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The clopidogrel resistance can be attenuated with triple antiplatelet therapy in patients undergoing drug-eluting stents implantation
International Journal of Cardiology 134 (2009) 351 – 355 www.elsevier.com/locate/ijcard
The clopidogrel resistance can be attenuated with triple antiplatelet therapy in patients undergoing drug-eluting stents implantation ☆ Chi Young Shim a , Se-Jung Yoon d , Sungha Park a,b , Jung-Sun Kim a , Jong Rak Choi c , Young-Guk Ko a,b , Donghoon Choi a,b,⁎, Jong-Won Ha a,b , Yangsoo Jang a,b , Namsik Chung a,b , Won-Heum Shim a,b , Seung-Yun Cho a,b a Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Cardiovascular Research Institute, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Laboratory Medicine, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea d Division of Cardiology, National Health Insurance Corporation Ilsan Hospital, Koyang, Republic of Korea
b c
Received 4 November 2007; received in revised form 17 January 2008; accepted 14 February 2008 Available online 24 June 2008
Abstract Background: Triple antiplatelet therapy may have a beneficial effect on prevention of thrombotic complication in patients undergoing coronary stenting. We investigated the prevalence of aspirin and clopidogrel resistance in patients treated with dual and triple antiplatelet regimen after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Methods: A total of 400 consecutive patients underwent successful PCI with DES were randomly assigned to therapy with dual antiplatelet regimens (aspirin plus clopidogrel, Group I, n = 200) and triple antiplatelet regimens (aspirin plus clopidogrel plus cilostazol, Group II, n = 200) At two weeks after PCI, aspirin and clopidogrel resistance were assayed in 379 patients (Group I, n = 186; Group II, n = 193) by using the VerifyNow System. Results: In Group I, 21 (11.3%) patients had aspirin resistance and 74 (40.0%) had clopidogrel resistance. In Group II, 19 (9.8%) were resistant to aspirin and 38 (19.7%) to clopidogrel. The aspirin reaction unit (ARU) was not significantly different between groups (448 ± 67 vs. 439 ± 64, P = 0.200), but the percent inhibition of clopidogrel was higher in Group II (41.4 ± 24.3%,) comparing with that of Group I (26.5 ± 18.7%, P b 0.001). Conclusion: With triple antiplatelet therapy, the prevalence of clopidogrel resistance can be attenuated in patients undergoing PCI with DES. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Antiplatelet therapy; Percutaneous coronary intervention; Aspirin resistance; Clopidogrel resistance; Cilostazol
1. Introduction
☆ This work was supported by two grants, grant from Ministry of Health and Welfare Republic of Korea (A000385) and Health 21 R&D Project grant (0412-CR02-0704-0001), from the Ministry of Health and Welfare, Republic of Korea. ⁎ Corresponding author. Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College of Medicine, 134 Sinchon-Dong, Seodaemun-Gu, Seoul, Republic of Korea, 120-752. Tel.: +82 2 2228 8449; fax: +82 2 393 2041. E-mail address: [email protected] (D. Choi).
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.02.016
Although dual antiplatelet therapy with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES), serious and unexpected complications can develop [1–5]. The heterogeneity in the platelet inhibitory response of aspirin and clopidogrel may contribute to complicated results such as stent thrombosis [6–10]. Cilostazol is a potent antiplatelet agent that has been found to selectively inhibit phosphodiesterase III [11,12], a mechanism different from adenosine diphosphate (ADP)
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Table 1 Baseline characteristics.
Demographics Age, years Male gender, n (%) Body mass index, kg/m2 Risk factors Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Smoking, n (%) Clinical presentation Stable angina, n (%) Unstable angina, n (%) Acute MI, n (%) Medical history Previous MI, n (%) Prior PCI, n (%) Previous CABG, n (%) Discharge medication Beta-blockers, n (%) ACE I or ARBs, n (%) CCBs, n (%) Nitrates, n (%) Statins, n (%)
Dual therapy (n = 186)
Triple therapy (n = 193)
P value⁎
61.3 ± 9.6 132 (71.0) 24.3 ± 4.1
60.8 ± 11.7 147 (76.2) 24.7 ± 3.1
0.638 0.287 0.537
37 (19.9) 64 (34.9) 19 (10.2) 51 (27.4)
49 (25.4) 77 (39.9) 22 (11.4) 57 (29.5)
0.284 0.572 0.711 0.407
75 (40.3) 75 (40.3) 36 (19.4)
73 (37.8) 80 (41.5) 40 (20.7)
0.455 0.298 0.518
24 (12.9) 29 (12.9) 3 (1.6)
25 (13.0) 25 (13.0) 3 (1.6)
0.469 0.665 0.874
158 (84.9) 86 (46.2) 67 (36.0) 173 (93.0) 87 (46.8)
166 (86.0) 79 (40.9) 64 (33.2) 179 (92.7) 98 (50.8)
0.866 0.299 0.652 0.904 0.528
Myocardial Infarction (TIMI) flow grade 3. Exclusion criteria were: contraindication to antiplatelet agents; previous allergy or intolerance of aspirin or clopidogrel; treatment with warfarin; active bleeding or at high risk of bleeding; known platelet dysfunction; abnormal platelet count (b 100,000/mm 3 ). Aspirin was initiated at least two days prior to stent implantation in patients who underwent elective stenting. Patients received a 300mg loading dose of clopidogrel at least 12h before the stenting. Stents were deployed according to standard techniques. During the procedure, patients received heparin to maintain an activated clotting time of ≥ 250s. The maintenance dose for each antiplatelet agent was 100mg once a day for aspirin, 75mg once a day for clopidogrel, and 100mg twice a day for cilostazol. Among the enrolled patients, 379 patients (Group I, n = 186; Group II, n = 193) could be followed as outpatients two weeks after PCI with DES. 2.2. Specimen collection
Abbreviations: MI = myocardial infarction, PCI = percutaneous coronary intervention, CABG = coronary artery bypass graft, ACE I = angiotensin converting enzyme inhibitor, ARBs = angiotensin receptor blockers, CCBs = calcium cannel blockers. ⁎P b 0.05 is considered significant.
Complete blood count and blood chemistry, including liver and renal function tests, were performed before and two weeks after the coronary stenting. Samples were obtained by antecubital venipunture and the initial 3 to 4mm of blood was discarded to avoid spontaneous platelet activation. The second samples were collected in tubes containing 3.2% citrate for rapid platelet-function assay. 2.3. Determination of aspirin resistance
receptor antagonists. Previous studies suggest that adding a cilostazol to aspirin and clopidogrel regimen, so called triple antiplatelet therapy, is more effective in preventing thrombotic complications after stenting than dual antiplatelet therapy [13,14]. But the exact mechanism of the beneficial impact of triple antiplatelet therapy remains unknown and the effect on responsiveness of aspirin and clopidogrel is also unclear. Therefore we evaluated the prevalence of aspirin and clopidogrel resistance in patients with triple antiplatelet therapy and compared our findings with dual antiplatelet therapy after PCI with DES. 2. Methods
VerifyNow-ASA (Accumetrics, San Diego, California) is a rapid platelet-function, cartridge-based assay designed to measure platelet agglutination in response to metallic cations and propyl gallate, which activate the cyclooxygenase-1 pathway. The assay is based on the ability of activated platelets to bind fibrinogen and results are expressed as aspirin reaction units (ARU). An ARU of ≥ 550 indicates the absence of aspirin-induced platelet dysfunction and is defined as aspirin resistance [15].
Table 2 Laboratory characteristics.
2.1. Study population From October 2006 to May 2007, 400 consecutive patients who underwent successful PCI with DES were randomly assigned to treatment with dual antiplatelet regimens (aspirin plus clopidogrel, Group I, n = 200) or triple antiplatelet regimens (aspirin plus clopidogrel plus cilostazol, Group II, n = 200) after successful coronary stenting. Inclusion criteria were: symptomatic coronary artery disease or documented myocardial ischemia (by treadmill exercise testing or sestamibi scan); angiographic evidence of ≥ 50% diameter stenosis or primary stenting in patients with acute myocardial infarction and postprocedure Thromobolysis In
Hemoglobin (g/dL) Platelet count (103 μL) Fasting glucose (mg/dL) Creatinine (mg/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) hs CRP (mg/dL)
Dual therapy (n = 186)
Triple therapy (n = 193)
P value⁎
13.1 ± 1.6 257 ± 65 95 ± 15 1.0 ± 0.4 176 ± 37 121 ± 42 49 ± 16 105 ± 29 1.9 ± 1.2
13.4 ± 1.9 265 ± 84 102 ± 28 1.0 ± 0.3 175 ± 37 132 ± 73 47 ± 11 102 ± 36 2.1 ± 1.6
0.397 0.492 0.266 0.676 0.848 0.336 0.473 0.610 0.355
Abbreviations: HDL = high density lipoprotein, LDL = low density lipoprotein, hs CRP = high sensitivity C-reactive protein. ⁎P b 0.05 is considered significant.
C.Y. Shim et al. / International Journal of Cardiology 134 (2009) 351–355 Table 3 Angiographic characteristics.
Angiographic diagnosis Single-vessel, n (%) Multi-vessel, n (%) Number of stents Stents/patient (mean) Treated artery LAD, n (%) LCx, n (%) RCA, n (%) Left main, n (%) Intermedius, n (%) Graft, n (%)
Dual therapy (n = 186)
Triple therapy (n = 193)
P value⁎
77 (41.4) 109 (58.6) 292 1.57
75 (38.9) 118 (61.1) 311 1.61
0.652 0.344 0.642
115 (61.8) 47 (25.3) 53 (28.5) 9 (4.8) 1 (0.5) 2 (1.1)
120 (62.2) 48 (24.9) 57 (29.5) 8 (4.1) 3 (1.6) 2 (1.0)
0.949 0.967 0.868 0.790 0.124 0.925
Abbreviations: LAD = left anterior descending artery, LCx = left circumflex artery, RCA = right coronary artery. ⁎P b 0.05 is considered significant.
2.4. Determination of clopidogrel resistance VerifyNow-P2Y12 (Accumetrics, San Diego, California) is a rapid platelet-function, cartridge-based assay designed to directly measure the effects of clopidogrel on the P2Y12 receptor. VerifyNow P2Y12 is more sensitive than ADPinduced platelet aggregometry and enhances specificity for the P2Y12 receptor by using prostaglandin E1 to attenuate P2Y1 activation [16]. The assay is also based on the ability of activated platelets to bind to fibrinogen. Results are expressed as P2Y12 reaction units (PRU) and percentage inhibition [16,17]. PRU reports the amount of P2Y12 receptor mediated aggregation specific to the platelet and are calculated as a function of the rate and extent of platelet aggregation in the ADP channel. Percentage inhibition is the percent change from baseline aggregation and is calculated from the PRU result and the “estimated baseline” result, which is an independent measurement based on the rate and extent of platelet aggregation in the TRAP (Thrombin Receptor Activating Peptide) channel [17]. The clopidogrel
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responsiveness can be evaluated without a baseline sample. This is possible because the device has a second channel of TRAP. There is very strong correlation between true inhibition that calculated using a baseline sample before clopidogrel treatment and % inhibition that calculated using an “estimated baseline” applying TRAP channel [16]. k inhibition ¼ ð1 PRU=estimated baselineÞ 100 The percent inhibition (%) of b 20% indicates the absence of clopidogrel-induced platelet dysfunction and was defined as clopidogrel resistance. 2.5. Statistical analysis Continuous variables are reported as mean ± standard deviation (SD) and categorical variables are presented as frequencies and percentages. Continuous variables were compared by unpaired Student's t test and categorical variables by chi-square test or Fisher's exact test. Analyses were performed using SPSS version 13.0 statistical software (SPSS Inc., Chicago, Illinois); statistical significance is indicated by a P value of b 0.05. 3. Results 3.1. Baseline characteristics The demographic and clinical details of the 379 patients are presented in Table 1. There were no significant differences between baseline characteristics of the two groups. Concomitant medication usage did not differ significantly between the groups. 3.2. Laboratory characteristics There were no significant differences between the two groups with regard to laboratory characteristics (Table 2).
Fig. 1. Antiplatelets responsiveness in the two groups. Aspirin responsiveness B. Clopidogrel responsiveness. Group I, dual antipletelet therapy; Group II, triple antipletelet therapy. Error bar; mean ± standard deviation.
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Table 4 Antiplatelet resistance test.
4. Discussion
and aspirin and who had undergone coronary stenting [13]. But the exact mechanism of beneficial effects of triple antiplatelet therapy was unknown. In addition, the previous studies examined bare-metal stents (BMS) usage and not DES as were used in our study. Resistance to clopidogrel is considered an important cause of stent thrombosis and may be more considerable in the era of DES. Our study was performed on patients who underwent coronary stenting with DES and is the first data to analyze the effect of additional use of cilostazol on overcoming clopidogrel resistance after PCI with DES. As was discussed earlier, aspirin resistance is commonly defined as an ARU greater than 550 [15], but clopidogrel resistance has been defined by several references using the VerifyNow system [18,19]. In some studies, clopidogrel responsiveness has been divided into three groups: clopidogrel responder N 30% inhibition rate; semi-responder 10– 30% inhibition rate; non-responder b 10% inhibition rate [18]. We also analyzed the prevalence of clopidogrel resistance in dual and triple antiplatelet therapy groups using the different definition described above. In the triple therapy group, the responder rate was higher and the rate of the nonresponder was lower than that observed in the dual therapy group (Fig. 2). It remains uncertain that the exact mechanism of the beneficial effect of additional cilostazol on the clopidogrel resistance. The mode of action of cilostazol is not fully understood although it is recognized to be different from that of acetylsalicylic acid. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors, inhibiting phosphodiesterase activity and suppressing cAMP degradation. The resultant increase in cAMP in platelets and blood vessels leads to inhibition of platelet aggregation and vasodilation [20]. It can be suggested that one of possible mechanisms reducing the prevalence of clopidogrel resistance is decreasing degranulation of aggregation factors such as ADP and serotonin from platelets following from decreased intracellular Ca2+ levels [21]. In fact, there were evidence that cilostazol inhibited ADPinduced platelet aggregation [22,23]. VerifyNow P2Y12
This study demonstrated that triple antiplatelet therapy might be more effective than dual antiplatelet therapy in reducing clopidogrel resistance after coronary stenting with DES. Although triple antiplatelet therapy significantly reduced the prevalence of clopidogrel resistance, we couldn't observe a reduction in the prevalence of aspirin resistance when compared with dual antiplatelet therapy. In a previous study, triple antiplatelet therapy seemed to be more effective in preventing thrombotic complications, such as stent thrombosis or major adverse cardiac events, after stenting without an increased risk of side effects when compared with a dual antiplatelet regimen [14]. One study revealed an additional attenuation in P-selectin expression of platelets was induced by short-term treatment of low dose cilostazol to those who had already been given clopidogrel
Fig. 2. Prevalence of clopidogrel resistance. White bars: dual antiplatelet therapy; black bars: triple antiplatelet therapy.
Aspirin resistance Prevalence, n (%) Aspirin reaction unit Clopidogrel resistance Prevalence, n (%) Inhibition rate, %
Dual therapy (n = 186)
Triple therapy (n = 193)
21 (11.3) 448 ± 67
19 (9.8) 439 ± 64
74 (40.0) 26.5 ± 18.7
38 (19.7) 41.4 ± 24.3
P value⁎
0.647 0.200 b0.001 b0.001
⁎P b 0.05 is considered significant.
3.3. Angiographic characteristics There were no significant differences in the anatomical characteristics between the 2 groups (Table 3). The frequency of multi-vessel disease and the number of coronary stents in patient were also similar. With regard to the composition of treated arteries, there were no significant differences. 3.4. The rates of aspirin and clopidogrel resistance Among the 379 studied patients, aspirin resistance was observed in 40 patients (10.6%) with the definition of RPFAASA ARU ≥ 550. One-hundred twelve patients (26.9%) met the definition of clopidogrel resistance. Twenty-one (11.3%) patients were resistant to aspirin and 74 (40.0%) to clopidogrel in Group I. Nineteen (9.8%) were resistant to aspirin and 38 (19.7%) to clopidogrel in Group II. There was no significant difference in the prevalence of aspirin resistance between groups (11.3% vs. 9.8%, P = 0.647), but we observed a significant reduction in the prevalence of clopidogrel resistance in Group II (40.0% vs. 19.7%, P b 0.001) (Fig. 1). The ARU was slightly lower in Group II but there was no statistical difference between groups (448 ± 67 vs. 439 ± 64, P = 200). However, the percentage inhibition was higher in Group II (41.4 ± 24.3%, P b 0.001) compared with that of Group I (26.5 ± 18.7%) (Table 4).
C.Y. Shim et al. / International Journal of Cardiology 134 (2009) 351–355
assay uses combination of ADP and PGE1 to directly measure the effect of clopidogrel on P2Y12 receptor. ADP is used to maximally activate the P2Y1 and P2Y12 receptor, whereas PGE1 is used to suppress the ADP-induced P2Y1 mediated increase in intracellular calcium level and reduce the activation contribution from P2Y1. Therefore, we believe that non specific inhibition of platelet activation may not have a significant effect on the result of clopidogrel resistance and aspirin resistance. The results from this study demonstrated the additive effect of cilostazol on clopidogrel resistance but not aspirin resistance. Perhaps this may be due to the fact that cilostazol may have a specific mechanism in inhibiting the ADP-P2Y12 mediated platelet inhibition. A few limitations of this study need to be addressed. Firstly, the sample size of the present study was relatively small, and therefore it was difficult to fully evaluate clinical outcomes, such as the incidence of stent thrombosis. Second, we didn't check the platelet activity with any other methodologies except the VerifyNow system. But, the VerifyNow system is already validated and approved in FDA for analyzing the aspirin and clopidogrel resistance. Also, this method can analyze the drug-specific responsiveness of platelets. Third, the drug compliance was estimated only depending on the history taking. Because we checked the clopidogrel resistance at 2 weeks after PCI, we believe that poor drug compliance would not have been a major limitation among this study population. In conclusion, with triple antiplatelet therapy, the prevalence of clopidogrel resistance can be attenuated in patients undergoing PCI with DES. Additional researches, including large-scale randomized clinical trials, should be implemented in order to compare the clinical outcomes of dual antiplatelet vs. triple antiplatelet therapy according to clopidogrel responsiveness. References [1] Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967–71. [2] Orford JL, Lennon R, Melby S, et al. Frequency and correlates of coronary stent thrombosis in the modern era: analysis of a single center registry. J Am Coll Cardiol 2002;40:1567–72. [3] Takahashi S, Kaneda H, Tanaka S, et al. Late angiographic stent thrombosis after sirolimus-eluting stent implantation. Circ J 2007;71:226–8. [4] Ishikawa T, Mutoh M, Fuda Y, et al. Documented subacute stent thrombosis within thirty days after stenting with sirolimus-eluting stent (Cypher) for acute myocardial infarction: a Japanese single center retrospective non-randomized study. Circ J 2006;70:1091–2. [5] Biondi-Zoccai GG, Agostoni P, Sangiorgi GM, et al. TRUE (Taxus in Real-Life Usage Evaluation) Study Investigators. Comparison of ticlopidine vs. clopidogrel in addition to aspirin after paclitaxel-eluting stent implantation: insights from the TRUE (Taxusin Real-life Usage Evaluation) Study. Int J Cardiol 2006;108:406–7.
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[6] Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirinresistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002;105:1650–5. [7] Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003;41:961–5. [8] Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908–13. [9] Gurbel PA, Samara WM, Bliden KP. Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis. Platelets 2004;15:95–9. [10] Almsherqi ZA, McLachlan CS, Mossop P, Deng Y. Optimal antiplatelet treatment for percutaneous coronary intervention: clopidogrel vs. ticlopidine. Int J Cardiol 2007;114:101–2. [11] Tanaka T, Ishikawa T, Hagiwara M, Onoda K, Itoh H, Hidaka H. Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor, on the contraction of vascular smooth muscle. Pharmacology 1988;36:313–20. [12] Kunishima T, Musha H, Eto F, et al. A randomized trial of aspirin versus cilostazol therapy after successful coronary stent implantation. Clin Ther 1997;19:1058–66. [13] Ahn JC, Song WH, Kwon JA, et al. Effects of cilostazol on platelet activation in coronary stenting patients who already treated with aspirin and clopidogrel. Korean J Intern Med 2004;19:230–6. [14] Lee SW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting. J Am Coll Cardiol 2005;46:1833–7. [15] Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after nonurgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004;43:1122–6. [16] Malinin A, Pokov A, Spergling M, et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res 2007;119:277–84. [17] Malinin A, Pokov A, Swaim L, Kotob M, Serebruany V. Validation of a VerifyNow-P2Y12® Cartridge for Monitoring Platelet Inhibition with Clopidogrel. Methods Find Exp Clin Pharmacol 2006;28:1–8. [18] Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003;89:783–7. [19] Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45:246–51. [20] Liu Y, Shakur Y, Yoshitake M, Kambayashi Ji J. Cilostazol (pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine uptake. Cardiovasc Drug Rev 2001;19:369–86. [21] Okuda Y, Kimura Y, Yamashita K. Cilostazol. Cardiovasc Drug Revs 1993;11:451–65. [22] Sudo T, Ito H, Ozeki Y, Kimura Y. Estimation of anti-platelet drugs on human platelet aggregation with a novel whole blood aggregometer by a screen filtration pressure method. Br J Pharmacol 2001;133:1396–404. [23] Woo SK, Kang WK, Kwon KI. Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans. Clin Pharmacol Ther 2003;71:246–52.
The clopidogrel resistance can be attenuated with triple antiplatelet therapy in patients undergoing drug-eluting stents implantation ☆ Chi Young Shim a , Se-Jung Yoon d , Sungha Park a,b , Jung-Sun Kim a , Jong Rak Choi c , Young-Guk Ko a,b , Donghoon Choi a,b,⁎, Jong-Won Ha a,b , Yangsoo Jang a,b , Namsik Chung a,b , Won-Heum Shim a,b , Seung-Yun Cho a,b a Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Cardiovascular Research Institute, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Laboratory Medicine, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea d Division of Cardiology, National Health Insurance Corporation Ilsan Hospital, Koyang, Republic of Korea
b c
Received 4 November 2007; received in revised form 17 January 2008; accepted 14 February 2008 Available online 24 June 2008
Abstract Background: Triple antiplatelet therapy may have a beneficial effect on prevention of thrombotic complication in patients undergoing coronary stenting. We investigated the prevalence of aspirin and clopidogrel resistance in patients treated with dual and triple antiplatelet regimen after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Methods: A total of 400 consecutive patients underwent successful PCI with DES were randomly assigned to therapy with dual antiplatelet regimens (aspirin plus clopidogrel, Group I, n = 200) and triple antiplatelet regimens (aspirin plus clopidogrel plus cilostazol, Group II, n = 200) At two weeks after PCI, aspirin and clopidogrel resistance were assayed in 379 patients (Group I, n = 186; Group II, n = 193) by using the VerifyNow System. Results: In Group I, 21 (11.3%) patients had aspirin resistance and 74 (40.0%) had clopidogrel resistance. In Group II, 19 (9.8%) were resistant to aspirin and 38 (19.7%) to clopidogrel. The aspirin reaction unit (ARU) was not significantly different between groups (448 ± 67 vs. 439 ± 64, P = 0.200), but the percent inhibition of clopidogrel was higher in Group II (41.4 ± 24.3%,) comparing with that of Group I (26.5 ± 18.7%, P b 0.001). Conclusion: With triple antiplatelet therapy, the prevalence of clopidogrel resistance can be attenuated in patients undergoing PCI with DES. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Antiplatelet therapy; Percutaneous coronary intervention; Aspirin resistance; Clopidogrel resistance; Cilostazol
1. Introduction
☆ This work was supported by two grants, grant from Ministry of Health and Welfare Republic of Korea (A000385) and Health 21 R&D Project grant (0412-CR02-0704-0001), from the Ministry of Health and Welfare, Republic of Korea. ⁎ Corresponding author. Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College of Medicine, 134 Sinchon-Dong, Seodaemun-Gu, Seoul, Republic of Korea, 120-752. Tel.: +82 2 2228 8449; fax: +82 2 393 2041. E-mail address: [email protected] (D. Choi).
0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.02.016
Although dual antiplatelet therapy with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES), serious and unexpected complications can develop [1–5]. The heterogeneity in the platelet inhibitory response of aspirin and clopidogrel may contribute to complicated results such as stent thrombosis [6–10]. Cilostazol is a potent antiplatelet agent that has been found to selectively inhibit phosphodiesterase III [11,12], a mechanism different from adenosine diphosphate (ADP)
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Table 1 Baseline characteristics.
Demographics Age, years Male gender, n (%) Body mass index, kg/m2 Risk factors Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Smoking, n (%) Clinical presentation Stable angina, n (%) Unstable angina, n (%) Acute MI, n (%) Medical history Previous MI, n (%) Prior PCI, n (%) Previous CABG, n (%) Discharge medication Beta-blockers, n (%) ACE I or ARBs, n (%) CCBs, n (%) Nitrates, n (%) Statins, n (%)
Dual therapy (n = 186)
Triple therapy (n = 193)
P value⁎
61.3 ± 9.6 132 (71.0) 24.3 ± 4.1
60.8 ± 11.7 147 (76.2) 24.7 ± 3.1
0.638 0.287 0.537
37 (19.9) 64 (34.9) 19 (10.2) 51 (27.4)
49 (25.4) 77 (39.9) 22 (11.4) 57 (29.5)
0.284 0.572 0.711 0.407
75 (40.3) 75 (40.3) 36 (19.4)
73 (37.8) 80 (41.5) 40 (20.7)
0.455 0.298 0.518
24 (12.9) 29 (12.9) 3 (1.6)
25 (13.0) 25 (13.0) 3 (1.6)
0.469 0.665 0.874
158 (84.9) 86 (46.2) 67 (36.0) 173 (93.0) 87 (46.8)
166 (86.0) 79 (40.9) 64 (33.2) 179 (92.7) 98 (50.8)
0.866 0.299 0.652 0.904 0.528
Myocardial Infarction (TIMI) flow grade 3. Exclusion criteria were: contraindication to antiplatelet agents; previous allergy or intolerance of aspirin or clopidogrel; treatment with warfarin; active bleeding or at high risk of bleeding; known platelet dysfunction; abnormal platelet count (b 100,000/mm 3 ). Aspirin was initiated at least two days prior to stent implantation in patients who underwent elective stenting. Patients received a 300mg loading dose of clopidogrel at least 12h before the stenting. Stents were deployed according to standard techniques. During the procedure, patients received heparin to maintain an activated clotting time of ≥ 250s. The maintenance dose for each antiplatelet agent was 100mg once a day for aspirin, 75mg once a day for clopidogrel, and 100mg twice a day for cilostazol. Among the enrolled patients, 379 patients (Group I, n = 186; Group II, n = 193) could be followed as outpatients two weeks after PCI with DES. 2.2. Specimen collection
Abbreviations: MI = myocardial infarction, PCI = percutaneous coronary intervention, CABG = coronary artery bypass graft, ACE I = angiotensin converting enzyme inhibitor, ARBs = angiotensin receptor blockers, CCBs = calcium cannel blockers. ⁎P b 0.05 is considered significant.
Complete blood count and blood chemistry, including liver and renal function tests, were performed before and two weeks after the coronary stenting. Samples were obtained by antecubital venipunture and the initial 3 to 4mm of blood was discarded to avoid spontaneous platelet activation. The second samples were collected in tubes containing 3.2% citrate for rapid platelet-function assay. 2.3. Determination of aspirin resistance
receptor antagonists. Previous studies suggest that adding a cilostazol to aspirin and clopidogrel regimen, so called triple antiplatelet therapy, is more effective in preventing thrombotic complications after stenting than dual antiplatelet therapy [13,14]. But the exact mechanism of the beneficial impact of triple antiplatelet therapy remains unknown and the effect on responsiveness of aspirin and clopidogrel is also unclear. Therefore we evaluated the prevalence of aspirin and clopidogrel resistance in patients with triple antiplatelet therapy and compared our findings with dual antiplatelet therapy after PCI with DES. 2. Methods
VerifyNow-ASA (Accumetrics, San Diego, California) is a rapid platelet-function, cartridge-based assay designed to measure platelet agglutination in response to metallic cations and propyl gallate, which activate the cyclooxygenase-1 pathway. The assay is based on the ability of activated platelets to bind fibrinogen and results are expressed as aspirin reaction units (ARU). An ARU of ≥ 550 indicates the absence of aspirin-induced platelet dysfunction and is defined as aspirin resistance [15].
Table 2 Laboratory characteristics.
2.1. Study population From October 2006 to May 2007, 400 consecutive patients who underwent successful PCI with DES were randomly assigned to treatment with dual antiplatelet regimens (aspirin plus clopidogrel, Group I, n = 200) or triple antiplatelet regimens (aspirin plus clopidogrel plus cilostazol, Group II, n = 200) after successful coronary stenting. Inclusion criteria were: symptomatic coronary artery disease or documented myocardial ischemia (by treadmill exercise testing or sestamibi scan); angiographic evidence of ≥ 50% diameter stenosis or primary stenting in patients with acute myocardial infarction and postprocedure Thromobolysis In
Hemoglobin (g/dL) Platelet count (103 μL) Fasting glucose (mg/dL) Creatinine (mg/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) hs CRP (mg/dL)
Dual therapy (n = 186)
Triple therapy (n = 193)
P value⁎
13.1 ± 1.6 257 ± 65 95 ± 15 1.0 ± 0.4 176 ± 37 121 ± 42 49 ± 16 105 ± 29 1.9 ± 1.2
13.4 ± 1.9 265 ± 84 102 ± 28 1.0 ± 0.3 175 ± 37 132 ± 73 47 ± 11 102 ± 36 2.1 ± 1.6
0.397 0.492 0.266 0.676 0.848 0.336 0.473 0.610 0.355
Abbreviations: HDL = high density lipoprotein, LDL = low density lipoprotein, hs CRP = high sensitivity C-reactive protein. ⁎P b 0.05 is considered significant.
C.Y. Shim et al. / International Journal of Cardiology 134 (2009) 351–355 Table 3 Angiographic characteristics.
Angiographic diagnosis Single-vessel, n (%) Multi-vessel, n (%) Number of stents Stents/patient (mean) Treated artery LAD, n (%) LCx, n (%) RCA, n (%) Left main, n (%) Intermedius, n (%) Graft, n (%)
Dual therapy (n = 186)
Triple therapy (n = 193)
P value⁎
77 (41.4) 109 (58.6) 292 1.57
75 (38.9) 118 (61.1) 311 1.61
0.652 0.344 0.642
115 (61.8) 47 (25.3) 53 (28.5) 9 (4.8) 1 (0.5) 2 (1.1)
120 (62.2) 48 (24.9) 57 (29.5) 8 (4.1) 3 (1.6) 2 (1.0)
0.949 0.967 0.868 0.790 0.124 0.925
Abbreviations: LAD = left anterior descending artery, LCx = left circumflex artery, RCA = right coronary artery. ⁎P b 0.05 is considered significant.
2.4. Determination of clopidogrel resistance VerifyNow-P2Y12 (Accumetrics, San Diego, California) is a rapid platelet-function, cartridge-based assay designed to directly measure the effects of clopidogrel on the P2Y12 receptor. VerifyNow P2Y12 is more sensitive than ADPinduced platelet aggregometry and enhances specificity for the P2Y12 receptor by using prostaglandin E1 to attenuate P2Y1 activation [16]. The assay is also based on the ability of activated platelets to bind to fibrinogen. Results are expressed as P2Y12 reaction units (PRU) and percentage inhibition [16,17]. PRU reports the amount of P2Y12 receptor mediated aggregation specific to the platelet and are calculated as a function of the rate and extent of platelet aggregation in the ADP channel. Percentage inhibition is the percent change from baseline aggregation and is calculated from the PRU result and the “estimated baseline” result, which is an independent measurement based on the rate and extent of platelet aggregation in the TRAP (Thrombin Receptor Activating Peptide) channel [17]. The clopidogrel
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responsiveness can be evaluated without a baseline sample. This is possible because the device has a second channel of TRAP. There is very strong correlation between true inhibition that calculated using a baseline sample before clopidogrel treatment and % inhibition that calculated using an “estimated baseline” applying TRAP channel [16]. k inhibition ¼ ð1 PRU=estimated baselineÞ 100 The percent inhibition (%) of b 20% indicates the absence of clopidogrel-induced platelet dysfunction and was defined as clopidogrel resistance. 2.5. Statistical analysis Continuous variables are reported as mean ± standard deviation (SD) and categorical variables are presented as frequencies and percentages. Continuous variables were compared by unpaired Student's t test and categorical variables by chi-square test or Fisher's exact test. Analyses were performed using SPSS version 13.0 statistical software (SPSS Inc., Chicago, Illinois); statistical significance is indicated by a P value of b 0.05. 3. Results 3.1. Baseline characteristics The demographic and clinical details of the 379 patients are presented in Table 1. There were no significant differences between baseline characteristics of the two groups. Concomitant medication usage did not differ significantly between the groups. 3.2. Laboratory characteristics There were no significant differences between the two groups with regard to laboratory characteristics (Table 2).
Fig. 1. Antiplatelets responsiveness in the two groups. Aspirin responsiveness B. Clopidogrel responsiveness. Group I, dual antipletelet therapy; Group II, triple antipletelet therapy. Error bar; mean ± standard deviation.
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Table 4 Antiplatelet resistance test.
4. Discussion
and aspirin and who had undergone coronary stenting [13]. But the exact mechanism of beneficial effects of triple antiplatelet therapy was unknown. In addition, the previous studies examined bare-metal stents (BMS) usage and not DES as were used in our study. Resistance to clopidogrel is considered an important cause of stent thrombosis and may be more considerable in the era of DES. Our study was performed on patients who underwent coronary stenting with DES and is the first data to analyze the effect of additional use of cilostazol on overcoming clopidogrel resistance after PCI with DES. As was discussed earlier, aspirin resistance is commonly defined as an ARU greater than 550 [15], but clopidogrel resistance has been defined by several references using the VerifyNow system [18,19]. In some studies, clopidogrel responsiveness has been divided into three groups: clopidogrel responder N 30% inhibition rate; semi-responder 10– 30% inhibition rate; non-responder b 10% inhibition rate [18]. We also analyzed the prevalence of clopidogrel resistance in dual and triple antiplatelet therapy groups using the different definition described above. In the triple therapy group, the responder rate was higher and the rate of the nonresponder was lower than that observed in the dual therapy group (Fig. 2). It remains uncertain that the exact mechanism of the beneficial effect of additional cilostazol on the clopidogrel resistance. The mode of action of cilostazol is not fully understood although it is recognized to be different from that of acetylsalicylic acid. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors, inhibiting phosphodiesterase activity and suppressing cAMP degradation. The resultant increase in cAMP in platelets and blood vessels leads to inhibition of platelet aggregation and vasodilation [20]. It can be suggested that one of possible mechanisms reducing the prevalence of clopidogrel resistance is decreasing degranulation of aggregation factors such as ADP and serotonin from platelets following from decreased intracellular Ca2+ levels [21]. In fact, there were evidence that cilostazol inhibited ADPinduced platelet aggregation [22,23]. VerifyNow P2Y12
This study demonstrated that triple antiplatelet therapy might be more effective than dual antiplatelet therapy in reducing clopidogrel resistance after coronary stenting with DES. Although triple antiplatelet therapy significantly reduced the prevalence of clopidogrel resistance, we couldn't observe a reduction in the prevalence of aspirin resistance when compared with dual antiplatelet therapy. In a previous study, triple antiplatelet therapy seemed to be more effective in preventing thrombotic complications, such as stent thrombosis or major adverse cardiac events, after stenting without an increased risk of side effects when compared with a dual antiplatelet regimen [14]. One study revealed an additional attenuation in P-selectin expression of platelets was induced by short-term treatment of low dose cilostazol to those who had already been given clopidogrel
Fig. 2. Prevalence of clopidogrel resistance. White bars: dual antiplatelet therapy; black bars: triple antiplatelet therapy.
Aspirin resistance Prevalence, n (%) Aspirin reaction unit Clopidogrel resistance Prevalence, n (%) Inhibition rate, %
Dual therapy (n = 186)
Triple therapy (n = 193)
21 (11.3) 448 ± 67
19 (9.8) 439 ± 64
74 (40.0) 26.5 ± 18.7
38 (19.7) 41.4 ± 24.3
P value⁎
0.647 0.200 b0.001 b0.001
⁎P b 0.05 is considered significant.
3.3. Angiographic characteristics There were no significant differences in the anatomical characteristics between the 2 groups (Table 3). The frequency of multi-vessel disease and the number of coronary stents in patient were also similar. With regard to the composition of treated arteries, there were no significant differences. 3.4. The rates of aspirin and clopidogrel resistance Among the 379 studied patients, aspirin resistance was observed in 40 patients (10.6%) with the definition of RPFAASA ARU ≥ 550. One-hundred twelve patients (26.9%) met the definition of clopidogrel resistance. Twenty-one (11.3%) patients were resistant to aspirin and 74 (40.0%) to clopidogrel in Group I. Nineteen (9.8%) were resistant to aspirin and 38 (19.7%) to clopidogrel in Group II. There was no significant difference in the prevalence of aspirin resistance between groups (11.3% vs. 9.8%, P = 0.647), but we observed a significant reduction in the prevalence of clopidogrel resistance in Group II (40.0% vs. 19.7%, P b 0.001) (Fig. 1). The ARU was slightly lower in Group II but there was no statistical difference between groups (448 ± 67 vs. 439 ± 64, P = 200). However, the percentage inhibition was higher in Group II (41.4 ± 24.3%, P b 0.001) compared with that of Group I (26.5 ± 18.7%) (Table 4).
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assay uses combination of ADP and PGE1 to directly measure the effect of clopidogrel on P2Y12 receptor. ADP is used to maximally activate the P2Y1 and P2Y12 receptor, whereas PGE1 is used to suppress the ADP-induced P2Y1 mediated increase in intracellular calcium level and reduce the activation contribution from P2Y1. Therefore, we believe that non specific inhibition of platelet activation may not have a significant effect on the result of clopidogrel resistance and aspirin resistance. The results from this study demonstrated the additive effect of cilostazol on clopidogrel resistance but not aspirin resistance. Perhaps this may be due to the fact that cilostazol may have a specific mechanism in inhibiting the ADP-P2Y12 mediated platelet inhibition. A few limitations of this study need to be addressed. Firstly, the sample size of the present study was relatively small, and therefore it was difficult to fully evaluate clinical outcomes, such as the incidence of stent thrombosis. Second, we didn't check the platelet activity with any other methodologies except the VerifyNow system. But, the VerifyNow system is already validated and approved in FDA for analyzing the aspirin and clopidogrel resistance. Also, this method can analyze the drug-specific responsiveness of platelets. Third, the drug compliance was estimated only depending on the history taking. Because we checked the clopidogrel resistance at 2 weeks after PCI, we believe that poor drug compliance would not have been a major limitation among this study population. In conclusion, with triple antiplatelet therapy, the prevalence of clopidogrel resistance can be attenuated in patients undergoing PCI with DES. Additional researches, including large-scale randomized clinical trials, should be implemented in order to compare the clinical outcomes of dual antiplatelet vs. triple antiplatelet therapy according to clopidogrel responsiveness. References [1] Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967–71. [2] Orford JL, Lennon R, Melby S, et al. Frequency and correlates of coronary stent thrombosis in the modern era: analysis of a single center registry. J Am Coll Cardiol 2002;40:1567–72. [3] Takahashi S, Kaneda H, Tanaka S, et al. Late angiographic stent thrombosis after sirolimus-eluting stent implantation. Circ J 2007;71:226–8. [4] Ishikawa T, Mutoh M, Fuda Y, et al. Documented subacute stent thrombosis within thirty days after stenting with sirolimus-eluting stent (Cypher) for acute myocardial infarction: a Japanese single center retrospective non-randomized study. Circ J 2006;70:1091–2. [5] Biondi-Zoccai GG, Agostoni P, Sangiorgi GM, et al. TRUE (Taxus in Real-Life Usage Evaluation) Study Investigators. Comparison of ticlopidine vs. clopidogrel in addition to aspirin after paclitaxel-eluting stent implantation: insights from the TRUE (Taxusin Real-life Usage Evaluation) Study. Int J Cardiol 2006;108:406–7.
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