Low-Molecular-Weight-Heparins in Percutaneous Coronary Interventions

AK Kar, I Dutta

Department of Cardiology, Institute of Postgraduate Medical Education and Research, Kolkata

Low-molecular-weight heparins (LMWHs) represent a major advancement in the management of patients with acute coronary syndrome (ACS) or as part of the strategy in candidates undergoing coronary interventions. LMWH are derived from unfractionated heparins (UFH) by chemical or enzymatic depolymerization. They have a mean molecular weight of 4000–5000, as compared to UFH which have a mean molecular weight of 15 000 (5000–30 000). UFH inhibit Factors Xa and IIa in a ratio of 1:1, whereas LMWH inhibit Factors Xa and IIa in ratios between 4:1 and 2:1, depending on their molecular weight. LMWH potentiate antithrombin (AT) III activity, but are relatively less efficient in binding thrombin, and thus lead to a higher ratio of anti-Factor Xa activity to anti-Factor IIa (antithrombin) activity. The anti-Factor Xa activity is particularly important, as it can prevent thrombin generation and interrupt feedback amplification of thrombin production. The thrombin-binding activity of heparin lies primarily in the higher weight glycosaminoglycan chains; therefore, the anti-Factor Xa/anti-Factor IIa ratio of various LMWH varies according to the molecular size of the subfractions they contain. The lesser antithrombin effects of LMWH lead to less prolongation of the activated partial thromboplastin time (aPTT) than UFH; thus, there is no need for aPTT monitoring during therapeutic use of LMWH. LMWH are more resistant to Factor IV-mediated inhibition of heparin activity and do not produce the same degree of platelet activation as UFH. The important pharmacologic characteristics that distinguish LMWH from UFH include: greater bioavailability; minimal plasma protein and vessel wall binding; more predictable and durable anticoagulant response (T˝ 2–4 times that of UFH); ease of subcutaneous or intravenous administration; and inhibition of acutephase release of von Willebrand factor in ACS.

LMWH have earned their place and established their superiority over UFH in the management of post-surgical deep vein thrombosis1,2 and ACS, including unstable angina (UA) and non-Q wave myocardial infarction (NQMI).3,4 The Efficacy and Safety of Subcutaneous Enoxaparin in Nonq-wave Coronary Events (ESSENCE) study5 showed enoxaparin plus aspirin to be superior to UFH plus aspirin in patients with ACS. The need for urgent revascularization was significantly lower in the enoxaparin group. The Heparin and Aspirin Reperfusion Therapy (HART II) study6 showed that enoxaparin was as effective as UFH as an adjunct to thrombolysis with tissue plasminogen activator (TPA), with a trend towards higher recanalization rates and less reocclusion at 5 or 7 days. Thus, several trials have shown that the LMWH enoxaparin offers the practical and potential pharmacologic advantages over UFH in multiple applications, and logically should also provide a similar benefit during percutaneous-coronary intervention (PCI).

However, during coronary and noncoronary interventions, UFH is conventionally used more frequently than LMWH. This is largely due to the fact that interventional cardiologists are sceptical about the efficacy of acute anticoagulation with LMWH. Furthermore, reversibility of the action of heparin is far more prompt and accurate with protamine in case of UFH than with LMWH. Clinicians are also concerned about the safety of a combination of LMWH with glycoprotein (Gp) IIb/IIIa inhibitors, and the safety of transition to the catheterization laboratory in patients who have already received LMWH on the floor.

From 1994 to 1998, four clinical trials using LMWH during or after PTCA were published7–10 (their results are summarized in Table 1), the most recent being the National Investigators Collaborating on Enoxaparin (NICE) trials 1,3 and 4 (Table 2). The use of LMWH eliminates the need for continuous IV infusion, anticoagulation monitoring, and dose adjustment associated with UFH.

Data from randomized, controlled clinical trials11,12 support the administration of LMWH and/or platelet Gp IIb/IIIa blockade in patients who present with non-STelevation ACS. Despite evidence-based support for administering LMWH and/or Gp IIb/IIIa receptor blockers to patients undergoing PCI and those presenting with ACS, algorithms for integrating these agents into clinical practice have not been determined. The NICE trials have evaluated this issue in detail, and the results of these trials are likely to have a major impact on the choice of adjunctive therapy during PCI.13–16

The NICE Story

In the NICE pilot study, 60 patients undergoing PCI were randomly assigned to receive either UFH 10 000 U as an IV bolus with supplemental doses to achieve a target activated clotting time (ACT) greater than 300 s or enoxaparin 1 mg/ kg IV bolus immediately before PCI. There were no differences in procedural outcomes or bleeding events observed between the treatment groups in this small randomized trial. Levels of Factor IIa activity were significantly higher in the UFH group, though Factor Xa activity was similar in the two treatment groups.

The pilot trial experience was expanded in the NICE 1 study in which 828 patients undergoing PCI without planned use of abciximab were administered enoxaparin 1 mg/kg within 15 min of arterial sheath insertion. All the patients received aspirin in addition, as an antiplatelet agent. The incidence of major noncoronary artery bypass grafting (CABG) related bleeding was 10.5%, and the composite clinical end-point [death, myocardial infarction (MI), need for urgent revascularization] at 30 days was 7.9%13,14 (Figs 1 and 2).

This large, multicenter experience suggests that intravenous enoxaparin in a dose of 1 mg/kg provides adequate, safe, and effective anticoagulation during PCI, the antithrombin efficacy (anti-Factor Xa activity) being similar to UFH administered as an IV bolus of 10 000 U. A comparison of the NICE 1 trial with the stent plus placebo subgroup (UFH 100 U/kg) of the EPISTENT trial (Figs 3 and 4) provides valuable insights, as both trials are comparable in size, and the definition of major and minor hemorrhage used in both are similar. Major non-CABG bleeding events, ischemic adverse outcomes, death, and need for urgent revascularization at 30 days were similar in both. Hence, it can be concluded that enoxaparin 1 mg/kg IV during PCI is as safe and effective as the contemporary experience utilizing a weight-adjusted heparin (UFH).

The NICE 4 trial: This trial was the first large-scale experience with the combination of an LMWH and a platelet Gp IIb/IIIa antagonist during PCI. Patients undergoing PCI with a Food and Drug Administration (FDA),USA-approved device (except rotational atherectomy) were administered enoxaparin 0.75 mg/kg as an IV bolus followed by a standard dose of abciximab (0.25 mg/kg IV bolus followed by 0.125 µg/kg/min to a maximum of 10 µg/kg). The reduced dose of enoxaparin was chosen to simulate the weight-adjusted reduction in heparin dose used in both the EPISTENT17 and EPILOG18 trials. Approximately 800 patients with an average age of 63 years were enrolled in 11 centers; multivessel PCI was performed in 52%, and stent deployment in 86%. Vascular sheaths were removed 4 hours following the enoxaparin bolus, and periprocedural ACT was not monitored. The primary end-point of NICE 4 was the incidence of major or minor bleeding and need for transfusion, secondary end-points being (i) clinical (death, MI, urgent revascularization), and (ii) biochemical changes (CK, CKMB elevation) in hospital and up to 30 days’ post-PCI. (Table 2).

Remarkably, there was no major non-CABG bleeding in the first 557 patients and the final analysis revealed a meager 0.2% incidence. The need for transfusion was also negligible. Comparing NICE 4 with the EPILOG trial (lowdose weight-adjusted heparin 70 U/kg plus abciximab) and the EPISTENT trial (stent plus abciximab) cohorts (Fig. 5), it was observed that a combination of low-dose enoxaparin 0.75 mg/kg and abciximab was safe and associated with a low incidence of non-CABG related bleeding. Addition of abciximab to 0.75 mg/kg of enoxaparin bolus was associated with a reduction of periprocedural ischemic events in the NICE 4 trial compared to the NICE 1 trial. Interestingly, abciximab-associated thrombocytopenia was lower in NICE 4 than in studies using abciximab plus UFH regimens. This might be related to the fact that enoxaparin is less likely than UFH to cause platelet activation or aggregation, or that thrombocytopenia may result from an interaction between abciximab and certain anticoagulants.17

The NICE 1 and NICE 4 trials demonstrated the safety and efficacy of enoxaparin alone and in combination with abciximab for procedural anticoagulation. The NICE 3 study16 investigated the use of enoxaparin with one of the three Gp IIb/IIIa antagonists (abciximab, tirofiban, eptifibatide) in patients with ACS (including PCI). It aimed to assess the safety of this combination in the catheterization laboratory with respect to bleeding and practicality of usage.

A total of 660 patients were enrolled with rest angina of less than 24 hours’ duration at 46 clinical centers in Canada and the United States. All the patients received IV enoxaparin 1 mg/kg b.d., aspirin 162–325 mg/day, and a Gp IIb/IIIa antagonist assigned by the institution at a standard dose. Clinical outcomes in NICE 3 were comparable to those of prior studies—the combination of enoxaparin and Gp IIb/IIIa antagonist did not result in excess major non-CABG bleeding events (Table 3). In addition, the study showed that additional UFH was not required for the study population treated with enoxaparin and a Gp IIb/IIIa antagonist during coronary intervention, and patients on combination therapy could safely undergo PCI.

Enoxaparin and Ticlopidine after Elective Stenting (ENTICES)Trial10 (Table 4)

Enoxaparin has been shown to be beneficial in patients requiring coronary stent implantation, and its use in combination with other antiplatelet regimens in stenting interventions was evaluated in this trial. One hundred twenty-three patients scheduled for elective intracoronary stenting were randomized (in a 2:1 ratio) to a combination of enoxaparin, ticlopidine, and aspirin; or to a conventional regimen of warfarin, UFH, dextran, dipyridamole, and aspirin. The composite clinical end-point of death, MI, stent thrombosis, CABG, repeat PTCA, and stroke at 30 days was significantly reduced in enoxaparin-treated patients than in the conventionally treated group. The incidence of vascular complications and major hemorrhage requiring transfusion was much less in enoxaparin recipients. This trial suggested that a modified antithrombotic regimen incorporating both antiplatelet and anticoagulant drugs may offer improved outcomes compared to anticoagulant therapy alone.

Intracoronary LMWH

In the POLONIA study,19 100 patients from 4 centers with single lesions (single-vessel coronary artery disease) were randomized to enoxaparin 10 mg administered intramurally prior to stent implantation, or systemic heparinization with 100 U/kg of UFH. Follow-up angiography at 6 months was performed in all but one patient. The results showed that local delivery of enoxaparin resulted in significant reduction in the incidence of restenosis and the revascularization rate compared with systemic heparinization. A few other trials are also currently evaluating the comparison of local delivery of enoxaparin before stenting with stenting alone.

Safety Considerations

The most common adverse effects reported are hemorrhagic complications. In most cases, these are minor bleeds, e.g. injection site ecchymosis, as would be expected with subcutaneous injections. In the ESSENCE study,3 for example, minor bleeding was significantly more common in patients receiving subcutaneous enoxaparin 1 mg/kg twice daily, than those receiving IV UFH (18.4% v. 14.2% at 30 days; p<0.001). There were no significant differences between the 2 treatment groups regarding the incidence of major hemorrhage. Similarly, when safety results from other large clinical trials are considered, major bleeding was reported in <6.5% of patients with CAD treated with enoxaparin 1 mg/kg twice daily or 40 mg once daily.3 Thus, there does not appear to be an increased risk of major bleeding with enoxaparin therapy in patients with ACS.

The other important concern is regarding reversibility of anticoagulant action. Unlike heparin, the action of LMWH can only be partially reversed with protamine (50%). The use of fresh frozen plasma to replenish coagulation factors has been advocated for LMWH.

Timing of PCI

The validated, weight-adjusted dose of enoxaparin to treat unstable angina patients also seems to be suitable for PCI within 8 hours of the last injection. In the study of "Percutaneous coronary intervention after subcutaneous enoxaparin pre-treatment in patients with unstable angina pectoris",20 carried out in the department of cardiology and the haemostasis laboratory of the University Hospital, Paris, France a total of 451 consecutive patients with UA/NQMI were treated for at least 48 hours with subcutaneous enoxaparin (1 mg/kg every 12 hours), cycled at 6 a.m. and 6 p.m. Two hundred ninety-three patients underwent a coronary angiography within 8 hours of the morning LMWH injection, followed by immediate PCI in 132 patients. PCI was performed without monitoring of coagulation and without any additional bolus of UF/LMWH heparin. There were no in-hospital abrupt closures or urgent revascularization needed in the PCI group. The incidence of death/MI rates in the PCI group was much lower than in those not undergoing catheterization. The 30-day major bleeding rate in the PCI group was also less than in those not undergoing catheterization. Sheath removal was done with manual or pneumatic compression more than 10 hours after the morning injection of enoxaparin. Importantly, enoxaparin was not restarted after PCI and the patients left the hospital the next morning.

This study convincingly shows that PCI can be performed safely within 8 hours in patients treated with LMWH, particularly enoxaparin, without additional anticoagulation. Whether the time window can be extended to 12 hours is a matter of debate and is being currently evaluated in the PEPCI trial (Pharmacokinetic Study of Enoxaparin in Percutaneous Coronary Interventions). Presumably, an additional bolus of anticoagulant may be beneficial in procedures performed between 8 and 12 hours of the last dose of the LMWH.

Role of Monitoring

The role of coagulation monitoring with the use of LMWH has also been evaluated in the study from France mentioned above.20 Anti-Factor Xa activity was measured from samples collected immediately before catheterization in all patients undergoing PCI. However, anti-Factor Xa measurements, obtained retrospectively, were not used for decision-making during PCI. During the period of medical stabilization before catheterization, in elderly patients and those with renal failure, anti-Factor Xa activity was measured 4 hours after the third injection, and the dose of enoxaparin adjusted, aiming at a target value of 0.5–1.0 U of anti-Factor Xa. The anti-Factor Xa activity at the time of catheterization was >0.5 IU/ml in 97.6% of patients, and it was stable over the 8-hour period after the injection of enoxaparin. The aPTT was also measured prior to catheterization and there was a weak but significant correlation with anti-Factor Xa activity.

From the above study, we can conclude that anti-Factor Xa activity need not be measured routinely before PCI done within 8 hours of the last dose of enoxaparin. However, in elderly patients and those with renal failure receiving a reduced dose of enoxaparin, anti-Factor Xa measurements may be beneficial.

Pilot studies are on for monitoring of LMWH in the setting of UA. A panel of assays to measure the tissue factor clotting time (TiFaCT) is being developed. The tests provide a functional measure of tissue factor, including its interaction with platelets and plasma components. The results can be obtained in 15 min–2 hours.

The issue of sheath removal following PCI has been addressed in the NICE 4 trial, in which the vascular sheath was removed 4 hours after the enoxaparin bolus dose without any increased incidence of puncture site complications. In the study reported from France mentioned above,20 the vascular sheath was pulled out >10 hours after the last enoxaparin injection.

Conclusions

In present day practice, when interventional cardiology is making rapid progress every day, it is worthwhile considering safer and easier adjunctive medications during the procedure. While UFH has been a trusted companion of interventionists for years, LMWH can offer an easier and assuring alternative of anticoagulation without compromising efficacy. The role of LMWH as an intracoronary injection for the prevention of stent complications is under evaluation and, if established, would certainly be a powerful weapon for the prevention of stent thrombosis. It is debatable whether the benefits demonstrated with enoxaparin can be extended to other LMWH. The US FDA classifies each LMWH as a distinct drug that cannot be interchanged with another. In the ESSENCE and TIMI-IIB studies, a combination of enoxaparin plus aspirin was more effective than that of UFH and aspirin. Inversely, in the FRIC study, dalteparin plus aspirin did not demonstrate such superiority. Evidence is also accumulating regarding the role of enoxaparin as an antithrombotic in the treatment of acute MI. Selection of an individual LMWH for a particular indication should reflect the level of evidence for a the agent in that condition. Thus, at present, evidence-based considerations favor the use of enoxaparin in the antithrombotic regimen of patients undergoing PCI.

Correspondence:

Professor AK Kar,
82A, Chowringhee Road,
Kolkata 700020.
e-mail: drkar2002@yahoo.co.in

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