Author + information
- Received May 7, 1999
- Revision received June 29, 1999
- Accepted August 27, 1999
- Published online December 1, 1999.
- Peter B Berger, MD, FACC∗,1,*,
- Malcolm R Bell, MB, BS, FACC∗,
- Charanjit S Rihal, MD, FACC∗,
- Henry Ting, MD∗,
- Gregory Barsness, MD∗,
- Kirk Garratt, MD, FACC∗,
- Victoria Bellot, MD∗,
- Verghese Mathew, MD, FACC∗,
- Steve Melby, RN∗,
- LaVon Hammes∗,
- Diane Grill, MS† and
- David R Holmes Jr., MD, FACC∗
- ↵*Reprint requests and correspondence: Dr. Peter Berger, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905
The study compared the safety and efficacy of ticlopidine with clopidogrel in patients receiving coronary stents.
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.
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).
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.
These data indicate that clopidogrel can be safely substituted for ticlopidine in patients receiving coronary stents.
Improvements in coronary stent design, deployment techniques, and antiplatelet therapy with ticlopidine and aspirin have reduced the frequency of stent thrombosis to <2% (1–4). However, ticlopidine is associated with frequent side effects including neutropenia and thrombotic thrombocytopenic purpura, which can be life-threatening (5,6).
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.
Between March and August 1998, a total of 500 consecutive patients underwent successful intracoronary stent implantation at the Mayo Clinic with clopidogrel and were compared with 827 patients who received ticlopidine for 14 days between May 1996 and October 1997 in a study of the use of ticlopidine for 14 days (10). Reasons for exclusion were: warfarin requirement for co-morbid conditions, research protocols requiring four weeks of ticlopidine, contraindications to aspirin or thienopyridines, cardiogenic shock, or patient refusal of access to medical records for research. This study was approved by the Mayo Clinic Institutional Review Board.
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.
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) >2× 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 >2× 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.
All patients were contacted by study coordinators; the medical records of patients suffering events were examined.
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 ttest. The Fisher exact test was used to compare event rates between the two cohorts.
Patients treated with clopidogrel had more adverse clinical characteristics than did ticlopidine-treated patients. Stent placement was more frequently elective in the clopidogrel cohort (Table 1).
Angiographic and procedural characteristics
Stents placed in the two groups differed; newer stents had been approved after the ticlopidine cohort had been treated. Low molecular weight heparin was administered less frequently to clopidogrel patients (Table 2).
The frequency of death, nonfatal infarction, stent thrombosis, and repeat angioplasty or bypass surgery were slightly lower among patients treated with clopidogrel, although the differences were not statistically significant (Fig. 1). The cumulative occurrence of death, myocardial infarction, stent thrombosis, and a repeat revascularization procedure was 1.6% in the ticlopidine group versus 0.8% in the clopidogrel group; the difference did not reach statistical significance. In addition, neutropenia and thrombotic thrombocytopenic purpura did not occur in any patient.
The important finding in this study is that clopidogrel administered for two weeks appears to be safe and effective in patients undergoing intracoronary stent implantation. Stent thrombosis and other adverse events occurred less frequently in patients treated with clopidogrel than ticlopidine despite more unfavorable clinical and anatomic characteristics among clopidogrel patients, although the differences were not significant.
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 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.
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.
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.
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).
The authors wish to gratefully acknowledge the hard work of the Catheterization Laboratory research nurses and study coordinators.
↵1 Dr. Berger is a member of an Advisory Board for Sanofi, which developed clopidogrel, and Bristol-Myers Squibb, which, with Sanofi, co-markets clopidogrel in the United States. He has also spoken at educational programs supported by Sanofi and Bristol-Myers Squibb, and received a total of <$10,000 of cumulative research support from Bristol-Myers Squibb, none of which was used for this study.
- adenosine diphosphate
- creatine phosphokinase
- creatine kinase–myocardial band
- Thrombolysis in Myocardial Infarction trial
- Received May 7, 1999.
- Revision received June 29, 1999.
- Accepted August 27, 1999.
- American College of Cardiology
- Bertrand M.E,
- Legrand V,
- Boland J,
- et al.
- MATTIS Investigators,
- Urban P,
- Macayo C,
- Rupprecht H.-J,
- et al.
- Bachmann F,
- Savcic M,
- Hauert J,
- Geudelin B,
- Kieffer G,
- Cariou R
- Berger P.B,
- Bell M.R,
- Grill D.E,
- Melby S,
- Holmes D.R Jr.
- Ellis S.G,
- Vandormael M.G,
- Cowley M.J,
- et al.
- Hall P,
- Nakamura S,
- Maiello L,
- et al.
- Rupprecht H.J,
- Darius Harald,
- Borkowski U,
- et al.
- Schühlen H,
- Kastrati A,
- Dirschinger J,
- et al.
- Easton J.D
- Antiplatelet Trialists’ Collaboration
- Moussa I,
- Oetgenn M,
- Roubin G,
- et al.