Yonsei Med J.  2012 Sep;53(5):906-914.

Effects of 600 mg versus 300 mg Loading Dose of Clopidogrel in Asian Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Long-Term Follow-Up Study

• Song PS
• Hahn JY
• Song YB
• Choi JH
• Choi SH
• Kang GH
• Ahn KT
• Lim WH
• Park KW
• Kim HS
• Gwon HC

Abstract

PURPOSE
The optimum loading dose of clopidogrel has not been established in Asian patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Our aim was to evaluate the impact of different clopidogrel loading doses on short- and long-term clinical outcomes in Asian STEMI patients undergoing primary PCI.
MATERIALS AND METHODS
We studied 691 STEMI patients undergoing primary PCI, loaded with 600 mg (n=381) or 300 mg (n=310) of clopidogrel. The primary outcome was major adverse cardiac events (MACEs), defined as a composite of all-cause death, reinfarction, or target vessel revascularization (TVR).
RESULTS
Baseline clinical and peri-procedural characteristics were mostly comparable between the 600 mg and 300 mg groups. There were no differences in 1 month MACEs as well as all-cause death, reinfarction, TVR, and stent thrombosis between the two groups. After a median follow-up of 921 days, MACEs [adjusted hazard ratio (HR) for the 600 mg group 1.79, 95% confidence interval (CI): 0.80-3.97, p=0.153], all-cause death (adjusted HR for the 600 mg group 0.97, 95% CI: 0.50-1.88, p=0.928), reinfarction (adjusted HR for the 600 mg group 1.03, 95% CI: 0.55-1.91, p=0.937), and TVR (adjusted HR for the 600 mg group 1.36, 95% CI: 0.68-2.69, p=0.388) did not differ between the two groups. These results were reliable even after analysis of propensity score-matched population, and were also constant among various subgroups.
CONCLUSION
A 600 mg loading dose of clopidogrel did not result in better short- and long-term clinical outcomes in Asian STEMI patients undergoing primary PCI.

Keyword

Clopidogrel; myocardial infarction; percutaneous transluminal coronary angioplasty

MeSH Terms

Angioplasty, Balloon, Coronary
Asian Continental Ancestry Group*
Follow-Up Studies*
Humans
Myocardial Infarction*
Percutaneous Coronary Intervention*
Stents
Thrombosis

Figure

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  Fig. 1 Long-term clinical outcomes in the overall population. Kaplan-Meier curves for the long-term clinical outcomes according to the clopidogrel loading doses in the overall population. (A) Cumulative rate of MACEs (major adverse cardiac events). (B) Cumulative rate of all-cause death. (C) Cumulative rate of reinfarction. (D) Cumulative rate of TVR (target vessel revascularization). HR, hazard ratio; CI, confidence interval.

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  Fig. 2 Long-term clinical outcomes in the propensity-matched population. Kaplan-Meier curves for the long-term clinical outcomes according to the clopidogrel loading doses in the propensity-matched population. (A) Cumulative rate of MACEs (major adverse cardiac events). (B) Cumulative rate of all-cause death. (C) Cumulative rate of reinfarction. (D) Cumulative rate of TVR (target vessel revascularization). HR, hazard ratio; CI, confidence interval.

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  Fig. 3 Subgroup analyses for major adverse cardiac events in nine various subgroups for clopidogrel doses comparison. CI, confidence interval; GP IIb/IIIa, glycoprotein IIb/IIIa receptor inhibitor; LAD, left anterior descending coronary artery as culprit vessel; MVCAD, multi-vessel coronary artery disease.

Reference

1. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001. 358:527–533.

2. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002. 288:2411–2420.

3. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005. 111:2099–2106.

4. Cuisset T, Frere C, Quilici J, Morange PE, Nait-Saidi L, Carvajal J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol. 2006. 48:1339–1345.

5. Dangas G, Mehran R, Guagliumi G, Caixeta A, Witzenbichler B, Aoki J, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol. 2009. 54:1438–1446.

6. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010. 376:1233–1243.

7. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007. 115:2344–2351.

8. Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009. 120:2271–2306.

9. Lee K, Lee SW, Lee JW, Kim SY, Youn YJ, Ahn MS, et al. The significance of clopidogrel low-responsiveness on stent thrombosis and cardiac death assessed by the verifynow p(2)y(12) assay in patients with acute coronary syndrome within 6 months after drug-eluting stent implantation. Korean Circ J. 2009. 39:512–518.

10. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009. 360:363–375.

11. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007. 5:2429–2436.

12. Jeong YH, Kim IS, Park Y, Kang MK, Koh JS, Hwang SJ, et al. Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study. JACC Cardiovasc Interv. 2010. 3:731–741.

13. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002. 41:913–958.

14. Chen KY, Rha SW, Li YJ, Poddar KL, Jin Z, Minami Y, et al. Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation. 2009. 119:3207–3214.

15. Jeong YH, Lee SW, Choi BR, Kim IS, Seo MK, Kwak CH, et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol. 2009. 53:1101–1109.

16. Park KH, Jeong MH, Lee MG, Ko JS, Lee SE, Kang WY, et al. Efficacy of triple anti-platelet therapy including cilostazol in acute myocardial infarction patients undergoing drug-eluting stent implantation. Korean Circ J. 2009. 39:190–197.

17. Choi CU, Rha SW, Oh DJ, Poddar KL, Na JO, Kim JW, et al. Standard versus high loading doses of clopidogrel in Asian ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention: insights from the Korea Acute Myocardial Infarction Registry. Am Heart J. 2011. 161:373–382.

18. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011. 305:1097–1105.

19. Manoukian SV, Feit F, Mehran R, Voeltz MD, Ebrahimi R, Hamon M, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol. 2007. 49:1362–1368.