The Influence of Smoking Status on the Pharmacokinetics and Pharmacodynamics of Clopidogrel and Prasugrel

Gurbel, Paul A.; Bliden, Kevin P.; Logan, Douglas; Kereiakes, Dean J.; Lasseter, Kenneth C.; White, Alex E.; Angiolillo, Dominick J.; Nolin, Thomas D.; Maa, Jen-Fue; Bailey, William L.; Jakubowski, Joseph A.; Ojeh, Clement K.; Jeong, Young Hoon; Tantry, Udaya S.; Baker, Brian

doi:10.1016/j.jacc.2013.03.037

Cited by 134 publications

(84 citation statements)

References 18 publications

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“…However, the mechanism remains unknown. [34][35][36] The effect of smoking on cytochrome P450 (CYP)1A2, which converts clopidogrel into its active metabolite, was provided as a rationale, 37 but this does not explain a similar smoker's paradox observed with prasugrel and ticagrelor, which have different mechanisms of action. 38 On the basis of our findings, we suggest that the beneficial effect is specifically due to the inhibition of ADP via the P2Y 12 receptor expressed on platelets because circulating ADP levels are elevated in smokers.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Jalkanen

Yegutkin

Hollmén

et al. 2015

Circulation Research

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Rationale: Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans. Objective: The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease. Methods and Results: Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5′-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease ( P <0.0001). Low CD39 activity was associated with disease progression ( P =0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia ( P =0.001). Statin use was associated with lower ADP ( P =0.041) and tended to associate with higher CD73 ( P =0.054), while lower ATP was associated with the use of angiotensin receptor blockers ( P =0.015). Conclusions: Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y 12 receptor antagonists more than their nonsmoking peers.

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Section: Discussionmentioning

confidence: 99%

Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Jalkanen

Yegutkin

Hollmén

et al. 2015

Circulation Research

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“…These paradoxically lower mortality rates were largely attributed to a cumulative effect of younger age, fewer comorbidities, lesser extent of CAD, and more aggressive treatment of acute MI in smokers. Alternatively, pathophysiological differences between smokers and nonsmokers with acute MI have also been postulated as a basis for this paradox, including a greater thrombus burden in smokers, leading to greater efficacy of thrombolytic therapy,14, 15, 16 and greater responsiveness to antiplatelet therapies 17, 18, 19, 20. Whether a true biochemical basis exists for the smoker's paradox remains inconclusive.…”

Section: Introductionmentioning

confidence: 99%

Smoker's Paradox in Patients With ST‐Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Gupta

Kolte

Khera

et al. 2016

JAHA

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BackgroundPrior studies have found that smokers undergoing thrombolytic therapy for ST‐segment elevation myocardial infarction have lower in‐hospital mortality than nonsmokers, a phenomenon called the “smoker's paradox.” Evidence, however, has been conflicting regarding whether this paradoxical association persists in the era of primary percutaneous coronary intervention.Methods and ResultsWe used the 2003–2012 National Inpatient Sample databases to identify all patients aged ≥18 years who underwent primary percutaneous coronary intervention for ST‐segment elevation myocardial infarction. Multivariable logistic regression was used to compare in‐hospital mortality between smokers (current and former) and nonsmokers. Of the 985 174 patients with ST‐segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, 438 954 (44.6%) were smokers. Smokers were younger, were more often men, and were less likely to have traditional vascular risk factors than nonsmokers. Smokers had lower observed in‐hospital mortality compared with nonsmokers (2.0% versus 5.9%; unadjusted odds ratio 0.32, 95% CI 0.31–0.33, P<0.001). Although the association between smoking and lower in‐hospital mortality was partly attenuated after baseline risk adjustment, a significant residual association remained (adjusted odds ratio 0.60, 95% CI 0.58–0.62, P<0.001). This association largely persisted in age‐stratified analyses. Smoking status was also associated with shorter average length of stay (3.5 versus 4.5 days, P<0.001) and lower incidence of postprocedure hemorrhage (4.2% versus 6.1%; adjusted odds ratio 0.81, 95% CI 0.80–0.83, P<0.001) and in‐hospital cardiac arrest (1.3% versus 2.1%; adjusted OR 0.78, 95% CI 0.76–0.81, P<0.001).ConclusionsIn this nationwide cohort of patients undergoing primary percutaneous coronary intervention for ST‐segment elevation myocardial infarction, we observed significantly lower risk‐adjusted in‐hospital mortality in smokers, suggesting that the smoker's paradox also applies to ST‐segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.

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“…The effect of clopidogrel response should preferably be in a more homogeneous subgroup because the influence of age, gender, and smoking status on CYP enzyme activity cannot be neglected. [46][47][48] The study by Collet et al had the highest effect size of all studies (5.4; 95% confidence interval: 2.3-12.5), and its exclusion from meta-analyses would have been justified based on its incomparable study characteristics. 49 Also from a clinical perspective, exclusion of the study by Collet et al is warranted: a decision about genotyping 60-to 70-yearold individuals should not be affected by a threefold higher effect size in young adults.…”

Section: • Egger Testmentioning

confidence: 99%

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users

Osnabrugge

Head

Zijlstra

et al. 2015

Genetics in Medicine

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Clopidogrel, in combination with aspirin, is a standard treatment for patients with acute coronary syndrome and is one of the top-selling drugs in the world.1,2 However, there is substantial interindividual variability in response. Polymorphisms of the cytochrome P450 (CYP) gene have been identified as a potential risk factor for nonresponse.3 This gene plays a central role in drug-metabolizing processes in the liver, and clopidogrel makes use of these processes to transform into an active metabolite capable of inhibiting platelet aggregation. Identification of CYP2C19 polymorphisms could lead to personalized treatment based on genotype in patients with acute coronary syndrome, and therefore, the US Food and Drug Administration recommends CYP2C19 genotyping for individualized antiplatelet management. 4 The association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel has been studied extensively, and several meta-analyses have summarized the results of those studies.5-8 Systematic reviews and meta-analyses are often considered the highest level of evidence, 9-11 and their popularity in the cardiovascular field increased almost 13 times as fast as the increase in number of published randomized clinical trials. 12However, the interpretation of meta-analyses is confusing when the conclusions of overlapping meta-analyses are discordant. Some meta-analyses on CYP2C19 loss-of-function and clinical efficacy of clopidogrel conclude that the association is proven, 7,8 whereas others conclude the opposite. 5,6 Our objective was to systematically evaluate the discordant evidence for the association between CYP2C19 loss-offunction alleles and clinical efficacy of clopidogrel through a critical methodological appraisal of published meta-analyses. MATERIALS AND METHODSOur review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement, 13 and we consulted the Cochrane Handbook for Systematic Reviews of Interventions for methodological aspects of meta-analyses. We systematically investigated how 11 overlapping meta-analyses on the association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel could yield contradictory outcomes. The results of the meta-analyses differed because more recent metaanalyses included more primary studies and some had not included conference abstracts. Conclusions differed because between-study heterogeneity and publication bias were handled differently across meta-analyses. All meta-analyses on the clinical end point observed significant heterogeneity and several reported evidence for publication bias, but only one out of eight statistically significant meta-analyses concluded that therefore the association was unproven and one other refrained from quantifying a pooled estimate because of heterogeneity. For the end point stent thrombosis, all meta-analyses reported statistically significant associations with CYP2C19 loss-of-function alleles with no statistically significant evidence for heterogeneity, b...

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The Influence of Smoking Status on the Pharmacokinetics and Pharmacodynamics of Clopidogrel and Prasugrel

Cited by 134 publications

References 18 publications

Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Smoker's Paradox in Patients With ST‐Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users

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