i n d i a n h e a r t j o u r n a l 6 7 ( 2 0 1 5 ) 9 3 e9 4
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/ihj
Editorial
Routine genotyping of patients on clopidogrel: Why the resistance? Ganesan Karthikeyan Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don't know. But there are also unknown unknowns. There are things we don't know we don't know. Donald Rumsfeld Clopidogrel is a pro-drug which requires conversion by several hepatic cytochrome P450 (CYP) isoenzymes to its active metabolite, which then irreversibly binds to platelet P2Y12 receptors and inhibits platelet activation. There is considerable variability in the response to clopidogrel in clinical practice.1 Some genetic polymorphisms in the CYP enzymes, particularly CYP2C19, have consistently been shown to be associated with higher residual platelet reactivity and ischemic cardiovascular events while on treatment with clopidogrel.2 As prasugrel and ticagrelol are not metabolized by these enzymes, these polymorphisms have little effect on platelet reactivity and ischemic events with these agents.3,4 Given that the lossof-function CYP2C19*2 allele (the variant most reproducibly associated with a reduced response to clopidogrel) is highly prevalent in the general population,1,5 it is reasonable to ask why genomic testing should not be used routinely to guide the choice of antiplatelet therapy, as Rath and colleagues report in this issue of the Journal. The answer to this question is not as simple as it appears at first glance. There are several issues to consider when evaluating the utility of a diagnostic test. First and foremost is the ability of the test to discriminate reliably between people who have the condition of interest and those who don't. Second, the detected condition should be reasonably common so as to make testing for it worthwhile. Third, a “positive” test should consistently be associated with the relevant clinical outcome. Finally, knowledge of the test result should help in improving clinical outcomes through appropriate treatment. Genotyping for the isoenzymes involved in clopidogrel metabolism easily
satisfies the first two conditions. Current genotyping assays are highly accurate, and they reliably and reproducibly identify variants of interest. Some of the loss-of-function alleles may be present in as many as half those tested, particularly in some ethnic groups. However, although these variants are clearly related to reduced platelet responsiveness to clopidogrel, their relationship to clinical outcomes is less certain. In a meta-analysis exploring this issue, Holmes and colleagues found that the presence of reduced function CYP2C19 alleles did not affect the rate of ischemic clinical events when only the adequately powered studies were considered (i.e., in those reporting 200 clinical events; RR 0.97, 95% CI 0.86e1.09).6 The “irrational exuberance” for clopidogrel pharmacogenomic testing was plausibly driven by publication bias and the related “small-study” effect.7 More importantly, there is no evidence to date that intervention based on knowledge of CYP2C19 status affects outcomes, as none of the studies were large enough to detect differences in clinical events. On the contrary, indirect evidence derived from studies involving targeted treatment of patients with reduced platelet responsiveness (due to any cause), suggests that clinical outcomes may not be affected. Two randomized studies targeting reduced responsiveness to clopidogrel (identified by functional testing and not based on CYP2C19 status) using higher clopidogrel doses,8 or prasugrel and glycoprotein IIb-IIIa antagonists,9 did not show improvement in clinical outcomes. The study by Rath et al does not provide any information either on the functional or clinical outcomes with switching to a different antiplatelet agent.
known and unknown unknowns The lack of effect of reduced function CYP2C19 alleles on clinical outcomes may seem intriguing, but it is important to
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.ihj.2015.04.008 0019-4832/Copyright © 2015, Cardiological Society of India. All rights reserved.
94
i n d i a n h e a r t j o u r n a l 6 7 ( 2 0 1 5 ) 9 3 e9 4
remember that our understanding of the determinants of platelet reactivity and its links to clinical outcomes is far from complete. For example, it is known that clinical and demographic factors such as age, diabetes, body-mass index, leftventricular function, drugedrug interactions and systemic inflammation, may all independently influence on-treatment platelet reactivity through multiple mechanisms.10 It should also be kept in mind that numerous other polymorphisms affecting other isoenzymes (including those that augment clopidogrel metabolism and action) may affect platelet responsiveness.11 Consequently, it is estimated that only about 12% of the variation in platelet responsiveness is explained by CYP2C19 polymorphisms.12 In assessing the value of routine genotyping for patients on clopidogrel in the Indian context, we must also consider the resultant increase in cost of therapy (both from the cost of testing and the cost of adding prasugrel or ticagrelol), its potential adverse impact on compliance and clinical outcomes. The idea of individualized medicine holds immense appeal for doctors, patients and the general public, and optimistically, will become feasible for many conditions in the future. But routine genotyping for patients on clopidogrel cannot be advocated until convincing data on a favorable impact on clinical outcomes becomes available.
references
1. Man M, Farmen M, Dumaual C, et al. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol. 2010;50:929e940. 2. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354e362.
3. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376:1312e1319. 4. Wallentin L, James S, Storey RF, et al, Investigators P. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376:1320e1328. 5. Mahadevan L, Yesudas A, Sajesh PK, et al. Prevalence of genetic variants associated with cardiovascular disease risk and drug response in the Southern Indian population of Kerala. Indian J Hum Genet. 2014;20:175e184. 6. Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and metaanalysis. JAMA. 2011;306:2704e2714. 7. Nissen SE. Pharmacogenomics and clopidogrel: irrational exuberance? JAMA. 2011;306:2727e2728. 8. Price MJ, Berger PB, Teirstein PS, et al, Investigators G. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305:1097e1105. 9. Collet JP, Cuisset T, Range G, et al, Investigators A. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100e2109. 10. Giusti B, Gori AM, Marcucci R, Abbate R. Relation of CYP2C19 loss-of-function polymorphism to the occurrence of stent thrombosis. Expert Opin Drug Metab Toxicol. 2010;6:393e407. 11. Society for Cardiovascular A, Interventions, Society of Thoracic S, Writing Committee M, Holmes Jr DR, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA Clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. Circulation. 2010;122:537e557. 12. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849e857.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/ihj
Editorial
Routine genotyping of patients on clopidogrel: Why the resistance? Ganesan Karthikeyan Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don't know. But there are also unknown unknowns. There are things we don't know we don't know. Donald Rumsfeld Clopidogrel is a pro-drug which requires conversion by several hepatic cytochrome P450 (CYP) isoenzymes to its active metabolite, which then irreversibly binds to platelet P2Y12 receptors and inhibits platelet activation. There is considerable variability in the response to clopidogrel in clinical practice.1 Some genetic polymorphisms in the CYP enzymes, particularly CYP2C19, have consistently been shown to be associated with higher residual platelet reactivity and ischemic cardiovascular events while on treatment with clopidogrel.2 As prasugrel and ticagrelol are not metabolized by these enzymes, these polymorphisms have little effect on platelet reactivity and ischemic events with these agents.3,4 Given that the lossof-function CYP2C19*2 allele (the variant most reproducibly associated with a reduced response to clopidogrel) is highly prevalent in the general population,1,5 it is reasonable to ask why genomic testing should not be used routinely to guide the choice of antiplatelet therapy, as Rath and colleagues report in this issue of the Journal. The answer to this question is not as simple as it appears at first glance. There are several issues to consider when evaluating the utility of a diagnostic test. First and foremost is the ability of the test to discriminate reliably between people who have the condition of interest and those who don't. Second, the detected condition should be reasonably common so as to make testing for it worthwhile. Third, a “positive” test should consistently be associated with the relevant clinical outcome. Finally, knowledge of the test result should help in improving clinical outcomes through appropriate treatment. Genotyping for the isoenzymes involved in clopidogrel metabolism easily
satisfies the first two conditions. Current genotyping assays are highly accurate, and they reliably and reproducibly identify variants of interest. Some of the loss-of-function alleles may be present in as many as half those tested, particularly in some ethnic groups. However, although these variants are clearly related to reduced platelet responsiveness to clopidogrel, their relationship to clinical outcomes is less certain. In a meta-analysis exploring this issue, Holmes and colleagues found that the presence of reduced function CYP2C19 alleles did not affect the rate of ischemic clinical events when only the adequately powered studies were considered (i.e., in those reporting 200 clinical events; RR 0.97, 95% CI 0.86e1.09).6 The “irrational exuberance” for clopidogrel pharmacogenomic testing was plausibly driven by publication bias and the related “small-study” effect.7 More importantly, there is no evidence to date that intervention based on knowledge of CYP2C19 status affects outcomes, as none of the studies were large enough to detect differences in clinical events. On the contrary, indirect evidence derived from studies involving targeted treatment of patients with reduced platelet responsiveness (due to any cause), suggests that clinical outcomes may not be affected. Two randomized studies targeting reduced responsiveness to clopidogrel (identified by functional testing and not based on CYP2C19 status) using higher clopidogrel doses,8 or prasugrel and glycoprotein IIb-IIIa antagonists,9 did not show improvement in clinical outcomes. The study by Rath et al does not provide any information either on the functional or clinical outcomes with switching to a different antiplatelet agent.
known and unknown unknowns The lack of effect of reduced function CYP2C19 alleles on clinical outcomes may seem intriguing, but it is important to
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.ihj.2015.04.008 0019-4832/Copyright © 2015, Cardiological Society of India. All rights reserved.
94
i n d i a n h e a r t j o u r n a l 6 7 ( 2 0 1 5 ) 9 3 e9 4
remember that our understanding of the determinants of platelet reactivity and its links to clinical outcomes is far from complete. For example, it is known that clinical and demographic factors such as age, diabetes, body-mass index, leftventricular function, drugedrug interactions and systemic inflammation, may all independently influence on-treatment platelet reactivity through multiple mechanisms.10 It should also be kept in mind that numerous other polymorphisms affecting other isoenzymes (including those that augment clopidogrel metabolism and action) may affect platelet responsiveness.11 Consequently, it is estimated that only about 12% of the variation in platelet responsiveness is explained by CYP2C19 polymorphisms.12 In assessing the value of routine genotyping for patients on clopidogrel in the Indian context, we must also consider the resultant increase in cost of therapy (both from the cost of testing and the cost of adding prasugrel or ticagrelol), its potential adverse impact on compliance and clinical outcomes. The idea of individualized medicine holds immense appeal for doctors, patients and the general public, and optimistically, will become feasible for many conditions in the future. But routine genotyping for patients on clopidogrel cannot be advocated until convincing data on a favorable impact on clinical outcomes becomes available.
references
1. Man M, Farmen M, Dumaual C, et al. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol. 2010;50:929e940. 2. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354e362.
3. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376:1312e1319. 4. Wallentin L, James S, Storey RF, et al, Investigators P. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376:1320e1328. 5. Mahadevan L, Yesudas A, Sajesh PK, et al. Prevalence of genetic variants associated with cardiovascular disease risk and drug response in the Southern Indian population of Kerala. Indian J Hum Genet. 2014;20:175e184. 6. Holmes MV, Perel P, Shah T, Hingorani AD, Casas JP. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and metaanalysis. JAMA. 2011;306:2704e2714. 7. Nissen SE. Pharmacogenomics and clopidogrel: irrational exuberance? JAMA. 2011;306:2727e2728. 8. Price MJ, Berger PB, Teirstein PS, et al, Investigators G. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305:1097e1105. 9. Collet JP, Cuisset T, Range G, et al, Investigators A. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100e2109. 10. Giusti B, Gori AM, Marcucci R, Abbate R. Relation of CYP2C19 loss-of-function polymorphism to the occurrence of stent thrombosis. Expert Opin Drug Metab Toxicol. 2010;6:393e407. 11. Society for Cardiovascular A, Interventions, Society of Thoracic S, Writing Committee M, Holmes Jr DR, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA Clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. Circulation. 2010;122:537e557. 12. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849e857.
