Prospective Comparison of Hemorrhagic Complications After Treatment With Enoxaparin

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1 Prospective Comparison of Hemorrhagic Complications After Treatment With Versus Unfractionated Heparin for Unstable Angina Pectoris or Non ST-Segment Elevation Acute Myocardial Infarction Scott D. Berkowitz, MD, Sandra Stinnett, PhD, Marc Cohen, MD, Gregg J. Fromell, MD, and Frederique Bigonzi, MD, on behalf of the ESSENCE Investigators* Patients with unstable angina pectoris (UAP) or non STsegment elevation acute myocardial infarction (AMI) are at risk of death or recurrent ischemic events, despite receiving aspirin and unfractionated heparin (). This study investigates the effect of the low molecular weight heparin, enoxaparin, on the incidence of hemorrhage and thrombocytopenia in relation to baseline characteristics and subsequent invasive procedures. Rates of hemorrhage and thrombocytopenia were analyzed for UAP or non ST-segment elevation AMI in patients included in the prospective, randomized, double-blind Efficacy and Safety of Subcutaneous in Non Q-wave Coronary Events (ESSENCE) study. Patients received either enoxaparin or, plus aspirin, for 2 to 8 days. The overall rate of major hemorrhage (at 30 days) was comparable between the 2 groups (6.5% for enoxaparin vs 7.0% for, p 0.6). The rate of major hemorrhage while on treatment was slightly higher in the enoxaparin group, but this was not significant (1.1% vs A number of studies have investigated low molecular weight heparins as an alternative to unfractionated heparin () in the management of unstable angina pectoris (UAP) or non ST-segment elevation acute myocardial infarction (AMI). 1 9 The Efficacy and Safety of Subcutaneous in Non Qwave Coronary Events (ESSENCE) study found a significant reduction in acute coronary events in patients with UAP or non Q-wave myocardial infarction treated with subcutaneous enoxaparin in comparison with intravenous. 4 However, concerns about the From the Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina; MCP Hahnemann University School of Medicine, Philadelphia, Pennsylvania; Aventis Pharma, Paris, France; and AstraZeneca, Wayne, Pennsylvania. This study and Dr. Cohen were supported by a grant from Aventis Pharma, Paris, France. Manuscript received May 31, 2001; revised manuscript received and accepted July 26, Address for reprints: Marc Cohen, MD, Cardiac Catheterization Lab, Mail Stop 119, Hahnemann University Hospital, Philadelphia, Pennsylvania marc.cohen@tenethealth.com *A list of the ESSENCE investigators can be found in N Engl J Med 1997;337: % for, p 0.204), as was the rate of major hemorrhage within 48 hours of coronary artery bypass grafting performed within 12 hours of treatment. However, the rate of minor hemorrhage was significantly higher in the enoxaparin group, with the majority being injection-site ecchymoses or hematomas (11.9% vs 7.2% with, p <0.001). Thrombocytopenia (platelet count <100,000 per mm 3 ) occurred mainly in association with coronary bypass surgery, with a similar rate in both groups. Thus, enoxaparin is a well-tolerated alternative to in the management of UAP or non ST-segment elevation AMI. Despite the more effective antithrombotic effect, which results in fewer ischemic events, enoxaparin is not associated with an increase in the rate of major hemorrhagic complications, and is not significantly associated with thrombocytopenia, but is associated with an increase in minor injection site ecchymosis by Excerpta Medica, Inc. (Am J Cardiol 2001;88: ) safety of antithrombotic treatment of UAP and/or non ST-segment elevation AMI are of paramount importance, particularly in view of the frequent requirement for invasive coronary revascularization procedures in patients with these syndromes, and of previous reviews comparing rates of bleeding observed with low molecular weight heparin The present study provides further details of the hemorrhagic events and development of thrombocytopenia in the ESSENCE trial, in which 32% of the patient cohort had revascularization procedures within the first 30 days. METHODS Patient population and treatment protocol: Full details of the ESSENCE study have been described previously in detail. 4 The ESSENCE study was a prospective, randomized, double-blind, parallel-group multicenter trial in patients with recent-onset angina at rest with additional evidence of underlying ischemic heart disease. All patients received aspirin, and were randomly assigned for 2 to 8 days to either enoxaparin 1 mg/kg administered subcutaneously every 12 hours, or a 5,000 U intravenous bolus of followed by a by Excerpta Medica, Inc. All rights reserved /01/$ see front matter The American Journal of Cardiology Vol. 88 December 1, 2001 PII S (01)

2 TABLE 1 Baseline Characteristics and Risk Factors of Patients With Major and Minor Bleeding (all-treated population) Major Bleeding Minor Bleeding Characteristic All-Treated Population (n 102) (n 107) (n 206) (n 128) Sex Men 2064 (66%) 72 (71%) 63 (59%) 121 (59%) 72 (56%) Women 1,043 (34%) 30 (29%) 44 (41%) 85 (41%) 56 (44%) Race Non-white 314 (10%) 6 (6%) 11 (10%) 14 (7%) 13 (10%) White 2,793 (90%) 96 (94%) 96 (90%) 192 (93%) 115 (90%) Age (yrs) Mean SD Median (25th 75th percentile) 65 (55 72) 68 (61 73) 66 (57 72) 65 (56 73) 68 (58 75) Weight (kg) Mean SD Median (25th 75th percentile) 78 (64 88) 80 (68 89) 77 (68 88) 79 (70 89) 77 (64 89) Body surface area (m 2 ) Mean SD Median (25th 75th percentile) 1.88 ( ) 1.92 ( ) 1.88 ( ) 1.89 ( ) 1.86 ( ) Smoker Current 748 (24%) 16 (16%) 22 (21%) 41 (20%) 23 (18%) Previous 268 (9%) 12 (12%) 6 (6%) 18 (9%) 8 (6%) Never 2,091 (67%) 74 (73%) 82 (77%) 147 (71%) 97 (76%) Obese 1,560 (50%) 45 (45%) 55 (51%) 108 (53%) 68 (53%) Prior aspirin use 1,926 (62%) 67 (66%) 72 (67%) 122 (60%) 84 (66%) Initial ECG changes 1,760 (57%) 67 (66%) 69 (65%) 120 (58%) 77 (60%) Final admission diagnosis Unstable angina 2,157 (69%) 65 (64%) 67 (63%) 144 (71%) 85 (67%) Non Q-wave MI 645 (21%) 31 (31%) 38 (36%) 40 (20%) 38 (30%) Q-wave MI 101 (3%) 3 (3%) 2 (2%) 6 (3%) 2 (2%) Creatinine clearance (mg/dl) Mean SD Median (25th 75th percentile) 77 (58 99) 77 (55 95) 76 (56 97) 80 (57 98) 68 (53 96) ECG electrocardiogram; obese body mass index of 26.9 kg/m 2 for women, 27.2 kg/m 2 for men. continuous infusion adjusted to the activated partial thromboplastin time (target range 55 to 85 seconds). The primary efficacy end point was the composite triple end point of death, myocardial infarction, and recurrent angina at the 14-day follow-up visit. If patients underwent coronary bypass surgery during the study, the patients randomized to receive enoxaparin may have been given additional (but no additional enoxaparin) during surgery. Safety end points: The primary safety end point was the incidence of hemorrhagic episodes by day 30 in the ESSENCE trial. Secondary safety analyses included the incidence of hemorrhagic episodes on treatment, defined as up to 2 hours after the end of the intravenous infusion for patients who received or within 12 hours of the last subcutaneous dose for patients treated with enoxaparin. Only adjudicated hemorrhagic events (subject to clinical events committee adjudication) are presented in this study. Major hemorrhage was defined as clinically overt bleeding associated with 1 of the following: death; transfusion of 2 U of packed red cells or whole blood; a decrease in hemoglobin levels of 30 g/l (1.9 mmol/l); and retroperitoneal, intracranial, or intraocular hemorrhage. Minor hemorrhage was defined as any clinically important bleeding that did not qualify as major hemorrhage. Platelet counts were performed on blood collected in ethylenediaminetetraacetic acid before randomization, on day 3 ( 1 day), and at the end of treatment ( 1 day). Moderate thrombocytopenia was defined as a nadir platelet count of 100,000/mm 3, and severe thrombocytopenia was defined as a nadir platelet count of 50,000/mm 3. Statistical analysis: The safety analyses for this study were performed on the all-treated population only (i.e., those patients who received 1 dose of trial drug). Hemorrhagic events were analyzed by incidence, severity, causality, consequences, and association with percutaneous coronary interventions. Subgroup analyses according to certain demographic and baseline variables were undertaken to ascertain correlates of bleeding complications. Pearson s chi-square tests were used to compare the impact of the different antithrombotic trial drugs on the changes in platelet count and hemoglobin during the 30-day period. All comparisons were 2-tailed statistical tests at a 5% significance level. RESULTS In the ESSENCE trial, 3,171 patients were randomized. A total of 3,107 patients received 1 dose of study treatment and were included in the present safety analyses. Baseline characteristics and use of nonstudy anticoagulants, aspirin, or other antiplatelet medications in the week before randomization were similar for both the enoxaparin and treatment groups (Table 1); both study drugs were administered for a median duration of 2.6 days. CORONARY ARTERY DISEASE/HEMORRHAGIC COMPLICATIONS AFTER ENOXAPARIN AND HEPARIN 1231

3 TABLE 2 Summary of Hemorrhagic Events at 30 Days (all-treated population) p Value Any major hemorrhage* 209 (6.7%) 102 (6.5%) 107 (7.0%) NS While on treatment 27 (0.9%) 17 (1.1%) 10 (0.7%) NS Associated with coronary bypass 159 (5.1%) 75 (4.8%) 84 (5.5%) NS Not associated with coronary bypass 50 (1.6%) 27 (1.7%) 23 (1.5%) Causing death 1 (0.03%) 0 1 (0.1%) NS Drop in hemoglobin 30 g/l (1.9 mmol/l) 159 (5.1%) 77 (4.9%) 82 (5.4%) NS Drop in hemoglobin 50 g/l loss 124 (3.9%) 58 (3.7%) 66 (4.3%) NS Resulted in transfusion 2 U of blood 167 (5.4%) 83 (5.3%) 84 (5.5%) NS Retroperitoneal, intracranial, or intraocular 3 (0.1%) 1 (0.1%) 2 (0.1%) NS Any minor hemorrhage (only) 298 (9.6%) 188 (11.9%) 110 (7.2%) Drug discontinued 53 (1.7%) 28 (1.8%) 25 (1.6%) NS Required transfusion ( 2 U of blood) 12 (0.4%) 5 (0.3%) 7 (0.5%) NS Serious as per investigator 13 (0.4%) 5 (0.3%) 8 (0.5%) Injection-site ecchymosis 132 (4.2%) 102 (6.5%) 30 (2.0%) Non injection-site ecchymosis 55 (1.8%) 31 (2.0%) 24 (1.6%) Any hemorrhage While on treatment 507 (16.3%) 290 (18.4%) 217 (14.2%) Leading to study drug discontinuation 216 (7.0%) 148 (9.4%) 68 (4.4%) Requiring transfusion ( 2 U of blood) 75 (2.4%) 43 (2.7%) 32 (2.1%) Causality* 195 (6.3%) 95 (6.0%) 100 (6.5%) Spontaneous 127 (4.1%) 77 (4.9%) 50 (3.3%) Secondary to surgery/instrumentation 387 (12.5%) 216 (13.7%) 171 (11.2%) Secondary to other trauma 21 (0.7%) 16 (1.0%) 5 (0.3%) *Subcategories are not mutually exclusive. Hemorrhagic events: Hemorrhagic events by 30 days are summarized in Table 2. At 30 days, the frequency of major hemorrhage was similar in both treatment groups. Some kind of hemorrhagic event (major or minor) occurred in a total of 507 patients (16%). The frequency of any hemorrhage was higher in the enoxaparin group compared with patients treated with. However, the difference in the hemorrhagic rate was a result of the higher number of minor hemorrhagic events in the enoxaparin group. These excess minor events were primarily injectionsite ecchymoses 5 cm in diameter and injection site hematoma 5 cm in diameter. Causality and outcome of hemorrhage:, 387 of 507 hemorrhagic events (76%) and 185 of 209 major hemorrhagic events (89%) were secondary to coronary bypass or percutaneous coronary intervention. Of all the major hemorrhagic events, 159 of 209 (76%) were associated with coronary artery bypass grafting. The incidence of major hemorrhage associated with coronary bypass was equivalent for both groups, and there was no difference between the groups in the outcome and type of major hemorrhage (Table 2). One instance of intracranial hemorrhage and 1 fatal major hemorrhage occurred, both in patients receiving. Hemorrhagic events by subgroup: Major hemorrhagic episodes by treatment, according to predefined potential baseline risk factors, can be found in Table 1. The overall frequency of hemorrhage varied substantially by continent and country, from the highest in South America (31%) to the lowest in Europe (8%). Further analysis of the subgroups revealed that major hemorrhage was more common in patients with renal impairment (defined as creatinine clearance 30 mg/ ml) treated with enoxaparin (4 of 28 enoxaparintreated patients with renal impairment had a major hemorrhage [14%] compared with 2 of 31 patients treated with [6%]). However, the small number of patients in this subgroup prevents firm conclusions being drawn from this finding., compared with all patients, patients with major hemorrhagic events tended to be slightly older. No differences were observed between patients with or without hemorrhage in terms of the maximum activated partial thromboplastin times measured before the hemorrhagic event in the group: the maximum activated partial thromboplastin time value before hemorrhage was 104 seconds, compared with the median value of 101 seconds in patients who did not experience hemorrhaging. Timing of hemorrhagic events and relation to invasive procedures: Of the 507 patients who experienced any hemorrhagic events within the first 30 days, 216 (43%) did so while on study treatment (Table 3). The total incidence of hemorrhage on treatment was higher in the enoxaparin group compared with the group (9.4% vs 4.4%, p 0.001), although the frequency of major hemorrhage while on treatment was comparable for the 2 groups (1.1% vs 0.7%, respectively, p 0.204). More patients in the group required invasive procedures during the study compared with the enoxaparin group (Table 4). A total of 144 patients underwent percutaneous coronary intervention within 12 hours of cessation of treatment; 7 of these patients experienced major hemorrhage. Fifteen of the 31 patients who underwent coronary bypass within 12 hours of cessation of treatment had major hemorrhage. Hematologic parameters: A total of 159 patients (5%) had 1 hemoglobin value that represented a decrease from baseline of 30 g/l (1.9 mmol/l) 1232 THE AMERICAN JOURNAL OF CARDIOLOGY VOL. 88 DECEMBER 1, 2001

4 TABLE 3 Summary of Adjudicated Hemorrhagic Event Incidence While on Study Medication (all-treated population) during the 30-day period. There were no statistically significant differences between treatments for changes in this value. Moderate thrombocytopenia (platelet count 100,000/mm 3 ) was similar for the 2 treatment groups (Table 5). The overall incidence of severe thrombocytopenia (platelet count 50,000/mm 3 )was 0.5%, and this event was most commonly associated with coronary bypass; no treatment differences were observed. Moderate thrombocytopenia was associated with a significantly higher risk of adverse clinical outcomes, including acute cardiac events, requirement for percutaneous procedures, major hemorrhage, major hemorrhage associated with coronary bypass, requirement for transfusion, and a decrease in hemoglobin of 30 g/l (p for all comparisons vs patients without thrombocytopenia). DISCUSSION The present study provides evidence, based on a blinded, randomized comparison, that enoxaparin is at least as safe as (with regard to major hemorrhage) in the management of UAP or non ST-segment Any major hemorrhage 27 (0.9%) 17 (1.1%) 10 (0.7%) Associated with coronary bypass 6 (0.2%) 4 (0.3%) 2 (0.1%) Causing death Drop in hemoglobin 30 g/l 16 (0.5%) 9 (0.6%) 7 (0.5%) Resulted in transfusion (with 2 U of blood) 21 (0.7%) 13 (0.8%) 8 (0.5%) Retroperitoneal, intracranial, or intraocular 1 (0.0%) 1 (0.1%) 0 Any hemorrhage 216 (7.0%) 148 (9.4%) 68 (4.4%) Leading to study drug discontinuation 69 (2.2%) 38 (2.4%) 31 (2.0%) Requiring transfusion (with 2 U of blood) 28 (0.9%) 16 (1.0%) 12 (0.8%) Causality* Spontaneous 83 (2.7%) 58 (3.7%) 25 (1.6%) Secondary to surgery/instrumentation 126 (4.1%) 86 (5.4%) 40 (2.6%) Secondary to other trauma 16 (0.5%) 13 (0.8%) 3 (0.2%) *Subcategories are not mutually exclusive. p 0.204; p TABLE 4 Hemorrhagic Events Within 48 Hours of Intervention in Patients Who Underwent Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting Within 12 Hours of Cessation of Treatment Patients undergoing coronary intervention 529 (17%) 236 (15%) 293 (19%) up to day 30 (n)* Coronary intervention within 12 h of 144 (4.5%) 60 (3.7%) 84 (5.4%) cessation of treatment Major hemorrhage within 48 h after 7 (4.9%) 4 (6.7%) 3 (3.6%) coronary intervention (within 12 h of cessation of treatment) Patients undergoing coronary bypass 412 (13%) 198 (12%) 214 (14%) Coronary bypass within 12 h of 31 (1.0%) 9 (0.6%) 22 (1.4%) cessation of treatment Major hemorrhage within 48 h after coronary bypass (within 12 h of cessation of treatment) 15 (48%) 5 (56%) 10 (46%) *p 0.002; p elevation AMI. Although the likelihood of any hemorrhagic event in the ESSENCE study was greater for enoxaparin-treated patients compared with -treated patients, the increase was almost wholly accounted for by a higher rate of minor hemorrhagic events, mainly injection site ecchymosis and hematoma. The incidence of major hemorrhage were similar for both treatment groups at 30 days, but was slightly higher in the enoxaparin group while on treatment, but not significantly so, as were the rate of blood transfusion and significant decreases in hemoglobin. It should be noted that in this study the definition of major hemorrhage was quite wide, including retroperitoneal hemorrhage and transfusion and a decrease in hemoglobin content of 30 g/l. Most hemorrhagic events occurred within the context of surgery or percutaneous coronary intervention, with similar numbers in the enoxaparin and groups having major hemorrhage related to coronary bypass. Similarly, noncoronary bypass related bleeding occurred at similar rates in the 2 treatment groups. The effect of anticoagulant therapy on bleeding associated with cardiac interventions is of considerable clinical importance, given the high frequency of percutaneous interventions following initial medical management of UAP and/or non ST-segment elevation AMI. 10,11 Fewer patients in the enoxaparin group required revascularization procedures up to day 30. The number of patients with major hemorrhage in the 48 hours after a percutaneous coronary intervention or coronary artery bypass grafting procedure performed within 12 hours of cessation of treatment was similar for patients receiving enoxaparin or, although the number of patients in each group was very small, due in part to the protocol recommendation that no revascularization procedures be performed within 48 hours of study treatment unless clinically indicated. For patients who underwent percutaneous coronary intervention or coronary bypass within 12 hours of treatment, the study protocol permitted the use of extra during the procedure in the enoxaparintreated patients, exposing these patients to a higher level of anticoagulant therapy. The increasing use of percutaneous coronary intervention in patients with UAP or non ST-segment elevation AMI has led to clinical studies to assess the safety of enoxaparin during percutaneous coronary intervention, and it has been shown that enoxaparin used as the only anticoagulant appears to be safe and effective. 13 Recently, a CORONARY ARTERY DISEASE/HEMORRHAGIC COMPLICATIONS AFTER ENOXAPARIN AND HEPARIN 1233

5 TABLE 5 Platelet Counts and Hemoglobin Levels During Treatment and Follow-Up (all-treated population) small single-center study investigated the affects of dalteparin 120 U/kg, administered twice daily subcutaneously, on bleeding following coronary bypass in patients with unstable angina. 14 Patients who received a dose of dalteparin within the 12 hours before surgery had a significantly greater blood loss (p 0.001) and increased need for blood transfusion (p 0.047) than patients who received intravenous, who underwent elective coronary bypass, or who last received dalteparin 12 hours before surgery Gurfinkel EP, Manos EJ, Mejail RI, Cerda MA, Duronto EA, Garcia CN, Daroca AM, Mautner B. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995;26: Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996;347: Klein W, Buchwald A, Hillis SE, Monrad S, Sanz G, Turpie AG, van der Meer J, Olaisson E, Undeland S, Ludwig K. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease (FRIC) study. Circulation 1997;96: p Value Over 30-day period Nadir platelet counts* 50,000/mm 3 16 (0.5%) 7 (0.4%) 9 (0.6%) ,000/mm 3 95 (3.1%) 43 (2.7%) 52 (3.4%) % decrease from baseline 110 (3.5%) 48 (3.0%) 62 (4.0%) On study medication Nadir platelet counts* 50,000/mm 3 2 (0.1%) 2 (0.1%) ,000/mm 3 15 (0.5%) 9 (0.6%) 6 (0.5%) % decrease from baseline 10 (0.3%) 8 (0.5%) 2 (0.1%) *Subcategories are mutually exclusive. On study medication defined as within 2 hours after discontinuation of heparin infusion, or within 12 hours after last enoxaparin injection. 4. Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman S, Langer A, Califf RM, Fox KA, Premmereur J, Bigonzi F. A comparison of lowmolecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337: FRAXiparine in Ischaemic Syndrome (FRAXIS) Investigators. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-q wave myocardial infarction. Eur Heart J 1999;20: FRagmin, and Fast Revascularisation during InStability in Coronary artery disease Investigators. Longterm low-molecular-mass heparin in unstable coronary artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354: Antman E, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein D, Bayes De Luna A, Fox K, Lablanche JM, Radley D, Premmereur J, Braunwald E. prevents death and cardiac ischemic events in unstable angina/non-q-wave myocardial infarction: Results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. Circulation 1999;100: Antman EM, Cohen M, Radley D, McCabe C, Rush J, Premmereur J, Braunwald E. Assessment of the treatment effect of enoxaparin for unstable angina/non-q wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation 1999;100: Goodman S, Cohen M, Bigonzi F, Gurfinkel EP, Radley DR, Le Louer V, Fromell GJ, Demers C, Turpie AG, Califf RM, Fox KA, Langer A, for the ESSENCE (Efficacy and Safety of Subcutaneous in Non-Q wave Coronary Events) Study Group. Randomized trial of low molecular weight heparin (enoxaparin) versus heparin for unstable coronary disease: one-year results of the ESSENCE study. J Am Coll Cardiol 2000;36: The TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-q-wave myocardial infarction: Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 1994;89: FRagmin, and Fast Revascularisation during InStability in Coronary artery disease Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354: Thomas DP. Does low molecular weight heparin cause less bleeding? Thromb Haemost 1997;78: Collet JP, Montalescot G, Lison L, Choussat R, Ankri A, Drobinski G, Sotirov I, Thomas D. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation 2001;103: Clark SC, Vitale N, Zacharias J, Forty J. Effect of low molecular weight heparin (fragmin) on bleeding after cardiac surgery. Ann Thorac Surg 2000;69: THE AMERICAN JOURNAL OF CARDIOLOGY VOL. 88 DECEMBER 1, 2001