perspec tives Several limitations of our study should be pointed out, the main one being a small sample size. Indeed, PAH is a rare disease, and bosentan-induced liver injury concerns only a few patients. Therefore, such a small sample size would have allowed only strong associations between SNPs and DILI to be detected, e.g., odds ratio of 16 for CYP2C9*3 (post hoc power analysis of 77%; nQuery Advisor version 7.0, Statistical Solutions Ltd., Cork, Ireland). This is particularly true for SNPs with low minor allele frequency, a point raised by Markova et al. The post hoc power calculation that they performed showed that the adjusted power-of-association analyses for DILI occurrence was 6% or lower for 11 of the 12 SNPs they tested.5 Even when our data were pooled with those of Markova et al. to increase the number of cases, CYP2C9 impaired function was not associated with bosentan-induced liver toxicity. The choice of serum alanine aminotransferase and aspartate aminotransferase levels as an outcome measure slightly increases the power but presents other issues. First, they are not as clinically relevant as DILI occurrence. Indeed, we chose to include patients who had discontinued bosentan for liver toxicity. Other issues are the fluctuation of serum alanine aminotransferase and aspartate aminotransferase levels over time and the potential confounders responsible for an increase in aminotransferase levels over time. In conclusion, unlike the results recently reported by Markova et al., this nested case–control study does not support CYP2C9*2 as a genetic marker of bosentan-induced liver injury. Other functional polymorphisms of genes involved in bosentan pharmacokinetics (SLCO1B1, SLCO1B3, and CYP2C9*3) or in hepatobiliary transporters affected by bosentan (ABCB11) were not associated with bosentan-induced hepatotoxicity either. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature. com/cpt ACKNOWLEDGMENTS This study was funded by grants from Grenoble University Hospital (Appel d’Offre DRCI 2011). We thank Alison Foote for critically reading and editing the manuscript.
CONFLICT OF INTEREST The authors declared no conflict of interest for the present study. M.R. and J.-L.C. have received research grants from Actelion, GSK and Pfizer for other studies. D.M. and M.H. have relationships with drug companies including Actelion, Bayer, GSK, Novartis, and Pfizer. In addition to being investigator in trials involving these companies, relationships include consultancy service and membership of scientific advisory boards. © 2014 ASCPT
1. Humbert, M. et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur. Respir. J. 30, 338– 344 (2007). 2. Dingemanse, J. & van Giersbergen, P.L. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin. Pharmacokinet. 43, 1089–1115 (2004). 3. Treiber, A., Schneiter, R., Hausler, S. & Stieger, B. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab. Dispos. 35, 1400–1407 (2007). 4. Fattinger, K. et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69,
223–231 (2001). 5. Markova, S.M. et al. Association of CYP2C9*2 with bosentan-induced liver injury. Clin. Pharmacol. Ther. 94, 678–686 (2013). 6. Markert, C., Burhenne, J., Weiss, J., Mikus, G. & Haefeli, W.E. CYP2C9 polymorphism is not a major determinant of bosentan exposure in healthy volunteers. Clin. Pharmacol. Ther. 95, 250–251 (2013). 7. Hartman, J.C., Brouwer, K., Mandagere, A., Melvin, L. & Gorczynski, R. Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes. Can. J. Physiol. Pharmacol. 88, 682–691 (2010). 8. Leslie, E.M., Watkins, P.B., Kim, R.B. & Brouwer, K.L. Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) by bosentan: a mechanism for species differences in hepatotoxicity. J. Pharmacol. Exp. Ther. 321, 1170–1178 (2007). 9. Fouassier, L. et al. Contribution of MRP2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J. Hepatol. 37, 184–191 (2002). 10. Fahrmayr, C. et al. Phase I and II metabolism and MRP2-mediated export of bosentan in a MDCKIIOATP1B1-CYP3A4-UGT1A1-MRP2 quadrupletransfected cell line. Br. J. Pharmacol. 169, 21–33 (2013).
Clopidogrel for Smokers and Aspirin for Nonsmokers?: Not So Fast CD Williams1 New data solidify a “smoker’s paradox” for clopidogrel, with current smokers appearing to respond better than nonsmokers. However, the clinical implications of this finding are unclear. This Commentary discusses the new data and puts it into clinical context. The term “smoker’s paradox” was originally used to describe the observation that smokers were more likely to survive an acute myocardial infarction (MI) than nonsmokers, a finding probably due to smokers often being younger and having fewer comorbidities at the time of first MI. More recently, though, the term
has been borrowed to describe the observation that smokers and nonsmokers respond differently to clopidogrel. Two recent studies have offered some insight into this phenomenon, and a clinical picture is beginning to emerge. As the role of the platelet in atherothrombosis is becoming better under-
1Oregon State University/Oregon Health and Science University College of Pharmacy, Portland, Oregon, USA. Correspondence: CD Williams ([email protected])
doi:10.1038/clpt.2014.52
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 6 | JUNE 2014
585
perspec tives stood, it is clear that it continues to be an important target for therapies aimed at preventing as well as treating acute cardiovascular disease (CVD) events. However, optimizing antiplatelet therapy remains a challenge. Although more potent platelet inhibition can further reduce CVD events, it also increases major bleeding episodes, including lifethreatening hemorrhages.1 One consistent challenge for newer therapies has been improving on the risk-to-benefit ratio of low-dose aspirin. In a trial more than a decade ago, the potent oral glycoprotein IIb/IIIa receptor antagonist sibrafiban failed to reduce CVD end points as compared with aspirin.2 More recently, the platelet thrombin receptor antagonist vorapaxar failed to improve outcomes when added to existing antiplatelet therapy, including aspirin.3 Earlier guidelines for the secondary prevention of ischemic stroke preferred Aggrenox (extended-release dipyridamole plus aspirin) over low-dose aspirin, but newer trials led to revised guidelines, which now give equal preference to both.4 Despite the generally favorable data for low-dose aspirin, however, one group of patients has remained problematic: those who smoke. In the Antithrombotic Trialists’ Collaboration (ATC) meta-analysis, aspirin was associated with a 17% relative risk reduction in nonsmokers but with no benefit in current smokers (hazard ratio (HR) 1.00 (95% CI 0.84–1.18)).5 In the Women’s Health Study, one of the largest trials included in the ATC meta-analysis, aspirin was associated with a significant 20% reduction in major CVD events in nonsmokers but a significant 30% increase in smokers.6 Whereas aspirin has been associated with reduced benefit in smokers, clopidogrel has been associated with increased benefit. Two subanalyses of large clinical trials reported in 2009 found clear evidence of a smoker’s paradox, with significantly greater benefit from clopidogrel seen in smokers than in nonsmokers.7,8 New evidence now adds significantly to these findings. First, a recent meta-analysis by Gagne et al. analyzed six trials of clopidogrel therapy and solidified the smoker’s paradox.9 586
Across the six trials, smokers derived a significant 25% reduction in major cardiovascular events whereas nonsmokers derived a much smaller (8%) benefit.9 The accompanying editorial declared that “prospective clinical studies are urgently needed to evaluate the impact of smoking on the efficacy of platelet inhibitors.”10 The second recent paper is a longawaited subanalysis of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial, which was a study of clopidogrel vs. aspirin monotherapy in patients with stable vascular disease.11 This study, too, found a significantly greater benefit of clopidogrel in smokers than in nonsmokers. But what should we do with this new information in clinical practice while we theoretically await those prospective trials in smokers that will probably never come (given that clopidogrel lost patent exclusivity in the United States in 2012)? First, it is important to note that the difference in aspirin effects by smoking status noted in the ATC meta-analysis pertained to primary prevention, yet all the data for clopidogrel are from secondaryprevention trials. Is aspirin less effective for secondary prevention in smokers as well? That is unlikely. Although the trials of aspirin for secondary prevention did not stratify outcomes by smoking status, these early studies did include a high percentage of smokers (as high as 60% in the Cardiff trial12), and the benefit of aspirin was robust in these trials. We can therefore assume that aspirin is effective for secondary prevention in patients who smoke. Second, five of the six trials in the metaanalysis by Gagne et al. were trials not only of secondary prevention but also of dual antiplatelet therapy vs. monotherapy, and four of those were in the setting of acute vascular injury (either acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI)).9 The sixth trial is the new analysis of the CAPRIE study.11 Therefore, five of the six trials in the meta-analysis were looking for an additive benefit of clopidogrel when added to aspirin. This sets a high bar for clopidogrel, and it is reasonable to assume that patients with higher residual risk who were on aspirin therapy would benefit more from the addition of clopidogrel.
Continued smoking increases the risk of recurrent MI by about 20%. This higher residual risk probably explains part, but probably not all, of the greater benefit of clopidogrel when added to aspirin. But, regardless of the reason for the finding, should we alter practice and stop using clopidogrel in addition to aspirin for ACS or PCI in patients who do not smoke? No. Although the benefit of clopidogrel therapy in nonsmokers was markedly reduced, that 8% reduction was still significant.9 Nonsmokers also experienced fewer bleeding episodes compared with smokers. Do these data have implications for patients with stable coronary disease? The new analysis of CAPRIE helps with this question. In that trial, more than 19,000 patients with stable vascular disease were ran domized to daily clopidogrel or aspirin and followed for an average of 1.9 years. In the new subanalysis, aspirin and clopidogrel had similar effects in nonsmokers (n = 13,515; HR 0.99, 95% CI 0.89–1.10), but clopidogrel was superior to aspirin in current smokers (n = 5,688; HR 0.76, 95% CI 0.64–0.90). The absolute risk reduction for major CVD events in current smokers was an impressive 2.5% (8.3% vs. 10.8%). Thus, the smoker’s paradox seems to hold for clopidogrel monotherapy as well. So what now? The authors of the subanalysis allow that the best course of action is to redouble our efforts at smoking cessation, and no one would disagree with that. But where smoking cessation fails, the suggestion is that clopidogrel should be preferred over aspirin. That is a reasonable course of action given the size and robustness of this subanalysis. However, post hoc analyses have limitations (as the authors admit), and continued use of aspirin for secondary prevention in patients who smoke is also sensible for two reasons. First, the analysis shows that aspirin is no less effective in smokers than in nonsmokers for secondary prevention of vascular disease (CVD event rate 10.6% in nonsmokers and 10.8% in smokers). That is a very useful addition to the literature because our previous data were focused on primary prevention.5 Second, the biological plausibility of a greater effect from clopidogrel in smokers VOLUME 95 NUMBER 6 | JUNE 2014 | www.nature.com/cpt
perspec tives remains suspect. The argument put forward by several authors is that, because clopidogrel requires bioactivation by cytochromes (primarily CYP2C19) and smoking upregulates cytochrome activity, then more active metabolite is generated in patients who smoke.8,9 Indeed, a difference in formation of the active metabolite has been found for clopidogrel in smokers vs. nonsmokers, and this difference is not present for prasugrel, which undergoes more reliable bioactivation mediated partly by esterases. However, the clinical importance of differential bioactivation of clopidogrel remains in doubt, and large clinical trials examining the impact of CYP2C19 genotype have come to different conclusions. Although it is possible that smoking exerts such a large influence on cytochrome phenotype that it can explain differences that cannot be found with cytochrome genotype, this is very unlikely. Nevertheless, if cytochrome activation by smoking does account for differences in clinical outcomes with clopidogrel, then it should also be evident when clopidogrel is compared with other thienopyridines that are not subject to the same variations in bioactivation. Specifically, newer thienopyridines should be more efficacious than clopidogrel in nonsmokers because clopidogrel would be less bioactivated in these patients and the newer agents would be equally active in both groups. Yet the opposite effect is seen in the clinical trials. As shown by Gagne et al. (the meta-analysis also looked at the limited data available with newer thienopyridines), both prasugrel and ticagrelor show superiority over clopidogrel, and the benefits are greater in smokers than in nonsmokers.9 This is the opposite of what we would expect, and the differ-
ence is substantial. In the TRILOGY trial (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes), which compared additive therapy with prasugrel vs. clopidogrel, there was a 46% reduction in major CVD events with prasugrel in the 1,566 smokers and a nonsignificant 6% increase in the 5,614 nonsmokers.1 So where are we left? Regardless of the explanation, the size and robustness of the findings of the CAPRIE subanalysis may be adequate to convince some clinicians to use clopidogrel instead of aspirin in patients with vascular disease who continue to smoke.11 Because clopidogrel is now fairly inexpensive, this is not an unreasonable approach. For others who feel that post hoc analyses must be confirmed with prospective trials, as well as for those who insist on plausible biological explanations for subgroup findings, it is reasonable to continue to use aspirin in all patients with vascular disease regardless of smoking status. For those clinicians, we are indebted to the authors of the new analysis of CAPRIE, who show that aspirin is no less effective for secondary prevention in patients who smoke. That in itself is a very important addition to a body of literature that continues to pose as many questions as it provides answers. ACKNOWLEDGMENT I thank Dominick Angiolillo for his thoughtful insights and discussion. CONFLICT OF INTEREST The author declared no conflict of interest. © 2014 ASCPT
1. Roe, M.T. et al.; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N. Engl. J. Med. 367, 1297–1309 (2012).
2. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. The symphony investigators. Sibrafiban versus aspirin to yield maximum protection from ischemic heart events post-acute coronary syndromes. Lancet 355, 337–345 (2000). 3. Morrow, D.A. et al.; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404–1413 (2012). 4. Furie, K.L. et al.; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42, 227–276 (2011). 5. Antithrombotic Trialists’ (ATT) Collaboration, Baigent, C. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009). 6. Ridker, P.M. et al. A randomized trial of lowdose aspirin in the primary prevention of cardiovascular disease in women. N. Engl. J. Med. 352, 1293–1304 (2005). 7. Berger J.S. et al.; CHARISMA Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 120, 2337–2344 (2009). 8. Desai, N.R., Mega, J.L., Jiang, S., Cannon, C.P. & Sabatine, M.S. Interaction between cigarette smoking and clinical benefit of clopidogrel. J. Am. Coll. Cardiol. 53, 1273–1278 (2009). 9. Gagne, J.J., Bykov, K., Choudhry, N.K., Toomey, T.J., Connolly, J.G. & Avorn, J. Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. BMJ 347, f5307 (2013). 10. Hirschl, M.M. Smoking status and the effects of antiplatelet drugs. BMJ 347, f5909 (2013). 11. Ferreiro, J.L., Bhatt, D.L., Ueno, M., Bauer, D. & Angiolillo, D.J. Impact of smoking on long-term outcomes in patients with atherosclerotic vascular disease treated with aspirin or clopidogrel: insights from the CAPRIE trial (clopidogrel versus aspirin in patients at risk of ischemic events). J. Am. Coll. Cardiol. 63, 769–777 (2014). 12. Elwood, P.C. & Sweetnam, P.M. Aspirin and secondary mortality after myocardial infarction. Lancet 2,1313–1315 (1979).
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 6 | JUNE 2014
587
CONFLICT OF INTEREST The authors declared no conflict of interest for the present study. M.R. and J.-L.C. have received research grants from Actelion, GSK and Pfizer for other studies. D.M. and M.H. have relationships with drug companies including Actelion, Bayer, GSK, Novartis, and Pfizer. In addition to being investigator in trials involving these companies, relationships include consultancy service and membership of scientific advisory boards. © 2014 ASCPT
1. Humbert, M. et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur. Respir. J. 30, 338– 344 (2007). 2. Dingemanse, J. & van Giersbergen, P.L. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin. Pharmacokinet. 43, 1089–1115 (2004). 3. Treiber, A., Schneiter, R., Hausler, S. & Stieger, B. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab. Dispos. 35, 1400–1407 (2007). 4. Fattinger, K. et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69,
223–231 (2001). 5. Markova, S.M. et al. Association of CYP2C9*2 with bosentan-induced liver injury. Clin. Pharmacol. Ther. 94, 678–686 (2013). 6. Markert, C., Burhenne, J., Weiss, J., Mikus, G. & Haefeli, W.E. CYP2C9 polymorphism is not a major determinant of bosentan exposure in healthy volunteers. Clin. Pharmacol. Ther. 95, 250–251 (2013). 7. Hartman, J.C., Brouwer, K., Mandagere, A., Melvin, L. & Gorczynski, R. Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes. Can. J. Physiol. Pharmacol. 88, 682–691 (2010). 8. Leslie, E.M., Watkins, P.B., Kim, R.B. & Brouwer, K.L. Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) by bosentan: a mechanism for species differences in hepatotoxicity. J. Pharmacol. Exp. Ther. 321, 1170–1178 (2007). 9. Fouassier, L. et al. Contribution of MRP2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J. Hepatol. 37, 184–191 (2002). 10. Fahrmayr, C. et al. Phase I and II metabolism and MRP2-mediated export of bosentan in a MDCKIIOATP1B1-CYP3A4-UGT1A1-MRP2 quadrupletransfected cell line. Br. J. Pharmacol. 169, 21–33 (2013).
Clopidogrel for Smokers and Aspirin for Nonsmokers?: Not So Fast CD Williams1 New data solidify a “smoker’s paradox” for clopidogrel, with current smokers appearing to respond better than nonsmokers. However, the clinical implications of this finding are unclear. This Commentary discusses the new data and puts it into clinical context. The term “smoker’s paradox” was originally used to describe the observation that smokers were more likely to survive an acute myocardial infarction (MI) than nonsmokers, a finding probably due to smokers often being younger and having fewer comorbidities at the time of first MI. More recently, though, the term
has been borrowed to describe the observation that smokers and nonsmokers respond differently to clopidogrel. Two recent studies have offered some insight into this phenomenon, and a clinical picture is beginning to emerge. As the role of the platelet in atherothrombosis is becoming better under-
1Oregon State University/Oregon Health and Science University College of Pharmacy, Portland, Oregon, USA. Correspondence: CD Williams ([email protected])
doi:10.1038/clpt.2014.52
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 6 | JUNE 2014
585
perspec tives stood, it is clear that it continues to be an important target for therapies aimed at preventing as well as treating acute cardiovascular disease (CVD) events. However, optimizing antiplatelet therapy remains a challenge. Although more potent platelet inhibition can further reduce CVD events, it also increases major bleeding episodes, including lifethreatening hemorrhages.1 One consistent challenge for newer therapies has been improving on the risk-to-benefit ratio of low-dose aspirin. In a trial more than a decade ago, the potent oral glycoprotein IIb/IIIa receptor antagonist sibrafiban failed to reduce CVD end points as compared with aspirin.2 More recently, the platelet thrombin receptor antagonist vorapaxar failed to improve outcomes when added to existing antiplatelet therapy, including aspirin.3 Earlier guidelines for the secondary prevention of ischemic stroke preferred Aggrenox (extended-release dipyridamole plus aspirin) over low-dose aspirin, but newer trials led to revised guidelines, which now give equal preference to both.4 Despite the generally favorable data for low-dose aspirin, however, one group of patients has remained problematic: those who smoke. In the Antithrombotic Trialists’ Collaboration (ATC) meta-analysis, aspirin was associated with a 17% relative risk reduction in nonsmokers but with no benefit in current smokers (hazard ratio (HR) 1.00 (95% CI 0.84–1.18)).5 In the Women’s Health Study, one of the largest trials included in the ATC meta-analysis, aspirin was associated with a significant 20% reduction in major CVD events in nonsmokers but a significant 30% increase in smokers.6 Whereas aspirin has been associated with reduced benefit in smokers, clopidogrel has been associated with increased benefit. Two subanalyses of large clinical trials reported in 2009 found clear evidence of a smoker’s paradox, with significantly greater benefit from clopidogrel seen in smokers than in nonsmokers.7,8 New evidence now adds significantly to these findings. First, a recent meta-analysis by Gagne et al. analyzed six trials of clopidogrel therapy and solidified the smoker’s paradox.9 586
Across the six trials, smokers derived a significant 25% reduction in major cardiovascular events whereas nonsmokers derived a much smaller (8%) benefit.9 The accompanying editorial declared that “prospective clinical studies are urgently needed to evaluate the impact of smoking on the efficacy of platelet inhibitors.”10 The second recent paper is a longawaited subanalysis of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial, which was a study of clopidogrel vs. aspirin monotherapy in patients with stable vascular disease.11 This study, too, found a significantly greater benefit of clopidogrel in smokers than in nonsmokers. But what should we do with this new information in clinical practice while we theoretically await those prospective trials in smokers that will probably never come (given that clopidogrel lost patent exclusivity in the United States in 2012)? First, it is important to note that the difference in aspirin effects by smoking status noted in the ATC meta-analysis pertained to primary prevention, yet all the data for clopidogrel are from secondaryprevention trials. Is aspirin less effective for secondary prevention in smokers as well? That is unlikely. Although the trials of aspirin for secondary prevention did not stratify outcomes by smoking status, these early studies did include a high percentage of smokers (as high as 60% in the Cardiff trial12), and the benefit of aspirin was robust in these trials. We can therefore assume that aspirin is effective for secondary prevention in patients who smoke. Second, five of the six trials in the metaanalysis by Gagne et al. were trials not only of secondary prevention but also of dual antiplatelet therapy vs. monotherapy, and four of those were in the setting of acute vascular injury (either acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI)).9 The sixth trial is the new analysis of the CAPRIE study.11 Therefore, five of the six trials in the meta-analysis were looking for an additive benefit of clopidogrel when added to aspirin. This sets a high bar for clopidogrel, and it is reasonable to assume that patients with higher residual risk who were on aspirin therapy would benefit more from the addition of clopidogrel.
Continued smoking increases the risk of recurrent MI by about 20%. This higher residual risk probably explains part, but probably not all, of the greater benefit of clopidogrel when added to aspirin. But, regardless of the reason for the finding, should we alter practice and stop using clopidogrel in addition to aspirin for ACS or PCI in patients who do not smoke? No. Although the benefit of clopidogrel therapy in nonsmokers was markedly reduced, that 8% reduction was still significant.9 Nonsmokers also experienced fewer bleeding episodes compared with smokers. Do these data have implications for patients with stable coronary disease? The new analysis of CAPRIE helps with this question. In that trial, more than 19,000 patients with stable vascular disease were ran domized to daily clopidogrel or aspirin and followed for an average of 1.9 years. In the new subanalysis, aspirin and clopidogrel had similar effects in nonsmokers (n = 13,515; HR 0.99, 95% CI 0.89–1.10), but clopidogrel was superior to aspirin in current smokers (n = 5,688; HR 0.76, 95% CI 0.64–0.90). The absolute risk reduction for major CVD events in current smokers was an impressive 2.5% (8.3% vs. 10.8%). Thus, the smoker’s paradox seems to hold for clopidogrel monotherapy as well. So what now? The authors of the subanalysis allow that the best course of action is to redouble our efforts at smoking cessation, and no one would disagree with that. But where smoking cessation fails, the suggestion is that clopidogrel should be preferred over aspirin. That is a reasonable course of action given the size and robustness of this subanalysis. However, post hoc analyses have limitations (as the authors admit), and continued use of aspirin for secondary prevention in patients who smoke is also sensible for two reasons. First, the analysis shows that aspirin is no less effective in smokers than in nonsmokers for secondary prevention of vascular disease (CVD event rate 10.6% in nonsmokers and 10.8% in smokers). That is a very useful addition to the literature because our previous data were focused on primary prevention.5 Second, the biological plausibility of a greater effect from clopidogrel in smokers VOLUME 95 NUMBER 6 | JUNE 2014 | www.nature.com/cpt
perspec tives remains suspect. The argument put forward by several authors is that, because clopidogrel requires bioactivation by cytochromes (primarily CYP2C19) and smoking upregulates cytochrome activity, then more active metabolite is generated in patients who smoke.8,9 Indeed, a difference in formation of the active metabolite has been found for clopidogrel in smokers vs. nonsmokers, and this difference is not present for prasugrel, which undergoes more reliable bioactivation mediated partly by esterases. However, the clinical importance of differential bioactivation of clopidogrel remains in doubt, and large clinical trials examining the impact of CYP2C19 genotype have come to different conclusions. Although it is possible that smoking exerts such a large influence on cytochrome phenotype that it can explain differences that cannot be found with cytochrome genotype, this is very unlikely. Nevertheless, if cytochrome activation by smoking does account for differences in clinical outcomes with clopidogrel, then it should also be evident when clopidogrel is compared with other thienopyridines that are not subject to the same variations in bioactivation. Specifically, newer thienopyridines should be more efficacious than clopidogrel in nonsmokers because clopidogrel would be less bioactivated in these patients and the newer agents would be equally active in both groups. Yet the opposite effect is seen in the clinical trials. As shown by Gagne et al. (the meta-analysis also looked at the limited data available with newer thienopyridines), both prasugrel and ticagrelor show superiority over clopidogrel, and the benefits are greater in smokers than in nonsmokers.9 This is the opposite of what we would expect, and the differ-
ence is substantial. In the TRILOGY trial (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes), which compared additive therapy with prasugrel vs. clopidogrel, there was a 46% reduction in major CVD events with prasugrel in the 1,566 smokers and a nonsignificant 6% increase in the 5,614 nonsmokers.1 So where are we left? Regardless of the explanation, the size and robustness of the findings of the CAPRIE subanalysis may be adequate to convince some clinicians to use clopidogrel instead of aspirin in patients with vascular disease who continue to smoke.11 Because clopidogrel is now fairly inexpensive, this is not an unreasonable approach. For others who feel that post hoc analyses must be confirmed with prospective trials, as well as for those who insist on plausible biological explanations for subgroup findings, it is reasonable to continue to use aspirin in all patients with vascular disease regardless of smoking status. For those clinicians, we are indebted to the authors of the new analysis of CAPRIE, who show that aspirin is no less effective for secondary prevention in patients who smoke. That in itself is a very important addition to a body of literature that continues to pose as many questions as it provides answers. ACKNOWLEDGMENT I thank Dominick Angiolillo for his thoughtful insights and discussion. CONFLICT OF INTEREST The author declared no conflict of interest. © 2014 ASCPT
1. Roe, M.T. et al.; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N. Engl. J. Med. 367, 1297–1309 (2012).
2. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. The symphony investigators. Sibrafiban versus aspirin to yield maximum protection from ischemic heart events post-acute coronary syndromes. Lancet 355, 337–345 (2000). 3. Morrow, D.A. et al.; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404–1413 (2012). 4. Furie, K.L. et al.; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42, 227–276 (2011). 5. Antithrombotic Trialists’ (ATT) Collaboration, Baigent, C. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009). 6. Ridker, P.M. et al. A randomized trial of lowdose aspirin in the primary prevention of cardiovascular disease in women. N. Engl. J. Med. 352, 1293–1304 (2005). 7. Berger J.S. et al.; CHARISMA Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 120, 2337–2344 (2009). 8. Desai, N.R., Mega, J.L., Jiang, S., Cannon, C.P. & Sabatine, M.S. Interaction between cigarette smoking and clinical benefit of clopidogrel. J. Am. Coll. Cardiol. 53, 1273–1278 (2009). 9. Gagne, J.J., Bykov, K., Choudhry, N.K., Toomey, T.J., Connolly, J.G. & Avorn, J. Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. BMJ 347, f5307 (2013). 10. Hirschl, M.M. Smoking status and the effects of antiplatelet drugs. BMJ 347, f5909 (2013). 11. Ferreiro, J.L., Bhatt, D.L., Ueno, M., Bauer, D. & Angiolillo, D.J. Impact of smoking on long-term outcomes in patients with atherosclerotic vascular disease treated with aspirin or clopidogrel: insights from the CAPRIE trial (clopidogrel versus aspirin in patients at risk of ischemic events). J. Am. Coll. Cardiol. 63, 769–777 (2014). 12. Elwood, P.C. & Sweetnam, P.M. Aspirin and secondary mortality after myocardial infarction. Lancet 2,1313–1315 (1979).
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 6 | JUNE 2014
587
