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Safety and efficacy of only 2 weeks of ticlopidine therapy in patients at increased risk of coronary stent thrombosis: Results from the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial
Safety and efficacy of only 2 weeks of ticlopidine therapy in patients at increased risk of coronary stent thrombosis: Results from the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial Peter B. Berger, MD,a Ken W. Mahaffey, MD,b Susan J. Meier,c Christopher E. Buller, MD,d Wayne Batchelor, MD,e Edward T. A. Fry, MD,f and James P. Zidar, MD,b for the ATLAST Investigators Rochester, Minn, Raleigh-Durham, NC, Collegeville, Pa, Vancouver, British Columbia, and Toronto, Ontario, Canada, and Indianapolis, Ind
Background Controversy exists regarding the frequency of late stent thrombosis among patients treated with intracoronary stents and the most appropriate duration of treatment with a thienopyridine that is required to prevent this complication.
Methods We analyzed the frequency of stent thrombosis and other ischemic events in the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial. In the ATLAST trial, 1102 patients at increased risk of stent thrombosis (ST-elevation myocardial infarction within 48 hours, diffuse distal disease, a large amount of thrombus, acute closure, residual dissection, etc) were randomly assigned to receive either enoxaparin (40 or 60 mg given every 12 hours for 14 days) or placebo; all patients received aspirin (325 mg daily) and ticlopidine (250 mg twice daily) for only 14 days. Results The primary end point, the 30-day combined incidence of death, nonfatal myocardial infarction, and urgent revascularization, was reached in 2.3% of patients (1.8% of patients taking enoxaparin vs 2.7% of patients taking placebo; P ⫽ .295). However, during the 15th through 30th days, the frequency of ischemic events was only 0.73%, and only 0.27% (3/1102) of patients had possible stent thrombosis (95% CI 0.06, 0.77).
Conclusion The frequency of stent thrombosis and other adverse ischemic events in the 15th through 30th days after stent placement in even high-risk stent patients treated with ticlopidine for only 2 weeks is low whether or not enoxaparin is administered. (Am Heart J 2002;143:841-6.)
Stent thrombosis is the most feared complication after stent placement. Ticlopidine reduces the frequency of stent thrombosis by ⬎50% but causes neu-
From the aMayo Clinic, Rochester, Minn, the bDuke Clinical Research Institute, RaleighDurham, NC, cRhone-Poulenc Rorer, Collegeville, Pa, dVancouver Hospital, Vancouver, Canada, the eTerrence Donnelly Heart Center, Toronto, Ontario, Canada, and fSt Vincent’s Hospital, Indianapolis, Ind. This study was supported by a grant from Aventis, Inc (formerly Rhone-Poulenc Rorer), Collegeville, Pa. Guest Editor for this manuscript was Neal S. Kleiman, MD, The Methodist Hospital, Houston, Tex. Submitted September 7, 2001; accepted November 26, 2001. Reprint requests: Peter Berger, MD, Mayo Clinic, Division of Cardiovascular Diseases, 200 First St SW, Rochester, MN 55905. E-mail: [email protected] © 2002 Mosby, Inc. All rights reserved. 0002-8703/2002/$35.00 ⫹ 0 4/1/121929 doi:10.1067/mhj.2002.121929
tropenia or thrombotic thrombocytopenic purpura (TTP) in 1% to 3% of patients; the risk of these complications increases as the duration of treatment with ticlopidine increases.1,2 Because data indicate that stent thrombosis is rare during the third and fourth weeks after stent placement, a shorter duration of ticlopidine therapy has been advocated to attempt to avoid these hematologic complications and other far more common side effects, such as nausea, diarrhea, and rash, which occur in as many as 20% of patients.3-6 Although stent thrombosis has been rare when ticlopidine is administered for only 2 weeks after stent placement, stent thrombosis in the weeks after ticlopidine is discontinued has been exceedingly rare in these reports.6 However, the optimal duration of therapy with ticlopidine or clopidogrel, another thienopyridine that does not cause neutropenia and
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only very rarely causes TTP, after stent placement remains controversial, and the most appropriate duration of antiplatelet therapy, particularly in patients at increased risk of stent thrombosis, remains unknown.7,8 Therefore, we performed this study to determine the frequency of stent thrombosis and other adverse ischemic events in the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial.9
Methods Study population ATLAST was a randomized, placebo-controlled trial examining the ability of enoxaparin to prevent major adverse clinical events in the 30 days after coronary stent placement.9 Previous studies have suggested possible benefit from such a regimen.10-12 The primary end point of the trial was frequency of death, nonfatal myocardial infarction, and urgent revascularization at 30 days. The primary end point of this analysis was the frequency of these events in the 15th through 30th days after ticlopidine and the study drug had been discontinued. Patients who were believed to be at increased risk of stent thrombosis on the basis of clinical, angiographic, or procedural characteristics and who underwent successful stent implantation at any of 80 participating sites were eligible for inclusion in the ATLAST trial. Specific inclusion criteria and the frequency with which they accounted for study entry were ST-elevation myocardial infarction within the preceding 48 hours (29%); diffuse (⬎40% narrowing ⬎1 cm beyond the stent) distal disease (22%); a large amount of intracoronary thrombus (intraluminal filling defect with contrast on 3 sides, occupying more than one third of the lumen) before the procedure or any remaining thrombus at the completion of the case (17%); recent total occlusion (Thrombolysis In Myocardial Infarction [TIMI] 0 or 1 flow believed to be ⬍7 days old on the basis of history, electrocardiographic [ECG] result, and angiography) (14%); abrupt or threatened closure before or during stent placement (13.7%); an ejection fraction ⬍35% (11%); uncovered residual dissection after completion of the case (9%); treatment of a degenerated vein graft ⬍4 mm in diameter (5%); target vessel ⱕ2.5 mm (4%); treatment of a bifurcation lesion (4%); filling defect within the stent (4%); a residual stenosis ⬎20% within the stent (3%); incomplete stent strut apposition (⬍1%); or TIMI flow ⬍3 at the end of the procedure (⬍1%). One entry criterion was present in 66% of patients, 2 were present in 24% of patients, and 3 or more were present in 7% of patients. There were 1102 patients who met these criteria and were enrolled and treated in the ATLAST study.
Medical therapy Patients were randomly assigned to receive enoxaparin or placebo. Patients weighing ⬍60 kg (n ⫽ 53, 9.6%) received 40 mg enoxaparin subcutaneously every 12 hours for 14 days, and patients weighing ⱖ60 kg (n ⫽ 500, 90.4%) received 60 mg enoxaparin subcutaneously every 12 hours for 14 days. Patients in the placebo group received subcutaneous placebo every 12 hours for 14 days beginning 4 to 10 hours
after sheath removal. All patients received aspirin (325 mg daily) for a minimum of 30 days, and ticlopidine (a 500-mg loading dose, followed by 250 mg twice daily) for only 14 days. Patients who received a platelet glycoprotein IIb/IIIa inhibitor at the time of stent placement or in the previous 72 hours were not eligible for inclusion in ATLAST.
Sample size determination The prespecified sample size for ATLAST was 2000 patients. However, the trial was stopped prematurely when a prespecified interim analysis by the Data and Safety Monitoring Committee revealed that the overall event rate in the trial was far lower than predicted. A decision was made by the study sponsor, supported by the Steering Committee, to discontinue the trial because the frequency of stent thrombosis even in high-risk patients had become so low with improvements in stent designs, deployment techniques, and antiplatelet therapy. In addition, the use of platelet glycoprotein IIb/ IIIa inhibitors, which were excluded in the trial, had become so widespread that the potential for benefit from enoxaparin in such patients was too infrequent.
Definitions Stent thrombosis was defined as reduced coronary blood flow within the stent on immediate repeat angiography, myocardial infarction in the distribution of the treated vessel, or unexplained death. A procedural infarction was defined as a creatine kinase–myocardial band (CK-MB) ⱖ3 times the upper limit of normal and CK-MB ⬎50% above prior nadir value. A myocardial infarction unrelated to a revascularization procedure could be diagnosed by either cardiac enzyme criteria or ECG criteria. Enzyme criteria included a CK-MB elevation above normal and at least 3% of total CK. Reinfarction was defined as reelevation of CK-MB to above the upper limit of normal if prior CK-MB was in the normal range or ⬎50% above the prior level when the prior level was elevated. ECG criteria included new Q waves in ⱖ2 anatomically contiguous leads. Procedural infarctions were not considered an end point in the trial; only events that occurred after the initiation of the study drug (enoxaparin or placebo) were analyzed. The mean time to initiation of the study drug was 5.6 ⫾ 0.2 hours (median, 3.4 hours) after the vascular sheath had been removed.
Statistical methods Results are presented as mean ⫾ standard deviation or as a percent of the total. Where event rates are reported, 95% CIs are reported in parentheses. Comparisons between groups were conducted by 1-way analysis of variance with treatment effect; all tests were 2-sided, with a 5% level of significance (␣ ⫽ .05).
Observation All patients underwent clinical assessment 14 days and 30 days after stent placement, and data were collected with standard case report forms. All patients with a suspected clinical end point event were adjudicated by an independent Clinical Events Committee unaware of treatment. The Clinical Events Committee examined all cardiac enzymes, ECG re-
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Table I. Baseline characteristics of the 1102 patients in the ATLAST study population
Characteristic Age, (y) (mean) Male Family history of CAD Prior smoker Current smoker Hypertension Hyperlipidemia Diabetes mellitus Prior CHF Previous MI Prior PTCA Prior CABG
Overall N ⴝ 1102 n (%) 60.1 ⫾ 0.3 834 (75.7) 574 (52.1) 152 (13.8) 359 (32.6) 633 (57.4) 594 (53.9) 288 (26.1) 89 (8.1) 341 (30.9) 300 (27.2) 200 (18.1)
Placebo N ⴝ 549 n (%)
Enoxaparin N ⴝ 553 n (%)
60.8 ⫾ 0.5 403 (73.4) 283 (51.5) 70 (12.8) 176 (32.1) 318 (57.9) 292 (53.2) 155 (28.2) 47 (8.6) 174 (31.7) 150 (27.3) 96 (17.5)
59.4 ⫾ 0.5 431 (77.9) 291 (52.6) 82 (14.8) 183 (33.1) 315 (57.0) 302 (54.6) 133 (24.1) 42 (7.6) 167 (30.2) 150 (27.1) 104 (18.8)
CAD, Coronary artery disease; CHF, congestive heart failure; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft surgery.
sults, and clinical notes when necessary of all patients believed to have experienced a clinical end point.
Results Baseline characteristics Baseline characteristics of the 1102 patients in the ATLAST study population are presented in Table I. Their mean age was 60.1 ⫾ 0.3 years; 76% were male patients. High-risk characteristics included diabetes in 26.1% and a prior infarction in 30.9%; prior angioplasty and coronary bypass procedures had been performed in 27.2% and 18.1% of patients, respectively. Baseline characteristics were well matched between the 2 treatment groups.
Angiographic and procedural characteristics Angiographic and procedural characteristics are displayed in Table II. Stents were placed for acute or threatened closure in 16.3% of patients and for suboptimal balloon angioplasty result in 13.4%; 35.0% of patients received ⬎1 stent.
Clinical events during ticlopidine administration The frequency of adverse ischemic events in the entire study population during the 14 days that ticlopidine was administered is shown in Figure 1. The primary end point was reached in 2.3% of patients (95% CI 1.47, 3.33); end points occurred in 1.8% (0.97, 3.30) of patients receiving enoxaparin versus 2.7% (1.54, 4.47) of patients receiving placebo (P ⫽ .295). However, in the 15th through 30th days, the frequency of any adverse ischemic events in the ATLAST study was only 0.73% (0.31, 1.43), and several events
Table II. Angiographic and procedural characteristics of the study population
Characteristic
Overall Placebo Enoxaparin N ⴝ 1102 N ⴝ 549 N ⴝ 553 n (%) n (%) n (%)
LVEF, mean (%) 50.8 51.0 LVEF ⬍ 35% 123 (11.2) 57 (10.4) Vessels diseased 1 579 (52.5) 295 (53.7) 2 325 (29.5) 161 (29.3) 3 197 (17.9) 92 (16.8) Indication for stent Elective 774 (70.2) 386 (70.3) Abrupt/threatened closure 180 (16.3) 91 (16.6) Suboptimal result 148 (13.4) 72 (13.1) Coronary vessel treated Left anterior descending 366 (33.2) 179 (32.6) Circumflex 229 (20.8) 113 (20.6) Right 432 (39.2) 214 (39.0) Vein graft 93 (5.2) 45 (8.2) Other 57 (5.2) 36 (6.6) Stents used Palmaz-Schatz 503 (45.6) 241 (43.9) GR I 52 (4.7) 27 (4.9) GR II 142 (12.9) 77 (14.0) Multi-Link 211 (19.1) 104 (18.9) Medtronic wiktor 27 (2.5) 11 (2.0) Other 245 (22.2) 128 (23.3) Stents placed per patient 1 716 (65.0) 357 (65.0) 2 278 (25.2) 141 (25.7) 3 76 (6.9) 36 (6.6) 4 25 (2.3) 12 (2.2) 5 4 (0.4) 2 (0.4) 6 3 (0.3) 1 (0.2) Stent length (mm) 18.3 ⫾ 0.2 18.4 ⫾ 0.3 Diameter of smallest stent (mm) 2.5 58 (5.3) 25 (4.6) 3.0 613 (55.6) 307 (55.9) 3.5 310 (28.1) 159 (29.0) ⱖ4.0 121 (10.9) 58 (10.5) Maximum activated 318 ⫾ 3.8 319 ⫾ 3.9 clotting time (s)
50.6 66 (11.9) 284 (51.4) 164 (29.7) 105 (19.0) 388 (70.2) 89 (16.1) 76 (13.7) 187 (33.8) 116 (21.0) 218 (39.4) 48 (3.8) 21 (3.8) 262 (47.4) 25 (4.5) 65 (11.8) 107 (19.3) 16 (2.9) 117 (21.2) 359 (64.9) 137 (24.8) 40 (7.2) 13 (2.4) 2 (0.4) 2 (0.4) 18.1 ⫾ 0.2
33 (6.0) 306 (55.3) 151 (27.3) 63 (11.3) 318 ⫾ 3.8
LVEF, Left ventricular ejection fraction; GR, Gianturco-Roubin.
occurred in the same patients. Only 0.27% (3/1102) of patients had definite or possible stent thrombosis (0.06-0.77). Neutropenia and TTP did not occur.
Frequency of clinical events The frequency of adverse ischemic events in the 15th through 30th days after ticlopidine was discontinued is shown in Figure 2. Only 3 patients had definite or possible stent thrombosis during this period. One patient had an anterior myocardial infarction, underwent stent placement in the left anterior descending artery within 48 hours of infarction, and was enrolled in ATLAST. The subsequent hospital course
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Figure 1
confirmed stent thrombosis; repeat coronary angioplasty was unsuccessful, and coronary artery bypass grafting was performed. The third patient had an anterior myocardial infarction, underwent stent placement in the left anterior descending artery within 48 hours of infarction, and was enrolled in ATLAST. This patient had an uneventful course without recurrent chest pain, ECG changes, or enzyme elevations. A routine electrocardiogram on day 28 revealed new Q waves in leads V3–V5, and the patient was considered to have had a nonfatal myocardial infarction and possible stent thrombosis by the Clinical Events Committee.
Bleeding
The frequency of clinical events after stent placement during the 14 days that ticlopidine was administered.
The frequency of major bleeding at 30 days was 1.6% in the placebo group versus 3.3% in the enoxaparin group (P ⫽ .08). The frequency of minor bleeding was 5.1% in the placebo group versus 25% in the enoxaparin group (P ⫽ .001).
Discussion Figure 2
The most important finding in this study is that among patients at increased risk for stent thrombosis not treated with platelet glycoprotein inhibitors, the frequency of stent thrombosis in the 15th through 30th days is low, even when ticlopidine is discontinued on the 14th day.
Ticlopidine
The frequency of clinical events in the 15th through 30th days after ticlopidine was discontinued.
was uneventful; the patient had no recurrent chest pain, ECG changes, or enzyme elevations. A routine electrocardiogram on day 30 revealed new Q waves in leads V1–V2 and new T-wave inversions in leads V2-V5 not present on an electrocardiogram the day after stent placement. The patient was considered to have had a nonfatal myocardial infarction and possible stent thrombosis according to the Clinical Events Committee. A second patient underwent stent placement in the left anterior descending artery and was enrolled in ATLAST. Twenty-two days after stent placement, this patient had an acute anterior infarction. Angiography
The frequency of coronary stent thrombosis in patients treated with aspirin and ticlopidine is lower than when aspirin and warfarin or aspirin alone is administered.3,4,13-16 Ticlopidine blocks 1 of the 3 types of adenosine diphosphate receptors, inhibiting up-regulation of glycoprotein IIb/IIIa receptors and impairing fibrinogen cross-linking of platelets.2 These effects last for the life of the platelet. Side effects from ticlopidine are common, the most serious of which are neutropenia and TTP, which is fatal in approximately 25% to 50% of cases.1,2 Neutropenia virtually never occurs with less than 2 weeks of therapy; TTP is rare with less than 2 weeks of therapy but does occur.1,2 Data from a study of 827 patients at the Mayo Clinic in whom ticlopidine was discontinued 14 days after stent placement revealed that there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures in the 15th through 30th days after ticlopidine had been stopped; stent thrombosis did not occur in any patient during this period (95% CI 0, 0.5).6 Other investigators have reported a 3.2% frequency of major adverse ischemic events between the 15th and 30th days in patients given warfarin sodium and aspirin after stent placement and concluded that a thienopyridine should be given for at least 4 weeks. However, because warfa-
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rin sodium delays the occurrence of stent thrombosis but does not reduce it, this conclusion is not persuasive.5 A preliminary analysis of 3676 patients who received ticlopidine for 4 weeks revealed that stent thrombosis between the 3rd and 4th weeks after stent placement, while ticlopidine was still being administered, occurred in 0.5% of patients.7 These investigators hypothesized that stent thrombosis may have been more frequent during the 3rd and 4th weeks had ticlopidine not been continued for 4 weeks and concluded that a thienopyridine should be given to all patients for at least 4 weeks after stent placement. It is not clear that the occurrence of stent thrombosis in patients taking ticlopidine in the 3rd and 4th weeks after stent placement is a strong argument that ticlopidine should be administered for at least 4 weeks. Nonetheless, the current study provides the strongest available data from a group of high-risk patients not likely to be included in any future studies— patients at increased risk for stent thrombosis not treated with a glycoprotein IIb/IIIa inhibitor who were treated with a thienopyridine for only 2 weeks. The results indicate that even when ticlopidine is discontinued after 2 weeks, the risk of stent thrombosis is low, well within the 95% CI of the Mayo Clinic study of early discontinuation of ticlopidine.6
Potential impact of enoxaparin on late stent thrombosis Enoxaparin may be effective at reducing stent thrombosis and other ischemic complications in ATLAST (odds ratio 0.65; 95% CI 0.29, 1.5), although such complications were infrequent and too few patients (n ⫽ 1102) were enrolled (caused in part by the premature termination of the study) to detect a significant difference between the 2 treatment arms.9 However, a reduction in stent thrombosis with enoxaparin might increase the risk of stent thrombosis rather than decrease it in the 15th through 30th days after stent placement after both enoxaparin and ticlopidine are discontinued if enoxaparin had the effect of delaying stent thrombosis that might otherwise have occurred earlier. A delay in the occurrence of stent thrombosis has been reported when platelet glycoprotein IIb/IIIa inhibitors have been administered.17 In this trial, however, an increase in late stent thrombosis in the enoxaparin group compared with the placebo group was not seen.
Late stent thrombosis in ATLAST It should be noted that 2 of the 3 patients in ATLAST considered to have stent thrombosis may not have actually experienced this event. Most patients with stent thrombosis develop the sudden onset of chest pain and experience Q-wave myocardial infarc-
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tion or death. In 2 patients in this study considered to have had possible stent thrombosis, there were no clinically apparent adverse events. It is possible that the ECG results evolved later than is typical from the enrolling myocardial infarction. However, even if all 3 of these patients did have stent thrombosis, the frequency of stent thrombosis in this study would be 0.27% (95% CI 0.06, 0.79), considerably less than the 1% to 3% frequency of neutropenia and TTP when ticlopidine is continued for 4 weeks.
Clopidogrel Clopidogrel is a thienopyridine closely related to ticlopidine in chemical structure and function. Clopidogrel has largely replaced ticlopidine after stent placement because ticlopidine causes neutropenia in ⬎1% of patients and TTP in approximately 0.2% of patients, which is fatal in 25% to 50% of cases. Clopidogrel is also approximately 30% less expensive than ticlopidine in the United States. Data from 3 randomized trials and 7 registries suggest that clopidogrel is as effective as ticlopidine at reducing stent thrombosis and that clopidogrel has far fewer side effects.18-28 Clopidogrel does not appear to cause neutropenia; it has been reported to cause TTP in 11 of ⬎3 million patients treated.29 The optimal duration of clopidogrel after stent placement is unknown. However, the 2 drugs are equipotent, and the difference between ticlopidine and clopidogrel is in the rapidity of action and frequency of side effects, so the substitution of clopidogrel for ticlopidine does not affect the primary issue this study addresses. Ongoing studies are examining the most appropriate duration of clopidogrel after stent placement. Data from the PCI-CURE study indicate that the frequency of death and myocardial infarction in patients treated with 30 days of clopidogrel was 3.1% versus 3.9% in patients treated with as much as 12 months of clopidogrel, a difference of 0.8%, representing 8 events prevented per 1000 patients treated (P ⫽ NS).30 There are no data in PCI-CURE about whether these events were caused by stent thrombosis. Data from this study suggest that the risk of stent thrombosis after 2 weeks of therapy with aspirin and a thienopyridine is so low that the likelihood of observing a reduction in the rate of stent thrombosis from a longer duration of therapy is remote.
Conclusions The frequency of stent thrombosis and other adverse ischemic events 15 to 30 days after stent placement in even high-risk stent patients treated with ticlopidine for only 2 weeks is low (0.27%), even when glycoprotein IIb/IIIa inhibitors are not used and whether or not enoxaparin is administered. The risk is less than the risk of severe neutropenia or TTP when ticlopidine is
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continued for 30 days. Therefore, ticlopidine should be discontinued 14 days after stent placement. The most appropriate duration of clopidogrel, which appears to be at least as effective as ticlopidine at preventing stent thrombosis but does not cause neutropenia and only rarely causes TTP, remains to be determined.
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Background Controversy exists regarding the frequency of late stent thrombosis among patients treated with intracoronary stents and the most appropriate duration of treatment with a thienopyridine that is required to prevent this complication.
Methods We analyzed the frequency of stent thrombosis and other ischemic events in the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial. In the ATLAST trial, 1102 patients at increased risk of stent thrombosis (ST-elevation myocardial infarction within 48 hours, diffuse distal disease, a large amount of thrombus, acute closure, residual dissection, etc) were randomly assigned to receive either enoxaparin (40 or 60 mg given every 12 hours for 14 days) or placebo; all patients received aspirin (325 mg daily) and ticlopidine (250 mg twice daily) for only 14 days. Results The primary end point, the 30-day combined incidence of death, nonfatal myocardial infarction, and urgent revascularization, was reached in 2.3% of patients (1.8% of patients taking enoxaparin vs 2.7% of patients taking placebo; P ⫽ .295). However, during the 15th through 30th days, the frequency of ischemic events was only 0.73%, and only 0.27% (3/1102) of patients had possible stent thrombosis (95% CI 0.06, 0.77).
Conclusion The frequency of stent thrombosis and other adverse ischemic events in the 15th through 30th days after stent placement in even high-risk stent patients treated with ticlopidine for only 2 weeks is low whether or not enoxaparin is administered. (Am Heart J 2002;143:841-6.)
Stent thrombosis is the most feared complication after stent placement. Ticlopidine reduces the frequency of stent thrombosis by ⬎50% but causes neu-
From the aMayo Clinic, Rochester, Minn, the bDuke Clinical Research Institute, RaleighDurham, NC, cRhone-Poulenc Rorer, Collegeville, Pa, dVancouver Hospital, Vancouver, Canada, the eTerrence Donnelly Heart Center, Toronto, Ontario, Canada, and fSt Vincent’s Hospital, Indianapolis, Ind. This study was supported by a grant from Aventis, Inc (formerly Rhone-Poulenc Rorer), Collegeville, Pa. Guest Editor for this manuscript was Neal S. Kleiman, MD, The Methodist Hospital, Houston, Tex. Submitted September 7, 2001; accepted November 26, 2001. Reprint requests: Peter Berger, MD, Mayo Clinic, Division of Cardiovascular Diseases, 200 First St SW, Rochester, MN 55905. E-mail: [email protected] © 2002 Mosby, Inc. All rights reserved. 0002-8703/2002/$35.00 ⫹ 0 4/1/121929 doi:10.1067/mhj.2002.121929
tropenia or thrombotic thrombocytopenic purpura (TTP) in 1% to 3% of patients; the risk of these complications increases as the duration of treatment with ticlopidine increases.1,2 Because data indicate that stent thrombosis is rare during the third and fourth weeks after stent placement, a shorter duration of ticlopidine therapy has been advocated to attempt to avoid these hematologic complications and other far more common side effects, such as nausea, diarrhea, and rash, which occur in as many as 20% of patients.3-6 Although stent thrombosis has been rare when ticlopidine is administered for only 2 weeks after stent placement, stent thrombosis in the weeks after ticlopidine is discontinued has been exceedingly rare in these reports.6 However, the optimal duration of therapy with ticlopidine or clopidogrel, another thienopyridine that does not cause neutropenia and
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only very rarely causes TTP, after stent placement remains controversial, and the most appropriate duration of antiplatelet therapy, particularly in patients at increased risk of stent thrombosis, remains unknown.7,8 Therefore, we performed this study to determine the frequency of stent thrombosis and other adverse ischemic events in the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial.9
Methods Study population ATLAST was a randomized, placebo-controlled trial examining the ability of enoxaparin to prevent major adverse clinical events in the 30 days after coronary stent placement.9 Previous studies have suggested possible benefit from such a regimen.10-12 The primary end point of the trial was frequency of death, nonfatal myocardial infarction, and urgent revascularization at 30 days. The primary end point of this analysis was the frequency of these events in the 15th through 30th days after ticlopidine and the study drug had been discontinued. Patients who were believed to be at increased risk of stent thrombosis on the basis of clinical, angiographic, or procedural characteristics and who underwent successful stent implantation at any of 80 participating sites were eligible for inclusion in the ATLAST trial. Specific inclusion criteria and the frequency with which they accounted for study entry were ST-elevation myocardial infarction within the preceding 48 hours (29%); diffuse (⬎40% narrowing ⬎1 cm beyond the stent) distal disease (22%); a large amount of intracoronary thrombus (intraluminal filling defect with contrast on 3 sides, occupying more than one third of the lumen) before the procedure or any remaining thrombus at the completion of the case (17%); recent total occlusion (Thrombolysis In Myocardial Infarction [TIMI] 0 or 1 flow believed to be ⬍7 days old on the basis of history, electrocardiographic [ECG] result, and angiography) (14%); abrupt or threatened closure before or during stent placement (13.7%); an ejection fraction ⬍35% (11%); uncovered residual dissection after completion of the case (9%); treatment of a degenerated vein graft ⬍4 mm in diameter (5%); target vessel ⱕ2.5 mm (4%); treatment of a bifurcation lesion (4%); filling defect within the stent (4%); a residual stenosis ⬎20% within the stent (3%); incomplete stent strut apposition (⬍1%); or TIMI flow ⬍3 at the end of the procedure (⬍1%). One entry criterion was present in 66% of patients, 2 were present in 24% of patients, and 3 or more were present in 7% of patients. There were 1102 patients who met these criteria and were enrolled and treated in the ATLAST study.
Medical therapy Patients were randomly assigned to receive enoxaparin or placebo. Patients weighing ⬍60 kg (n ⫽ 53, 9.6%) received 40 mg enoxaparin subcutaneously every 12 hours for 14 days, and patients weighing ⱖ60 kg (n ⫽ 500, 90.4%) received 60 mg enoxaparin subcutaneously every 12 hours for 14 days. Patients in the placebo group received subcutaneous placebo every 12 hours for 14 days beginning 4 to 10 hours
after sheath removal. All patients received aspirin (325 mg daily) for a minimum of 30 days, and ticlopidine (a 500-mg loading dose, followed by 250 mg twice daily) for only 14 days. Patients who received a platelet glycoprotein IIb/IIIa inhibitor at the time of stent placement or in the previous 72 hours were not eligible for inclusion in ATLAST.
Sample size determination The prespecified sample size for ATLAST was 2000 patients. However, the trial was stopped prematurely when a prespecified interim analysis by the Data and Safety Monitoring Committee revealed that the overall event rate in the trial was far lower than predicted. A decision was made by the study sponsor, supported by the Steering Committee, to discontinue the trial because the frequency of stent thrombosis even in high-risk patients had become so low with improvements in stent designs, deployment techniques, and antiplatelet therapy. In addition, the use of platelet glycoprotein IIb/ IIIa inhibitors, which were excluded in the trial, had become so widespread that the potential for benefit from enoxaparin in such patients was too infrequent.
Definitions Stent thrombosis was defined as reduced coronary blood flow within the stent on immediate repeat angiography, myocardial infarction in the distribution of the treated vessel, or unexplained death. A procedural infarction was defined as a creatine kinase–myocardial band (CK-MB) ⱖ3 times the upper limit of normal and CK-MB ⬎50% above prior nadir value. A myocardial infarction unrelated to a revascularization procedure could be diagnosed by either cardiac enzyme criteria or ECG criteria. Enzyme criteria included a CK-MB elevation above normal and at least 3% of total CK. Reinfarction was defined as reelevation of CK-MB to above the upper limit of normal if prior CK-MB was in the normal range or ⬎50% above the prior level when the prior level was elevated. ECG criteria included new Q waves in ⱖ2 anatomically contiguous leads. Procedural infarctions were not considered an end point in the trial; only events that occurred after the initiation of the study drug (enoxaparin or placebo) were analyzed. The mean time to initiation of the study drug was 5.6 ⫾ 0.2 hours (median, 3.4 hours) after the vascular sheath had been removed.
Statistical methods Results are presented as mean ⫾ standard deviation or as a percent of the total. Where event rates are reported, 95% CIs are reported in parentheses. Comparisons between groups were conducted by 1-way analysis of variance with treatment effect; all tests were 2-sided, with a 5% level of significance (␣ ⫽ .05).
Observation All patients underwent clinical assessment 14 days and 30 days after stent placement, and data were collected with standard case report forms. All patients with a suspected clinical end point event were adjudicated by an independent Clinical Events Committee unaware of treatment. The Clinical Events Committee examined all cardiac enzymes, ECG re-
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Table I. Baseline characteristics of the 1102 patients in the ATLAST study population
Characteristic Age, (y) (mean) Male Family history of CAD Prior smoker Current smoker Hypertension Hyperlipidemia Diabetes mellitus Prior CHF Previous MI Prior PTCA Prior CABG
Overall N ⴝ 1102 n (%) 60.1 ⫾ 0.3 834 (75.7) 574 (52.1) 152 (13.8) 359 (32.6) 633 (57.4) 594 (53.9) 288 (26.1) 89 (8.1) 341 (30.9) 300 (27.2) 200 (18.1)
Placebo N ⴝ 549 n (%)
Enoxaparin N ⴝ 553 n (%)
60.8 ⫾ 0.5 403 (73.4) 283 (51.5) 70 (12.8) 176 (32.1) 318 (57.9) 292 (53.2) 155 (28.2) 47 (8.6) 174 (31.7) 150 (27.3) 96 (17.5)
59.4 ⫾ 0.5 431 (77.9) 291 (52.6) 82 (14.8) 183 (33.1) 315 (57.0) 302 (54.6) 133 (24.1) 42 (7.6) 167 (30.2) 150 (27.1) 104 (18.8)
CAD, Coronary artery disease; CHF, congestive heart failure; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft surgery.
sults, and clinical notes when necessary of all patients believed to have experienced a clinical end point.
Results Baseline characteristics Baseline characteristics of the 1102 patients in the ATLAST study population are presented in Table I. Their mean age was 60.1 ⫾ 0.3 years; 76% were male patients. High-risk characteristics included diabetes in 26.1% and a prior infarction in 30.9%; prior angioplasty and coronary bypass procedures had been performed in 27.2% and 18.1% of patients, respectively. Baseline characteristics were well matched between the 2 treatment groups.
Angiographic and procedural characteristics Angiographic and procedural characteristics are displayed in Table II. Stents were placed for acute or threatened closure in 16.3% of patients and for suboptimal balloon angioplasty result in 13.4%; 35.0% of patients received ⬎1 stent.
Clinical events during ticlopidine administration The frequency of adverse ischemic events in the entire study population during the 14 days that ticlopidine was administered is shown in Figure 1. The primary end point was reached in 2.3% of patients (95% CI 1.47, 3.33); end points occurred in 1.8% (0.97, 3.30) of patients receiving enoxaparin versus 2.7% (1.54, 4.47) of patients receiving placebo (P ⫽ .295). However, in the 15th through 30th days, the frequency of any adverse ischemic events in the ATLAST study was only 0.73% (0.31, 1.43), and several events
Table II. Angiographic and procedural characteristics of the study population
Characteristic
Overall Placebo Enoxaparin N ⴝ 1102 N ⴝ 549 N ⴝ 553 n (%) n (%) n (%)
LVEF, mean (%) 50.8 51.0 LVEF ⬍ 35% 123 (11.2) 57 (10.4) Vessels diseased 1 579 (52.5) 295 (53.7) 2 325 (29.5) 161 (29.3) 3 197 (17.9) 92 (16.8) Indication for stent Elective 774 (70.2) 386 (70.3) Abrupt/threatened closure 180 (16.3) 91 (16.6) Suboptimal result 148 (13.4) 72 (13.1) Coronary vessel treated Left anterior descending 366 (33.2) 179 (32.6) Circumflex 229 (20.8) 113 (20.6) Right 432 (39.2) 214 (39.0) Vein graft 93 (5.2) 45 (8.2) Other 57 (5.2) 36 (6.6) Stents used Palmaz-Schatz 503 (45.6) 241 (43.9) GR I 52 (4.7) 27 (4.9) GR II 142 (12.9) 77 (14.0) Multi-Link 211 (19.1) 104 (18.9) Medtronic wiktor 27 (2.5) 11 (2.0) Other 245 (22.2) 128 (23.3) Stents placed per patient 1 716 (65.0) 357 (65.0) 2 278 (25.2) 141 (25.7) 3 76 (6.9) 36 (6.6) 4 25 (2.3) 12 (2.2) 5 4 (0.4) 2 (0.4) 6 3 (0.3) 1 (0.2) Stent length (mm) 18.3 ⫾ 0.2 18.4 ⫾ 0.3 Diameter of smallest stent (mm) 2.5 58 (5.3) 25 (4.6) 3.0 613 (55.6) 307 (55.9) 3.5 310 (28.1) 159 (29.0) ⱖ4.0 121 (10.9) 58 (10.5) Maximum activated 318 ⫾ 3.8 319 ⫾ 3.9 clotting time (s)
50.6 66 (11.9) 284 (51.4) 164 (29.7) 105 (19.0) 388 (70.2) 89 (16.1) 76 (13.7) 187 (33.8) 116 (21.0) 218 (39.4) 48 (3.8) 21 (3.8) 262 (47.4) 25 (4.5) 65 (11.8) 107 (19.3) 16 (2.9) 117 (21.2) 359 (64.9) 137 (24.8) 40 (7.2) 13 (2.4) 2 (0.4) 2 (0.4) 18.1 ⫾ 0.2
33 (6.0) 306 (55.3) 151 (27.3) 63 (11.3) 318 ⫾ 3.8
LVEF, Left ventricular ejection fraction; GR, Gianturco-Roubin.
occurred in the same patients. Only 0.27% (3/1102) of patients had definite or possible stent thrombosis (0.06-0.77). Neutropenia and TTP did not occur.
Frequency of clinical events The frequency of adverse ischemic events in the 15th through 30th days after ticlopidine was discontinued is shown in Figure 2. Only 3 patients had definite or possible stent thrombosis during this period. One patient had an anterior myocardial infarction, underwent stent placement in the left anterior descending artery within 48 hours of infarction, and was enrolled in ATLAST. The subsequent hospital course
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Figure 1
confirmed stent thrombosis; repeat coronary angioplasty was unsuccessful, and coronary artery bypass grafting was performed. The third patient had an anterior myocardial infarction, underwent stent placement in the left anterior descending artery within 48 hours of infarction, and was enrolled in ATLAST. This patient had an uneventful course without recurrent chest pain, ECG changes, or enzyme elevations. A routine electrocardiogram on day 28 revealed new Q waves in leads V3–V5, and the patient was considered to have had a nonfatal myocardial infarction and possible stent thrombosis by the Clinical Events Committee.
Bleeding
The frequency of clinical events after stent placement during the 14 days that ticlopidine was administered.
The frequency of major bleeding at 30 days was 1.6% in the placebo group versus 3.3% in the enoxaparin group (P ⫽ .08). The frequency of minor bleeding was 5.1% in the placebo group versus 25% in the enoxaparin group (P ⫽ .001).
Discussion Figure 2
The most important finding in this study is that among patients at increased risk for stent thrombosis not treated with platelet glycoprotein inhibitors, the frequency of stent thrombosis in the 15th through 30th days is low, even when ticlopidine is discontinued on the 14th day.
Ticlopidine
The frequency of clinical events in the 15th through 30th days after ticlopidine was discontinued.
was uneventful; the patient had no recurrent chest pain, ECG changes, or enzyme elevations. A routine electrocardiogram on day 30 revealed new Q waves in leads V1–V2 and new T-wave inversions in leads V2-V5 not present on an electrocardiogram the day after stent placement. The patient was considered to have had a nonfatal myocardial infarction and possible stent thrombosis according to the Clinical Events Committee. A second patient underwent stent placement in the left anterior descending artery and was enrolled in ATLAST. Twenty-two days after stent placement, this patient had an acute anterior infarction. Angiography
The frequency of coronary stent thrombosis in patients treated with aspirin and ticlopidine is lower than when aspirin and warfarin or aspirin alone is administered.3,4,13-16 Ticlopidine blocks 1 of the 3 types of adenosine diphosphate receptors, inhibiting up-regulation of glycoprotein IIb/IIIa receptors and impairing fibrinogen cross-linking of platelets.2 These effects last for the life of the platelet. Side effects from ticlopidine are common, the most serious of which are neutropenia and TTP, which is fatal in approximately 25% to 50% of cases.1,2 Neutropenia virtually never occurs with less than 2 weeks of therapy; TTP is rare with less than 2 weeks of therapy but does occur.1,2 Data from a study of 827 patients at the Mayo Clinic in whom ticlopidine was discontinued 14 days after stent placement revealed that there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures in the 15th through 30th days after ticlopidine had been stopped; stent thrombosis did not occur in any patient during this period (95% CI 0, 0.5).6 Other investigators have reported a 3.2% frequency of major adverse ischemic events between the 15th and 30th days in patients given warfarin sodium and aspirin after stent placement and concluded that a thienopyridine should be given for at least 4 weeks. However, because warfa-
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rin sodium delays the occurrence of stent thrombosis but does not reduce it, this conclusion is not persuasive.5 A preliminary analysis of 3676 patients who received ticlopidine for 4 weeks revealed that stent thrombosis between the 3rd and 4th weeks after stent placement, while ticlopidine was still being administered, occurred in 0.5% of patients.7 These investigators hypothesized that stent thrombosis may have been more frequent during the 3rd and 4th weeks had ticlopidine not been continued for 4 weeks and concluded that a thienopyridine should be given to all patients for at least 4 weeks after stent placement. It is not clear that the occurrence of stent thrombosis in patients taking ticlopidine in the 3rd and 4th weeks after stent placement is a strong argument that ticlopidine should be administered for at least 4 weeks. Nonetheless, the current study provides the strongest available data from a group of high-risk patients not likely to be included in any future studies— patients at increased risk for stent thrombosis not treated with a glycoprotein IIb/IIIa inhibitor who were treated with a thienopyridine for only 2 weeks. The results indicate that even when ticlopidine is discontinued after 2 weeks, the risk of stent thrombosis is low, well within the 95% CI of the Mayo Clinic study of early discontinuation of ticlopidine.6
Potential impact of enoxaparin on late stent thrombosis Enoxaparin may be effective at reducing stent thrombosis and other ischemic complications in ATLAST (odds ratio 0.65; 95% CI 0.29, 1.5), although such complications were infrequent and too few patients (n ⫽ 1102) were enrolled (caused in part by the premature termination of the study) to detect a significant difference between the 2 treatment arms.9 However, a reduction in stent thrombosis with enoxaparin might increase the risk of stent thrombosis rather than decrease it in the 15th through 30th days after stent placement after both enoxaparin and ticlopidine are discontinued if enoxaparin had the effect of delaying stent thrombosis that might otherwise have occurred earlier. A delay in the occurrence of stent thrombosis has been reported when platelet glycoprotein IIb/IIIa inhibitors have been administered.17 In this trial, however, an increase in late stent thrombosis in the enoxaparin group compared with the placebo group was not seen.
Late stent thrombosis in ATLAST It should be noted that 2 of the 3 patients in ATLAST considered to have stent thrombosis may not have actually experienced this event. Most patients with stent thrombosis develop the sudden onset of chest pain and experience Q-wave myocardial infarc-
Berger et al 845
tion or death. In 2 patients in this study considered to have had possible stent thrombosis, there were no clinically apparent adverse events. It is possible that the ECG results evolved later than is typical from the enrolling myocardial infarction. However, even if all 3 of these patients did have stent thrombosis, the frequency of stent thrombosis in this study would be 0.27% (95% CI 0.06, 0.79), considerably less than the 1% to 3% frequency of neutropenia and TTP when ticlopidine is continued for 4 weeks.
Clopidogrel Clopidogrel is a thienopyridine closely related to ticlopidine in chemical structure and function. Clopidogrel has largely replaced ticlopidine after stent placement because ticlopidine causes neutropenia in ⬎1% of patients and TTP in approximately 0.2% of patients, which is fatal in 25% to 50% of cases. Clopidogrel is also approximately 30% less expensive than ticlopidine in the United States. Data from 3 randomized trials and 7 registries suggest that clopidogrel is as effective as ticlopidine at reducing stent thrombosis and that clopidogrel has far fewer side effects.18-28 Clopidogrel does not appear to cause neutropenia; it has been reported to cause TTP in 11 of ⬎3 million patients treated.29 The optimal duration of clopidogrel after stent placement is unknown. However, the 2 drugs are equipotent, and the difference between ticlopidine and clopidogrel is in the rapidity of action and frequency of side effects, so the substitution of clopidogrel for ticlopidine does not affect the primary issue this study addresses. Ongoing studies are examining the most appropriate duration of clopidogrel after stent placement. Data from the PCI-CURE study indicate that the frequency of death and myocardial infarction in patients treated with 30 days of clopidogrel was 3.1% versus 3.9% in patients treated with as much as 12 months of clopidogrel, a difference of 0.8%, representing 8 events prevented per 1000 patients treated (P ⫽ NS).30 There are no data in PCI-CURE about whether these events were caused by stent thrombosis. Data from this study suggest that the risk of stent thrombosis after 2 weeks of therapy with aspirin and a thienopyridine is so low that the likelihood of observing a reduction in the rate of stent thrombosis from a longer duration of therapy is remote.
Conclusions The frequency of stent thrombosis and other adverse ischemic events 15 to 30 days after stent placement in even high-risk stent patients treated with ticlopidine for only 2 weeks is low (0.27%), even when glycoprotein IIb/IIIa inhibitors are not used and whether or not enoxaparin is administered. The risk is less than the risk of severe neutropenia or TTP when ticlopidine is
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continued for 30 days. Therefore, ticlopidine should be discontinued 14 days after stent placement. The most appropriate duration of clopidogrel, which appears to be at least as effective as ticlopidine at preventing stent thrombosis but does not cause neutropenia and only rarely causes TTP, remains to be determined.
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