Applied Radiology

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 efficacy.

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 heparin-induced thrombocytopenia. ^1,2 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. ^3-5 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 PCI.

Pharmacology

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 9000 daltons. ^6,7 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. ^6-9 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. ^6,7

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). ^6,8 This is accomplished through interaction of a pentasaccharide-sequence-containing chain (present in both UFH and LMWHs) with antithrombin (Figure 1). ^6-8 The difference in mechanism of action lies in the fact that, in addition to anti-Xa activity, UFH also demonstrates antithrombin activity. ⁹ Unfractionated heparin initially forms a complex with AT and this complex subsequently binds with thrombin leading to its inhibition. ¹⁰ 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. ⁹ Therefore, the ratio of factor Xa to II inhibition is approximately 1.25 to 1 for UFH and approximately 2­4 to 1 for LMWHs. ^6,7 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. ^6,7 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). ¹¹ Conceptually, LMWHs predominately exert their anticoagulant effects by preventing thrombin generation, whereas UFH both inhibits thrombin activity and, to a lesser degree, prevents thrombin generation.

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 effect. ^6,7 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 platelet aggregation. ¹² 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 trials

Clinical trial data focusing on the procedural use of LMWHs during PCI are limited. Collet et al ¹³ studied 451 consecutive patients admitted with an acute coronary syndrome who were treated with subcutaneous enoxaparin. ¹³ 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. ¹³ 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 major bleeding.

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. ¹⁴ 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 anticoagulation.

Marmur et al ¹⁵ 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. ¹⁵

The NICE investigators defined a dosing protocol for the procedural use of enoxaparin. ¹⁶ 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. ¹⁷ 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 antagonist. ¹⁶ 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. ¹⁸

Based on the NICE trials, ¹⁶ the PEPCI study, ¹⁸ and work done by Collet et al, ¹³ 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.

Heparin-induced thrombocytopenia

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 ¹⁹ 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%, to 94%. ^19-21 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.

Conclusion

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.