Myonecrosis after Elective Percutaneous Coronary Intervention: Effect of Clopidogrel-Statin Interaction

Sadi Gulec, MD, Cagdas Ozdol, MD, Uzeyir Rahimov, MD, Yusuf Atmaca, MD, Deniz Kumbasar, MD, Cetin Erol, MD
Sadi Gulec, MD, Cagdas Ozdol, MD, Uzeyir Rahimov, MD, Yusuf Atmaca, MD, Deniz Kumbasar, MD, Cetin Erol, MD
Myocardial injury after percutaneous coronary interventions has been recognized as a frequent and prognostically important event.1 Multiple institutions have now reported follow-up studies of percutaneous revascularization, and the evidence supports a relation between the elevation of cardiac enzymes and poorer clinical outcomes during subsequent clinical evaluations.1–4 Recent studies presented evidence that statin therapy before percutaneous coronary interventions (PCI) is associated with a marked improvement in short- and long-term prognosis.5,6 Reduction in procedure-related myocardial injury has been proposed as one of the plausible mechanisms accounting for this survival benefit.7,8 Clopidogrel, a novel thienopyridine, is a widely prescribed agent for sustained platelet inhibition during and after coronary stenting.9 Recently, two different investigator groups10,11 reported that clopidogrel activation requires the cytochrome P450 (CYP) 3A4 system and that antiplatelet activity of clopidogrel is substantially inhibited by atorvastatin, which is also metabolized by the CYP3A4 pathway. By contrast, this inhibitory effect was not noted for pravastatin, which is not a CYP3A4 substrate.12 However, the clinical relevance of this ex vivo clopidogrel-atorvastatin interaction has not been validated yet. In the current study, we sought to assess whether the incidence of procedure-related myocardial injury, assessed by cardiac troponin T (cTnT) release, is altered when clopidogrel is coadministered with a statin that is predominantly CYP3A4-metabolized. Methods Study population. In this retrospective study, all patients who underwent successful coronary stenting of a de novo stenosis for angina pectoris and/or positive stress test at the Ankara University Ibn-i Sina Hospital from December 2002 to August 2003 were screened for eligibility. Exclusion criteria were: (1) acute coronary syndromes within 4 weeks; (2) elevated baseline cTnT and/or creatine kinase (CK)-MB; (3) cardiac surgery within 4 weeks; (4) renal insufficiency; (5) stenosis located in venous or arterial bypass grafts; (6) periprocedural use of glycoprotein IIb/IIIa receptor inhibitors; and (7) side branch occlusion during the procedure. Debulking devices were not involved in the stenting procedure. Eligible patients were divided into 3 groups according to baseline statin status: (1) patients receiving a predominantly CYP3A4-metabolized statin (atorvastatin and simvastatin, Group 1); (2) patients receiving a predominantly a non-CYP3A4-metabolized statin (pravastatin and fluvastatin, Group 2); and (3) patients receiving “no statin” at the time of coronary stenting (Control group). All patients gave written informed consent and local ethics committee approved the study protocol. cTnT and CK-MB measurements. All cardiac marker measurements were obtained at baseline and 8 and 16 hours after the procedures according to previously reported consensus statement.1 Elecsys 1010 immunoassay analyzer and Elecsys Troponin T STAT (third generation) kits (Roche Diagnostics Systems, Mannheim) were used for the quantitative measurement of cTnT. The normal reference values of cTnT, according to the manufacturer’s instructions, were between 0.00–0.10 ng/ml. The CK-MB mass was measured by using an immunoenzymatic “sandwich” method (Access analyzer, Bekmann Diagnostics). The upper limit of normal (ULN) value for CK-MB mass was 4 ng/ml, according to manufacturer’s instructions. Periprocedural myocardial infarction (MI) was defined by a rise in CK-MB isoform by 3 times the ULN or development of new Q-waves associated with CK-MB and/or cTnT elevation consistent with myocardial necrosis. The study was blinded with respect to endpoint evaluation and to statin administration. Statistical analysis. Analyses were performed using a SPSS software package (version 10.0 for Windows, SPSS Inc., Chicago, Illinois). Data are expressed as numbers and percentages for discrete variables and as means ± SD for continuous variables. The chi-square analysis with Yates’ correction was used to assess the significance of differences between dichomatous variables. Continuous variables were compared by Student’s t-test or Mann-Whitney rank sum test. Pearson’s correlation coefficient was calculated between peak postprocedural cTnT and peak CK-MB. Univariate analysis of 33 prespecified factors determining postprocedural elevation of cTnT included: age, sex, present cigarette smoking, presentation of hypertension, diabetes, family history of coronary artery disease, history of myocardial infarction, history of coronary bypass surgery, use of CYP3A4-metabolized statins, non-CYP3A4-metabolized statins, beta blockers, calcium channel blockers, nitrates, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, diuretics, drugs affecting CYP3A4 system13 duration of statin therapy before the procedure, the plasma levels of high sensitive C-reactive protein (hs-CRP), fibrinogen, total cholesterol, low- and high-density lipoprotein and triglyceride before the procedure, angiographic variables including the presence of multivessel coronary disease, percent diameter stenosis, left anterior descending intervention, lesion morphology, stent length, balloon diameter, number of implanted stents, maximum balloon inflation time, maximum balloon inflation pressure, and multivessel intervention. Multivariate analyses were performed in logistic regression and forward stepping manner to adjust for the characteristics that were significant correlates (with p p = 0.049). The overall incidences of postprocedural cTnT and CK-MB elevation were 30.8% and 24.6%, respectively. Significant correlation was present between the peakpostprocedural cTnT andCK-MB (r = 0.68; p p = 0.2). Of note, Group 2 patients were less likely to exhibit a rise in postprocedural CK-MB relative to Group 1 patients (1/37 versus 38/114; p p = 0.01). These patients were also noted to have significantly lower levels of peak cTnT and CK-MB (0.03 ± 0.03 and 2.23 ± 0.87) compared with the Group 1 patients (0.20 ± 0.39 and 5.27 ± 7.36; p p p = 0.001, respectively). However, Group 1 patients were comparable to control patients in the incidence of CK-MB elevation above ULN and the peak levels of cTnT and CK-MB after coronary stenting. Figure 1 illustrates the postprocedural troponin T status according to different statin regimens at the time of the procedure. Notably, Group 2 patients were less likely to experience procedure-related cTnT elevation relative to Group 1 patients and relative to controls (p = 0.004 and p p p = NS). Table 2 lists the univariate and multivariate correlates with the postprocedural elevation of cTnT for the current study cohort. Univariate correlates (with p p = 0.006 and p = 0.008, respectively). Nonetheless, CYP3A4-metabolized statin therapy did not exhibit any significant benefit over “no statin” therapy before the procedure (OR: 0.77, 95% CI: 0.39–1.52; p = 0.45). Other independent predictors for troponin elevation were type B2/C lesion morphology (OR: 2.33, 95% CI: 1.19–4.60; p = 0.014) and number of implanted stents (OR: 1.62, 95% CI: 1.09–2.41; p = 0.016). Discussion A growing body of evidence suggest that pretreatment with statins may improve postprocedural clinical outcomes in patients undergoing stent implantation,5,6 at least in part, by reducing periprocedural myocardial necrosis.7,8 Recent ex vivo finding by Lau et al.10 that coadministration of atorvastatin inhibits the antiplatelet activity of clopidogrel in a dose-dependent manner by competing with clopidogrel for metabolism in the CYP3A4 system raises the question of whether statin-clopidogrel interaction may worsen clinical outcomes. Since trials proposing beneficial effects of statins on postprocedural cardiac marker elevation7,8 has been performed in the absence of concurrent clopidogrel therapy, we conducted a retrospective analysis to observe if postprocedural TnT elevation differs between statin groups according to their route of metabolism in a cohort of 216 patients who were pretreated with clopidogrel for coronary stent implantation. As a result, we found that pravastatin and fluvastatin (neither of which is metabolized by CYP3A4 system), but not atorvastatin and simvastatin (both are CYP3A4 substrates), are associated with a reduction in the incidence of troponin elevation comparing with controls with no periprocedural statin use. Elevation of cardiac enzymes, which significantly correlates with myocellular necrosis14 is a common event after PCI procedures.15,16 Distal embolization of platelet rich emboli is suggested as one of the plausible mechanisms accounting for this enzyme elevation after PCI, particularly in saphenous vein grafts.17,18 We have previously demonstrated that pretreatment with thienopyridines reduces procedure-related myocardial injury in patients undergoing elective coronary stenting.19,20 Glycoprotein IIb/IIIa inhibitors were also shown to prevent a substantial proportion of procedure-related injuries by, at least in part, reducing distal embolization.21–22 It is, therefore, tempting to speculate that the concomitant use of a CYP3A4-metabolized statin in the current study, has limited the ability of clopidogrel to achieve sustained platelet inhibition, which in turn promoted distal embolization. Thus, the loss of clopidogrel efficacy may have offset the cardioprotective effects of statins so that a CYP3A4-metabolized statin use did not exhibit any benefit over no-statin use before the procedure. Our finding that patients receiving a CYP3A4-metabolized statin at doses greater than or equal to 20 mg/day were at higher risk for postprocedural troponin elevation than patients receiving 10 mg/day of these agents further supports the ex vivo finding of Lau et al.10 that the inhibitor effect of atorvastatin on clopidogrel activity was dose-dependent. On the other hand, our results contrast somewhat to a recent trial which suggests that antecedent therapy with atorvastatin does not affect the clopidogrel benefit in patients with acute coronary syndromes.23 In that study, Weinbergen et al. failed to find any significant differences in clinical outcomes between atorvastatin therapy and other statin therapies in the presence of clopidogrel. We noted, however, that 59% of the patients in their “other statin therapies” group were receiving simvastatin, which is also metabolized by CYP3A4 system and is predicted to exhibit pharmacological properties similar to atorvastatin.12 Thus, it is not unexpected for atorvastatin and simvastatin users to exhibit similar clinical outcomes in the presence of clopidogrel medication. Results from post hoc analysis of a randomized, placebo-controlled clopidogrel trial by Saw et al.24 also seem to contradict our results. They reported that the benefit of clopidogrel after PCI was similar with the concurrent use of different statins, irrespective of their route of metabolism. However, statin dosages were not documented in that study. Thus, the contradiction of our data and their results can be explained by the insufficient statin dose in their study cohort to achieve clinically relevant interaction with clopidogrel. In support of this hypothesis, the incidence of troponin positivity among patients receiving 10 mg/day of CYP3A4-metabolized statins in the current study did not differ from that of patients receiving non-CYP3A4-metabolized statins (6/52 versus 3/37, respectively; p = NS). Likewise, the recent study by Mitsios et al.25 in 21 patients with acute coronary syndromes concluded that the coadministration of 10 mg dose of atorvastatin and clopidogrel does not have an adverse interaction in platelet function and does not affect the clinical outcome. Limitations. The major limitations of the present study are small sample size and the retrospective, nonrandomized design. Although the design is retrospective, systematical questioning of all study patients for prespecified demographic and clinical variables before initiation and prospectively collected angiographic and procedural data did provide us the opportunity to control for most, if not all, of the confounders. Despite the nonrandomized allocation into statin subgroups, no significant differences in baseline characteristics were noted between the CYP3A4- and non-CYP3A4-metabolized statin users. The only exception was the type B2/C lesion morphology which tended to be more prevalent among Group 1 patients with statistical significance (p = 0.049). Taken together with the small sample size to gain adequate power from the multivariate analysis performed, higher risk lesions in Group 1 patients could possibly confound our observation that postprocedural TnT elevation is more frequent in CYP3A4-metabolized statin users. Importantly, as we did not measure the antiplatelet activity of clopidogrel when statins were coadministered, our data did not mean that concomitant use of CYP3A4-metabolized statins alter the antiplatelet activity of clopidogrel. However, three studies10,11,26 have already demonstrated that antiplatelet activity of clopidogrel is impaired by the concomitant use of a CYP3A4-metabolizad statin. While interpreting our results, one should also keep in mind that our results may not be extrapolated to PCI procedures performed under treatment with GP IIb/IIIa inhibitors since patients with GP IIb/IIIa inhibitor use was excluded from the study. On the other hand, the very high incidence of postprocedural TnT elevation of > 0.10 ng/ml observed in this cohort may re-emphasize the importance of GP IIb/IIIa use during elective PCI in high-risk patients/lesions, and raises a question concerning the applicability of relying on aspirin, clopidogrel, and heparin as the pharmacologic adjunct to PCI in these patients with a nontoward consideration of adding a GP IIb/IIIa inhibitor to potentially reduce the incidence of myonecrosis. Conclusions In this retrospective, nonrandomized study, we found that stenting-related myocardial injury is reduced when clopidogrel is coadministered with pravastatin and fluvastatin, but not with atorvastatin and simvastatin. This data suggest that the ex vivo finding of a negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel may be of clinical significance. Our results, however, should be interpreted in the context of a preliminary observation that definitely requires conformation in a larger randomized clinical trial before concluding that the use of a non-CYP3A4-metabolized statin should be preferred when concurrent use of clopidogrel is required. Acknowledgement. The authors thank Dr Atilla Halil Elhan for his expert assistance.
1. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241–251. 2. Kizer JR, Muttrej MR, Matthai WH, et al. Role of cardiac troponin T in the long-term risk stratification of patients undergoing percutaneous coronary intervention. Eur Heart J 2003;24:1314–1322. 3. Cantor WJ, Newby LK, Christenson RH, et al. Prognostic significance of elevated troponin I after percutaneous coronary intervention. J Am Coll Cardiol 2002;39:1738–1744. 4. Nageh T, Sherwood RA, Thomas MR. Prognostic implications of cardiac marker elevation after percutaneous coronary intervention. Circulation 2002;105:e73. 5. Chan AW, Bhatt DL, Chew DP, et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation 2002;105:691–696. 6. Chan AW, Bhatt DL, Chew DP, et al Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation 2003;107:1750–1756. 7. Herrmann J, Lerman A, Baumgart D, et al. Pre-procedural statin medication reduces the extent of peri-procedural non-Q-wave myocardial infarction. Circulation 2002;106:2180–2183. 8. Aronow HD, Quinn MJ, Gurm HS, et al. Myocardial necrosis is halved in patients undergoing elective percutaneous coronary intervention who are pretreated with lipidlowering therapy (Abstr.). J Am Coll Cardiol 2002;39:32A. 9. Bertrand ME, Ruppert HJ, Peterson J, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624–629. 10. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: A new drug-drug interaction. Circulation 2003;107:32–37. 11. Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome p450 3A and is inhibited by atorvastatin. Drug Metab Dispos 2003;31:53–59. 12. Horsmans Y. Differential metabolism of statins: Importance in drug-drug interactions. Eur Heart J Supplements 1999;1(Suppl T):T7–T12. 13. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000;38:41–57. 14. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation. Circulation 2001;103:2780–2783. 15. Garbarz E, Lung B, Lefevre G, et al. Frequency and prognostic value of cardiac troponin I elevation after coronary stenting. Am J Cardiol 1999;84:515–518. 16. Bonz AW, Lengenfelder B, Strormann J, et al. Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition on troponin release in elective percutaneous coronary interventions after pre-treatment with aspirin and clopidogrel (TOPSTAR Trial). J Am Coll Cardiol 2002;40:662–668. 17. Klein LW, Kramer BL, Howard E, Lesch M. Incidence and clinical significance of transient creatine kinase elevation and the diagnosis of non-Q wave myocardial infarction associated with coronary angiography. J Am Coll Cardiol 1991;17:621–626. 18. Liu MW, Douglas JS Jr, Lembo NJ, King SB III. Angiographic predictors of a rise in serum creatine kinase (distal embolization) after balloon angioplasty of saphenous vein coronary artery bypass grafts. Am J Cardiol 1993;72:514–517. 19. Atmaca Y, Gulec S, Ertas F, et al. The prevention of minor myocardial injury with ticlopidine pretreatment in patients undergoing elective coronary stenting. Int J Cardiol 2003;87:151–157. 20. Atmaca Y, Dandachi R, Gulec S, et al. Comparison of clopidogrel versus ticlopidine for prevention of minor myocardial injury after elective coronary stenting. Int J Cardiol 2003;87:143–149. 21. The Epic Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956–961. 22. Van de Werf F. More evidence for a beneficial effect of platelet glycoprotein IIb/IIIa blockade during coronary interventions — Latest results from the EPILOG and CAPTURE trials. Eur Heart J 1996;17:325–326. 23. Weinbergen H, Gitt AK, Schiele R, et al. Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies. Am J Cardiol 2003;92:285–288. 24. Saw J, Steinhubl SR, Berger P, et al. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003;108:921–924. 25. Mitsios JV, Papathanasiou AI, Rodis FI, et al. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation 2004;109:1335–1338. 26. Neubauer H, Gunesdogan B, Hanefeld C, et al. Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function — A flow cytometry study. Eur Heart J 2003;24:1744–1749.