Author + information
- Received October 1, 1996
- Revision received February 10, 1997
- Accepted February 26, 1997
- Published online June 1, 1997.
- ↵*Dr. Elliott M. Antman, Brigham and Women’s Hospital, Department of Medicine, Cardiovascular Division, 75 Francis Street, Boston, Massachusetts 02115. E-mail: firstname.lastname@example.org.
Objectives. The Thrombolysis in Myocardial Infarction (TIMI) 11A trial compared the safety and tolerability of two weight-adjusted regimens of subcutaneous injections of enoxaparin, a low molecular weight heparin, in patients with unstable angina/non–Q wave myocardial infarction (NQMI).
Background. The optimal dose of enoxaparin in patients with arterial disorders has not been established.
Methods. Patients with unstable angina/NQMI were treated over a 14-day period in an open label dose-ranging trial. During the in-hospital phase, patients received either 1.25 mg/kg body weight (dose tier 1) or 1.0 mg/kg (dose tier 2) of enoxaparin subcutaneously every 12 h. A fixed dose of either 60 mg (body weight ≥65 kg) or 40 mg (body weight <65 kg) was administered subcutaneously every 12 h after hospital discharge.
Results. In an initial cohort of 321 patients (dose tier 1), the rate of major bleeding through 14 days was 6.5% and occurred predominantly at instrumented sites. In a second cohort of 309 patients (dose tier 2), the rate of major hemorrhage was reduced to 1.9%. In both dose tiers, only 3% to 5% of patients withdrew consent for subcutaneous injections during the home treatment phase. Through 14 days, the incidence of death, recurrent myocardial infarction or recurrent ischemia requiring revascularization was 5.6% in dose tier 1 and 5.2% in dose tier 2.
Conclusions. An acute phase regimen of enoxaparin (1.0 mg/kg every 12 h) is associated with an acceptable rate of major hemorrhage during the in-hospital phase. There is a high rate of patient compliance during the home treatment phase. A Phase III trial is now underway to test the benefits of uninterrupted treatment with enoxaparin during both the in-hospital and outpatient treatment phases.
(J Am Coll Cardiol 1997;29:1474–82)
Experimental and clinical observations ([1–7]) suggest that both platelet activation and thrombin generation are important in the pathophysiology of unstable angina and non–Q wave myocardial infarction (NQMI), leading to the recommendation that aspirin and intravenous heparin be prescribed to treat these conditions. When unfractionated heparin is administered, there is wide variability in the anticoagulant effect caused by heparin binding to several plasma proteins ([8, 9]). The amount of these plasma proteins varies among disease states and among normal subjects. Response to unfractionated heparin is therefore unpredictable, and anticoagulation blood monitoring is mandatory.
In contrast, low molecular weight heparins (LMWHs) have minimal protein binding, excellent bioavailability and a predictable anticoagulant response ([8, 10, 11]). LMWHs also have a number of potential safety advantages compared with unfractionated heparin. Capillary permeability to plasma proteins and microvascular bleeding is increased by unfractionated heparin (by formation of a protein–glycosaminoglycan complex) but not by LMWH (). LMWHs are also associated with a reduced potential for thrombocytopenia ().
Enoxaparin, a LMWH (4,300 daltons) with an anti-Factor Xa (anti-Xa)/anti-Factor IIa (anti-IIa) ratio of 3:1, is approved in several countries for the prevention and treatment of deep vein thrombosis (). On the basis of clinical trial results and studies in normal volunteers, a range of mean anti-Xa activity of 0.5 to 1.0 IU/ml was found to be effective for treatment of venous disorders (); however, the optimal dose for treatment of arterial disorders is unknown. The purpose of the present Phase II trial (Thrombolysis in Myocardial Infarction [TIMI] 11A) was to evaluate the safety and tolerability of two doses of enoxaparin in patients with unstable angina/NQMI, in preparation for a future trial comparing enoxaparin and unfractionated heparin.
The trial was conducted between July 1995 and January 1996 at 45 enrolling centers in the United States, as described in the Appendix A.
1.1 Eligibility Criteria.
To be eligible for inclusion in the trial, patients must have had evidence of ischemic heart disease and experienced unstable angina/NQMI, with one of the following three presentations within the preceding week: 1) rest angina ≥5 min; 2) new-onset angina (Canadian Cardiovascular Society classification III or greater severity, beginning within 2 months of presentation); or 3) increasing angina (previously diagnosed angina that was distinctly more frequent, longer in duration or occurring at a lower threshold). To confirm the presence of ischemic heart disease, patients must have met at least one of the following criteria: 1) history of typical myocardial ischemic-type discomfort; 2) electrocardiographic changes (ST segment deviation or T wave inversion, or both) in association with ischemic discomfort; 3) a history of previous myocardial infarction; 4) positive results on a previous exercise tolerance test; 5) previous coronary artery bypass graft surgery (CABG) or percutaneous transluminal coronary angioplasty (PTCA); or 6) a previous coronary angiogram showing a 50% stenosis of a major epicardial coronary vessel.
Patients were excluded from the study if any of the following were present: 1) evolving Q wave myocardial infarction or thrombolytic therapy within 24 h of enrollment or intention to administer thrombolytic therapy for the patient’s presenting chest pain syndrome; 2) creatinine ≥2.0 mg/dl; 3) CABG within the previous 2 months; 4) history of heparin-induced thrombocytopenia; 5) contraindications to anticoagulation or aspirin, including intracerebral hemorrhage <2 months; 6) an international normalized ratio >1.4 or a continuous infusion of unfractionated heparin; or 7) other existing medical condition, such as the presence of a prosthetic heart valve, requiring continuous anticoagulation.
1.2 Study Protocol.
TIMI 11A was an open label study designed to evaluate the safety and tolerability of two doses of enoxaparin in treatment regimens consisting of two phases: 1) an in-hospital phase (intravenous bolus of 30 mg followed immediately by subcutaneous injection every 12 h of a weight-adjusted dose) for a minimum of 48 h; and 2) an outpatient phase of prolonged fixed subcutaneous dosing (60 mg for patients ≥65 kg and 40 mg for patients <65 kg) every 12 h. In patients undergoing diagnostic or successful interventional catheterization procedures, the fixed dose regimen of enoxaparin was started before hospital discharge and was continued as outpatient therapy. The total treatment period, including the weight-adjusted and fixed-dose periods, was 14 days.
The original plan was for an ascending dose-ranging trial to evaluate a weight-adjusted dose of enoxaparin of 1.25 mg/kg body weight every 12 h (dose tier 1) in the first cohort of patients and 1.5 mg/kg every 12 h in a second group of patients. However, because of an unacceptable rate of major hemorrhage observed after enrolling 321 patients in the 1.25-mg/kg every 12 h dose (see Statistical methods), the trial was reconfigured as a descending dose-ranging trial, with the second cohort (309 patients) receiving 1.0 mg/kg every 12 h (dose tier 2).
During the course of the treatment period, patients could undergo diagnostic catheterization either with the study drug, with no anticoagulation or with unfractionated heparin at the discretion of the treating physician. All interventional coronary procedures were to be performed using unfractionated heparin after a minimum activated clotting time of 350 s had been achieved, followed subsequently by readministration of study drug.
After diagnostic and interventional catheterization procedures, the arterial sheath was to be removed no sooner than 7 to 8 h after the previous enoxaparin dose (i.e., beyond the peak anti-Xa effect). For patients undergoing a diagnostic catheterization or a successful interventional procedure, subcutaneous injections of enoxaparin every 12 h were restarted in the fixed dose described earlier at least 24 h after the last subcutaneous injection. For those patients undergoing complicated procedure (e.g., stent implantation, thrombus visualized in culprit vessel, dissection of culprit vessel), it was recommended that subcutaneous injections of enoxaparin be restarted at least 2 h after sheath removal and full hemostasis had been achieved; the first injection was half of the fixed dose, and subsequent injections every 12 h were at the full fixed dose.
If patients were referred for CABG, the study drug was to be discontinued at least 12 h before the scheduled operation and subsequent anticoagulation provided with unfractionated heparin at the treating physician’s discretion.
1.3 Laboratory Tests.
At enrollment into the study, at hospital discharge and at the final outpatient visit, measurement of hemoglobin and a platelet count were obtained.
Before and after both the third and last weight-adjusted doses of enoxaparin, blood specimens were obtained for measurement of anti-Xa activity. Venous blood samples were drawn by venipuncture before (trough) and 3 to 5 h after (peak) the third weight-adjusted dose of enoxaparin and again on the last day of weight-adjusted dosing. Blood samples were collected in glass tubes (Becton Dickinson) containing 0.109 mol/liter sodium citrate and inhibitors of platelet activation as an anticoagulant mixture (9:1 vol/vol) and were centrifuged at 3,000gfor 15 min at +4°C. Plasma was frozen and stored at −80°C until analysis.
Plasma anti-Xa activity was determined by amidolytic assay using the specific chromogenic substrate CBS 3139 and bovine Factor Xa as reagents (Dioagnostica Stago) ([16, 17]). The enoxaparin standard calibrated against LMWH dose tier 1 was used as a reference. The anti-Xa assay characteristics were as follows: quantification limit 0.025 IU of anti-Xa/ml, linearity over the 0.0- to 0.4-IU anti-Xa/ml calibration range, linear response of serial dilution (0.4- to 10-IU anti-Xa/ml range), reproducibility within 4% to 12% and accuracy in the 96% to 110% range. All samples were analyzed in duplicate.
1.4 Concomitant Medications.
All patients received 325 mg of aspirin at enrollment and 100 to 325 mg daily thereafter for the duration of the study. Other antianginal therapy, including beta-adrenergic blocking agents, nitrates and calcium channel blocking agents, was administered at the discretion of the treating physician.
1.5 Study End Points.
All study end points were reviewed and classified by an Events Review Committee. The primary end point, major hemorrhage occurring within 2 weeks of enrollment, was defined as at least one of the following: 1) a clinically overt hemorrhage resulting in a fall ≥3 gm/dl in hemoglobin; or 2) a retroperitoneal, intracranial or intraocular hemorrhage. Episodes of bleeding that were clinically overt but did not meet these criteria were considered minor hemorrhages.
Efficacy end points were also ascertained at 2 weeks after enrollment and included the following: 1) death (all-cause mortality); 2) myocardial infarction not present at enrollment was defined as elevation of creatine kinase, MB fraction, levels above normal (twice normal after PTCA and five times normal after CABG) or the development of new Q waves in two or more contiguous leads (); or 3) recurrent ischemia requiring revascularization, defined as either rest pain followed by a coronary revascularization procedure during the same hospital period or rapid clinical deterioration (e.g., hypotension, cardiac arrest, cardiogenic shock or persistent life-threatening arrhythmia) necessitating emergency revascularization.
1.6 Statistical Methods.
Rates of major hemorrhage averaging 3.3% (95% confidence interval [CI] 0% to 6%) were found in a review of the collective experience in 484 patients in trials involving intravenous unfractionated heparin therapy for unstable angina/NQMI ([7, 19–21]). A subset analysis in the TIMI IIIB trial () revealed that hemorrhagic events occurred in 3.2% (95% CI 2.1% to 4.3%) of the 735 patients who received heparin and placebo (invasive and conservative strategies pooled). On the basis of the range of these data, an estimate of the risk of major hemorrhage with unfractionated heparin in previous clinical trials of ∼4% was established. To obtain a reliable estimate of the major hemorrhage rate, up to 500 patients were scheduled for enrollment into each dose tier to ensure that at least 300 evaluable patients would be enrolled (defined as receiving at least four consecutive weight-adjusted doses of enoxaparin). An unacceptable rate of major hemorrhage for enoxaparin therapy was prospectively defined such that the lower bound of its 90% CI was ≥4.0%. On the basis of a minimal sample size of 300 patients for an evaluable cohort, if at least 19 patients experienced a major hemorrhage (6.3%, 90% CI 4.0% to 8.7%) in a given dose tier, the anticipated rate of major hemorrhage with unfractionated heparin would be exceeded. Routine monitoring of the major hemorrhage rate was performed by the Operations Committee during the course of the trial. After 321 patients had been enrolled in dose tier 1, 21 (6.5%) experienced a major hemorrhage, thus exceeding the prespecified guidelines, and no further patients were enrolled in that dose tier. The weight-adjusted dose was reduced to 1.0 mg/kg every 12 h (dose tier 2), and a second cohort of 309 patients was enrolled.
The data presented in this report compare the findings in patients in dose tier 1 and dose tier 2. Because patients were assigned to dose tiers sequentially rather than in a randomized fashion, the proportion experiencing the primary end point in the two dose tiers was compared by calculating the event rate and its 95% CI. However, comparison of baseline characteristics was performed using the chi-square test for categoric variables and either two-tailed ttests or Wilcoxon rank sum tests for continuous variables. Data for continuous variables are presented as median (25th, 75th percentile). The cumulative probability of developing the primary safety and primary efficacy end points through 14 days was calculated by the Kaplan-Meier method for both dose tiers; differences were compared by the log-rank statistic. Differences associated with a p value ≤0.05 were considered significant.
2.1 Baseline Characteristics.
The characteristics of the patients enrolled in the two dose tiers are shown in Table 1. No significant differences were seen between the dose groups. The majority of patients were white men with a previous history of angina. The qualifying episode of ischemic discomfort occurred a median of 12.6 h before enrollment in dose tier 1 and 21.1 h in dose tier 2. Approximately 80% of patients in both groups had received aspirin in the week before enrollment. Although 123 (38%) of patients in dose tier 1 and 163 (53%) in dose tier 2 had received intravenous heparin during the previous week, only 15 patients in dose tiers 1 (4.7%) and 2 (4.9%) had received it up to 1 h before enrollment into the study.
2.2 Study Drug Treatment.
The intravenous bolus dose of 30 mg of enoxaparin was received by 98% of patients in dose tier 1 and 97% of patients in dose tier 2; 99% of patients initiated dosing with the weight-adjusted regimen in both dose tiers (Table 2). Weight-adjusted dosing was administered for a median of 39 h in dose tier 1 and 27 h in dose tier 2. The trough and peak anti-Xa activity levels were significantly higher in dose tier 1 than dose tier 2 (Table 2). However, within both dose tiers, the peak anti-Xa activity measured after the last weight-adjusted dose was similar to that measured after the third weight-adjusted dose.
Of the 321 patients in dose tier 1, 212 (66%) began treatment with the fixed dose regimen, which was continued for a median of 10 days. Similarly, of the 309 patients in the second dose tier, 231 (75%) began treatment with the fixed dose regimen, which was continued for a median of 11 days.
The total duration of treatment with study drug was nearly 2 weeks in both dose tiers (Table 2).
2.3 Compliance with Study Drug Regimen.
The duration of the in-hospital phase was a median of 3 days in both dose tiers (Table 3). Of the 321 patients in dose tier 1, 156 (49%) discontinued dosing during the in-hospital phase. In 34 patients (11%), the study drug was stopped because of bleeding as per the protocol and in 35 (11%) because of CABG. In 15 patients (5%) in dose tier 1, treatment was discontinued at the patient’s request. Although a similar proportion of patients in dose tier 2 had the study drug discontinued while in the hospital for CABG (7%) or at their request (3%), a significantly smaller proportion (6%) had treatment stopped because of bleeding (p = 0.03) than patients in dose tier 1.
The duration of the outpatient phase was a median of 10 days in both dose tiers (Table 3). The study drug was discontinued in 27 (16%) and 32 (17%) patients during the outpatient phase in dose tiers 1 and 2, respectively. However, <5% of patients requested discontinuation of treatment in both dose tiers.
2.4 Safety Analyses.
Major hemorrhage occurred in 21 patients (6.5%, 95% CI 4.2% to 10.0%) in dose tier 1 (Fig. 1). In 17 patients (5.3%), bleeding was at an instrumented site and occurred a median of 34.8 h after a procedure. In 5 patients (1.6%), bleeding occurred spontaneously (gastrointestinal [n = 2], retroperitoneal [n = 1], urinary tract [n = 1], unidentified [n = 1]). One patient had both instrumented site and spontaneous bleeding. In 18 (86%) of 21 patients, the hemorrhage occurred in the hospital, whereas in 3 it occurred within 4 days of discharge.
Major hemorrhage occurred in six patients (1.9%, 95% CI 0.8% to 4.4%) in dose tier 2 (Fig. 1). In five patients (1.6%), bleeding was at an instrumented site and occurred a median of 34.5 h after a procedure. In one patient (0.3%), a major hemorrhage occurred spontaneously (skin). In four (67%) of six patients, the hemorrhage occurred in the hospital, whereas in two it occurred after discharge (within 24 h in one patient and on day 10 in the other).
The cumulative probability of experiencing a major hemorrhage for patients undergoing a procedure and those not undergoing a procedure is plotted in Fig. 2. In both dose tiers, the patients undergoing a procedure had a significantly higher rate of major hemorrhage. The probability of a major hemorrhage was significantly higher in dose tier 1 than dose tier 2 patients undergoing a procedure (7.9% vs. 2.7%, p = 0.011) but similar in the two dose tiers for those patients not undergoing a procedure (1.5% vs. 0%, p = NS).
Several consistent observations across both tiers were made in the patients experiencing a major hemorrhage (Table 4). They tended to be older, lighter in weight and were more likely to have received intravenous nitrates, unfractionated heparin (for catheterization procedures) and other antiplatelet agents in addition to aspirin. In addition, the peak anti-Xa levels tended to be higher in patients experiencing a major hemorrhage than those not experiencing a major hemorrhage. The peak anti-Xa levels during the study were highest in dose tier 1 patients who experienced a major hemorrhage (Table 4).
Thrombocytopenia (platelet count <100,000/mm3) occurred in two patients (0.7%) in dose tier 2 but in no patients in dose tier 1.
2.5 Efficacy Analyses.
As shown in Table 5, the incidence, through 14 days, of the sum of death, nonfatal (re)infarction or recurrent ischemia requiring revascularization was similar in the two dose tiers. No significant differences were observed in the distribution of the elements of the composite efficacy end point. Of the 18 patients (5.6%) in dose tier 1 experiencing at least one of the components of the efficacy end point by day 14 after enrollment, the event occurred before discharge in 15 and between 2 and 5 days of discharge in 3 patients. Similarly, of the 16 patients (5.2%) in dose tier 2 with efficacy end points, the event occurred before hospital discharge in 13 and between 1 and 6 days after discharge in 3 patients. The cumulative probability of experiencing an efficacy end point event in the two dose tiers is plotted in Fig. 3. A similar temporal pattern was observed with the majority of events occurring within the first 8 days of enrollment.
Encouraging results have been reported ([22, 23]) in pilot trials of treatment of patients with unstable angina using doses of LMWHs that yield anti-Xa activity levels needed for prophylaxis against deep vein thrombosis. Recent clinical trials ([24, 25]) of dalteparin and nadroparin in unstable angina with doses higher than those used for prevention of venous disorders have shown these agents to be superior to aspirin alone for preventing the composite end point of death or nonfatal ischemia/infarction without an increase in the rate of major hemorrhage compared with that expected with unfractionated heparin. However, at the initial dose of dalteparin used in the Fragmin During Instability in Coronary Artery Disease (FRISC) study () (150 IU/kg every 12 h), a 6% incidence of major bleeding was observed that was decreased to 0.8% when the dose was reduced (120 IU/kg every 12 h), underscoring the need to perform dose-ranging trials as new antithrombotic regimens are investigated for unstable angina/NQMI.
The findings of the TIMI-11A trial indicate that treatment with enoxaparin during the hospital phase using a weight-adjusted regimen of 1.25 mg every 12 h is associated with a rate of major hemorrhage (6.5%) higher than that seen in trials with unfractionated heparin (4%) ([7, 18–21]). The rate of bleeding in dose tier 1 was greatest in patients undergoing a procedure (7.9%) and markedly exceeded the rates observed in dose tier 1 patients not undergoing a procedure as well as the subsets of dose tier 2 patients who did and did not undergo a procedure (Fig. 2).
3.1 Anti-Xa Activity.
The antithrombotic activity of enoxaparin appears to be due to a combination of inhibition of thrombin generation (anti-Xa activity), inhibition of thrombin activity (anti-IIa activity), inhibition of platelet aggregation and release of tissue factor pathway inhibitor ([8, 11, 26]). No single measurement of hematologic function has emerged as the best indicator of the level of antithrombotic activity of enoxaparin. However, the most frequently measured variable is anti-Xa activity, which has been proposed as an important metric of the biologic activity of LMWHs in general.
Although in vitro measurements of the anti-Xa/anti-IIa activity ratio for enoxaparin are in the 3:1 range, the kinetics of clearance of these two activities are different in vivo, producing in vivo anti-Xa/anti-IIa ratios that change over time after subcutaneous injections. Because the clearance of anti-IIa activity of enoxaparin is >2.5 times as fast as that of anti-Xa activity, in vivo anti-Xa/anti-IIa activity ratios of 12:1 may be achieved several hours after injection of a dose ().
The attainment of higher peak anti-Xa activity levels in dose tier 1 than in dose tier 2 is consistent with the previously described () dose-dependent increase in anti-Xa activity with enoxaparin. On the basis of clearance rates of anti-Xa and anti-IIa activity, it is likely that for a greater proportion of time after a weight-adjusted dose of enoxaparin, patients in dose tier 1 might have not only had higher levels of anti-Xa activity than patients in dose tier 2, but also experienced longer periods of relatively greater inhibition of thrombin generation than inhibition of thrombin activity. This would be expected to be less well tolerated in patients with a recent violation of vascular integrity where thrombin generation is needed to maintain the integrity of a hemostatic plug. The observations in Fig. 2are consistent with this hypothesis because the higher rate of major hemorrhage in dose tier 1 was observed predominantly in patients undergoing instrumentation.
As shown in Table 2andTable 4, peak anti-Xa activity levels after the last weight-adjusted dose were similar to those measured after the third weight-adjusted dose. This suggests that there is no accumulation of anti-Xa activity with multiple injections and that a weight-adjusted dose of 1.0 mg/kg every 12 h is unlikely to yield anti-Xa levels in the range where the risk of major hemorrhage is increased, even in patients undergoing catheterization procedures (Fig. 2). Further measures that are likely to minimize the risk of instrumented site bleeding include 1) meticulous attention to the interval between doses (e.g., at least 12 h) to avoid “stacking” of additional anti-Xa activity on top of that from the previous injection, and 2) allowing at least 7 to 8 h to elapse before pulling vascular access sheaths to avoid removal when anti-Xa activity is maximal after a dose (e.g., 3.5 to 5 h).
The pilot experience in the TIMI 11A trial with respect to clinical outcome through 14 days suggests that the lower risk of major hemorrhage with a weight-adjusted dose of 1.0 mg/kg every 12 h was not achieved at the expense of efficacy. The data presented in Table 5reveal a similar rate of the composite primary efficacy end point in the two dose tiers. The temporal pattern of development of clinical events with both dose regimens of enoxaparin showed the greatest incidence of events over the first 8 days followed by a slower rate of development of events through day 14 (Fig. 3). There was no abrupt increase in events after hospital discharge (at a median of 3 days from enrollment). Thus, there was no rebound in events in association with a reduction in the level of antithrombotic therapy from the weight-adjusted in-hospital regimen to the fixed-dose outpatient regimen of enoxaparin. Follow-up data to date also fail to reveal any rebound increase in events after discontinuation of the outpatient enoxaparin regimen at day 14 (Fig. 3). These observations compare favorably with reports ([28, 29]) of a rebound in the rate of clinical events after discontinuation of infusions of unfractionated heparin for unstable angina.
3.2 Clinical Implications.
Enoxaparin is an attractive therapeutic agent for the treatment of unstable angina. The high anti-Xa/anti-IIa activity ratio offers the potential advantage over unfractionated heparin of greater inhibition of the coagulation cascade at a more proximal step, leading to a combined reduction in thrombin generation and thrombin activity. The high bioavailability with subcutaneous administration and prolonged duration of action of enoxaparin make the simple regimen of twice-daily injections for both inpatients and outpatients a viable possibility. The results of the TIMI-11A trial have defined a weight-adjusted acute phase regimen of 1.0 mg/kg every 12 h as a well tolerated dose and also indicate a high rate of patient compliance with the home treatment phase. A Phase III trial in patients with unstable angina, the TIMI 11B trial, is now underway to examine the relative benefits of a strategy of uninterrupted subcutaneous enoxaparin during both the acute and chronic phases of treatment versus the current practice of administering intravenous unfractionated heparin only during the acute phase.
A.1 Participating Investigators and Clinical Centers for the TIMI 11A Trial
Study Chairman’s Office: Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Study Chairman: Eugene Braunwald, MD; Principal Investigator: Elliott M. Antman, MD; Project Director: Carolyn H. McCabe, BS; Project Manager: Susan J. Marble, RN, MS; Co-Investigator: Christopher P. Cannon, MD.
Sponsor: Rhône-Poulenc Rorer, Collegeville, Pennsylvania. Senior Associate Director, Cardiovascular Diseases: Jerome Premmereur, MD; Project Director: Mark Todd.
Data Coordinating Center: Corning Besselaar, Inc., Princeton, New Jersey. Project Director: Larry Meinert, MD, MPH; Coordinator: Iris Houlihan; Biostatistician: Toyoko Oguri, MS; Data Management: Juan Torres; Programmer: Lawrence Rausch.
Events Review Committee: Michael Gibson, MD; Elliott M. Antman, MD, Christopher P. Cannon, MD.
Anti-Xa Core Laboratory: Croix de Berney, France: Francoise Collignon, PhD.
Steering Committee: The members of the Steering Committee include members of the Study Chairman’s Office and the Principal Investigators from the TIMI 11A Clinical Centers.
2Clinical Centers. Washington County Medical Center, Hagerstown, Maryland: Gary Papuchis, MD, Sharon Etter. Munroe Regional Medical Center, Ocala, Florida: Robert Feldman, MD, Brandi Merchant. Jewish Hospital, Saint Louis, Missouri: Patricia Cole, MD, Lynn Coulter. Baptist Medical Center/Alabama, Montgomery, Alabama: Paul Moore, MD, Mark Platt, Ernest Parker. Sarasota Memorial Hospital, Sarasota, Florida: Martin Frey, MD, Torey Browning. University of Alabama, Birmingham, Alabama: William Rogers, MD, Terri Morgan. University of Minnesota Hospitals and Clinics, Minneapolis, Minnesota: David Laxson, MD, Cheryl Iacarella, Betsy Christenson. Baystate Medical Center, Springfield, Massachusetts: Marc Schweiger, MD, Barbara Burkott, Deborah Warwick. Brookdale Hospital Medical Center, Brooklyn, New York: Hal Chadow, MD, Maureen Matheson. Hennepin County Medical Center, Minneapolis, Minnesota: Timothy Henry, MD, Charlene Bosjolie, Lorri Knox. St. Luke’s/Roosevelt Hospital Center, New York, New York: Judith S. Hochman, MD, Robert Leber, MD, Angela Palozzi, MD, Mary McAnulty, Deborah Tormey. Nassau County Medical Center, East Meadow, New York: Israel Freeman, MD, Laura Teplitz, Margaret Alex. St. Paul’s Hospital, Vancouver, British Columbia, Canada: Christopher Thompson, MD, Charlene Hooper, Brenda Mercier. University of Texas/Medical Branch at Galveston, Galveston, Texas: David Cutler, MD, Dana Sprott. Alta Bates Medical Center, Berkeley, California: Robert Greene, MD, Eileen Healy, Vickie Perry. University of Massachusetts Medical Center, Worcester, Massachusetts: Richard C. Becker, MD, Steven Ball. Brigham and Women’s Hospital, Boston, Massachusetts: James M. Kirshenbaum, MD, Jill Jarvis. Central Suffolk Hospital, Riverhead, New York: Thomas Falco, MD, Kate Rush, Cindy Zaleski. Emerson Hospital, Concord, Massachusetts: Steven Herson, MD, Gail Carey. Hartford Hospital, Hartford, Connecticut: Raymond McKay, MD, Jill Cloutier. Henry Ford Hospital, Detroit, Michigan: Steven Borzak, MD, A. Christian Held, MD, Stephen T. Smith, MD, Lori Douthat. Hospital of the Good Samaritan, Los Angeles, California: Thomas Shook, MD, Lucille Junio. Hunterdon Medical Center, Flemington, New Jersey: Austin Kutscher, Jr., MD, Janet McMahon. Michigan Heart and Vascular Institute, Ypsilanti, Michigan: James Bengtson, MD, MPH, Mary Adolphson. SUNY/Downstate University Hospital, Brooklyn, New York: Tak Kwan, MD, Rosa Julien. Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada: Anthony Fung, MD, Christopher Buller, MD, Cheryl Davies; Catherina van Beek. Cedars-Sinai Medical Center, Los Angeles, California: Prediman Shah, MD, Mitchell Gheorghiu, MD. Community Hospital of Tallahassee, Tallahassee, Florida: Patrick Bianchi, MD, Kim Sanders. LDS Hospital, Salt Lake City, Utah: Jeffrey Anderson, MD, Ann Allen. Ohio State University Medical Center, Columbus, Ohio: Raymond Magorien, MD, Laurie McCloud, AnnMarie Thomas. West Roxbury Veterans Affairs Medical Center, West Roxbury, Massachusetts: C. Michael Gibson, MD, Diane Lapsley. Atlanta Veterans Affairs Medical Center, Decatur, Georgia: Jeffrey Marshall, MD, Alberta Lane. Loyola University Medical Center, Maywood, Illinois: Eric Grassman, MD, Ellen Galbraith. Miami Veterans Affairs Medical Center, Miami, Florida: Simon Chakko, MD, Donald Koggan, MD. Presbyterian Hospital of Dallas, Dallas, Texas: Darryl Kawalsky, MD, Malou Arnold. St. Vincent’s Hospital, Worcester, Massachusetts: Richard Bishop, MD, Tammy Brunelle, Patricia Arsenault. University of Texas/Hermann Hospital, Houston, Texas: H. Vernon Anderson, MD, Lynette Weigelt, Julie Manning. Winthrop University Hospital, Mineola, New York: Richard Steingart, MD, Suzanne Bilodeau, Mary Ellen Coglianese. Doctor’s Hospital of Sarasota, Sarasota, Florida: Martin Frey, MD, Torey Browning. Mary Rutan Hospital, Bellafontaine, Ohio: Evan W. Dixon, MD, Ronda Neal. Montefiore Medical Center, Bronx, New York: Hiltrud Mueller, MD, Joseph Cosico, Linda Kunkel. St. John’s Queens Hospital, Elmhurst, New York: Gregory Macina, MD, Marie Kikel, Marya Pier. Sturdy Memorial Hospital, Attleboro, Massachusetts: Charles Peter Rogers, MD, Susan Dolan, Suzanne Nordstrom. Scripps Clinic and Research Foundation, La Jolla, California: Paul Tierstein, MD, Glenda Haas. West Los Angeles Veterans Affairs Medical Center, Los Angeles, California: Malcolm Bersohn, MD, Carole Silbar.
☆ This study was sponsored by Rhône-Poulenc Rorer Pharmaceuticals Inc., Collegeville, Pennsylvania; additional support was provided by Boehringer Mannheim Corp., Indianapolis, Indiana.
↵2 In order of number of patients enrolled; Principal Investigator is listed first.
- anti-Factor IIa (thrombin)
- anti-Factor Xa
- coronary artery bypass graft surgery
- confidence interval
- low molecular weight heparin
- non–Q wave myocardial infarction
- percutaneous transluminal coronary angioplasty
- Thrombolysis in Myocardial Infarction
- Received October 1, 1996.
- Revision received February 10, 1997.
- Accepted February 26, 1997.
- The American College of Cardiology
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