Aug 31, 2014 Plavix clopidogrel bisulfate 75 mg tablet. Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research CDER.
- Loading With 600 mg Clopidogrel in Patients With Coronary Artery Disease With and Without Chronic Clopidogrel Therapy. Adnan Kastrati, MD;.
- Effects of 600 mg versus 300 mg Loading Dose of Clopidogrel in Asian Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary.
- Plavix official prescribing information for healthcare professionals. Includes: indications, dosage, adverse reactions, pharmacology and more.
- The HORIZON results showed that a 600-mg compared with a 300-mg loading dose of clopidogrel was associated with lower 30-day rates of mortality, reinfarction, and.
- Pre-treating STEMI patients waiting to undergo PCI with a 600 mg loading dose of clopidogrel is safe and effective compared with a 300 mg loading dose, according to.
Loading With 600 mg Clopidogrel in Patients With Coronary Artery Disease With and Without Chronic Clopidogrel Therapy
Conclusions After loading with 600 mg of clopidogrel, the full antiplatelet effect of the drug is achieved after 2 hours.
Abstract Background— It is not known whether further suppression of platelet function can be achieved with clopidogrel beyond that provided by currently recommended loading and maintenance doses. We performed a comparative assessment of the antiplatelet effects of a 600-mg loading dose of clopidogrel given to patients with and without chronic clopidogrel therapy. Methods and Results— Those eligible for this prospective study were aspirin-treated patients with suspected or documented coronary artery disease admitted to hospital for coronary angiography. Two series of 20 consecutive patients each were assessed in this study. The first series included patients who had never received clopidogrel (first-use group); the second series included patients on chronic therapy with a daily dose of 75 mg clopidogrel for ≥1 month (chronic therapy group). Blood samples were drawn before and 6 hours after oral administration of 600 mg clopidogrel for aggregometry and flow cytometry studies. In the first-use group, loading with 600 mg clopidogrel inhibited ADP 5 μmol/L–induced platelet aggregation from 90±9% to 51±19% (P<0.001). In the chronic therapy group, loading with 600 mg clopidogrel yielded further inhibition of ADP 5 μmol/L–induced platelet aggregation in addition to that achieved by the maintenance dose of 75 mg/d, from 52±14% to 33±12% (P<0.001). In both groups, 600 mg clopidogrel loading significantly inhibited ADP-induced expression of glycoprotein IIb/IIIa and P-selectin receptors. Conclusions— Further platelet inhibition can be achieved with clopidogrel in addition to that provided by currently recommended loading and maintenance doses. Higher doses may be warranted after assessment of their clinical efficacy and safety. Clopidogrel has become a mainstay of the pharmacological therapy for patients with atherosclerotic cardiovascular disease,1 especially in those undergoing percutaneous coronary interventions.2,3 Despite the widespread use of clopidogrel, several aspects of its pharmacokinetics, optimal dosing and length of therapy, and its drug interactions are still unclear.4,5 A loading dose of 600 mg clopidogrel is associated with a rapid platelet-inhibitory effect comparable to that seen in patients on chronic clopidogrel therapy.6 When given before percutaneous coronary intervention, loading with 600 mg clopidogrel obviates the need for glycoprotein (GP) IIb/IIIa inhibitors in patients with low to moderate risk.7 A clopidogrel dose of 75 mg/d is commonly used during chronic therapy. This dose has been selected because it leads to antiplatelet effects equivalent to those of 500 mg/d ticlopidine, the first of the thienopyridine drugs used clinically.8 Nevertheless, it is still not known whether further suppression of platelet function can be achieved with clopidogrel in addition to that provided by the currently recommended maintenance dose of 75 mg/d and loading dose of 300 to 600 mg. To address this question, we performed a comparative assessment of the antiplatelet effects of a 600-mg loading dose of clopidogrel given to patients with coronary artery disease with and without ongoing chronic clopidogrel therapy. Clopidogrel Loading in First-Use Patients Platelet aggregation induced by 5 and 20 μmol/L ADP was significantly reduced at 6 hours after administration of the loading dose of 600 mg clopidogrel compared with the preloading values in this group (P<0.001; Figure). In addition, 20 μmol/L ADP–induced expression of GP IIb/IIIa (from 738±26 to 705±42; P=0.005) and P-selectin (from 335±21 to 274±39; P<0.001) receptors on platelets was significantly reduced with 600 mg clopidogrel. Clopidogrel Loading in Patients With Chronic Therapy Loading with 600 mg clopidogrel caused intensive inhibition of ADP-induced aggregation in this group for both 5 and 20 μmol/L ADP concentrations (P<0.001; Figure). In addition, 20 μmol/L ADP–induced expression of GP IIb/IIIa (from 694±62 to 682±69; P=0.001) and P-selectin (from 284±64 to 256±47; P<0.001) receptors on the platelets was significantly reduced with 600 mg clopidogrel. Discussion This study focused on the magnitude of platelet inhibition achieved with a loading dose of 600 mg clopidogrel in patients with and without chronic therapy with clopidogrel. The results may be summarized as follows. First, a 600-mg loading dose of clopidogrel given to patients not previously treated with this drug achieved a degree of platelet inhibition similar to that seen with chronic therapy of 75 mg/d. Second, a 600-mg loading dose of clopidogrel given to patients on chronic 75-mg/d therapy further suppressed platelet aggregation. As long as a higher degree of platelet inhibition remains the goal of peri-interventional and long-term antithrombotic therapy in patients with coronary artery disease, the findings of the present study may have relevant implications with regard to the dosing of a key treatment option such as clopidogrel. The fact that loading with 600 mg clopidogrel yields a substantially greater degree of platelet inhibition in patients on chronic therapy with 75 mg/d suggests that higher clopidogrel doses might be needed during chronic therapy. Moreover, this finding may provide support for the general use of clopidogrel loading in patients undergoing percutaneous coronary interventions regardless of the presence or absence of prior chronic clopidogrel therapy. Additionally, the more pronounced inhibition observed with clopidogrel loading in patients on chronic therapy compared with patients without previous treatment with clopidogrel suggests that the degree of platelet inhibition attainable can be augmented and that a dose of clopidogrel of >600 mg could provide even more effective loading for patients with no treatment before percutaneous coronary intervention. Another interesting finding is the lower C-reactive protein level in patients on chronic clopidogrel therapy. Because there were no significant differences between the 2 study groups with regard to baseline characteristics, this finding might be attributed to the antiinflammatory effects described for clopidogrel.11 In addition, the variability in platelet response to clopidogrel as shown in the Figure may be an indication that point-of-care testing of platelet inhibition may help to individualize peri-interventional antithrombotic therapy
Pil Sang Song,1,2 Joo-Yong Hahn, 1 Young Bin Song,1 Jin-Ho Choi,1 Seung-Hyuk Choi,1 Gu Hyun Kang,3 Kye Taek Ahn,4 Woo-Hyun Lim,5 Kyung Woo Park,5 Hyo-Soo Kim,5 and Hyeon-Cheol Gwon1 1Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2Division of Cardiology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea. 3Division of Cardiology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea. 4Division of Cardiology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea. 5Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, Seoul, Korea. Corresponding author. Corresponding author: Dr. Joo-Yong Hahn, Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: 82-2-3410-6653, Fax: 82-2-3410-6278, Email: ude.ukks@nhahyj INTRODUCTION The loading of clopidogrel before percutaneous coronary intervention (PCI) has become a standard procedure since several randomized trials demonstrated the efficacy of clopidogrel loading.1,2 Several studies have shown that the standard 300 mg loading dose of clopidogrel is inadequate to optimally inhibit platelet reactivity, and a 600 mg dose of clopidogrel has been reported to show superior outcomes in patients with stable angina3 or non ST-segment elevation acute coronary syndrome,4 undergoing PCI. Although recent studies reported that a 600 mg loading dose of clopidogrel reduced adverse ischemic events in patients undergoing primary PCI for ST-segment elevation myocardial infarction (STEMI),5,6 there are incomplete data on long-term clinical outcomes beyond 1 year and few studies have targeted Asian populations. Therefore, we evaluated the short- and long-term effects of 600 mg versus 300 mg clopidogrel loading doses on clinical outcomes in Asian STEMI patients undergoing primary PCI. Study limitations There are several limitations to our study. First, the sample size of the present study was relatively small, and therefore would not allow for drawing a definite conclusion. Second, this study was not a randomized study. The clopidogrel loading dosage was left to the discretion of the treating physician. Despite our effort to adjust for potential confounders by using multivariable models and propensity score match analysis, it is likely that unmeasured covariates could have contributed to the observed differences in clinical outcomes. Third, our evaluation of clinical outcomes was limited by the fact that bleeding events were not included in our analysis. Bleeding events have been known to play a role in the mortality of STEMI patients.19 In conclusion, in Asian patients undergoing primary PCI for STEMI, the use of a 600 mg loading dose compared with a 300 mg loading dose of clopidogrel did not reduce the incidence of MACEs, all-cause death, reinfarction, target vessel revascularization, or stent thrombosis. Further study for clopidogrel loading doses in this subset of patients is needed to improve clinical outcomes. 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. [PubMed] 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. [PubMed] 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. [PubMed] 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. [PubMed] 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. [PubMed] 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. [PubMed] 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. [PubMed] 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. [PubMed] 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. [PMC free article] [PubMed] 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. [PubMed] 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. [PubMed] 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. [PubMed] 13. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002;41:913–958. [PubMed] 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. [PubMed] 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. [PubMed] 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. [PMC free article] [PubMed] 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. [PubMed] 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. [PubMed] 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. [PubMed]','url':'http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423857/','og_descr':'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 ...
But they point out that this study confirms previous observations that the 600-mg dose of clopidogrel gives better platelet inhibition than a 300-mg dose.
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