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T
HE INCITING EVENT IN AN ACUTE nary syndromes (ACSs), and as an adjunct to percutaneous coronary intervention (PCI).
coronary syndrome (ACS) typi- Data Sources We searched MEDLINE for articles from 1990 to 2002 using the in-
cally involves disruption of a dex terms heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight
vulnerable atherosclerotic heparin, myocardial infarction, unstable angina, coronary angiography, coronary an-
plaque with superimposed thrombosis, gioplasty, thrombolytic therapy, reperfusion, and drug therapy, combination. Addi-
leading to varying degrees of occlusion tional data sources included bibliographies of articles identified on MEDLINE, inquiry
of the culprit artery.1-3 ST-elevation myo- of experts and pharmaceutical companies, and data presented at recent national and
cardial infarction (STEMI) is usually as- international cardiology conferences.
sociated with complete thrombotic oc- Study Selection We selected for review randomized trials comparing LMWHs against
clusion of the culprit artery,4 while either unfractionated heparin or placebo for treatment of ACS, as well as trials and reg-
nonocclusive thrombus is the typical istries examining clinical outcomes, pharmacokinetics, and/or phamacodynamics of LMWHs
finding associated with unstable angina/ in the setting of PCI. Of 39 studies identified, 31 fulfilled criteria for analysis.
non–ST-elevation myocardial infarc- Data Extraction Data quality was determined by publication in the peer-reviewed
tion (UA/NSTEMI).5,6 Tissue factor ex- literature or presentation at an official cardiology society–sponsored meeting.
posed following plaque rupture leads to Data Synthesis The LMWHs are recommended by the American Heart Associa-
activation of the coagulation cascade and tion and the American College of Cardiology for treatment of unstable angina/non–
generation of factor Xa (FIGURE 1).7 ST-elevation myocardial infarction. Clinical trials have demonstrated similar safety with
Thrombin is formed, which leads to fi- LMWHs compared with unfractionated heparin in the setting of PCI and in conjunc-
brin deposition, platelet activation, and tion with glycoprotein IIb/IIIa inhibitors. Finally, LMWHs show promise as an anti-
thrombotic agent for the treatment of ST-elevation myocardial infarction.
ultimately the formation of a stable clot.8
Given the central role of thrombin in Conclusions The LMWHs could potentially replace unfractionated heparin as the
the pathogenesis of ACSs, an antithrom- antithrombotic agent of choice across the spectrum of ACSs. In addition, they show
promise as a safe and efficacious antithrombotic agent for PCI. However, further study
botic agent is an important element in
is warranted to define the benefit of LMWHs in certain high-risk subgroups before
therapy, regardless of whether ST eleva- their use can be universally recommended.
tion is present. However, there are im- JAMA. 2003;289:331-342 www.jama.com
portant limitations associated with un-
fractionated heparin (currently the most
commonly used antithrombotic agent), METHODS Author Affiliations: TIMI Study Group, Brigham and
which has prompted a search for alter- Studies for this review were identified Women’s Hospital, Boston, Mass.
Financial Disclosures: Dr Giugliano has received hono-
native compounds.9 One promising class using MEDLINE searches, reviewing ref- raria from Aventis for educational programs. Dr Antman
of agents is the low-molecular-weight erence lists, and conferring with ex- has received clinical research grants from Aventis.
Corresponding Author and Reprints: Robert P.
heparins (LMWHs), which offer poten- perts and pharmaceutical companies. Giugliano, MD, SM, TIMI Study Group, 350 Long-
tial advantages in terms of clinical effi- The medical subject headings used were wood Ave, First Floor Offices, Boston, MA 02115
(e-mail: rgiugliano@partners.org).
cacy, safety, and ease of use in the set- heparin, enoxaparin, dalteparin, nadro- Clinical Cardiology Section Editor: Michael S. Lauer,
ting of ACS. parin, tinzaparin, low molecular weight MD, Contributing Editor.
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003—Vol 289, No. 3 331
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LMWH IN ACS AND PCI
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LMWH IN ACS AND PCI
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LMWH IN ACS AND PCI
The combination of tirofiban and mary efficacy end point between either antithrombotic therapy in this setting.
enoxaparin was studied in 1224 pa- enoxaparin and unfractionated hepa- The LMWHs are attractive as long-
tients presenting with STEMI in the rin monotherapy groups (15.4% vs term antithrombotic agents by virtue of
Treatment of Enoxaparin and Tirofi- 17.3%) or between enoxaparin and un- their safety profile and ease of use,
ban in Acute Myocardial Infarction fractionated heparin combination groups prompting several trials to evaluate their
(TETAMI) trial. Patients ineligible for fi- (16.1% vs 17.2%). Major bleeding was use in the outpatient setting following
brinolysis were randomized in a 2⫻2 rare and not statistically different among an acute coronary event.18-20,31
fashion to receive either enoxaparin (in- all 4 groups. Although the clinical benefit of inhos-
travenous 30-mg bolus and subcutane- pital LMWH therapy is maintained up
ous injection of 1 mg/kg twice daily) or Duration of Therapy of LMWH to 1 year following the index event32
unfractionated heparin (intravenous 70 in UA/NSTEMI (hazard ratio, 0.88; 95% confidence in-
U/kg bolus and 15 U/kg per hour infu- Evidence suggests that the prothrom- terval, 0.81-0.97; P=.008 for the com-
sion) with or without tirofiban (intra- botic state associated with an ACS may bined end point of death, MI, or urgent
venous 10-µg/kg bolus and 0.1-µg/kg per persist for several months following the revascularization), no additional ben-
minute infusion) for 2 to 8 days.27 There index event,28-30 providing a biologi- efit from use of LMWH beyond hospi-
were no differences noted in the pri- cally plausible rationale for prolonged tal discharge has been convincingly
Table 2. Characteristics of Trials of Low-Molecular-Weight Heparin and Glycoprotein IIb/IIIa Inhibitor Combination for the Treatment
of Unstable Angina/Non–ST-Elevation MI
LMWH Group Control Group
Table 3. Clinical Efficacy and Major Non-CABG Bleeding in Trials Combining Low-Molecular-Weight Heparin and Glycoprotein IIb/IIIa
Inhibitor Combination for the Treatment of Unstable Angina/Non−ST-Elevation MI
Treatment Effect, % Major Non-CABG Bleeding, %
334 JAMA, January 15, 2003—Vol 289, No. 3 (Reprinted) ©2003 American Medical Association. All rights reserved.
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LMWH IN ACS AND PCI
demonstrated among UA/NSTEMI pa- and Fast Revascularization During In- ever, this benefit was not sustained at 6
tients.17,18,31,33 In addition, an increase in stability in Coronary Artery Disease months. Because this difference was ob-
bleeding with prolonged LMWH treat- (FRISC II) did significantly lower the served only in patients randomized to
ment has been noted.17 overall risk of death, MI, and revascu- the conservative arm of FRISC II,34 the
Prolonged treatment with subcutane- larization at 30 days compared with pla- investigators suggested that prolonged
ous injections of dalteparin in Fragmin cebo (3.1% vs 5.9%; P=.002).33 How- antithrombotic therapy may offer ben-
No. of No. of
Trial Subjects Dose and Duration Subjects Drug Fibrinolytic Therapy Bleeding Definition
Dalteparin
FRAMI94* 247 Subcutaneous 150 IU/kg 270 Placebo Streptokinase Any intracranial
twice daily throughout hemorrhage or
hospitalization bleeding requiring
transfusion or surgical
intervention
BIOMACS48 54 First dose: subcutaneous 47 Placebo Streptokinase Composite†
100 IU/kg; second dose:
120 IU/kg at 12 h
ASSENT PLUS49 224 30 IU/kg intravenous bolus 210 Unfractionated Tissue plasminogen Composite‡
and then subcutaneous heparin activator
120 IU/kg twice daily for
4 to 7 d
Enoxparin
ASENOX50 154 40-mg intravenous bolus and 158 Unfractionated Streptokinase§ NA
then subcutaneous heparin
1 mg/kg twice daily
for 2-3 d
Baird et al51 149 40-mg intravenous bolus and 151 Unfractionated Streptokinase, Bleeding requiring at least
then subcutaneous heparin anistreplase, tissue temporary cessation
40 mg three times daily plasminogen activator of study drug
for 4 d
AMI-SK45 253 30-mg intravenous bolus and 243 Placebo Streptokinase Composite㛳
then subcutaneous
1 mg/kg twice daily
for 3-8 d
HART II46 200 30-mg intravenous bolus and 200 Unfractionated Tissue plasminogen TIMI Major¶
then subcutaneous heparin activator
1 mg/kg twice daily
for 3 or more days
ENTIRE-TIMI 2347# 324 ±30-mg intravenous bolus 159 Unfractionated Tenecteplase or half dose TIMI Major¶
and then subcutaneous heparin of tenecteplase with
1 mg/kg twice daily abciximab
during hospitalization
(maximum of 8 d)
ASSENT 395 2040 30-mg intravenous bolus and 2035 Unfractionated Tenecteplase Any bleed requiring
then subcutaneous heparin transfusion,
1 mg/kg twice daily intervention because
during hospitalization of hemodynamic
(maximum of 7 d) compromise, or both
ASSENT 3 PLUS52 818 Prehospital dose of 30-mg 821 Unfractionated Tenecteplase Any bleed requiring
intravenous bolus and heparin transfusion,
then subcutaneous intervention because
1 mg/kg twice daily of hemodynamic
(maximum 7 d) compromise, or both
Abbreviations: AMI-SK, Acute Myocardial Infarction-Streptokinase; ASENOX, Accelerated Streptokinase and Enoxaparin; ASSENT, Assessment of the Safety and Efficacy of a New
Thrombolytic; BIOMACS, Biochemical Markers in Acute Coronary Syndromes; ENTIRE-TIMI 23, Enoxaparin Antithrombin Therapy for ST-Elevation Thrombolysis in Myocardial In-
farction; FRAMI, Fragmin in Acute Myocardial Infarction; HART II, second trial of Heparin and Aspirin Reperfusion Therapy; LMWH, low-molecular-weight heparin; NA, data not avail-
able.
*Analysis restricted to 517 of 776 original patients with evaluable echocardiograms.
†Symptomatic decrease in hemoglobin of more than 20 g/L, need for transfusion, intracranial, intramuscular or joint bleed, treatment cessation due to bleeding or death from
bleeding.
‡Decrease in hemoglobin of more than 20 g/L in association with symptoms or 40 g/L regardless of symtoms, any intraocular, intraspinal, intracranial or retroperitoneal bleeding,
and bleeding leading to death. Analysis of bleeding rates performed for patients on treatment.
§Accelerated regimen of 1.5 mU infused over 20 minutes.
㛳Death from bleeding, transfusion higher than 2 U of blood, higher than 3 g/dL (not associated with coronary artery bypass graft surgery), any intracerebral hemorrhage, intraocular
or retroperitoneal bleeding, or any bleeding requiring surgical or percutaneous intervention.
¶Major bleeding criteria: more than 5 g/dL drop in hemoglobin (or, when hemoglobin not available, a ⬎15% drop in hematocrit); any intracranial hemorrhage or cardiac tamponade.
#Pooled results of all patients treated with enoxaparin compared with all patients treated with unfractionated heparin.
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003—Vol 289, No. 3 335
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LMWH IN ACS AND PCI
efit as a medical bridge to PCI in pa- ST-Elevation Myocardial Infarction (Acute MI-Streptokinase [AMI-SK],45
tients for whom invasive procedures are Necessity for Adjunctive Antithrom- second trial of Heparin and Aspirin
delayed. botic Therapy in Thrombolytic Regi- Reperfusion Therapy [HART II46], and
mens. The effectiveness of pharmaco- Enoxaparin Antithrombin Therapy for
Benefit of LMWHs logical reperfusion for STEMI depends ST-Elevation Thrombolysis in MI
in High-Risk Subgroups on the balance between fibrinolytic and [ENTIRE-TIMI 2347]) and 1 trial with
A statistically significant benefit of prothrombotic activity. Fibrinolysis dalteparin (second trial of Biochemical
prolonged dalteparin treatment com- enhances the prothrombotic state asso- Markers in ACSs [BIOMACS II48]). Use
pared with placebo was demonstrated ciated with STEMI by promoting the gen- of adjunctive LMWH resulted in im-
in the subgroup of patients in FRISC eration and release of thrombin follow- proved late coronary artery patency rates
and FRISC II who presented with ing successful clot lysis,39-41 and activating (3%-16% absolute improvement in TIMI
elevated baseline troponin-T levels.35,36 the coagulation cascade, leading to fur- 2 flow45-47 and TIMI 3 flow49) and a ten-
Moreover, an analysis of Efficacy and ther platelet activation.42-44 Therefore, dency toward higher TIMI 3 flow rates
Safety of Subcutaneous Enoxaparin in there is sound theoretical rationale to (1%-17% absolute improvement45-49)
Unstable Angina and Non–Q-Wave support the use of concurrent antithrom- compared with unfractionated heparin
MI/Thrombolysis in MI (ESSENCE/ botic therapy to enhance the process of (Table 5). Adjunctive LMWH may also
TIMI 11B) demonstrated that com- fibrinolysis in STEMI. be associated with improved tissue level
pared with unfractionated heparin, Results of Randomized Clinical Tri- perfusion following fibrinolysis as-
enoxaparin blunted the increase in als of LMWH in STEMI. To date, 8 sessed using ST-segment resolution and
event rates associated with higher phase 2 trials and 2 large exploratory other noninvasive composite measure-
baseline risk,37 and among those who clinical trials have been completed that ments of reperfusion seen with enoxa-
underwent invasive therapy.38 How- evaluate LMWH with fibrinolytic parin in the AMI-SK45 and Accelerated
ever, the effects of early mechanical therapy in STEMI (T ABLE 4 and Streptokinase and Enoxaparin
revascularization may minimize any TABLE 5). Infarct-related arterial pat- (ASENOX50) trials, respectively. Rates of
early differences attributable to pro- ency following fibrinolysis has been other significant clinical events such
longed antithrombotic therapy.34 evaluated in 3 trials with enoxaparin late infarct-related arterial reocclu-
Table 5. Clinical Efficacy and Major Bleeding in Trials of LMWH in ST-Elevation Myocardial Infarction
Efficacy, % Major Bleeding, %*
Absolute Absolute
Primary Efficacy Timing of Risk Risk
Trial Outcome Outcome LMWH Control Difference LMWH Control Difference
Dalteparin
FRAMI94† Reduction in left 9d 14.2 21.9 7.7 (P = .02) 2.9 0.3 2.6 (P = .006)
ventricular thrombus
and arterial
thromboembolism
BIOMACS48 TIMI 3 flow 20-28 h 68 51 17 3.7 0 3.7
ASSENT PLUS49 TIMI 3 flow 4-7 d 69.3 62.5 6.8 3.6 5.2 −1.6
Enoxparin
ASENOX50 Mortality 30 d 7.1 8.2 −1.1
0 0 0
Reperfusion (noninvasive Not defined 79.8 75.9 3.9
measurement‡)
Baird51 Composite§ 3 mo 26 36 −10 (P = .04) 2.7 4 −1.3
AMI-SK45 TIMI 3 flow 5-10 d 70 58 12 (P = .01) 4.8 2.8 2
HART II46 Infarct-related artery 90 min 80.1 75.1 5㛳 3.6 3 0.6
patency
ENTIRE-TIMI 2347¶ TIMI 3 flow 60 min 51 50 1 5.2 3.8 1.4
ASSENT 395 Composite# 30 d 11.4 15.4 −4 (P⬍.001) 3.0 2.2 0.8
ASSENT 3 PLUS52 Composite# 30 d 14.2 17.4 −3.2 (P = .08) 4.0 2.8 1.2
Abbreviations: AMI-SK, Acute Myocardial Infarction-Streptokinase; ASENOX, Accelerated Streptokinase and Enoxaparin; ASSENT, Assessment of the Safety and Efficacy of a New
Thrombolytic; BIOMACS, Biochemical Markers in Acute Coronary Syndromes; ENTIRE-TIMI 23, Enoxaparin Antithrombin Therapy for ST-Elevation Thrombolysis in Myocardial
Infarction; FRAMI, Fragmin in Acute Myocardial Infarction; HART II, second trial of Heparin and Aspirin Reperfusion Therapy; LMWH, low molecular-weight heparin.
*See column 7 in Table 4 for definitions of major bleeding.
†Analysis restricted to 517 of 776 original patients with evaluable echocardiograms.
‡Composite of rapid resolution of chest pain; rapid peak of creatine kinase within 9 hours of drug administration; and rapid resolution of ST elevation higher than 50%.
§End point of death, reinfarction, or rehospitalization.
㛳Lower bound of 95% confidence interval was −2%, fulfilling prespecified definition for noninferiority (lower bound of 95% confidence interval for noninferiority = −10%).
¶Pooled analysis of all patients treated with unfractionated heparin compared with all patients treated with enoxaparin.
#End point of death, in-hospital reinfarction, and in-hospital refractory ischemia.
336 JAMA, January 15, 2003—Vol 289, No. 3 (Reprinted) ©2003 American Medical Association. All rights reserved.
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LMWH IN ACS AND PCI
sion45,46,49 and recurrent ischemia47,48,51 This safety concern of enoxaparin management of both UA/NSTEMI34,53
were reduced with LMWH compared among elderly patients will be ad- and STEMI.54 Compared with the large
with unfractionated heparin. Finally, dressed in the ongoing (ExTRACT- amount of literature evaluating LMWHs
similar bleeding rates were found with TIMI 25) trial. This double-blind, par- for the medical management of
LMWH compared with unfractionated allel group trial is randomizing UA/NSTEMI, there are fewer data evalu-
heparin in the majority of completed tri- approximately 21 000 fibrinolysis- ating LMWHs in the invasive setting.
als (Table 5). eligible STEMI patients in a 1:1 fash- Accordingly, while the ACC, AHA, Euro-
However, preliminary results pre- ion to receive either adjunctive unfrac- pean Society of Cardiology, and the
sented at the AHA 2002 Scientific Ses- tionated heparin (intravenous 60- American College of Chest Physicians
sions from the third Assessment of the IU/kg bolus and 12-IU/kg infusion per have all acknowledged the safety and
Safety and Efficacy of a New Throm- hour) or enoxaparin (intravenous potential pharmacological advantages of
bolytic PLUS (ASSENT 3 PLUS) un- 30-mg bolus and a subcutaneous in- LMWH over unfractionated hepa-
derscore the need for continued evalu- jection of 1 mg/kg twice daily). Of note, rin,55-57 none of these organizations have
ation of the safety of LMWH as an patients older than 75 years will not re- endorsed the use of LMWH as the pre-
adjunct to fibrinolysis.52 Among 1639 ceive the intravenous bolus of enoxa- ferred antithrombotic agent in the inva-
patients with STEMI receiving te- parin and will receive only 75% of the sive management of UA/NSTEMI. Nev-
necteplase and either enoxaparin or un- subcutaneous injection dose. The pri- ertheless, data suggest that LMWH
fractionated heparin in a prehospital mary end point is a composite of all- monotherapy is safe and efficacious in
setting, higher rates of both major cause mortality and nonfatal reinfarc- the setting of elective and urgent PCI
bleeding (4.0% vs 2.8%) and intracra- tion within 30 days of randomization. (TABLE 6 and TABLE 7). In addition, sev-
nial hemorrhage (2.2% vs 1.0%; P=.05) eral trials have also demonstrated the
were seen in the enoxaparin group com- Low-Molecular-Weight Heparin safety and efficacy using LMWH in com-
pared with the unfractionated heparin and PCI bination with a glycoprotein IIb/IIIa
group. There was a significant interac- The issue of LMWH treatment in com- inhibitor (TABLE 8 and TABLE 9).
tion between patient age and risk of bination with PCI is becoming increas- Unfractionated heparin retains sev-
bleeding because almost all cases of in- ingly relevant given the results of eral attractive properties compared with
tracerebral hemorrhage were con- several studies demonstrating the supe- LMWH in the invasive setting, includ-
fined to patients older than 75 years. riority of an invasive approach for the ing low cost, complete reversibility with
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003—Vol 289, No. 3 337
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LMWH IN ACS AND PCI
protamine, and the availability of an eas- during invasive cardiac procedures has adopted. The currently accepted thera-
ily interpretable and standardized point- not been prospectively defined. peutic activity of LMWH in PCI (anti-
of-care test (activated clotting time).58 Since LMWH does not appreciably Xa, ⬎0.5-1.8 IU/mL) is based primar-
In contrast, protamine is able to fully re- affect either the activated partial throm- ily on clinical data from the deep venous
verse the effect of LMWH on throm- boplastin time or activated clotting time, thrombosis literature 60 and dose-
bin, but only 60% of its anti-Xa activ- clinical trials have focused on the ranging studies in UA/NSTEMI.61 In
ity.59 It remains controversial whether anti-Xa activity as a surrogate to as- TIMI 11A, enoxaparin administered as
routine monitoring of anticoagulation is sess the level of anticoagulation. Al- an intravenous 30-mg bolus followed
needed with LMWH in the catheteriza- though now commercially available, by a subcutaneous injection of 1 mg/kg
tion laboratory.12,13,60 Moreover, the op- routine monitoring of anticoagulation twice daily generated trough anti-Xa
timal level of anticoagulation for LMWH with LMWH has not been universally activity of 0.5 IU/mL and peak activity
Table 7. Major Bleeding and Event Rates of Trials Using Low-Molecular-Weight Heparin Alone in PCI*
Event Rate, % Major Bleeding, %
Absolute Absolute
Primary Timing of Risk Risk
Trial Efficacy Outcome Outcome LMWH Control Difference LMWH Control Difference
REDUCE64 Death, MI, or Within 30 wk 33.3 32 1.3 2.3 2.6 −0.3
revascularization
Rabah et al65 TIMI 3 flow Post-PCI 97 93 4
3.3 0 3.3
Ischemic complications Within 30 d 0 10 −10
Choussat et al73 Death, MI, or urgent Within 30 d 2.5 ... ... 0.4 ... ...
revascularization
PEPCI72† Death, MI, or urgent Within 30 d 5.4 ... ... 0 ... ...
revascularization
NICE 168 Death, MI, or urgent Within 30 d 7.7 ... ... 1.1 ... ...
revascularization
Collet et al67 Death or MI Within 30 d 3.0 ... ... 0.8 ... ...
ESSENCE/TIMI 11B38‡ Death or MI Within 43 d 3.3 5.9 −2.6 (P = .06) 5.4 6.2 −0.8
FRISC II(Invasive)34 Death or MI Within 6 mo 9.4 ... ... 1.6 ... ...
Abbreviations: ESSENCE/TIMI, Efficacy and Safety Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI/Thrombolysis in Myocardial Infarction; FRISC II, second Fragmin
and Fast Revascularization During Instability in Coronary Artery Disease; LMWH, low-molecular-weight heparin; MI, myocardial infarction; PEPCI, Pharmacokinetic Study of Enoxa-
parin in Patients Undergoing Coronary Intervention; PCI, percutaneous coronary intervention; REDUCE, Reduction of Restenosis After PTCA, Early Administration of Reviparin in a
Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation; ellipses indicate no control group.
*Characteristics of trials are listed in Table 6.
†Sixteen patients received concomitant eptifibatide and 6 patients received concomitant abciximab. Analysis is for all 40 patients who received enoxaparin and underwent PCI.
‡Analysis restricted to patients who underwent PCI in hospital.
§The use and type of LMWH was not mandated by protocol and its use was per physician preference. Analysis restricted to patients who received LMWH alone during PCI.
Table 8. Characteristics of Trials of Low-Molecular-Weight Heparin in Combination With Glycoprotein IIb/IIIa Inhibitors in PCI*
LMWH Group
Timing of PCI Control Group
Glycoprotein Relative to
No. of Drug or IIb/ Last LMWH No. of
Trial Study Population Subjects Preparation Dose and Duration IIIa Inhibitor Dose† Subjects Drug
NICE 468 Elective or urgent PCI 818 Enoxaparin 0.75 mg/kg intravenous Abciximab Immediately ... ...
for 1 dose
Kereiakes et al70 Elective or urgent PCI 103 Dalteparin 40 IU/kg intravenous Abciximab Immediately ... ...
for 1 dose; 60
IU/kg intravenously
for 1 dose
CRUISE77 Elective or urgent PCI 129 Enoxaparin 0.75 mg/kg intravenous Eptifibatide Immediately 132 Unfractionated
for 1 dose heparin
NICE 371‡ Unstable angina/ 283 Enoxaparin 1 mg/kg subcutaneous Tirofiban, At physician’s ... ...
non−ST-segment twice daily eptifibatide, discretion
elevation MI or abciximab
Abbreviations: ACUTE, Antithrombotic Combination Using Tirofiban and Enoxaparin; LMWH, low-molecular-weight heparin; MI, myocardial infarction; PCI, percutaneous coronary
intervention; ellipses indicate no control group.
*Event rates for clinical efficacy and safety end points for these trials are in Table 9.
†No loading dose was given prior to PCI except for in the NICE 3 trial in which a 0.3-mg intravenous dose was given if PCI was more than 8 hours after last subcutaneous dose. No
supplemental anticoagulation was performed in any of these trials.
‡Analysis restricted to patients undergoing PCI who were treated with both enoxaparin and a glycoprotein IIb/IIIa inhibitor and with 30-day follow-up data available. Three of 43
patients treated with enoxaparin alone also had PCI.
§Analysis restricted to patients undergoing PCI treated with both an LMWH and lamifiban.
338 JAMA, January 15, 2003—Vol 289, No. 3 (Reprinted) ©2003 American Medical Association. All rights reserved.
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LMWH IN ACS AND PCI
of 1.1 IU/mL, with a low rate (2.7%) of fractionated heparin has been substi- safe and efficacious, with bleeding and
major hemorrhage among patients un- tuted for LMWH prior to angiography clinical event rates similar to historical
dergoing PCI.61 Several trials have dem- and coronary intervention if the last controls (Table 7 and Table 9). Ongo-
onstrated that reliable levels of anti-Xa LMWH dose was given more than 8 to ing large trials (ie, A to Z,74 SYNERGY75)
activity consistently greater than the 0.5 12 hours before the procedure.34,38,62,63 will yield additional information on the
IU/mL threshold may be obtained us- Second, a number of pilot trials have safety and efficacy of enoxaparin and gly-
ing various doses of LMWH when ad- evaluated the use of LMWH as the sole coprotein IIb/IIIa inhibition in the PCI
ministered several days or immedi- anticoagulant throughout angiography setting.
ately before PCI (TABLE 10). and intervention without changing to
From the available data, 2 strategies unfractionated heparin.25,64-73 How- Current Recommendations and
have emerged guiding the use of LMWH ever, these 2 strategies have not been di- Observations From Clinical Trials
(with or without concomitant glycopro- rectly compared. With the limited data Unstable Angina/Non–ST-Elevation
tein IIb/IIIa inhibition) for PCI. First, un- available, both approaches appear to be MI. Based on the available evidence, the
Table 9. Clinical Efficacy and Major Bleeding in Trials of LMWH in Combination With Glycoprotein IIb/IIIa Inhibitors in PCI*
Event Rate, % Major Bleeding, %
Absolute Absolute
Timing of Risk Risk
Trial Primary Efficacy Outcome Outcome LMWH Control Difference LMWH Control Difference
NICE 468 Death, MI, urgent revascularization Within 30 d 6.8 ... ... 0.4 ... ...
Kereiakes70 Death, MI, urgent revascularization In hospital 11.1† ... ... 3.7† ... ...
17.1‡ ... ... 2.6‡ ... ...
CRUISE77 Death, MI, urgent revascularization Within 48 h 8.5 7.6 0.9 2.5 1.6 0.9
NICE 371§ Death, MI, recurrent ischemia Within 30 d 11.3㛳 ... ... 1.4㛳 ... ...
Abbreviations: ACUTE, Antithrombotic Combination Using Tirofiban and Enoxaparin; LMWH, low-molecular-weight heparin; MI, myocardial infarction; PCI, percutaneous coronary
intervention; ellipses indicate no control group.
*Characteristics of trials are listed in Table 8.
†Data observed with 40 IU/kg intravenous dose of dalteparin.
‡Data observed with 60 IU/kg intravenous dose of dalteparin.
§Analysis restricted to patients undergoing PCI who were treated with both enoxaparin and a glycoprotein IIb/IIIa inhibitor and with 30-day follow-up data available. Three of 43
patients treated with enoxaparin alone also had PCI.
㛳Pooled analysis of all glycoprotein IIb/IIIa inhibitors in combination with enoxaparin.reated with both a LMWH and lamifiban.
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, January 15, 2003—Vol 289, No. 3 339
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LMWH IN ACS AND PCI
2002 ACC and AHA guidelines list the lus of dalteparin.70 Enoxaparin may be Critical revision of the manuscript for important in-
tellectual content: Wong, Giugliano, Antman.
use of either LMWH or unfractionated given subcutaneously at a dose of 1 Statistical expertise: Giugliano.
heparin as a class I recommendation for mg/kg twice daily without the need for Administrative, technical, or material support: Antman.
Study supervision: Giugliano, Antman.
the treatment of UA/NSTEMI (level of further supplementation if PCI is per-
evidence, A).57 In addition, use of enoxa- formed within 8 hours.38,67,68 An addi-
parin is preferred over unfractionated tional 0.3-mg/kg intravenous bolus REFERENCES
heparin (class IIA; level of evidence, A), should be given if PCI is performed be- 1. Ambrose JA. Plaque disruption and the acute coro-
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340 JAMA, January 15, 2003—Vol 289, No. 3 (Reprinted) ©2003 American Medical Association. All rights reserved.
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