|
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
|
|
|
|||||||||
|
|||||||||||
|
J Am Coll Cardiol, 1999; 34:1891-1894 © 1999 by the American College of Cardiology Foundation |
* Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
Section of Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
Manuscript received May 7, 1999; revised manuscript received June 29, 1999, accepted August 27, 1999.
Reprint requests and correspondence: Dr. Peter Berger, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905
 |
Abstract |
|---|
 Top Abstract MethodsResultsDiscussionReferences |
|---|
The study compared the safety and efficacy of ticlopidine with clopidogrel in patients receiving coronary stents.
BACKGROUND
Stent thrombosis is reduced when ticlopidine is administered with aspirin. Clopidogrel is similar to ticlopidine in chemical structure and function but has fewer side effects; few data are available about its use in stent patients.
METHODS
We compared 30-day event rates in 500 consecutive coronary stent patients treated with aspirin and clopidogrel (300 mg loading dose immediately prior to stent placement, and 75 mg/day for 14 days) to 827 consecutive stent patients treated with aspirin and ticlopidine (500 mg loading dose and 250 mg twice daily for 14 days).
RESULTS
Patients treated with clopidogrel had more adverse clinical characteristics including older age, more severe angina, and more frequent infarction within the prior 24 h. Nonetheless, mortality was 0.4% in clopidogrel patients versus 1.1% in ticlopidine patients; nonfatal myocardial infarction occurred in 0% versus 0.5%, stent thrombosis in 0.2% versus 0.7%, bypass surgery or repeat angioplasty in 0.4% versus 0.5%, and any event occurred in 0.8% versus 1.6% of patients, respectively (p = NS). Based on the observed 30-day event rate of 1.6% with ticlopidine, the statistical power of the study was 43% to detect an even rate of 0.5% with clopidogrel, and 75% to detect an event rate with of 4% with clopidogrel, with a p value of 0.05.
CONCLUSIONS
These data indicate that clopidogrel can be safely substituted for ticlopidine in patients receiving coronary stents.
| ||||||||||
Clopidogrel is a thienopyridine closely related to ticlopidine in chemical structure and function but with fewer side effects, and clopidogrel does not cause neutropenia or thrombotic thrombocytopenic purpura (7,8). Clopidogrel can also achieve platelet inhibition more rapidly (9). We performed this prospective study to determine the risk of stent thrombosis and other adverse events among patients receiving intracoronary stents in whom clopidogrel was administered with aspirin.
|
Methods |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
Primary end point. The primary end point was the occurrence of death, nonfatal myocardial infarction, stent thrombosis, and need for coronary bypass surgery or repeat angioplasty within 30 days.
Stent procedure and medical therapy.
Stents were implanted as previously described (10). All patients received aspirin 
325 mg. Clopidogrel was given as a 300-mg load in the catheterization laboratory immediately before stent implantation followed by 75 mg/day for 14 days. Ticlopidine was given as a 500-mg load immediately before stent implantation, 250 mg that evening, and 250 mg twice daily for 14 days. During the procedure, weight-adjusted heparin was given to achieve an activated clotting time of 300 s. When abciximab was given at the discretion of the interventional cardiologist, lower doses of heparin were administered. Patients at increased risk of stent thrombosis (with acute myocardial infarction or a suboptimal result) were treated with subcutaneous enoxaparin 30 to 60 mg or ardeparin 4,000 to 12,000 U twice daily for 10 to 14 days at the discretion of their cardiologist.
Definitions.
Lesions were prospectively characterized by the modified American College of Cardiology/American Heart Association classification scheme (11). Successful stent placement was defined as stent delivery with achievement of a residual stenosis 
20% and Thrombolysis in Myocardial Infarction (TIMI) flow grade 3. Periprocedural myocardial infarction was defined as prolonged chest pain or a creatine kinase (CK) >2x normal or an elevated CK-MB (creatine kinase–myocardial band) and new Q waves. Myocardial infarction after discharge was diagnosed when two of three criteria were met: prolonged chest pain, CK elevation >2x normal or elevated CK-MB, or new Q waves or significant ST-T changes. Stent thrombosis was diagnosed if an angiogram revealed thrombus with diminished (<TIMI flow grade 3), myocardial infarction occurred in the distribution of the stented vessel, or after sudden death.
Follow-up. All patients were contacted by study coordinators; the medical records of patients suffering events were examined.
Statistics. Results are presented as mean ± 1 SD or a percent of the total. Clinical and procedural characteristics were compared using either Pearson’s chi-square or the Student t test. The Fisher exact test was used to compare event rates between the two cohorts.
|
Results |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
|
|
|
|
Discussion |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
Ticlopidine.
The clinical outcome of stent patients treated with aspirin and ticlopidine is better than when aspirin and warfarin (1–4) or aspirin alone (3,12,13) is administered. Ticlopidine interferes with ADP-induced platelet-fibrinogen binding by inhibiting up-regulation of glycoprotein IIb/IIIa receptors for the life of the platelet (6). Side effects are common; the most serious are neutropenia and thrombocytopenic purpura, which is often fatal (5,6). Full platelet inhibition from ticlopidine requires 5 days of treatment but can be shortened to 3 days with a 500-mg loading dose (6). Larger loading doses frequently cause nausea and are not generally used. The peak occurrence of stent thrombosis in the first few days following stent placement may be due to the slow onset of action of ticlopidine (14–16).
Clopidogrel. Clopidogrel is closely related to ticlopidine in chemical structure and function (7,8). The platelet inhibition achieved with clopidogrel 75 mg per day is equivalent to that achieved with ticlopidine 250 mg twice daily (7). The risk reduction achieved with clopidogrel in the CAPRIE study among 19,185 patients with vascular disease was identical to that achieved with ticlopidine in three randomized trials that included 3,471 vascular disease patients, suggesting that clopidogrel and ticlopidine have similar efficacy (8,17,18).
However, there are reasons to believe that clopidogrel might be more effective than ticlopidine in stent patients. Loading doses of clopidogrel up to 375 mg are well tolerated and speed the onset of platelet inhibition (9). One hour after a 375-mg loading dose, platelet response to ADP was inhibited by 55% in healthy volunteers, far more rapid inhibition than can achieved with ticlopidine (6,9). Clopidogrel does not cause neutropenia or thrombotic thrombocytopenic purpura, has fewer minor side effects, and is 25% to 30% less expensive (6,8).
In the current study, one patient in whom clopidogrel had been discontinued suffered stent thrombosis. The 95% confidence intervals for one case in 500 patients are 0.01% to 1.1%, and 0–0.74% if only patients who were taking clopidogrel are analyzed (0 events in 500 patients). Larger randomized studies are needed to determine whether stent thrombosis is significantly less frequent with clopidogrel than with ticlopidine.
Unanswered questions. Stent thrombosis occurring >14 days after stent deployment is very rare in patients treated with aspirin and a thienopyridine (11,15). It is unclear whether clopidogrel need be discontinued after two weeks, since, unlike ticlopidine, clopidogrel does not cause hematologic abnormalities with longer treatment duration. However, in 1,327 patients treated with dual antiplatelet therapy in this study, stent thrombosis did not occur during the second two weeks. The optimal loading dose of clopidogrel is also unknown.
Study limitations. The stent designs placed were different in the two groups. However, stent thrombosis rates were similar in the stent equivalency trials comparing the Palmaz-Schatz stent, which was the most frequently used stent in the ticlopidine patients, with the newer stents used in the clopidogrel patients.
Because of the small number of events, the study lacked sufficient statistical power to determine with certainty whether clinically significant differences existed between the two treatment arms. In a study of this size, if the true 30-day event rate with ticlopidine was 1.6% (as observed in this study), the statistical power would be 43% to detect an event rate with clopidogrel of 0.5% with a p value of 0.05. The study had 75% power to detect an event rate with clopidogrel of 4.0% with a p value of 0.05. Hence, the results of this study suggesting equivalency should be viewed with caution, and should be considered in context with other studies suggesting equivalency rather than as a definitive study on its own.
Conclusions. The results of this study suggest that clopidogrel is at least as effective as ticlopidine at preventing stent thrombosis and other adverse events within 30 days in patients undergoing coronary stent implantation (19).
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractMethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  R. A. Harrington, R. C. Becker, C. P. Cannon, D. Gutterman, A. M. Lincoff, J. J. Popma, G. Steg, G. H. Guyatt, and S. G. Goodman Antithrombotic Therapy for Non-ST-Segment Elevation Acute Coronary Syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 670S - 707S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Wenaweser, C. Rey, F. R. Eberli, M. Togni, D. Tuller, S. Locher, A. Remondino, C. Seiler, O. M. Hess, B. Meier, et al. Stent thrombosis following bare-metal stent implantation: success of emergency percutaneous coronary intervention and predictors of adverse outcome Eur. Heart J., June 2, 2005; 26(12): 1180 - 1187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Authors/Task Force Members, S. Silber, P. Albertsson, F. F. Aviles, P. G. Camici, A. Colombo, C. Hamm, E. Jorgensen, J. Marco, J.-E. Nordrehaug, et al. Guidelines for Percutaneous Coronary Interventions: The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology Eur. Heart J., April 2, 2005; 26(8): 804 - 847. [Full Text] [PDF]
|
|
|
|
|
|
J. J. Popma, P. Berger, E. M. Ohman, R. A. Harrington, C. Grines, and J. I. Weitz Antithrombotic Therapy During Percutaneous Coronary Intervention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 576S - 599S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Chan, D. J. Moliterno, P. B. Berger, G. W. Stone, P. M. DiBattiste, S. L. Yakubov, S. K. Sapp, K. Wolski, D. L. Bhatt, E. J. Topol, et al. Triple antiplatelet therapy during percutaneous coronary intervention is associated withimproved outcomes including one-year survival: Results from the do tirofiban and reoprogive similar efficacy outcome trial (TARGET) J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1188 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mehran, E. D. Aymong, D. T. Ashby, T. Fischell, H. Whitworth Jr, R. Siegel, W. Thomas, S. C. Wong, R. Narasimaiah, A. J. Lansky, et al. Safety of an Aspirin-Alone Regimen After Intracoronary Stenting With a Heparin-Coated Stent: Final Results of the HOPE (HEPACOAT and an Antithrombotic Regimen of Aspirin Alone) Study Circulation, September 2, 2003; 108(9): 1078 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Jneid, D. L. Bhatt, R. Corti, J. J. Badimon, V. Fuster, and G. S. Francis Aspirin and Clopidogrel in Acute Coronary Syndromes: Therapeutic Insights From the CURE Study Arch Intern Med, May 26, 2003; 163(10): 1145 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Matsagas, I. A. Jagroop, G. Geroulakos, and D. P. Mikhailidis The Effect of a Loading Dose (300 mg) of Clopidogrel on Platelet Function in Patients with Peripheral Arterial Disease Clinical and Applied Thrombosis/Hemostasis, April 1, 2003; 9(2): 115 - 120. [Abstract] [PDF]
|
|
|
|
|
|
J. L. Orford, R. Lennon, S. Melby, P. Fasseas, M. R. Bell, C. S. Rihal, D. R. Holmes, and P. B. Berger Frequency and correlates of coronary stent thrombosis in the modern era: Analysis of a single center registry J. Am. Coll. Cardiol., November 6, 2002; 40(9): 1567 - 1572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Waksman, A. E. Ajani, E. Pinnow, E. Cheneau, L. Leborgne, R. Dieble, A. B. Bui, L. F. Satler, A. D. Pichard, K. K. Kent, et al. Twelve Versus Six Months of Clopidogrel to Reduce Major Cardiac Events in Patients Undergoing {gamma}-Radiation Therapy for In-Stent Restenosis: Washington Radiation for In-Stent restenosis Trial (WRIST) 12 Versus WRIST PLUS Circulation, August 13, 2002; 106(7): 776 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Hongo, J. Ley, S. E. Dick, and R. R. Yee The effect of clopidogrel incombination with aspirin whengiven before coronary artery bypass grafting J. Am. Coll. Cardiol., July 17, 2002; 40(2): 231 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Izaguirre-Avila, A. D. l. Penia-Diaz, F. Barinagarrementeria-Aldatz, H. Gonzailez-Pacheco, A. E. Ramirez-Gutierrez, J. L. Ruiz-Sandoval, A. Quiroz-Martinez, and C. Cantu-Brito Effect of Clopidogrel on Platelet Aggregation and Plasma Concentration of Fibrinogen in Subjects with Cerebral or Coronary Atherosclerotic Disease Clinical and Applied Thrombosis/Hemostasis, April 1, 2002; 8(2): 169 - 177. [Abstract] [PDF]
|
|
|
|
|
|
D. L. Bhatt, M. E. Bertrand, P. B. Berger, P. L. L'Allier, I. Moussa, J. W. Moses, G. Dangas, M. Taniuchi, J. M. Lasala, D. R. Holmes, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting J. Am. Coll. Cardiol., January 2, 2002; 39(1): 9 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Wohrle, E Al-Khayer, U Grotzinger, C Schindler, M Kochs, V Hombach, and M Hoher Comparison of the heparin coated vs the uncoated Jostent(R)--no influence on restenosis or clinical outcome Eur. Heart J., October 1, 2001; 22(19): 1808 - 1816. [Abstract] [PDF]
|
|
|
|
|
|
M. Taniuchi, H. I. Kurz, and J. M. Lasala Randomized Comparison of Ticlopidine and Clopidogrel After Intracoronary Stent Implantation in a Broad Patient Population Circulation, July 31, 2001; 104(5): 539 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Schuhlen, A. Kastrati, J.u. Pache, J. Dirschinger, and A. Schomig Incidence of thrombotic occlusion and major adverse cardiac events between two and four weeks after coronary stent placement: analysis of 5,678 patients with a four-week ticlopidine regimen J. Am. Coll. Cardiol., June 15, 2001; 37(8): 2066 - 2073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Smith Jr, J. T. Dove, A. K. Jacobs, J. Ward Kennedy, D. Kereiakes, M. J. Kern, R. E. Kuntz, J. J. Popma, H. V. Schaff, D. O. Williams, et al. ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines): A report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines (Committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty) endorsed by the Society for Cardiac Angiography and Interventions J. Am. Coll. Cardiol., June 15, 2001; 37(8): 2239 - 2239. [Full Text] [PDF]
|
|
|
|
|
|
R. Waksman, A. E. Ajani, R. L. White, E. Pinnow, R. Dieble, A. B. Bui, M. Taaffe, L. Gruberg, G. S. Mintz, L. F. Satler, et al. Prolonged Antiplatelet Therapy to Prevent Late Thrombosis After Intracoronary {{gamma}}-Radiation in Patients With In-Stent Restenosis : Washington Radiation for In-Stent Restenosis Trial Plus 6 Months of Clopidogrel (WRIST PLUS) Circulation, May 15, 2001; 103(19): 2332 - 2335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Rauch, J. I. Osende, V. Fuster, J. J. Badimon, Z. Fayad, and J. H. Chesebro Thrombus Formation on Atherosclerotic Plaques: Pathogenesis and Clinical Consequences Ann Intern Med, February 6, 2001; 134(3): 224 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Patrono, B. Coller, J. E. Dalen, G. A. FitzGerald, V. Fuster, M. Gent, J. Hirsh, and G. Roth Platelet-Active Drugs : The Relationships Among Dose, Effectiveness, and Side Effects Chest, January 1, 2001; 119(1_suppl): 39S - 63S. [Full Text] [PDF]
|
|
|
|
|
|
J. J. Popma, E. M. Ohman, J. Weitz, A. M. Lincoff, R. A. Harrington, and P. Berger Antithrombotic Therapy in Patients Undergoing Percutaneous Coronary Intervention Chest, January 1, 2001; 119(1_suppl): 321S - 336S. [Full Text] [PDF]
|
|
|
|
|
|
P.J. De Feyter and D. Foley Coronary stent implantation: a panacea for the interventional cardiologist? Eur. Heart J., November 1, 2000; 21(21): 1719 - 1726. [PDF]
|
|
|
|
 |
|
 F. L. Paradiso-Hardy, C. M. Angelo, K. L. Lanctot, and E. A. Cohen Hematologic dyscrasia associated with ticlopidine therapy: evidence for causality Can. Med. Assoc. J., November 1, 2000; 163(11): 1441 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Al Suwaidi, P. B. Berger, and D. R. Holmes Jr Coronary Artery Stents JAMA, October 11, 2000; 284(14): 1828 - 1836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Dieter Risk of neutropenia with clopidogrel J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1436 - 1436. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Helft, J. I. Osende, S. G. Worthley, A. G. Zaman, O. J. Rodriguez, E. I. Lev, M. E. Farkouh, V. Fuster, J. J. Badimon, and J. H. Chesebro Acute Antithrombotic Effect of a Front-Loaded Regimen of Clopidogrel in Patients With Atherosclerosis on Aspirin Arterioscler. Thromb. Vasc. Biol., October 1, 2000; 20(10): 2316 - 2321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Moshfegh, M. Redondo, F. Julmy, W. A. Wuillemin, M. U. Gebauer, A. Haeberli, and B. J. Meyer Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy J. Am. Coll. Cardiol., September 1, 2000; 36(3): 699 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. W. Klein and J. E. Calvin Use of clopidrogel in coronary stenting: what was the question? J. Am. Coll. Cardiol., December 1, 1999; 34(7): 1895 - 1898. [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Lowe, R. G. Fahmy, M. M. Kavurma, A. Baker, C. N. Chesterman, and L. M. Khachigian Catalytic Oligodeoxynucleotides Define a Key Regulatory Role for Early Growth Response Factor-1 in the Porcine Model of Coronary In-Stent Restenosis Circ. Res., October 12, 2001; 89(8): 670 - 677. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | SUBSCRIPTIONS | CURRENT ISSUE | PAST ISSUES | CARDIOSOURCE | SEARCH | HELP | FEEDBACK |
