Catheterization and Cardiovascular Interventions 77:182–190 (2011)

Heparin or Enoxaparin Anticoagulation for Primary

Percutaneous Coronary Intervention
David Brieger,1,2 MBBS, PhD, FACC, Jean-Philippe Collet,2 MD, PhD, Johanne Silvain,2 MD,
Antoine Landivier,2 MD, Olivier Barthélémy,2 MD, Farzin Beygui,2 MD, PhD,
Anne Bellemain-Appaix,2 MD, Anne Mercadier,3 MD, Remi Choussat,2 MD,
Nicolas Vignolles,2 BSc, Dominique Costagliola,4 MD, and Gilles Montalescot,2* MD, PhD
Objectives: The aim of this study was to compare efficacy and safety outcomes among
patients receiving enoxaparin or unfractionated heparin (UFH) while undergoing percutane-
ous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).
Background: Primary PCI (pPCI) for ST elevation has traditionally been supported by UFH.
The low molecular weight heparin enoxaparin may provide better outcomes when used for
pPCI. Methods: Consecutive eligible patients (580) undergoing pPCI enrolled in the prospec-
tive electronic Pitié-Salpêtrière registry of ischemic coronary syndromes (e-PARIS) registry
were grouped according to whether they received UFH or enoxaparin as the sole anticoagu-
lant. Logistic regression modeling, propensity-weighted adjustment, and sensitivity analy-
ses were used to evaluate efficacy and safety endpoints for enoxaparin vs. UFH. Results:
Enoxaparin was administered to 346 patients and UFH to 234 without ACT or anti-Xa guided
dose adjustment. PCI was performed through the radial artery in 90%, with frequent (75%)
use of GPIIb/IIIa antagonists. Patients receiving enoxaparin were more likely to be therapeu-
tically anticoagulated during the procedure (68% vs. 50%, P < 0.0001) and were less likely to
experience death or recurrent myocardial infarction (MI) in hospital (adjusted OR 0.28 95%
CI (0.12–0.68) or by 30 days (adjusted OR 0.35 95% CI 0.16–0.81). All cause mortality was
also reduced in hospital (adjusted OR 0.32, 95% CI (0.12–0.85) and to 30 days (adjusted OR
0.40 95% CI 0.17–0.99). Other ischemic endpoints were similarly reduced with enoxaparin.
Thrombolysis in myocardial infarction (TIMI) major bleeding events were numerically fewer
among patients receiving enoxaparin (1.2% vs. 2.6%, P 5 0.2). Conclusions: In patients with
STEMI presenting for PCI, enoxaparin was associated with a reduction in all ischemic com-
plications, more frequent therapeutic anticoagulation, and no increase in major bleeding
when compared against unfractionated heparin. VC 2010 Wiley-Liss, Inc.

Key words: myocardial infarction; primary PCI; anticoagulants

1
Department of Cardiology, Concord Hospital, University of R. Choussat has no conflict of interest to declare. N. Vignolles has no conflict of interest to
declare. D. Costagliola has received travel grants, consultancy fees, honoraria or study grants
Sydney, Sydney, Australia
2 from various pharmaceutical companies including Abbott, Boehringer-Ingelheim, Bristol-
Institut de Cardiologie (APHP), INSERM U937 and Univ Paris Myers-Squibb, Gilead Sciences, Glaxo-Smith-Kline, Janssen-Cilag, Merck-Sharp & Dohme-
6, Pitié-Salpêtrière Hospital, Paris, France Chibret and Roche. G. Montalescot discloses the following relationships: Research Grants (to
3
French Blood Establishment, Pitié-Salpêtrière Hospital, Paris, France the Institution) from Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Med-
4 tronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération
Epidemiology and Therapeutic Strategy, INSERM U943 and Univ
Française de Cardiologie, Société Française de Cardiologie, ITC Edison, Pfizer; consulting or
Pierre et Marie Curie, Pitié-Salpêtrière Hospital, Paris, France lecture fees from Accumetrics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers
Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Menarini, MSD, Novartis, Portola, Sanofi-Aventis,
Conflict of interest: D. Brieger has received research grants from Sanofi-Aventis, Eli Lilly, Schering-Plough and The Medicines Company.
Merck/Schering Plough, National Heart Foundation of Australia. He has served as a consultant
on advisory boards for Sanofi-Aventis, Eli Lilly, Boerhinger Ingelheim, AstraZeneca, Merck/
*Correspondence to: Gilles Montalescot, MD, PhD, Institut de Cardi-
Schering Plough. J.P. Collet has received research grant (to the institution) from Bristol-Myers
Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, ologie, Bureau 236, Centre Hospitalier Universitaire Pitié-Salpêtrière,
Stago, Fondation de France, INSERM, Fédération Française de Cardiologie, and Société Fran- AP-HP, 47 Blvd de l’Hôpital, Paris 75013, France.
çaise de Cardiologie. J.P. Collet has served as a consultant (honoraria for past two years) for E-mail: gilles.montalescot@psl.aphp.fr
consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees
from Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly. J. Silvain has received research
grants from Sanofi-Aventis, Daiichi-Sankyo, Eli Lilly, INSERM, Fédération Française de Car- Received 15 March 2010; Revision accepted 19 May 2010
diologie and Société Française de Cardiologie; consultant fees from Daiichi-Sankyo and Eli
Lilly; and lecture fees from AstraZeneca, Daiichi-Sankyo and Eli Lilly. Antoine Landivier has DOI 10.1002/ccd.22674
no conflict of interest to declare. O. Barthélémy has no conflict of interest to declare. F. Beygui
Published online 7 October 2010 in Wiley Online Library
has received lecture fees from Roche, Sanofi-Aventis, Pfizer and Astellas. A. Bellemain-
Appaix has no conflict of interest to declare. A. Mercadier has no conflict of interest to declare. (wileyonlinelibrary.com)

V
C 2010 Wiley-Liss, Inc.
 Enoxaparin in Primary PCI 183

INTRODUCTION Syndromes (e-PARIS registry), a prospective ‘‘all-

comers’’ database of patients presenting to this hospital
Primary percutaneous coronary intervention (PCI)
for management of their acute coronary syndrome.
for ST elevation is widely supported by the anticoagu-
This analysis was undertaken in patients undergoing
lant unfractionated heparin (UFH), [1] despite the fact
primary or rescue percutaneous coronary intervention
that the evidence supporting heparin for this indication
(pPCI) for acute STEMI in whom the anticoagulant
is derived from very limited populations [2]. The clini-
regimen was known. All patients received either UFH
cal limitations of UFH include a variable and unreliable
or LMWH. The selection of anticoagulant was made
anticoagulant response, accompanied by inconsistent ef-
by the first medical contact physician (mobile emer-
ficacy and risk of bleeding [3]. These limitations have
gency unit, hospital emergency room, or responsible
spurred the development of alternative anticoagulants
clinician if the patient was transferred from a hospital
with improved pharmacokinetic and clinical profiles.
ward). This decision was independent of the clinician
The low molecular weight heparin enoxaparin is an al-
performing the intervention and the cardiologist man-
ternative anticoagulant characterized by more predictable
aging the patient. Patients who received both UFH and
and stable anticoagulation without the need for continuous
therapeutic doses of LMWH in this acute phase were
infusion or anticoagulant monitoring [3]. Enoxaparin has
excluded from this analysis to enable a true compari-
an established role in patients with non-ST elevation acute
son between the two anticoagulants [9]. All patients—
coronary syndromes [4,5], and more recent evidence has
except those with a recent history of bleeding or with
accrued favoring this drug in the management of ST-seg-
ongoing bleeding—received double antiplatelet therapy
ment elevation myocardial infarction (STEMI) [6], includ-
with intravenous (IV) aspirin (ASA) and oral clopidog-
ing those undergoing PCI. In a nonrandomized subgroup
rel. Most patients also received a bolus of Abciximab,
analysis of the Enoxaparin and Thrombolysis Reperfusion
either at first medical contact, or upon arrival in the
for Acute Myocardial Infarction Treatment (ExTRACT)-
catheterization laboratory [12]. Primary PCI was rou-
Thrombolysis in Myocardial Infarction (TIMI) 25 study
tinely performed by radial access using 6 French sheaths
[7], of 2,178 patients undergoing PCI while receiving
with selective thrombus aspiration and systematic stent
study drug, there was no increase in major bleeding with a
implantation where appropriate. In the absence of indi-
reduction in the primary ischaemic endpoint [8].
cation for long term anticoagulation (e.g., atrial fibrilla-
The Facilitated Intervention with Enhanced Reperfu-
tion, mechanical prosthesis) or MI complication (e.g.,
sion Speed to Stop Events (FINESSE) trial [9] incorpo-
left ventricular thrombus, coronary slow flow) anticoa-
rated a nonrandomized prospective substudy of enoxa-
gulation was limited to doses for prevention of deep
parin (759 patients) vs. UFH (1,693 patients) [10].
vein thrombosis after the pPCI procedure.
Less major bleeding was found with enoxaparin, and
Patients included in this study arrived at the cath-
in contrast to the findings of the main study, lower
eterization laboratory for PCI via one of several
death, myocardial infarction (MI), urgent revasculariza-
routes, each of which may have been associated
tion, or refractory ischemia through 30 days was asso-
with differences in delays and precatheterization
ciated with enoxaparin vs. UFH.
care. Patients who self presented to the hospital
There is therefore emerging evidence that enoxaparin
emergency department were transferred directly
supported PCI for STEMI is associated with fewer ische-
from the ED, if they presented to a regional hospi-
mic events and less bleeding than UFH. At our hospital,
tal, this involved hospital transfer with inherent
we have experience in the use of both UFH and LMW
delays. Finally, some patients experienced their cor-
heparin for patients undergoing coronary intervention in
onary event while in-patients undergoing treatment
the acute setting [11]. In this report, we compare out-
for another medical condition, and were transferred
comes among patients with STEMI undergoing primary
to the catheterization laboratory from the ward, a
PCI stratified according to the anticoagulation they
process that was also frequently associated with
received prior to and during their coronary intervention.
patient delay. To ensure an inclusive evaluation of
Our goal was to determine whether the favorable out-
real world management, all patients were included
comes observed in patients receiving low molecular
regardless of the mode by which they arrived to the
weight heparin (LMWH) in the clinical trials were repli-
catheterization laboratory. In addition, we did not
cated in our real world clinical experience.
restrict our population to those presenting within 12
hr of symptom onset but included those presenting
METHODS
at any time with ongoing symptoms or clinical
Patient Population instability and an indication for primary PCI.
Patients for this study were identified from the elec- Approval for this analysis was provided by the Pitié-
tronic Pitié-Salpêtrière Registry of Ischemic Coronary Salpêtrière Institutional Review Board.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
184 Brieger et al.
Assessment of Anticoagulation
Blood was collected for evaluation of coagulation
status at both the beginning and completion of the cor-
onary intervention. Anticoagulation levels were meas-
ured using anti-Xa activity specifically calibrated for
enoxaparin and UFH (Rotachrom Assay for LMWH or
UFH, Stago, Asnières, France). The recommended
therapeutic levels of anti-Xa were 0.5–1.5 IU/ml for
enoxaparin and 0.2–0.6 IU/ml for UFH. Adequate anti-
coagulation during the procedure was defined if the
anti-Xa assay showed the patient be within the thera-
peutic range at either the beginning of the procedure,
the conclusion of the procedure or both.
Definitions
Death was defined as any death. In-hospital out-
comes were based on medical examination, medical
records, ECG, and troponin I level. Recurrent MI
(ReMI) during hospital admission was defined as recur-
rent chest pain with recurrent ST elevation and a fur-
ther rise in troponin. Recurrent ischemia was defined
as recurrent chest pain with or without ECG changes
in the absence of further troponin elevation. Repeat
urgent intervention was identified if the procedure was
preceded by clinical documentation of ischemia and
the artery treated was the initial culprit vessel. Bleed-
ing events were reported by the clinician responsible
for the patient, subjectively classified as either major
or minor. Objective evaluation of bleeding was also
performed according to the TIMI, and Safety and Effi-
cacy of Enoxaparin in Percutaneous Coronary Interven-
tion Patients, an International Randomized Evaluation
(STEEPLE) definitions [13,14]. The main objectives
were death or reMI for efficacy and major bleeding for
safety. We also evaluated the other composite end-
points of death, reMI, urgent revascularization; death,
reMI, urgent revascularization or recurrent ischemia;
TIMI major or minor bleeding.
Thirty day clinical outcomes were obtained by tele-
phone call by clinic research associates.
Statistical Analyses
Categorical variables are expressed as frequencies
and percents, and continuous variables are given as
mean
standard deviation (SD). Comparisons between
groups of patients according to the anticoagulant
received were performed by ANOVA for continuous
variables and Chi2 or Fisher exact test for categorical
variables. Multivariate logistic regression was used to
adjust for differences in prognostically important varia-
bles. The prognostic significance of most baseline clin-
ical, biochemical, and procedural characteristics were
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
evaluated by regressing each against the outcome of
in-hospital death and those that retained a P < 0.25 by
univariate analysis were entered into a baseline multi-
variate model. This model also included other variables
that differed significantly in distribution between
patients receiving UFH and LMWH. Backwards step-
wise elimination was then used to arrive at the final
model which comprised age, TIMI STEMI risk score,
mode of hospital presentation, access site (femoral vs.
radial), receipt of fibrinolysis, loading dose of clopi-
dogrel on arrival (300 mg vs. >300 mg), time from
symptom onset to first medical contact, troponin level
on presentation as well as selection of anticoagulant
therapy. A propensity score for treatment with UFH
was calculated using logistic regression, based on the
baseline characteristics listed in Table I. A propensity
score weight was then calculated as the inverse of the
propensity score for patients receiving UFH, and as the
inverse of 1- propensity score for patients receiving
LMW heparin. The multivariate model above was then
weighted by this score to develop a propensity score
weighted regression model.
Finally, additional sensitivity analyses were con-
ducted by evaluating death or reMI outcomes in (1)
patients presenting within 12 hr of symptom onset
only, (2) nontransfer patients, that are those who pre-
sented with STEMI to Pitié-Salpêtrière as their primary
hospital. The statistical analyses were performed with
SAS software, version 9.2 (SAS Institute).
RESULTS
Patient Characteristics
Six hundred ninety-four patients with STEMI were con-
sidered for this analysis. Fifty-one patients were excluded
because their mode of anticoagulation was not docu-
mented, 32 patients because they received both UFH and
LMWH and 31 patients because they were participating in
the concomitant FINESSE study and possibly receiving
blinded fibrinolytic therapy. The study population therefore
comprised 580 patients. Two hundred thirty-four patients
received UHF and 346 LMWH (Fig. 1).
UFH was administered initially as an intravenous
bolus dose (68
17 IU/kg, total dose 5,000
1,250
IU) at first medical contact. LMWH was given as a
subcutaneous injection at first medical contact (0.95

0.16 mg/kg, total dose 70
12 mg) or as an intrave-
nous injection in the catheterization laboratory (0.51

0.11 mg/kg, total dose 36
8 mg).
The mean age (62 years) and sex distribution (77%
male) of this population was consistent with most trials
of STEMI. Overall they were relatively high risk with
a high prevalence of diabetes (21%), mean TIMI risk
 Enoxaparin in Primary PCI 185

TABLE I. Baseline Characteristics

UFH (n ¼ 234) enox (n ¼ 346) P value
Age, year (mean
SD) 63.8
14 61.9
14 0.16
Male 190(81.2) 262(75.7) 0.12
BMI, Kg/m2 (mean
SD) 25.5
4 25.8
4 0.50
Diabetes 42(18.2) 77(22.3) 0.23
Current smoker 97(41.7) 146(42.2) 0.79
Family history 61(26.3) 74(21.4) 0.18
Hyperlipidaemia 91(39.1) 159(46.0) 0.11
Hypertension 99(43.9) 191(44.8) 0.66
History of myocardial infarction 30 (13.0) 42(12.3) 0.78
History of PCI 31(13.4) 38(11.1) 0.41
History of CABG 4(1.7) 11(3.2) 0.27
History of oral Anti platelet drugs 59(25.3) 62(18) 0.03
TIMI risk score (mean
SD) 3.8
2.7 3.7
2.5 0.87
TIMI score 5 84(35.9) 118(34.7) 0.77
Systolic BP, mm Hg (mean
SD) 128
24 128
26 0.96
HR on presentation 78
18 78
18 0.86
CrCl, ml/min (mean
SD) 81.1
33 83.2
38 0.50
Anterior MI 104(44.4) 144(41.6) 0.50
TIMI risk score (mean
SD) 3.8
2.7 3.7
2.5 0.87
TIMI score 5 84(35.9) 118(34.7) 0.77
Killip 1 201(85.9) 287(82.95) 0.34
Shock 8(3.4) 21(6.1) 0.15
Cardiac arrest 8(3.4) 19(5.5) 0.25
Symptoms to first medical contact (mins, mean
SD) 261.6
456 342.8
593 0.08
Patients presenting later than 12 hr of the onset of symptoms (%) 18 (7.7) 44 (12.7) 0.05
TnI (admission), UI/l (mean
SD) 9.2
26 10.7
28 0.52
In hours presentation (%) 134(57.3) 173(50) 0.09
Mode of hospital arrival <0.0001
Medical Intensive care ambulance (SAMU) 137(58.5) 173(50.0)
Fire fighting service emergency care (Sapeur Pompiers) 56(23.9) 12(3.5)
Hospital ward 9(3.9) 39(11.3)
Transfer from other ED 27(11.5) 57(16.5)
Directly to ED 5(2.1) 65(18.8)
Aspirin on arrival 216(92.3) 323(93.4) 0.63
Clopidogrel on arrival 213(92) 322(93.1) 0.37
Clopidogrel load dose > 300mg 65 (27.8) 139 (40.2) 0.002
Abciximab 174(74.4) 262(75.7) 0.71
Thrombolysis 21(9.0) 12(3.5) 0.005
Radial access 210(89.7) 308(89.0) 0.78
BMI, body mass index; BP, blood pressure; CrCl, creatinine clearance; ED, emergency department; HR, heart rate; TnI, troponin I.

score of 3.7, and >15% presenting with cardiac
decompensation (Killip class >1).
The two treatment groups were well matched for most
baseline characteristics (Table I). Patients receiving UFH
were more likely to have been taking oral antiplatelet
agents prior to presentation (25.3% vs. 18%, P ¼ 0.03).
Patients receiving LMWH tended to present later af-
ter the onset of symptoms than those on UFH (342.8
min vs. 261.6 min), although this difference did not
reach conventional statistical significance (P ¼ 0.08).
More than 90% of patients received aspirin and clo-
pidogrel and approximately three quarters received
abciximab. There was no difference in rates of receipt
of antiplatelet therapy following arrival between the
two groups although patients receiving enoxaparin
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
were more likely to be loaded with a larger dose of
clopidogrel (>300 mg) than those receiving UFH.
Thrombolytic therapy was infrequent, but more com-
mon among patients receiving UFH. In 9 of 10 cases,
PCI was performed through the radial artery and this
was equally frequent in both treatment arms.
Clinical follow-up to 30 days was available for 554
patients (follow up rate of 95.5%).
Anticoagulation
Adequate anticoagulation during the procedure with
the predefined therapeutic ranges (0.2–0.6 IU for UFH
and 0.5–1.5 IU for LMWH) at either the beginning of the
procedure, the conclusion of the procedure, or both was
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
186 Brieger et al.

Fig. 1. Identification of patients for inclusion in this study from e-Paris Registry. [Color fig-
ure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

found in more than 68% of patients receiving LMWH,

and only 50% of UFH patients (P < 0.0001, Fig. 2).

Clinical Outcomes
Efficacy. Relative to patients receiving UFH, those
receiving LMWH were significantly less likely to experi-
ence in-hospital death (3.2% vs. 7.3%, P ¼ 0.03), recur-
rent MI (0.6% vs. 2.6%, P ¼ 0.04), and urgent revascu-
larization (6.4% vs. 8.6%, P ¼ 0.04) (Table II). Recur-
rent ischemia was also numerically less frequent with
LMWH than with UFH (4.3% vs. 6.0%). Following mul-
tivariate adjustment, in-hospital mortality remained signif-
icantly less frequent with LMWH (adjusted OR 0.32,
95% CI (0.12–0.85), propensity adjusted OR (0.18, 95%
CI (0.09–0.38). In addition, the double endpoint of death
or reMI was recorded less frequently with LMWH than
with UFH (adjusted OR 0.28, 95% CI (0.12–0.68), pro-
pensity adjusted OR 0.26, 95% CI 0.15–0.47) as were the
other composite end points of death, recurrent MI or
Fig. 2. Proportion of patients therapeutically anticoagulated
urgent revascularization, and death, recurrent MI, urgent during PCI. [Color figure can be viewed in the online issue,
revascularization or recurrent ischemia (see Table II). which is available at wileyonlinelibrary.com.]
From hospital discharge to 30 days, there were a fur-
ther three deaths, no further MI, and 18 patients requir- endpoints incorporating urgent revascularization and
ing repeat target vessel revascularization. Three recurrent ischaemia remained less frequent among
patients experienced recurrent ischemia without pro- patients receiving LMWH, following propensity
ceeding to further revascularization. Death from admis- weighted adjustment (Table III).
sion to 30 days remained significantly less common Several sensitivity analyses were performed. For
among patients receiving LMWH (adjusted OR 0.4, patients presenting within 12 hr of the onset of symp-
95% CI 0.17–0.99, propensity adjusted OR 0.27, 95% toms, the benefit of LMWH was similar to that seen in
CI 0.14–0.54) as did the composite of death or reMI the whole cohort [in-hospital death or MI adjusted OR
(adjusted OR 0.35, 95% CI 0.16–0.81, propensity 0.36, 95% CI (0.14–0.97), P ¼ 0.04, 30 day adjusted
adjusted OR 0.29, 95% CI 0.17–0.52). The composite death or MI OR 0.43, 95% (0.17–1.08), P ¼ 0.07]
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
 Enoxaparin in Primary PCI 187

TABLE II. In-Hospital Ischemic Events

UFH
(n ¼ 234) enox (346) P OR (95% CI) P Adj ORa (95% CI) P Adj ORb (95% CI) P
Death 17(7.3) 11(3.2) 0.02 0.42 (0.19–0.91) 0.03 0.32 (0.12–0.85) 0.02 0.18 (0.09–0.38) <0.0001
ReMI 6(2.6) 2(0.6) 0.04 0.22 (0.04–1.1) 0.07 0.15(0.02–1.2) 0.07 0.16 (0.05–0.58) 0.005
Urgent revasc 20(8.6) 22(6.4) 0.04 0.25 (0.07–0.94) 0.04 0.26 (0.06–1.2) 0.08 0.13 (0.04–0.38) 0.0002
Recurrent Ischemia 14(6.0) 15(4.3) 0.37 0.71(0.34–1.50) 0.37 0.84(0.34–2.07) 0.70 0.70(0.35–1.39) 0.31
Death/ReMI 22(9.4) 13(3.8) 0.005 0.38(0.19–0.76) 0.007 0.28(0.12–0.68) 0.005 0.26 (0.15–0.47) <0.0001
Death/ReMI/urgent revasc 24(10.3) 15(4.3) 0.005 0.4(0.20–0.77) 0.007 0.36(0.16–0.80) 0.01 0.31 (0.18–0.53) <0.0001
Death/ReMI/urgent 30(12.8) 25(7.2) 0.02 0.53(0.30–0.93) 0.03 0.52(0.27–1.00) 0.05 0.39(0.24–0.62) <0.0001
revasc/recurrent ischemia
ReMI, recurrent myocardial infarction; Revasc, revascularization.
b
Adjusted for age, TIMI STEMI risk score, mode of hospital presentation (pompiers vs. SAMU vs other), access site (femoral vs. radial), receipt of
fibrinolysis, plavix dose on arrival, time from symptom to first medical contact, troponin level on presentation.
b
Propensity score-weighted model.

TABLE III. Ischaemic Events from Admission to 30 Days

UFH
(n ¼ 234) enox (346) P OR (95% CI) P value Adj ORa P Adj ORb P
Death 18(7.3) 13(3.8) 0.04 0.47 (0.23–0.98) 0.04 0.40 (0.17–0.99) 0.05 0.27 (0.14–0.54) 0.0002
Death/ReMI 23(9.8) 15(4.3) 0.009 0.42(0.21–0.82) 0.01 0.35(0.16–0.81) 0.01 0.29 (0.17–0.52) <0.0001
Death/ReMI/Urgent revasc 28(12.0 23(6.7) 0.03 0.52(0.29–0.93) 0.02 0.60(0.31–1.15) 0.12 0.53(0.33–0.85) 0.009
Death/ReMI/Urgent 39(16.7) 40(11.6) 0.08 0.65(0.41–1.05) 0.08 0.72(0.42–1.24) 0.23 0.63(0.42–0.92) 0.02
revasc/recurrent ischaemia
a
Adjusted for age, TIMI STEMI risk score, mode of hospital presentation (pompiers vs SAMU vs. other), access site (femoral vs. radial), receipt of
fibrinolysis, plavix dose on arrival, time from symptom to first medical contact, troponin level on presentation. Abbreviations as for Table II.
b
Propensity score weighted model.

(Table AI). When the analysis was restricted to patients TABLE IV. In-Hospital Bleeding events
presenting directly to this hospital for primary care [ei- UFH Enoxaparin P value
ther via Medical intensive care ambulance (SAMU), Major bleeding 16(6.8) 16(4.3) 0.34
Fire fighting service emergency care (Sapeur Pomp- Minor bleeding 21(9.0) 35(10.1) 0.65
iers), or directly from the Pitié-Salpêtrière emergency TIMI Major bleeding 6(2.6) 4(1.2) 0.2
department], the benefit of LMWH again persisted: in- TIMI Minor bleeding 8(3.4) 10(2.9) 0.72
STEEPLE Major bleeding 21(9.0) 27(7.8) 0.62
hospital death or MI adjusted OR: 0.24, 95% CI (0.09– STEEPLE Minor bleeding 12(5.1) 16(4.6) 0.78
0.67), P ¼ 0.007, 30 day death or MI adjusted OR
0.32, 95% CI (0.13–0.83), P ¼ 0.01 (Table AII).
Safety. There were no significant differences in ment and propensity weighting adjustment. Each of the
bleeding complications between the two treatment hierarchical composite endpoints of death or MI, death/
groups whether clinician reported, or objectively deter- MI or urgent revascularization, and death/MI/urgent re-
mined by TIMI or STEEPLE bleeding scales. How- vascularization or recurrent ischemia was significantly
ever, bleeding events were numerically fewer among reduced. There was a significant reduction in-hospital
patients receiving LMWH, with the exception of clini- mortality, which persisted to 30 days (adjusted OR
cian determined minor bleeding (Table IV). 0.40, 95% CI (0.17–0.99), as did the composite of
death or MI (adjusted OR 0.35, 95% CI (0.16–0.81).
The mean time from onset of symptoms to first med-
DISCUSSION
ical contact tended to be longer for patients receiving
In this study, we found that when compared with enoxaparin with a greater proportion of patients treated
UFH, enoxaparin supported primary PCI was associ- more than 12 hr after the onset of symptoms. The
ated with more effective anticoagulation at the time of impact of this difference on outcomes is uncertain; it
the procedure, a significantly lower rate of in-hospital may introduce a survival bias because most patients
and 30 day ischemic events, and a trend toward less who die following MI do so early after the onset of
bleeding. The improvement in efficacy outcomes was their event, but on the other hand delays to reperfusion
consistent for each evaluated manifestation of coronary are associated with poorer outcome [15,16]. Sensitivity
ischemia and persisted following multivariate adjust- analyses restricted to patients presenting within 12 hr
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
188 Brieger et al.
of the onset of symptoms showed an improvement in
ischemic outcomes similar to that of the study group as
a whole excluding this selection bias as contributing to
the result of the study. A second group more likely to
receive LMWH was those presenting from other hospi-
tals or the ward. Studies in broader ACS patients have
shown that where there is discretion involved in
the decision to perform coronary intervention, such as
may occur in these patients, PCI tends to be offered to
those at lower risk [17] introducing another potential
survival bias. Analyses restricted to patients delivered
to our hospital catheterization laboratory or emergency
department as first port of call, again showed the
reduction in ischemic outcomes consistent with that
seen in the whole cohort confirming that different
modes of arrival to the catheterization laboratory did
not materially affect the outcome of our analyses.
Our striking reduction of in-hospital death and the
composite of death/MI are consistent with a number of
reports from other registries that compared LMWH to
UFH. The French Registry on Acute ST-Elevation and
Non-ST-Elevation Myocardial Infarction (FAST-MI)
reported a 58% decreased in-hospital mortality
(adjusted OR 0.42, 95% CI 0.19–0.89) among their
STEMI cohort [18]. The German Acute Coronary Syn-
dromes (ACOS) registry reported a 67% reduction in
death or MI (adjusted OR 0.33, 95% CI 0.15–0.72)
among patients undergoing pPCI, and in the German
MITRA-plus registry enoxaparin in patients with pPCI
was associated with a reduction in death or reinfarction
of 58% (odds ratio 0.42, 95% CI 0.2–0.8) [19,20].
The incorporation of routine measurement of anti-Xa
activity is a valuable component of our study as there
is limited guidance available regarding optimal anti-Xa
levels in patients undergoing PCI supported by enoxa-
parin [21,22]. In a subanalysis of the STEEPLE study,
anti-Xa levels above 0.9 IU/ml in patients receiving
enoxaparin were associated with increased bleeding,
whereas no clear relationship was found between anti-
Xa levels and ischemic events, possibly because of the
low-risk characteristics of the population [23]. The rec-
ommended therapeutic anti-Xa range used in our study
of 0.5 to 1.5 IU/ml is extrapolated from an evaluation
of unselected patients with unstable angina and non
ST-elevation MI undergoing PCI where it was found
that the 30-day mortality rate was increased threefold
in patients with anti-Xa levels less than 0.5 IU/ml com-
pared with the patients with anti-Xa levels in the range
of 0.5–1.2 IU/ml (P ¼ 0.004) [11]. Dosage guidance
for UFH are similarly insecure, although our own data
suggest anti-Xa levels of 0.2–0.6 IU/ml, provide more
reliable estimates of therapeutic anticoagulation than
ACT, (unpublished results), and were the levels
adopted for the therapeutic range in our study. Using
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
these definitions, almost 70% of patients receiving enox-
aparin were more likely to be within our defined thera-
peutic range of anticoagulation whereas only 50% of
patients on UFH were therapeutic during the procedure,
confirming previous reports [1,13,24]. In contrast to
STEEPLE, we did find a reduction in ischaemic events
in patients receiving enoxaparin in this much higher risk
population. This is the first time to our knowledge that
an association between more frequent achievement of
therapeutic anticoagulation during PCI in a STEMI pop-
ulation and a reduction in ischaemic outcomes has been
shown. Further work in this study and others should
provide the opportunity to further refine the optimal
therapeutic range for enoxaparin in these patients.
The reduction in ischemic outcomes in randomized
trials of patients with NSTEACS and patients with
STEMI receiving fibrinolysis has, in some studies,
been at the cost of increased major bleeding [7,25]. In
our study, however, major bleeding tended to be
lower following administration of enoxaparin, than
following UFH, whether the bleed was investigator
determined or measured objectively by TIMI or
STEEPLE grades. Our data are consistent with previ-
ous registry analyses of STEMI patients undergoing
pPCI; most have shown a trend toward less bleeding,
and none have reported significantly increased bleed-
ing with enoxaparin [19,20,26]. The brief duration of
anticoagulant therapy required for the coronary inter-
vention appears to represent an optimal setting for in-
travenous LMWH therapy, with the generation of an
immediate and consistent reliable anticoagulant effect,
and minimization of both ischaemic and bleeding
complications relative to UFH [13,27].
The use of LMWH in the formal substudy of FI-
NESSE was associated with a significant reduction in
nonintracranial TIMI major bleeding (OR 0.55, 95%
CI 0.31–0.99, P ¼ 0.047), comparable to the reduction
observed in our study (OR 0.47, 95%CI 0.13–1.69, P
¼ 0.24). Absolute bleeding events were much more
frequent in FINESSE than in our study: (TIMI major
bleeding of 2.9% vs. 4.6% in FINESSE and 1.2% vs.
2.6% in our study, with LMWH and UFH respec-
tively), despite our registry including patients at higher
risk than would be enrolled in a clinical trial. This was
likely contributed to by the one-third of patients in FI-
NESSE received lytic therapy while fewer than 10%
were thrombolyzed in our study. In addition, almost
90% of our patients underwent PCI via the radial artery,
an infrequent mode of access in FINESSE. This
approach eliminates femoral access site complications,
the most common source of bleeding following PCI. In
a recent comprehensive meta-analysis comparing radial
with femoral access, the former was associated with a
73% reduction in bleeding complications [28]. The low

event rates of major bleeding recorded in our study may
explain the observation that despite the same magnitude
of treatment effect as in previous studies like FINESSE,
the difference did not reach statistical significance.
Limitations of our study include its nonrandomized
design and the unblinded nature of the therapies pro-
vided. Use of UFH was not guided by ACT as is com-
mon in US practice; however, the doses of heparin
administered were comparable to those in contempo-
rary trials of patients with STEMI undergoing primary
PCI. There were differences between the populations
with regard to other therapies received and the propor-
tion of patients presenting late after the onset of symp-
toms. In addition, there were differences in the preho-
spital care offered to patients in the different treatment
groups which may have contributed to differences in
outcomes. We attempted to control for these differences
by developing an inclusive multivariate model for
adjusted analyses. We performed additional propensity
weighting adjustments to our analyses to further control
for differences in baseline characteristics with further
strengthening of the apparent benefit of LMW heparin.
In addition, we performed sensitivity analyses restricted
to patients presenting within 12 hr of the onset of symp-
toms, and those presenting directly to our hospital for
primary coronary intervention. In both of these patient
subgroups, the benefit of enoxaparin was consistent with
the benefit found in the population as a whole.
In conclusion, in our single centre registry of
patients with STEMI presenting for PCI, with frequent
use of Glycoprotein (GP) IIb/IIIa inhibition and radial
access, use of the LMWH enoxaparin was associated
with significant reduction in ischaemic complications
when compared against UFH. This was accompanied
by a greater likelihood of therapeutic anticoagulation
during the procedure, and no increase in major bleed-
ing. These data contribute to accumulating evidence
from ‘‘real world’’ clinical practice, suggesting that
enoxaparin may play a role in primary PCI, and await
confirmation from the ongoing randomized ATOLL
(Acute STEMI Treated with primary angioplasty and in-
travenous enoxaparin Or UFH to Lower ischemic and
bleeding events at short- and Long-term follow-up) trial.
REFERENCES
1. Chew DP, Bhatt DL, Lincoff AM, Moliterno DJ, Brener SJ,
Wolski KE, Topol EJ. Defining the optimal activated clotting
time during percutaneous coronary intervention: Aggregate
results from 6 randomized controlled trials. Circulation 2001;
103:961–966.
2. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused
updates: ACC/AHA guidelines for the management of patients
with ST-elevation myocardial infarction (updating the 2004
guideline and 2007 focused update) and ACC/AHA/SCAI
Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
Enoxaparin in Primary PCI 189
guidelines on percutaneous coronary intervention (updating the
2005 guideline and 2007 focused update) a report of the Ameri-
can College of Cardiology Foundation/American Heart Associa-
tion Task Force on Practice Guidelines. J Am Coll Cardiol
2009;54:2205–2241.
3. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin:
The Seventh ACCP Conference on Antithrombotic and Throm-
bolytic Therapy. Chest 2004;126(3 Suppl):188S–203S.
4. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and
bleeding complications among patients randomized to enoxa-
parin or unfractionated heparin for antithrombin therapy in non-
ST-Segment elevation acute coronary syndromes: A systematic
overview. JAMA 2004;292:89–96.
5. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007
guidelines for the management of patients with unstable angina/
non-ST-Elevation myocardial infarction: A report of the Ameri-
can College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Writing Committee to Revise the
2002 Guidelines for the Management of Patients With Unstable
Angina/Non-ST-Elevation Myocardial Infarction) developed in
collaboration with the American College of Emergency Physi-
cians, the Society for Cardiovascular Angiography and Interven-
tions, and the Society of Thoracic Surgeons endorsed by the
American Association of Cardiovascular and Pulmonary Reha-
bilitation and the Society for Academic Emergency Medicine. J
Am Coll Cardiol 2007;50:e1–e157.
6. Carter NJ, McCormack PL, Plosker GL. Enoxaparin: A review
of its use in ST-segment elevation myocardial infarction. Drugs
2008;68:691–710.
7. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin ver-
sus unfractionated heparin with fibrinolysis for ST-elevation
myocardial infarction. N Engl J Med 2006;354:1477–1488.
8. Gibson CM, Murphy SA, Montalescot G, et al. Percutaneous
coronary intervention in patients receiving enoxaparin or unfrac-
tionated heparin after fibrinolytic therapy for ST-segment eleva-
tion myocardial infarction in the ExTRACT-TIMI 25 trial. J
Am Coll Cardiol 2007;49:2238–2246.
9. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in
patients with ST-elevation myocardial infarction. N Engl J Med
2008;358:2205–2217.
10. Montalescot G, Ellis SG, De Belder MA, et al. Enoxaparin in
primary and facilitated percutaneous coronary intervention. A
Formal Prospective Nonrandomised Substudy of the FINESSE
(Facilitated INtervention with Enhanced Reperfusion Speed to
Stop Events) Trial. JACC Cardiovasc Interv, in press.
11. Montalescot G, Collet JP, Tanguy ML, Ankri A, Payot L,
Dumaine R, Choussat R, Beygui F, Gallois V, Thomas D. Anti-
Xa activity relates to survival and efficacy in unselected acute
coronary syndrome patients treated with enoxaparin. Circulation
2004;110:392–398.
12. Montalescot G, Antoniucci D, Kastrati A, Neumann FJ, Boren-
tain M, Migliorini A, Boutron C, Collet JP, Vicaut E. Abcixi-
mab in primary coronary stenting of ST-elevation myocardial
infarction: A European meta-analysis on individual patients’
data with long-term follow-up. Eur Heart J 2007;28:443–449.
13. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus
unfractionated heparin in elective percutaneous coronary inter-
vention. N Engl J Med 2006;355:1006–1017.
14. Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL,
Bell WR, Knatterud G, Robertson TL, Terrin ML. Thrombolysis
in myocardial infarction (TIMI) trial—Phase I: Hemorrhagic
manifestations and changes in plasma fibrinogen and the fibrino-
lytic system in patients treated with recombinant tissue plasmino-
gen activator and streptokinase. J Am Coll Cardiol 1988;11:1–11.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd.
190 Brieger et al.

15. Zhou Z, Rahme E, Abrahamowicz M, Pilote L. Survival bias Elevation Myocardial Infarction Patients Who Receive Reperfu-
associated with time-to-treatment initiation in drug effectiveness sion Therapy: Results from the Nationwide French FAST-MI
evaluation: A comparison of methods. Am J Epidemiol 2005; Registry. Presented at American College of Cardiology 2007 An-
162:1016–1023. nual Meeting, New Orleans, LA, 2007; Abstract 1025–1094.
16. De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time 27. Dumaine R, Borentain M, Bertel O, Bode C, Gallo R, White
delay to treatment and mortality in primary angioplasty for HD, Collet JP, Steinhubl SR, Montalescot G. Intravenous low-
acute myocardial infarction: Every minute of delay counts. Cir- molecular-weight heparins compared with unfractionated heparin
culation 2004;109:1223–1225. in percutaneous coronary intervention: Quantitative review of
17. Fox KA, Anderson FA Jr, Dabbous OH, Steg PG, Lopez-Sen- randomized trials. Arch Intern Med 2007;167:2423–2430.
don J, Van de Werf F, Budaj A, Gurfinkel EP, Goodman SG, 28. Jolly SS, Amlani S, Hamon M, Yusuf S, Mehta SR. Radial ver-
Brieger D. Intervention in acute coronary syndromes: Do sus femoral access for coronary angiography or intervention and
patients undergo intervention on the basis of their risk charac- the impact on major bleeding and ischemic events: A systematic
teristics? The Global Registry of Acute Coronary Events review and meta-analysis of randomized trials. Am Heart J
(GRACE). Heart 2007;93:177–182. 2009;157:132–140.
18. Danchin N, Coste P, Ferrieres J, et al. Comparison of thrombol-
ysis followed by broad use of percutaneous coronary interven-
tion with primary percutaneous coronary intervention for ST- APPENDIX
segment-elevation acute myocardial infarction: Data from the
french registry on acute ST-elevation myocardial infarction
TABLE AI. Sensitivity Analyses: Relative Outcomes When
(FAST-MI). Circulation 2008;118:268–276.
Analysis Restricted to Patients Presenting Within 12 h of the
19. Zeymer U, Gitt A, Junger C, Bauer T, Heer T, Koeth O, Wien-
Onset of Symptoms
bergen H, Zahn R, Senges J. Efficacy and safety of enoxaparin
in unselected patients with ST-segment elevation myocardial in- P
farction. Thromb Haemost 2008;99:150–154. OR (95%)CI P ADJ OR VALUE
20. Zeymer U, Gitt A, Zahn R, Junger C, Bauer T, Heer T, Koeth Hospital events
O, Senges J. Efficacy and safety of enoxaparin in combination Death/ReMI 0.44 (0.2–0.97) 0.04 0.36 (0.14–0.97) 0.04
with and without GP IIb/IIIa inhibitors in unselected patients Death/ReMI/ 0.47(0.23–0.07) 0.04 0.47(0.20–1.10) 0.08
with ST segment elevation myocardial infarction treated with urgent revasc
primary percutaneous coronary intervention. EuroIntervention Events to 30 days
2009;4:524–528. Death/ReMI 0.46(0.21–0.97) 0.04 0.43(0.17–1.08) 0.07
21. Welsh RC, Gordon P, Westerhout CM, Buller CE, O’Neill B, Death/ReMI/ 0.60(0.32–1.11) 0.1 0.72 (0.35–1.48) 0.37
Armstrong PW. A novel enoxaparin regime for ST elevation urgent revasc
myocardial infarction patients undergoing primary percutaneous
coronary intervention: A WEST sub-study. Catheter Cardiovasc Abbreviations as for Table II.
Interv 2007;70:341–348.
22. Labeque JN, Jais C, Dubos O, et al. Prehospital administration of
enoxaparin before primary angioplasty for ST-elevation acute myo-
cardial infarction. Catheter Cardiovasc Interv 2006;67:207–213.
23. Montalescot G, Cohen M, Salette G, Desmet WJ, Macaya C,
Aylward PE, Steg PG, White HD, Gallo R, Steinhubl SR. TABLE AII. Sensitivity Analyses: Relative Outcomes When
Impact of anticoagulation levels on outcomes in patients under- Analysis Restricted to Primary Referrals (not via Other
going elective percutaneous coronary intervention: Insights from Hospital ED or Hospital Ward)
the STEEPLE trial. Eur Heart J 2008;29:462–471. P
24. Brener SJ, Moliterno DJ, Lincoff AM, Steinhubl SR, Wolski OR (95%)CI P ADJ OR VALUE
KE, Topol EJ. Relationship between activated clotting time and
Hospital events
ischemic or hemorrhagic complications: Analysis of 4 recent
Death/ReMI 0.35(0.16–0.80) 0.01 0.24 (0.09–0.67) 0.007
randomized clinical trials of percutaneous coronary intervention.
Death/ReMI/ 0.39(0.18–0.83) 0.01 0.35(0.15–0.86) 0.02
Circulation 2004;110:994–998.
urgent revasc
25. Murphy SA, Gibson CM, Morrow DA, et al. Efficacy and safety
Events to 30 days
of the low-molecular weight heparin enoxaparin compared with
Death/ReMI 0.41(0.19–0.88) 0.02 0.32(0.13–0.83) 0.01
unfractionated heparin across the acute coronary syndrome
Death/ReMI/ 0.51(0.26–0.96) 0.04 0.58(0.28–1.20) 0.14
spectrum: A meta-analysis. Eur Heart J 2007;28:2077–2086.
urgent revasc
26. Danchin N, Collet JP, Marco J. Use of Low Molecular Weight
Heparin is Associated with Improved In-Hospital Survival of ST- Abbreviations as for Table II.

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Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).