”




Cornel JH, Becker RC, Goodman SG et al. Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes: Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2012:Epub ahead of print.



·         The PLATO study was funded by AstraZeneca, which also provided funds to the Uppsala Clinical Research Center and Duke Clinical Research for the subgroup analysis.

·         Dr. Cornel reports receiving advisory board fees from AstraZeneca and Eli Lilly/Daiichi Sankyo and consulting for Merck.


Related Stories:

·         Signs Point to Relationship Between Clopidogrel Efficacy, Cigarette Smoking

·         Better Clopidogrel Response Seen with Increased Smoking Levels

·         Ticagrelor Shows More Rapid, Powerful Platelet Inhibition Than Clopidogrel



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