Nadim A. Geloo, MD
received his medical degree from the Medical College of Virginia,
Richmond, VA. He completed his general and interventional
cardiology training at East Carolina University, Greenville, NC, in
June 2002. Currently, he is an Associate with Prince William
Cardiology in Manassas, VA.
Joseph D. Babb, MD, FACC, FSCAI
is Professor of Medicine, Director of Cardiovascular Disease
Fellowship and Director of the Cardiac Catheterization Laboratories
at East Carolina University. He is the immediate past-president of
the Society of Cardiac Angiography and Interventions.
Low-molecular-weight heparins (LMWHs) have enjoyed
increasing use in clinical cardiology. Their safety and efficacy
in the management of patients with acute coronary syndrome has
been documented by multiple large, prospective, randomized
trials. Low-molecular-weight heparins display pharmacodynamic
properties that allow for a predictable and reliable level of
anticoagulation. Thus, extending their use during percutaneous
coronary intervention (PCI) seems attractive. Data are now
emerging on the procedural use of LMWHs for PCI. Although
limited, initial data appears encouraging that LMWHs can be used
safely and effectively in patients undergoing PCI with or without
concurrent glycoprotein IIb/IIIa receptor use. This article will
review the available literature on the procedural use of LMWHs
with particular attention to pharmacodynamics, safety, and
From the very early days of coronary interventions, procedural
use of intravenous (IV) unfractionated heparin (UFH) has been
employed widely and has been accepted universally. The use of
heparin in the cardiac catheterization laboratory was a natural
extension of its clinical use (eg, acute coronary syndrome and
myocardial infarction). There are limitations to the use of IV UFH,
however, including an unpredictable level of anticoagulation and
Following numerous clinical trials, low-molecular-weight heparins
(LMWHs) have begun to be used in the management of acute coronary
syndromes. In particular, the ESSENCE, TIMI IIB, and FRISC trials
demonstrated the safety and efficacy of LMWHs versus UFH in the
setting of acute coronary syndromes.
These trials and others led to an exploration of the use of
procedural LMWHs during percutaneous coronary intervention (PCI).
This article will review the pharmacodynamics, safety, and efficacy
of LMWHs as it relates to procedural anticoagulation during
A product of the enzymatic degradation of heparin, LMWHs consist
of chains of varying lengths and molecular weights. The average
molecular weight of the LMWH product is 4500 to 5000 daltons, with
approximately 90% of the product falling in the range of 2000 to
In comparison, UFH has a molecular weight in the range of 2000 to
30,000 daltons, reflecting a wide range of chain lengths. The
plasma half-life of LMWHs administered subcutaneously is
approximately 5 hours; with IV administration, the half-life is
approximately 4 hours.
As measured by anti-factor Xa activity, LMWHs have a higher and
more reliable bioavailability than UFH (exceeding 90% for LMWHs
versus a range of 10% to 90% for UFH). This is a reflection of
decreased binding of LMWHs to plasma proteins.
Mechanism of action
The mechanisms of action of UFH and LMWHs are similar in that
both act to inhibit factor Xa by conferring a conformational change
in antithrombin (AT).
This is accomplished through interaction of a
pentasaccharide-sequence-containing chain (present in both UFH and
LMWHs) with antithrombin (Figure 1).
The difference in mechanism of action lies in the fact that, in
addition to anti-Xa activity, UFH also demonstrates antithrombin
Unfractionated heparin initially forms a complex with AT and this
complex subsequently binds with thrombin leading to its inhibition.
The formation of this complex (UFH-AT-thrombin) requires a chain
that not only contains the critical pentasacchride sequence but
also contains at least an additional 15 sacchrides (minimum of 18
required to form the complex); UFH contains this longer chain but
LMWHs do not.
Therefore, the ratio of factor Xa to II inhibition is approximately
1.25 to 1 for UFH and approximately 24 to 1 for LMWHs.
Specifically, the Xa:II inhibition ratio for dalteparin (Fragmin,
Pharmacia Corp.; Peapack, NJ) is 2.7:1 and for enoxaparin (Lovenox,
Rhone-Poulenc Rorer, Inc.; Collegeville, PA) is 3.8:1.
Consequently, while the activated clotting time (ACT) reflects the
degree of anticoagulation of UFH, it does not reliably do so when
using all LMWHs (dalteparin does appear to reliably prolong ACT due
to Xa:II inhibition ratio of 2.7:1).
Conceptually, LMWHs predominately exert their anticoagulant effects
by preventing thrombin generation, whereas UFH both inhibits
thrombin activity and, to a lesser degree, prevents thrombin
Advantages of LMWHs
Low-molecular-weight heparins may have some pharmacologic and
clinical advantages over UFH (Table 1). First, LMWHs have a higher
bioavailability when compared with UFH due to less binding of LMWHs
to plasma proteins, macro-phages, and endothelial cells. This
favorable bioavailability leads to a more predictable anticoagulant
Additionally, the longer half-life of LMWHs, coupled with a more
predictable level of anticoagulation, allows for a consistent and
sustained effect; thus, the need for frequent rebolusing and
monitoring, as is required with UFH, is nearly eliminated. Another
reported advantage of LMWHs is that they also suppress the release
of von Willebrand factor, thereby promoting the inhibition of
In this manner, LMWHs affect both aspects of clot formation: they
not only decrease thrombin generation, leading to decreased fibrin,
but they also appear to have specific antiplatelet effects.
Clinical trial data focusing on the procedural use of LMWHs
during PCI are limited. Collet et al
studied 451 consecutive patients admitted with an acute coronary
syndrome who were treated with subcutaneous enoxaparin.
Of these, 293 underwent PCI within 8 hours of the morning dose of
LMWH. Antifactor Xa activity was measured and 97.6% of patients had
an anti-Xa activity level above the lower limit of the therapeutic
range. Furthermore, there was no significant decrement in anti-Xa
activity in patients who underwent PCI at <4 hours from
injection versus those who underwent PCI at 6 to 8 hours
postinjection. This indicated that there was a reliable and stable
level of anticoagulation over an 8-hour period from the last
subcutaneous injection of enoxaparin. The investigators found that
at 30 days the group undergoing PCI had a death and myocardial
infarction (MI) rate of 3% versus 6.2% for the entire population
and 10.8% for the group that did not undergo angiography.
Importantly, there was no significant increase in major or minor
bleeding between the PCI group and the entire population or between
the PCI group and the group that did not undergo angiography.
This important trial demonstrated that PCI could be done safely and
effectively in patients with an acute coronary syndrome who were
treated with the LMWH enoxaparin.
Another important trial studied the use of several dose regimens
of an LMWH (dalteparin) in conjunction with a glycoprotein IIb/IIIa
(GP IIb/IIIa) receptor antagonist during PCI in a
non-placebo-controlled trial. A total of 107 patients were
enrolled; 4 patients had received subcutaneous dalteparin before
PCI. The remaining 103 patients, who had not received prior
subcutaneous dalteparin, were allocated randomly to receive either
40 IU/kg or 60 IU/kg of IV dalteparin at the time of PCI. Of the 4
patients who received prior subcutaneous dalteparin, 3 patients
were given no additional IV dalteparin at the time of PCI and 1 was
given 40 IU/kg IV. The 40 IU/kg group was terminated early after 3
patients were found to have thrombus either angiographically or in
the guide catheter; subsequent patients received only 60 IU/kg of
IV dalteparin. By the end of the trial, a total of 76 patients
received the 60 IU/kg dose. The investigators found a more
consistent level of anticoagulation at 30 minutes and at 4 hours
post IV bolus in the 60 IU/kg group (as measured by anti-Xa
activity). There was 1 death in the total group and the combined
endpoint of death, MI, and urgent revascularization occurred in 16
patients--the majority of which was due to MI, with 15 patients
having three times the normal level of creatinine kinase MB. Major
bleeding occurred in only three patients. This pilot study
demonstrated that the combination of an LMWH (dalteparin) and a GP
IIb/IIIa receptor antagonist may be used in patients with an acute
coronary syndrome undergoing PCI without an untoward effect on
An interesting aspect of this study was the measurement of ACT
with dalteparin. Due to its relatively lower ratio of Xa:II
inhibition (2.7:1 versus 3.8:1 for enoxaparin), ACT may be used to
monitor the level of anticoagulation.
This ability to monitor anticoagulation with ACT may offer an
advantage. ACT monitors are widely available in hospitals
performing PCI, and most operators are comfortable using this
parameter as a means to measure the level of procedural
Marmur et al
proposed a protocol for dosing dalteparin based on achieving an ACT
goal of 200 in the absence GP IIa/IIIa receptor antagonist or ACT
goal of 175 if there is concurrent use of a GP IIb/IIIa receptor
antagonist (Figure 2). According to their protocol, patients are
bolused initially with either 80 IU/kg or 60 IU/kg of dalteparin
based on an initial ACT of <130 or >130, respectively. If
patients do not reach the determined ACT goal by 2 minutes after
bolus injection, they are rebolused with 20 IU/kg of dalteparin
every 2 minutes until the ACT goal is achieved.
The NICE investigators defined a dosing protocol for the
procedural use of enoxaparin.
The NICE 1 trial used an enoxaparin dose of 1 mg/kg in the absence
of a GP IIb/IIIa receptor antagonist; this dose resulted in 0.5%
incidence of noncoronary artery bypass graft (CABG)
surgery-related bleeding. When the investigators compared the 7.9%
incidence of the composite endpoint of death, MI, and urgent
revascularization in their patient population to the stent plus
placebo arm in the Evaluation of Platelet GP IIb/IIIa Inhibitor for
Stenting Trial (EPISTENT) (a similar group of patients receiving
UFH with no abciximab [ReoPro; Centocor, Malvern, PA]), they found
no significant difference.
Similarly, the 0.5% incidence of non-CABG surgery-related bleeding
was also not significantly different. The NICE 4 trial studied the
use of procedural enoxaparin in conjunction with abciximab.
Enoxaparin was given as a 0.75 mg/kg bolus along with standard
bolus and infusion of abciximab. Vascular sheaths were removed 4
hours postprocedure. There was an overall low incidence (0.2%) of
major non-CABG surgery-related bleeding. Based on this data, the
NICE investigators have recommended the following protocol for
patients who have not received enoxaparin in the previous 12 hours
prior to PCI: 1 mg/kg IV bolus of enoxaparin in patients not
receiving a GP IIb/IIIa receptor antagonist versus a bolus of 0.75
mg/kg of IV enoxaparin in conjunction with a GP IIb/IIIa receptor
Additional information on enoxaparin dosing was provided by the
PEPCI study; this trial used measurement of anti-Xa activity and
phamacokinetic modeling to demonstrate that patients who had
received their last subcutaneous dose of enoxaparin 8 to 12 hours
prior to PCI would benefit from an additional 0.3 mg/kg IV bolus at
the start of PCI.
Based on the NICE trials,
the PEPCI study,
and work done by Collet et al,
a dosing strategy for enoxaparin has been suggested (Figure 3). If
patients have received their last subcutaneous dose of enoxaparin
within the previous 8 hours prior to PCI, no additional enoxaparin
is needed. If the last subcutaneous dose was administered 8 to 12
hours prior to PCI, then an additional 0.3 mg/kg IV dose should be
considered. Finally, if the patient has not received enoxaparin in
the 12 hours preceding PCI, a 1 mg/kg IV bolus of enoxaparin can be
given in the absence of a GP IIb/IIIa receptor antagonist, or a
0.75 mg/kg IV bolus of enoxaprin can be given if concurrent use of
a GP IIb/IIIa receptor antagonist is planned.
In addition to bleeding complications occurring with both UFH
and LMWHs, another important concern is the incidence of
heparin-induced thrombocytopenia (HIT). Although HIT may occur with
LMWHs, Warkentin et al
have reported that it is much more common with UFH. Various reports
have suggested a high cross-reactivity of LMWHs with the
heparin-dependent antiplatelet antibody ranging from 40%, to 79%,
At this time, the use of LMWHs as anticoagulation in patients with
established HIT or its use in patients with a previous history of
HIT has not been well studied and no widely accepted
recommendations exist. Therefore, an alternative mode of
anticoagulation should be considered in patients with established
HIT or a previous history of HIT.
In conclusion, LMWHs have been used with increasing frequency in
clinical cardiology; numerous trials have now demonstrated the
safety and efficacy of LMWHs in the setting of acute coronary
syndromes. In the United States, the majority of patients diagnosed
with an acute coronary syndrome undergo cardiac catheterization.
Therefore, an extension of the use of LMWHs to the cardiac
catheterization laboratory has been evaluated by multiple clinical
trials. Although limited, these trials have demonstrated that the
procedural use of LMWHs for PCI--alone or in conjunction with GP
IIb/IIIa receptor antagonists--is both safe and effective. If
confirmed by ongoing trials, the use of LMWHs will be an attractive
option during PCI.