Enoxaparin in the Treatment of Deep
Vein Thrombosis With or Without
Pulmonary Embolism*
An Individual Patient Data Meta-analysis
Patrick Mismetti, MD, PhD; Sara Quenet, MS; Mark Levine, MD, MSc;
Geno Merli, MD; Herve´ Decousus, MD; Eric Derobert, MS; and
Silvy Laporte, MS, PhD
Study objectives:
Low-molecular-weight heparins have been compared with unfractionated
heparin (UFH) for treatment of deep vein thrombosis (DVT). However, a comparison of their
efficacy in the presence or absence of pulmonary embolism (PE) has not been studied. We
estimated the efficacy and safety of enoxaparin vs UFH in patients with proximal DVT
with/without symptomatic PE using a meta-analysis of individual data from randomized
con-trolled trials.
Design and setting:
Randomized controlled trials were identified from MEDLINE, EMBASE,
abstracts from international meetings on venous thromboembolism (VTE), previous
meta-analyses, and trial data provided by the sponsor.
Participants:
For inclusion, randomized controlled trials had to be properly randomized; include
patients with objectively diagnosed DVT; compare enoxaparin twice daily with UFH; use
objective methods to assess recurrent symptomatic VTE, major bleeding, and death at 3 months;
and include blind evaluation of clinical events.
Measurements:
A meta-analysis was performed using the logarithm of the relative risk (RR)
method. Enoxaparin in DVT treatment with/without symptomatic PE was considered noninferior
to UFH for preventing VTE at 3 months if the upper limit of the 95% confidence interval (CI) of
the RR (enoxaparin/UFH) was lower than a prespecified noninferiority margin (1.61). No increase
in major bleeding or mortality should be observed.
Results:
The meta-analysis included individual data from three randomized controlled trials (749
patients and 754 patients in the enoxaparin and UFH groups, respectively). The observed RR
(enoxaparin/UFH) of VTE was 0.81 (95% CI, 0.52 to 1.26) for the intention-to-treat population
(RR, 0.70; 95% CI, 0.43 to 1.13; for per-protocol analysis). Results did not differ for patients with
clinical PE (235 patients; RR, 0.84) and without clinical PE (1,268 patients; RR, 0.71), with a
nonsignificant heterogeneity test between groups (p
ⴝ
0.76). A trend in favor of enoxaparin was
observed for reduced mortality and major bleeding.
Conclusions:
The efficacy and safety of enoxaparin vs UFH for DVT treatment is not modified by
the presence of symptomatic PE.
(CHEST 2005; 128:2203–2210)
Key words:deep vein thrombosis; enoxaparin; low-molecular-weight heparin; meta-analysis; noninferiority; pulmonary embolism; unfractionated heparinAbbreviations: CI⫽confidence interval; DVT⫽deep vein thrombosis; LMWH⫽low-molecular-weight heparin; PE⫽pulmonary embolism; PREPIC⫽Pre´vention du Risque d’Embolie Pulmonaire par Interruption Cave; RR⫽relative risk; UFH⫽unfractionated heparin; VTE⫽venous thromboembolism
V
enous thromboembolism (VTE) is a frequent
and serious disease
1that encompasses both deep
vein thrombosis (DVT) and pulmonary embolism
(PE). Unfractionated heparin (UFH) has proved to
be effective in the initial treatment of VTE, and the
efficacy and safety of low-molecular-weight heparins
(LMWHs) for the initial treatment of VTE is well
established. Indeed, several meta-analyses
2–9of
stud-ies in patients with VTE and one meta-analysis
10in
patients with nonmassive PE (including PE trials, PE
strata, and PE subgroups of DVT trials) have shown
that LMWH treatment is at least as effective and
safe for initial treatment as UFH. Finally, LMWHs
tend to be prescribed more than UFH
11because
they are more convenient to use
12and are feasible in
outpatients, thus reducing costs.
11,13–20As noted by
the experts of the 2004 American College of Chest
Physicians consensus conference,
11recommenda-tions about the initiation of UFH or LMWH for
nonmassive PE treatment and DVT are largely based
on the findings in patients with DVT. This is
as-sumed to be appropriate, since DVT and PE are
considered to be manifestation of a single clinical
entity,
21often present together,
11,22–24and share
some risk factors.
25However, as some products are
registered only for patients presenting with DVT,
some physicians prefer to systematically check for
the absence of PE before treating patients
present-ing with DVT.
Previous meta-analyses have not been able to
address whether the efficacy and safety of LMWH
compared to UFH in the treatment of DVT are
modified by the presence of PE because they were
based on summarized published data. Meta-analyses
based on data from individual patients have several
advantages over those based on published data.
26 –29Particularly, by providing greater flexibility in
analy-sis, they allow assessment of the homogeneity of the
effects of treatments between patient subgroups.
However, a difficulty encountered with these
meta-analyses is obtaining exhaustive data when assessing
a therapeutic class composed of different
prepara-tions from different pharmaceutical companies. To
ensure an exhaustive meta-analysis, we focused on
enoxaparin, as we had access to individual patient
data from all randomized trials comparing
enoxapa-rin with UFH. Furthermore, the number of patients
included in these trials afford important statistical
power. Enoxaparin is one of the most prescribed
LMWHs worldwide, and it is currently used as the
reference treatment to assess new anticoagulants in
the treatment of DVT.
30,31The purpose of this individual patient data
meta-analysis of randomized trials comparing enoxaparin
with UFH was to assess the noninferiority of
enox-aparin in the treatment of DVT with or without
associated symptomatic PE. This approach enabled
assessment of whether the effect of enoxaparin
compared with UFH is modified by the presence of
symptomatic PE.
Methods and Materials
Identification of Randomized Controlled Trials
We attempted to identify all published and unpublished randomized controlled trials that compared enoxaparin with UFH for the treatment of DVT with or without associated symptomatic PE. We searched MEDLINE and EMBASE elec-tronic databases from January 1980 to January 2004 using the following groups of key words: “deep-vein thrombosis” or “thromboembolism” or “pulmonary embolism,” and “random-ized” or “randomised” or “controlled trial” or “meta-analysis,” and “UFH” or “LMWH” or “enoxaparin” or “Lovenox” or “Clexane.” We reviewed abstracts from international meetings on VTE. Furthermore, we identified the enoxaparin trials included in the last meta-analyses that compared the efficacy and safety of LMWH with UFH in the treatment of DVT. Finally, the sponsor provided us with information regarding the existence of all such studies.
Selection of Randomized Controlled Trials
Two investigators independently assessed trials for possible inclusion, and a third investigator resolved any disagreements. To be included, trials had to be properly randomized (proper generation of the treatment allocation sequence and proper concealment of the allocation sequence); include patients with objectively diagnosed DVT with or without associated symptom-atic PE; compare enoxaparin with UFH; and use objective methods to confirm the diagnosis of the following clinical out-comes: recurrent symptomatic VTE, major bleedings, and death at 3 months. In each trial, clinical events had to be assessed by an independent, blinded, central adjudication committee. Further-more, individual patient data had to be available. Only patients allocated to enoxaparin, 1 mg/kg bid, were included in this meta-analysis. All other regimens were considered in a sensitivity analysis.
Clinical Events
Clinical events considered of interest for the analysis of efficacy were documented symptomatic VTE recurrences (either DVT or PE) up to 3 months. The definition of events was very similar between trials: DVT was confirmed by ultrasonography and/or venography; PE was confirmed by high-probability lung scan, pulmonary angiography, or autopsy. For analysis of safety, major bleeding was assessed at 10 days and 3 months. Bleeding events were considered to be major when they were clinically overt and associated with a decrease in hemoglobin level of at least 20 g/L or with transfusion of at least 2 U of packed RBCs. Intracranial and retroperitoneal bleeding, and bleeding that required surgical intervention were also considered major. All other bleeding events were considered minor. Finally, we analyzed data on death at 3 months.
Database Composition
After the selection of trials, individual patient data were supplied for analysis by the sponsor or by contacting the main investigator. Then, the database was built up independently of the sponsor. All data were pooled in a common file with information on baseline patient characteristics and occurrence of major clinical events. All data were thoroughly checked for consistency, plausibility, and integrity of randomization and follow-up. All variables were standardized in terms of units, formats, and labels. For this analysis, 3-month clinical events *From the Thrombosis Research Group (Drs. Mismetti,
Decou-sus, and Laporte, and Ms. Quenet), Clinical Pharmacology Department, University Hospital Bellevue, Saint-Etienne, France; Department of Medicine (Dr. Levine), McMaster Uni-versity, Hamilton, ON, Canada; Division of Internal Medicine (Dr. Merli), Department of Medicine, Thomas Jefferson Univer-sity, Philadelphia, PA; and Laboratoire Aventis (Mr. Derobert), Paris, France.
Funding for this research was provided by Laboratoire Aventis, a subsidiary of the Sanofi Aventis group.
Manuscript received November 16, 2004; revision accepted March 4, 2005.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).
Correspondence to: Sara Quenet, MS, Thrombosis Research Group, Clinical Pharmacology Department, University Hospital Bellevue, F-42055 Saint-Etienne, France; e-mail: sara.quenet@ chu-st-etienne.fr
were included if they occurred within 92 days of patient enroll-ment. Therefore, results could differ from those reported in the publications describing each trial because the latter may have considered events to be at 3 months, whereas some may have occurred a few days beyond 92 days after enrollment. Further-more, because we also standardized definitions of clinical events, the count of clinical events could differ from those reported in publications describing each trial. However, outcome events that were not validated by the independent, blinded, central adjudi-cation committees in each trial were not included in this analysis. Therefore, the meta-analysis presents a high degree of adherence to the specifications in the individual study protocols. Finally, a statistician verified the final database entries.
Statistical Analysis
Individual patient data from each trial were summarized in two-by-two tables for each end point. Meta-analyses were then performed using appropriate software (EasyMA2000; University of Lyon; http://www.spc.univ-lyon1.fr/easyma.dos).32 As a first descriptive approach, adjusted clinical event rates and the asso-ciated 95% confidence interval (CI) were estimated by combin-ing the data of each trial weighted by the inverse of the variance. Then a meta-analysis was performed using the logarithm of the relative risk (RR) and Mantel-Haenszel methods.33,34The results obtained were similar; therefore, only those from the logarithm of the RR method are presented. Heterogeneity between studies was tested with the Cochran Q test, and a random effect model was planned in the event of unexplained heterogeneity between trials.34
Concerning the efficacy criteria (VTE recurrence), the objec-tive was to demonstrate noninferiority,ie, that the 95% CI of RR (enoxaparin/UFH) did not contain the a priori noninferiority margin. This margin was prespecified when writing the protocol of the meta-analysis,ie, before pooling the data. The data used to establish this margin were taken from the only available trial assessing UFH vs no treatment or inadequate treatment in the treatment of VTE.35 In this trial, the incidence of VTE at 6 months was 20.0% for placebo and 6.7% for UFH, giving an RR (UFH/placebo) of 0.33 (95% CI, 0.11 to 0.97). The 95% CI was too wide because of the small number of patients (n⫽120) included in this trial; therefore, the noninferiority limit was calculated with the average efficacy of UFH relative to placebo that was the observed 67% relative reduction. On the basis of general principles from regulatory guidelines36,37 and previous noninferiority studies14,30,38 comparing LMWH with UFH, we considered clinically acceptable to preserve 70% of the effect size for UFH relative to placebo39: 67%⫻0.70⫽47% relative re-duction (RR [enoxaparin/placebo]⫽0.53) Then, the limit of noninferiority of RR (enoxaparin/UFH) must be equal to RR (enoxaparin/placebo)/RR (UFH/placebo), which is 0.53/0.33 or 1.61. Noninferiority of enoxaparin relative to UFH would be established if the upper limit of the 95% CI of the RR (enoxapa-rin/UFH) is⬍1.61. In addition to the noninferiority analysis, an imputed placebo analysis was used to indirectly validate a
treatment superior to the placebo by determining log RR (enox-aparin/placebo)⫽log RR (enoxaparin/UFH)⫹log RR (UFH/ placebo).40 – 43
Meta-analyses were performed both on the intention-to-treat population (all randomized patients) and per-protocol population to reinforce the results, as recommended for such a noninferior-ity approach.44The per-protocol analysis excluded patients with-out a proven DVT, patients who were randomized twice, patients who had received heparin for ⬎48 h before randomization, patients who had received heparin for⬍5 days, and patients who had not received the allocated heparin treatment.
The impact of an initial symptomatic PE at entry on the efficacy and safety of enoxaparin compared with UFH was assessed in a subgroup analysis. To verify that the effect of enoxaparin vs UFH was not modified in the absence or presence of symptomatic PE, heterogeneity Cochran Q tests between subgroups were performed.
Sensitivity analyses were also performed to further establish the robustness of our results. First, we examined the impact of an initial PE, whether asymptomatic or symptomatic. Then, we examined the effect of excluding patients who were also ran-domly allocated to filter placement. Finally, we examined the effect of including another regimen of enoxaparin: 1.5 mg/kg qd. For safety criteria (major bleedings and deaths), results were considered as statistically significant when the upper and lower limits of the 95% CI of the RR were both⬎1 or⬍1.
Results
Descriptive Results
A total of five studies
13,23,45– 47comparing
enoxapa-rin with UFH for the treatment of DVT were
identified. Of these, one trial was excluded because
clinical events at 3 months were not reviewed blindly
by an independent committee.
46Another study was
excluded because included patients presented with
PE, with or without associated DVT, rather than
DVT with or without associated PE, there was no
proper generation of the allocation sequence
(alter-nate odd and even numbers) for randomization and
clinical events were not reviewed blindly by an
independent committee.
47Overall, three studies
were selected, including a total of 1,503 patients
(Table 1).
13,23,45Baseline characteristics are given in Table 2 for all
trials and for the total meta-analysis population.
Mean age
⫾
SD was 63
⫾
16 years. The initial DVT
was mainly proximal, except in the study by Merli et
al,
45in which DVT was distal in 19% of patients. All
patients included in the study by Levine et al
13Table 1—Study Design of Eligible Trials
Trials/Year Design
Follow-up Duration
Randomized Patients
(Enoxaparin/UFH, No.) Randomization Procedure
Assessment of Outcomes
Levine et al13/1996 Open 3 mo 501 (247/254) Telephone from a central site Blind
PREPIC, Decousus et al23/1998 Open ⬎2 yr 400 (195/205) Central computer-telephone system Blind Merli et al45/2001 Open 6 mo 602 (312/290)* Ascending number of sealed treatment kits Blind *Patients randomly allocated to receive enoxaparin, 1.5 mg/kg qd, were included in a sensitivity analysis.
presented with DVT without clinical PE, because
clinical PE was an exclusion criteria. Concomitant,
symptomatic, nonmassive PE occurred in 36% of
patients included in the Pre´vention du Risque
d’Embolie Pulmonaire par Interruption Cave
(PREPIC) study
23and 15% of patients included in
the study by Merli et al.
45Overall, 235 of the 1,503
patients (16%) presented with initial symptomatic
PE, 121 in the UFH group and 114 in the enoxaparin
twice-daily group. The treatment groups had similar
baseline characteristics.
At 3 months, outcomes were assessed in 1,439 of
the 1,503 randomized patients (724 patients in the
enoxaparin group and 715 patients in the UFH
group). Outcome information was missing for 48
patients who died before the end of follow-up and
had not experienced recurrent VTE, and for 16
patients who were lost to follow-up. At 3 months, the
estimated incidence of VTE recurrence in the UFH
group was 5.7% (95% CI, 4.0 to 7.4) [Table 3]. The
incidences of DVT and PE were 4.4% (95% CI, 2.9
to 6.0) and 1.8% (95% CI, 0.8 to 2.8), respectively.
Enoxaparin vs UFH in the Treatment of DVT With
or Without Associated Symptomatic PE
With respect to VTE, the pooled estimate from all
the trials revealed an RR of 0.81 (95% CI, 0.52 to
1.26) on the intention-to-treat population without
heterogeneity among studies (p
⫽
0.98). Because
the upper limit of the 95% CI was below the
prespecified noninferiority margin of 1.61,
enoxapa-rin can be considered to be noninferior to UFH in
terms of the prevention of VTE in patients
present-ing a DVT with or without associated PE. Uspresent-ing the
imputed placebo analysis, extrapolation of the
effi-cacy of enoxaparin relative to placebo yields a RR of
0.27 (95% CI, 0.08 to 0.87), indirectly revealing a
significant difference between enoxaparin and
pla-cebo in terms of VTE.
The observed RR reduction for VTE includes both
DVT recurrence (RR, 0.79; 95% CI, 0.48 to 1.30)
and PE occurrence (RR, 0.63; 95% CI, 0.27 to 1.44)
[Table 4]. On the basis of the per-protocol
popula-tion including 1,350 patients, enoxaparin was still
found to be noninferior to UFH (RR, 0.70; 95% CI,
0.43 to 1.13) because the upper limit of the 95% CI
was
⬍
1.61.
Consistency of the Results Between Patients With
or Without Associated Symptomatic PE
When considering patients with and without
symptomatic PE at entry, 235 of the 1,503 patients
presented an initial symptomatic PE. Compared
with the group of patients with isolated DVT, this
group included a larger percentage of women (52%
vs 44%, respectively) and more patients with a
history of VTE (33% vs 24%, respectively) [Table 5].
In the UFH group, patients with an initial
symp-tomatic PE were at a nonsignificantly higher risk of
Table 2—Baseline Characteristics of the Patient Population (nⴝ1,503)*
Characteristics Levine et al13 (n⫽501) PREPIC, Decousus et al23 (n⫽400) Merli et al45 (n⫽602) Meta-analysis (n⫽1,503) Age, yr 58⫾17 72⫾11 61⫾16 63⫾16 Male gender 303 (60) 190 (48) 331 (55) 824 (55)
Body mass index⬎30 kg/m2 NR 57 (14) 137 (14) 194 (20)
History of VTE 88 (18) 141 (35) 151 (25) 380 (25)
Cancer 103 (21) 56 (14) 92 (15) 251 (17)
Surgery within the past 3 mo 96 (19) 43 (11) 120 (20) 259 (17)
Chronic cardiac or respiratory insufficiency NR 86 (22) 63 (10) 149 (15)
Recent immobilization NR 85 (21) 78 (13) 163 (16)
Initial symptomatic DVT NR 342 (86) 579 (96) 921 (92)
Proximal DVT 501 (100) 400 (100) 459 (81) 1,360 (93)
Initial PE NR 197 (49) 193 (32) 390 (39)
Symptomatic initial PE 0 145 (36) 90 (15) 235 (16)
*Data are presented as mean⫾SD or No. (%). NR⫽no recorded data.
Table 3—VTE Recurrences and Major Bleedings at 3 mo According to Treatment in Each Study*
Variables Enoxaparin UFH
VTE recurrences
Levine et al13 13/237 17/247
PREPIC, Decousus et al23 10/186 12/193
Merli et al45 11/301 13/275
Adjusted incidence, % (95% CI) 4.5 (3.0 to 6.0) 5.7 (4.0 to 7.4) Major bleeding
Levine et al13† 8/239 7/239
PREPIC, Decousus et al23 10/189 11/193
Merli et al45 6/297 15/278
Adjusted incidence, % (95% CI) 2.9 (1.6 to 4.1) 4.3 (2.8 to 5.7) *Data are presented as No. of patients/total patients unless otherwise
indicated.
†There was one more bleeding event compared with the original results since events occurring after a thromboembolic event were not considered in the original trial.
VTE recurrence (8.2%; 95% CI, 3.2 to 13.1) than
patients without initial symptomatic PE (4.8%; 95%
CI, 3.1 to 6.6). In particular, patients with initial
symptomatic PE had more PE recurrences than
patients without initial symptomatic PE (4.9%; 95%
CI, 1.0 to 8.9; vs 1.3%; 95% CI, 0.4 to 2.3,
respec-tively).
When comparing the efficacy of enoxaparin vs
UFH, there was no significant difference in patients
with an initial symptomatic PE and patients without
symptomatic PE (Fig 1). We observed an RR
reduc-tion for VTE of 29% for patients with initial DVT
and symptomatic PE (RR, 0.71; 95% CI, 0.28 to
1.81) and 16% for patients with DVT alone (RR,
0.84; 95% CI, 0.51 to 1.38), yielding a nonsignificant
heterogeneity test between groups (p
⫽
0.76). This
means that the effect of enoxaparin vs UFH is not
modified by the presence of a PE. The per-protocol
analysis confirmed this finding (RR, 0.46; 95% CI,
0.15 to 1.47; and RR, 0.78; 95% CI, 0.46 to 1.34,
respectively). When considering total PE, whether
symptomatic or asymptomatic, results were similar
between patients presenting with DVT and PE and
patients presenting with DVT alone (data not
shown).
Sensitivity Analyses
Excluding patients who were randomly allocated
to filter placement or including patients who
re-ceived enoxaparin, 1.5 mg/kg qd, did not change the
study findings. Enoxaparin was still found to be
noninferior to UFH in reducing the incidence of
VTE (Table 4).
Safety Analysis
In the UFH group, 2.0% of patients (95% CI, 1.0
to 3.0) had major bleeding at 10 days and 4.3% of
patients (95% CI, 2.8 to 5.7) had major bleeding at 3
months. In the enoxaparin group, 2.2% of patients
(95% CI, 1.1 to 3.2) had major bleeding at 10 days
and 2.9% of patients (95% CI, 1.6 to 4.1) had major
bleeding at 3 months. Enoxaparin at 3 months
reduced major bleeding by 26% (RR, 0.74; 95% CI,
0.43 to 1.25) compared with UFH in patients with
initial DVT with or without associated PE.
At 3 months, the estimated incidence of death was
5.8% in the UFH group (95% CI, 4.1 to 7.6) and
3.3% in the enoxaparin group (95% CI, 2.0 to 4.5).
There was no statistical evidence of heterogeneity
among studies. Enoxaparin reduced mortality by
31% (RR, 0.69; 95% CI, 0.43 to 1.10) compared with
UFH in patients with initial DVT with or without
associated PE.
Discussion
Results from this meta-analysis suggest that in
terms of VTE recurrences, major bleeding, and
death, enoxaparin is as effective and safe as UFH in
the treatment of DVT with or without associated
symptomatic PE. Similar results were found when
comparing enoxaparin and UFH in patients
present-ing with a DVT and PE and in patients presentpresent-ing
with DVT alone. Emphasizing the robustness of our
results, estimates of treatment effect were
un-changed regardless of population considered
(inten-tion-to-treat or per-protocol population, population
without patients randomly allocated to filter
place-ment, or population with patients who received
enoxaparin, 1.5 mg/kg qd).
Table 4 —Efficacy Results From the Sensitivity Analyses, Enoxaparin vs UFH*
Variables Primary Analysis
Excluding Patients Randomly Allocated to Filter Placement
Including Patients Who Received Enoxaparin, 1.5 mg/kg qd
VTE 0.81 (0.52 to 1.26) 0.74 (0.46 to 1.19) 0.86 (0.57 to 1.29)
DVT 0.79 (0.48 to 1.30) 0.73 (0.42 to 1.26) 0.87 (0.55 to 1.38)
PE 0.63 (0.27 to 1.44) 0.61 (0.25 to 1.46) 0.60 (0.27 to 1.29)
*Data are presented as RR (95% CI).
Table 5—Baseline Characteristics of Patients According to the Presence of an Initial Symptomatic
PE* Characteristics Patients With Isolated DVT (n⫽1,268) Patients With DVT and Symptomatic PE (n⫽235) Age, yr 62⫾16 68⫾15 Male gender 711 (56) 113 (48)
Body mass index⬎30 kg/m2† 151 (20) 43 (19)
History of VTE 303 (24) 77 (32)
Cancer 215 (17) 36 (15)
Surgery within the past 3 mo 234 (18) 25 (11) Chronic cardiac or respiratory
insufficiency‡
109 (14) 40 (17)
Recent immobilization‡ 132 (17) 31 (13)
Proximal DVT§ 1,148 (93) 212 (93)
*Data are presented as mean⫾SD or No. (%). †Information was not available for 533 patients. ‡Information was not available in one trial.13
These results are consistent with the
recommen-dations of the 2004 American College of Chest
Physicians consensus conference on antithrombotic
therapy
11and
of
the
Groupe
d’Etude
sur
l’He´mostase et la Thrombose,
48which state that
patients with DVT or PE would benefit from the
same therapeutic approach (UFH or LMWH), with
the latter being more attractive because of its good
safety profile and its superior convenience.
At 3 months, the incidence of VTE recurrence,
PE, and DVT in the UFH group were 5.7%, 4.4%,
and 1.8%, respectively. These data are consistent
with data from clinical trials assessing UFH, with the
exception of data from the Tinzaparine ou He´parine
Standard: E´valuations dans l’Embolie pulmonaire
study,
49which reported a lower rate of recurrence
(1.9%). The incidence of deaths observed in the
meta-analysis is consistent with data from the
liter-ature. However, the incidence of major bleeding at 3
months is higher (4.3%) than that reported in clinical
trials.
6This could be explained by the patients of the
PREPIC study,
23who can be considered as patients
at higher risk of bleeding. The RRs of VTE
recur-rence with enoxaparin compared with UFH were
0.81 (95% CI, 0.52 to 1.26) for the whole population
and 0.71 (95% CI, 0.43 to 1.13) in the per-protocol
population. Considering these results and the
a
priori
noninferiority margin of 1.61, this
meta-anal-ysis of three clinical trials showed that enoxaparin is
noninferior to UFH in terms of efficacy. In addition,
even if there was a trend in favor of enoxaparin in
terms of major bleeding and death, no statistically
significant difference was detected between
treat-ments.
As previously described in the literature,
50the
estimated incidence of PE and of VTE at 3 months
in the UFH group was higher in patients presenting
an initial symptomatic PE (4.9% and 8.2%,
respec-tively) than in patients without initial symptomatic
PE (1.3% and 4.8%, respectively). The present study
indicates that the efficacy of enoxaparin is not
mod-ified by the presence of an initial symptomatic PE.
However, because of the modest number of patients
presenting with initial symptomatic PE (275
pa-tients), estimates of efficacy and safety were not very
precise. Compared with UFH, enoxaparin reduced
the risk for VTE recurrence by 16% in patients with
DVT alone and by 29% in patients with DVT plus
symptomatic PE. This result is consistent with
re-sults of a recent meta-analysis by Quinlan et al,
10who found that LMWH reduced the risk for VTE
recurrence in PE patients by 28% at 3 months with
an odds ratio of 0.72 (95% CI, 0.40 to 1.48). In
conclusion, our data show that enoxaparin is as
effective and safe as UFH for the initial treatment of
DVT with or without associated symptomatic PE,
apart from massive PE.
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