(Circulation. 1999;100:1602-1608.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Assessment of the Treatment Effect of Enoxaparin for Unstable Angina/Non–Q-Wave Myocardial Infarction
TIMI 11B–ESSENCE Meta-Analysis
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital (E.M.A., C.H.M., E.B.), Boston, Mass; Hahnemann University Hospital (M.C.), Philadelphia, Pa; and Rhône-Poulenc Rorer (D.R., J.R., J.P.), Collegeville, Pa. Rhône-Poulenc Rorer manufactures Lovenox (enoxaparin).
Correspondence to Elliott M. Antman, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail eantman{at}rics.bwh.harvard.edu
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Abstract |
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Background—Two phase III trials of enoxaparin for unstable angina/non–Q-wave myocardial infarction have shown it to be superior to unfractionated heparin for preventing a composite of death and cardiac ischemic events. A prospectively planned meta-analysis was performed to provide a more precise estimate of the effects of enoxaparin on multiple end points.
Methods and Results—Event rates for death, the composite end points of death/nonfatal myocardial infarction and death/nonfatal myocardial infarction/urgent revascularization, and major hemorrhage were extracted from the TIMI 11B and ESSENCE databases. Treatment effects at days 2, 8, 14, and 43 were expressed as the OR (and 95% CI) for enoxaparin versus unfractionated heparin. All heterogeneity tests for efficacy end points were negative, which suggests comparability of the findings in TIMI 11B and ESSENCE. Enoxaparin was associated with a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment, and this benefit was sustained through 43 days. Enoxaparin's treatment benefit was not associated with an increase in major hemorrhage during the acute phase of therapy, but there was an increase in the rate of minor hemorrhage.
Conclusions—The accumulated evidence, coupled with the simplicity of subcutaneous administration and elimination of the need for anticoagulation monitoring, indicates that enoxaparin should be considered as a replacement for unfractionated heparin as the antithrombin for the acute phase of management of patients with high-risk unstable angina/non–Q-wave myocardial infarction.
Key Words: enoxaparin • heparin • meta-analysis • anticoagulants
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Introduction |
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In 1982, Telford and Wilson1 introduced the idea of the administration of intravenous heparin for the treatment of the acute phase of unstable angina. This was followed by several important clinical trials evaluating the effect of heparin alone and in combination with aspirin.2 3 4 The benefits of intravenous heparin from such trials was judged to be sufficiently compelling that authoritative bodies recommended its use in the routine management of patients with unstable angina/non–Q-wave myocardial infarction.5 6 7 This recommendation has been embraced widely by clinicians, making it difficult to conduct trials of new antithrombin therapies in which patients might be randomized to treatment with placebo.8
Despite its extensive penetration into clinical practice, unfractionated heparin suffers from several important disadvantages. It has an unpredictable anticoagulant effect, necessitating frequent testing to adjust the dose being administered to the patient.9 Although it can be administered subcutaneously, this is of limited effectiveness because of its low and variable bioavailability, and it usually must be delivered by a continuous intravenous infusion. Additional drawbacks include a tendency to a rebound increase in thrombotic events after cessation of its use, sensitivity to the inhibitory effects of platelet factor 4, and the risk of heparin-associated thrombocytopenia and thrombosis.10 Low-molecular-weight heparins offer the advantages of a stable and predictable anticoagulant response to a given dose, eliminating the need for hematologic monitoring, and much simpler administration via the subcutaneous route.11 12 13 These features alone might convince some clinicians to substitute a low-molecular-weight heparin in situations in which they would prescribe unfractionated heparin even if the 2 treatments were of equal efficacy. The decision to use a low-molecular-weight heparin would be even more attractive if it were also more efficacious than intravenous unfractionated heparin, especially in a serious condition such as unstable angina/non–Q-wave myocardial infarction.14 TIMI 11B and ESSENCE, 2 phase III randomized trials, have independently demonstrated superiority of enoxaparin over unfractionated heparin in reducing a composite of death and serious cardiac ischemic events in patients with unstable angina/non–Q-wave myocardial infarction.15 16 Neither TIMI 11B nor ESSENCE was designed with sufficient power to detect statistically significant treatment effects of enoxaparin on end points other than the composite ones used in the individual trials. Therefore, the objective of this prospectively planned meta-analysis was to provide more statistically robust estimates of the treatment effects of enoxaparin on death and serious cardiac ischemic events individually and in various combinations, particularly death and nonfatal myocardial infarction, as well as major hemorrhage in patients with unstable angina/non–Q-wave myocardial infarction.15 16
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Methods |
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Data Acquisition
The details of TIMI 11B and ESSENCE have been reported previously.15 16 Important aspects of the enrollment criteria and doses of study drug are summarized in Table 1
. Prespecified end points of
interest include all-cause mortality, recurrent myocardial infarction
(defined by ECG and serum marker criteria),15 16 urgent
revascularization,15 and major
hemorrhage.15 16
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Statistical Analysis
For each individual trial and for the combination of the 2
trials, the OR for enoxaparin versus unfractionated heparin was
estimated along with its 95% CI for each end point of interest at days
2 (period of direct comparison of unfractionated heparin versus
enoxaparin), 8 (end of acute phase of management), 14 (time of
ascertainment of primary end point in ESSENCE), and 43 (end of
outpatient phase in TIMI 11B). For assessment of internal
consistency of the observations on the treatment effect of
enoxaparin, 3 separate methods of pooling the trial results were used:
(1) Peto method comparing observed minus expected
events,17 (2) Mantel-Haenszel method for combining
information from a series of 2x2 tables,18 19 and (3) the
random-effects model of DerSimonian and Laird.20 21 The
Peto and Mantel-Haenszel methods differ in the method of calculation of
variances of the summary OR and may on occasion yield different
results, as pointed out by Greenland et al.22 The
random-effects model includes between-study differences in treatment
effects in the calculation of the variances and may lead to wider CIs
when heterogeneity among trials is
observed.20 21 For each of the 3 methods of evaluating the
treatment effect of enoxaparin, heterogeneity testing
was performed to screen for any important differences
(P
0.05) between TIMI 11B and
ESSENCE.23
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Results |
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The TIMI 11B and ESSENCE trials were similar in that both trials enrolled patients with unstable angina/non–Q-wave myocardial infarction and excluded patients who presented with ST-segment-elevation myocardial infarction (Table 1
). The
control group in both trials received intravenous
unfractionated heparin adjusted to a similar target activated
partial thromboplastin time range via nomograms at each enrolling
hospital; a double-blind design was used. The subcutaneous dose of
enoxaparin for the acute phase of management was 1.0 mg/kg every 12
hours in both trials; in TIMI 11B, the first subcutaneous dose was
preceded by an intravenous bolus of 30 mg of enoxaparin.
The median duration of therapy with unfractionated heparin was similar
in the 2 trials (3.0 days in TIMI 11B and 2.6 days in ESSENCE). By
protocol design, the median duration of acute-phase treatment with
enoxaparin was longer in TIMI 11B at 4.6 days compared with 2.6 days in
ESSENCE. Also, by protocol design, a reduced dose of enoxaparin was
administered in the outpatient phase in TIMI 11B but not in ESSENCE
(Table 1). Long term follow-up was performed in ESSENCE at 3
months and 1 year after randomization; this provided the database for
extraction of events in ESSENCE through 43 days and permitted pooling
of the findings with TIMI 11B. 24
Meta-Analysis Findings
Meta-analyses of each of the end points of interest
revealed similar estimates of the ORs and CIs for the treatment effect
of enoxaparin for each of the 3 pooling methods. There was no
statistically significant evidence of heterogeneity
between TIMI 11B and ESSENCE with respect to the efficacy end points.
The findings shown in Tables 2
and 3 and Figures 1 and 2
were calculated by the Peto method.
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The composite end point of death/nonfatal myocardial infarction was
consistently 
20% lower at all time points in the group that
received enoxaparin (Table 2; Figure 1). Statistical
significance for the reduction in this end point was observed at day 8
(OR 0.77; 95% CI 0.62 to 0.95; P=0.02) and persisted
through follow-up at 14 days (OR 0.79; 95% CI 0.65 to 0.96;
P=0.02) and 43 days (OR 0.82; 95% CI 0.69 to 0.97;
P=0.02). The absolute difference in event rates for
death/nonfatal myocardial infarction between the pooled unfractionated
heparin group and the enoxaparin group increased from 1.2% at day 8 to
1.5% at day 43.
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A significant treatment benefit of enoxaparin on the composite end
point of death/nonfatal myocardial infarction/urgent
revascularization was observed at day 2 (OR 0.77;
95% CI 0.63 to 0.94; P=0.012). As shown in Table 2
and Figure 2, a highly significant treatment benefit continued
to be observed through 43 days (OR 0.80; 95% CI 0.71 to 0.91;
P=0.0005). The absolute difference in pooled event rates
widened from 1.4% at day 2 to 3.2% at day 43. Based on the absolute
event rates in Table 2 for the pooled treatment groups, 31
patients would need to be treated to prevent 1 event by day 43.
Beginning at day 8, a trend toward a lower mortality rate was observed
in the pooled enoxaparin group (OR 0.80; 95% CI 0.56 to 1.16) that
continued to be observed through day 43 (OR 0.84; 95% CI 0.66 to 1.08)
(Table 2).
During acute-phase treatment, the pooled rate of major
hemorrhage was 1.3% in the enoxaparin group and 1.1% in the
unfractionated heparin group (OR 1.23; 95% CI 0.80 to 1.89;
P=0.35) (Table 3). During the same
acute-phase treatment period, the pooled rate of minor
hemorrhage was 10.0% in the enoxaparin group and 4.3% in the
unfractionated heparin group (OR 2.38; 95% CI 1.98 to 2.85;
P<0.0001) (Table 3).
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Discussion |
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Compared with unfractionated heparin, the traditional antithrombin, enoxaparin treatment is associated with a 20% reduction in clinical events in patients with unstable angina/non–Q-wave myocardial infarction. The treatment benefit of enoxaparin occurs within 48 hours and is persistent, with a quantitatively similar relative treatment effect observed at day 2 and day 43 (Figures 1
and 2). The reduction in events with enoxaparin is
achieved without a significant increase in the rate of major
hemorrhage during the acute phase of therapy, although
the rate of minor hemorrhages was significantly increased. In
the face of increasing event rates between day 2 and day 43 in the
unfractionated heparin group, the stable relative treatment effect of
enoxaparin occurs by a commensurate increase in the absolute difference
in event rates over the same time period (Table 2). The findings
favoring enoxaparin are statistically robust given (1) the lack of
heterogeneity for efficacy end points between TIMI 11B
and ESSENCE; (2) consistency of the treatment effect
examined across multiple efficacy end points (Table 2), which
suggests that the observations were not driven predominantly by any
single element in the composite end points examined; and (3) the level
of statistical significance observed (Table 2).
Potential Mechanisms of Superiority Over Unfractionated
Heparin
The incomplete and variable inhibition of thrombin by
intravenous unfractionated heparin stems in part from a
relatively low bioavailability due to extensive nonspecific binding to
serum proteins, macrophages, and endothelial
cells.13 25 26 The catalytic activity of heparin
preparations that inhibit factor IIa and factor Xa resides in those
glycosaminoglycan chains that contain a
pentasaccharide sequence required for high-affinity binding to
antithrombin.13 High-affinity material is further
subdivided into chains that are >18 saccharides and therefore
above the critical length mass (ACLM), which can inhibit both factor
IIa and factor Xa, and those that are below the critical length mass
(BCLM), which are capable only of inhibiting factor Xa.13
The BCLM:ACLM ratio of unfractionated heparin is 1:1, whereas
low-molecular-weight heparins have ratios >1, leading to a higher
anti–factor Xa:anti–factor IIa ratio. This provides a distinct
kinetic advantage by inhibiting early steps in the coagulation cascade
and inhibiting thrombin generation. Maintenance of a sufficient
concentration of anti–factor IIa activity in low-molecular-weight
heparin preparations is necessary to simultaneously inhibit
thrombin activity.11 27
Features of enoxaparin that may permit a greater degree of suppression of thrombin generation than with unfractionated heparin include a higher anti–factor Xa:anti–factor IIa ratio (3.8:1) and a prolonged duration of anti–factor Xa activity. Brieger and Dawes28 reported that the anti–factor Xa activity of enoxaparin was detectable up to a week after administration, probably as a result of sequestration in tissue stores. Several investigators27 29 have noted that the greater bioavailability of enoxaparin (91%) produces a higher level of anti–factor IIa activity than with unfractionated heparin, potentially producing a greater degree of inhibition of thrombin activity. Additional pharmacological advantages of enoxaparin that may be operative in its superiority over unfractionated heparin include less sensitivity to the inhibitory effects of platelet factor 4, a greater capacity to release tissue-factor–pathway inhibitor, a lower propensity to promote activation and aggregation of platelets, and potential antiplatelet effects via higher degrees of suppression of von Willebrand factor.30 31 32 33 34 35
Comparison With Other Low-Molecular-Weight Heparins
The low-molecular-weight heparins vary in their average molecular
weight, anti–factor Xa:anti–factor IIa ratio, relative patterns of
distribution of ACLM and BCLM chains, ionic nature (sodium or calcium
salt), release profile of tissue-factor–pathway inhibitor,
and potential to cause bleeding in experimental
preparations.36 Enoxaparin is distinguished from both
dalteparin and nadroparin by a higher anti–factor Xa:anti–factor IIa
ratio, a lower average molecular weight, a higher proportion of
glycosaminoglycan species <2000 Da, and a greater
ability to inhibit thrombin generation.37 38 Given
considerations such as those noted above, it has been emphasized that
it is an oversimplification to consider low-molecular-weight
preparations to have a class effect, and it therefore seems
inappropriate to conduct meta-analyses of clinical trials that
use different low-molecular-weight heparins.12 36 39 40
Accordingly, we restricted our meta-analysis to trials of
enoxaparin.
In addition to distinctions in pharmacological properties, differences in trial design must be considered when studies of low-molecular-weight heparins for unstable angina/non–Q-wave myocardial infarction are compared. Phase III trials with dalteparin and nadroparin failed to show superiority of those agents compared with unfractionated heparin.41 42 Of note, the times from the qualifying episode of ischemic discomfort to enrollment in the FRIC (FRagmin during Instability in Coronary artery disease) and FRAXIS (FRAXiparine in Ischemic Syndromes) studies were up to 72 and 48 hours, respectively.41 42 In addition, both of those trials included patients with exacerbations of effort angina, and only 16% of patients in FRIC and FRAXIS had a non–Q-wave myocardial infarction at enrollment. In contrast, TIMI 11B and ESSENCE restricted enrollment to patients with rest angina within the prior 24 hours, and higher proportions of patients had a non–Q-wave myocardial infarction at enrollment (35% in TIMI 11B and 21% in ESSENCE). The lower risk profile of patients in FRIC and FRAXIS, use of low-molecular-weight heparins with lower anti–factor Xa:anti–factor IIa ratios, and different distribution of ACLM and BCLM chains may have combined to bias those trials to a null effect. In the case of dalteparin, it is unlikely that a higher dose would have permitted superiority to emerge, because a dose of 150 IU/kg every 12 hours was previously found to be associated with unacceptable levels of bleeding, necessitating a reduction to 120 IU/kg every 12 hours.43
Comparison With Direct Antithrombins
Clinical trials with direct antithrombins were designed around the
hypothesis that they would be more effective than unfractionated
heparin owing to inhibition of both fluid-phase and clot-bound
thrombin. However, experience with direct antithrombins has been
disappointing to date.44 45 46 47 48 Initial phase III trials of
hirudin were stopped prematurely owing to excessive bleeding, which
indicates a safety limitation on the dose that can be administered
clinically.44 45 46 Subsequent trials with reduced doses of
hirudin showed mixed results, with some studies showing no benefit over
unfractionated heparin and others showing a small reduction in events,
primarily nonfatal myocardial infarction.49 50 51
Meta-analysis of the hirudin trials in
nonthrombolytic-treated patients showed an initial
reduction in death/nonfatal myocardial infarction at 3 days (OR 0.72;
P=0.0002) but a decrease in the magnitude of the treatment
effect, which was no longer significant by 35 days (OR 0.90;
P=0.057), possibly owing to rebound activation of the
coagulation cascade after cessation of
treatment.51 52
Clinical Implications
The 20% reduction in clinical events with enoxaparin is of a
magnitude that most clinicians would consider sufficient to change
their practice pattern. Health economic analysis of the
benefits of enoxaparin in the ESSENCE trial show it to be a dominant
strategy that simultaneously lowers total costs of care and
reduces the rates of important clinical events.53 The
durable treatment effect of enoxaparin also compares quite favorably
with the more transitory benefits of intravenously
administered direct antithrombins. The accumulated evidence, coupled
with the simplicity of subcutaneous administration and elimination of
the need for anticoagulation monitoring, indicates that enoxaparin
should now be considered as a replacement for unfractionated heparin as
the antithrombin for the acute phase of management of patients with
high-risk unstable angina/non–Q-wave myocardial infarction.
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Acknowledgments |
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This study was supported by a grant from Rhône-Poulenc Rorer (Collegeville, Pa), which manufactures Lovenox (enoxaparin).
Received April 14, 1999; revision received July 2, 1999; accepted July 26, 1999.
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E. M. Antman, M. Cohen, P. J. L. M. Bernink, C. H. McCabe, T. Horacek, G. Papuchis, B. Mautner, R. Corbalan, D. Radley, and E. Braunwald The TIMI Risk Score for Unstable Angina/Non-ST Elevation MI: A Method for Prognostication and Therapeutic Decision Making JAMA, August 16, 2000; 284(7): 835 - 842. [Abstract] [Full Text] [PDF]
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E. M. Ohman, C. B. Granger, R. A. Harrington, and K. L. Lee Risk Stratification and Therapeutic Decision Making in Acute Coronary Syndromes JAMA, August 16, 2000; 284(7): 876 - 878. [Full Text] [PDF]
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S. Kaul and P. K. Shah Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin? J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1699 - 1712. [Abstract] [Full Text] [PDF]
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 Meta-Analysis Confirms Benefit of Enoxaparin in Unstable Angina Journal Watch Emergency Medicine, December 1, 1999; 1999(1201): 4 - 4. [Full Text]
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 Low-Molecular-Weight Heparin Improves Outcomes in Unstable Coronary Syndromes Journal Watch (General), October 22, 1999; 1999(1022): 4 - 4. [Full Text]
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E. M. Antman, C. H. McCabe, E. P. Gurfinkel, A. G. G. Turpie, P. J. L. M. Bernink, D. Salein, A. Bayes de Luna, K. Fox, J.-M. Lablanche, D. Radley, et al. Enoxaparin 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, October 12, 1999; 100(15): 1593 - 1601. [Abstract] [Full Text] [PDF]
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