Direct Versus Indirect Thrombin Inhibition in Percutaneous Coronary Intervention (Part I)

Heparin Heparin has been used to prevent intravascular thrombosis and clotting on the surface of equipment used during percutaneous coronary interventions (PCI) since Andreas Gruentzig performed the first angioplasty.¹ In fact, the development of coronary angioplasty and of coronary artery bypass surgery would probably not have been possible without heparin. However, with the availability of low molecular weight heparin (LMWH) and the approval of bivalirudin, a direct thrombin inhibitor for use during PCI, the question is more and more frequently asked whether heparin should be replaced in PCI. The purpose of this paper is to critically review the evidence for the use of heparins (indirect thrombin inhibitors) and direct thrombin inhibitors during PCI. Structure and mechanism of action of heparin. Commercial heparin is prepared by extraction from either bovine lung or porcine intestine.² The final purification and sanitation steps typically yield 30,000–50,000 U/animal when using porcine intestines.² Heparin can vary with respect to molecular size and anticoagulant activity. It is a heterogeneous mixture of numerous polysaccharide chains with differing molecular weights ranging from 5,000 to over 40,000 daltons.² Heparin obtained from different species or tissues differs structurally. Bovine lung heparin has greater affinity for thrombin than porcine intestinal heparin; this is partially due to bovine heparin’s higher level of sulfation and higher molecular weight.² In order to inactivate thrombin, heparin must bind to both antithrombin (AT) and thrombin, forming a ternary complex.³ Heparin’s anticoagulant effect relies upon a unique pentasaccharide sequence that binds with high affinity to AT;^4–6 however, only 20–50% of the polysaccharide chains in heparin have this unique pentasaccharide sequence.2,7–9 These pentasaccharide-containing heparin chains must be at least 18 saccharide units in length to form the heparin:AT:thrombin complex (Figure 1). In the absence of heparin, AT is a naturally occurring but slow thrombin inhibitor. The heparin:AT interaction produces conformational changes in AT and accelerates its inhibition of thrombin, factor Xa, and factor IXa.¹⁰ Heparin catalysis of factor Xa inhibition does not require bridging between factor Xa and AT. Since almost all the heparin chains are at least 18 units long, heparin has equivalent inhibitory activity against thrombin and factor Xa.³ However, when thrombin is bound to fibrin, the heparin:AT complex is less able to access and inhibit thrombin.⁹ Furthermore, with respect to anti Xa activity, the heparin:AT complex is unable to inhibit factor Xa bound to the surface of activated platelets.¹¹Pharmacokinetics/pharmacodynamics. Heparin must be given by injection since it is not absorbed when administered orally.¹⁰ Heparin is cleared via a biphasic process combining rapid saturable and slower first-order mechanisms. The saturable phase is influenced by heparin’s non-specific binding to surface receptors on endothelial cells and macrophages,^12–14 as well as heparin-binding proteins. The slower non-saturable clearance mechanism is predominantly renal.^15–17 The clearance rate of heparin is dose-dependent with the apparent biologic half-life increasing from approximately 30 minutes following an intravenous (IV) bolus of 25 U/kg to approximately 60 minutes after an IV bolus dose of 100 U/kg.^15–18 The variation in heparin molecular weight, ranging from 5,000–40,000 daltons, influences heparin clearance because higher molecular weight species are cleared from circulation more rapidly than low molecular weight species. Clearance of heparin thus depends on two primary sets of factors: 1) the dose administered; and 2) patient-related factors such as age, renal and hepatic function, and the presence of an inflammatory state that can increase the plasma concentration of heparin-binding proteins. These factors can result in increased variability of the pharmacokinetics of the drug and place these patients at increased risk for adverse events. Despite evidence of increased bleeding complications in patients with renal impairment, there is no recommendation for reduced heparin dosing in patients with renal impairment.¹⁸Laboratory monitoring of heparin. The anticoagulant effect of heparin is typically monitored using the activated partial thromboplastin time (aPTT). The aPTT test is sensitive to the inhibiting effects of heparin on thrombin, factor Xa and factor IXa with moderate correlation between aPTT levels and heparin concentrations.^19,3 The aPTT is sensitive over a plasma heparin concentration range of 0.1–1.0 U/ml and is therefore a useful test to monitor heparin therapy in patients receiving prolonged infusions of heparin. The aPTT becomes prolonged beyond measurable levels at heparin concentrations > 1.0 U/ml.¹⁰ Therefore, the aPTT is not suitable for monitoring patients undergoing PCI where plasma levels may be in the range of 1.0–5.0 U/ml.¹⁰ For PCI, the activated clotting time (ACT) is the standard monitoring test. At the latter range of heparin concentrations, the correlation between heparin levels and ACT is superior to that with aPTT.¹⁰Limitations of heparin. Heparin remains the most widely used indirect thrombin inhibitor in clinical practice despite its well-know limitations (Table 1). Low molecular weight heparins. Commercially produced low molecular weight heparins (LMWHs) are prepared from standard unfractionated heparin (UFH) through a chemical or enzymatic depolymerization process.²⁸ The type of heparin initially chosen, the purity of the starting material, and the technology used to achieve depolymerization all contribute to variations in the final LMWH preparation. LMWHs are widely used in Europe for the prevention or treatment of thrombosis in the venous system and in recent years have gained wider use in the United States. Data demonstrating the utility of LMWH in the medical management of unstable coronary syndromes have led to a further increase in their use. Structure and mechanism of action of low molecular weight heparin. LMWHs have a mean molecular weight of 4,000–5,000 daltons, about one third the size of UFH. Like UFH, they are heterogeneous in molecular size (ranging from 1,000–10,000 daltons) and in anticoagulant activity.¹⁰ Because LMWHs are comprised predominantly of smaller polysaccharide chains that take longer to clear from plasma, they possess a longer half-life than UFH. The plasma half-life of LMWH ranges from 2–4 hours after intravenous injection and 3–6 hours after a subcutaneous injection. ²⁹ LMWHs produce their anticoagulant effect by binding to AT via the same pentasaccharide sequence found in UFH (Figure 1).²⁹ Much like UFH, this unique pentasaccharide sequence is found on fewer than one third of the LMWH molecules. Only 25–50% of the LMWH chains are long enough to bridge antithrombin to thrombin; consequently, LMWHs have less inhibitory activity against thrombin than against factor Xa.^29–33 Factor Xa inhibition does not require bridging between factor Xa and AT. Therefore, the smaller pentasaccharide-containing chains in LMWH retain their ability to catalyze factor Xa inhibition. LMWHs bind to non-specific proteins less avidly than heparin, a property that contributes to better bioavailability and more predictable anticoagulation with LMWH compared to UFH.³⁴ Because nearly all UFH molecules contain at least 18 saccharide units, the antifactor Xa:antifactor IIa ratio is 1:1. Commercially available LMWHs have anti Xa to anti IIa ratios that vary between 4:1 and 2:1.²⁹ The molecular size distribution in LMWHs can predict their antifactor Xa:antifactor IIa ratio. LMWHs with a greater proportion of shorter chains (under 18 saccharide units) have higher antifactor Xa:antifactor IIa ratios. The clinical consequences of these differences, however, are unknown. Pharmacokinetics/pharmacodynamics of LMWH. LMWHs exhibit less non-specific protein binding,³⁵ less interaction with platelets,³⁵ and less antithrombin activity compared to unfractionated heparin.^{12,30,35–44} LMWHs are cleared predominantly by renal mechanisms, whereas UFH is cleared by a combination of renal and hepatic mechanisms.²⁹ The biological half-life of LMWH increases in patients with renal failure.^45,46 Laboratory monitoring of LMWH. Unlike UFH, the anticoagulant effect of LMWH, as a class, is not widely perceived to be measurable by using the aPTT or the ACT. The uncertainty regarding measurements of the anticoagulant activity of LMWH with these tests can become a critical issue in acute coronary syndromes where the need for PCI may require exact understanding of the patient’s anticoagulation status before and during the procedure. Currently, the only test that is broadly accepted to gauge the anticoagulation status of a patient who has received a LMWH is an anti-factor Xa test. The test is time-consuming, costly and not readily available at point of care, leaving the cardiologist without a rapid and reliable test for determining anticoagulation levels in patients receiving LMWH. Limitations of LMWH. Many of the limitations previously described for UFH may apply to LMWH. Although to a lesser extent, in comparison to UFH, LMWH demonstrates non-specific protein binding,^17,19,35 and appears unable to effectively inhibit clot-bound thrombin.⁹ LMWH also cross-reacts with heparin antibodies and has been reported to cause thrombocytopenia.⁴⁰ Specifically for the PCI setting, the perceived inability to measure the level of anticoagulation using the standard ACT test, as well as its longer plasma half-life, may make LMWH a less than ideal anticoagulant in the catheterization laboratory. Clinical studies:Evidence for a rlationship between ACT levels and clinical outcomes in PCI Measuring anticoagulant effect. The activated clotting time is the preferred point of care test for monitoring the anticoagulant effect of heparin in the cardiac catheterization laboratory. ACT values are linearly related to heparin concentrations in the range used in PCI.⁴⁷ Additionally, the ACT can provide a rapid measure of the level of anticoagulation while in the catheterization lab. The HemoTec (HemoTec, Inc., Englewood, Colorado) and Hemochron devices (International Technidyne Corporation, Edison, New Jersey) are the two most commonly used for measuring ACT in the cardiac catheterization laboratories in the United States. PCI without a glycoprotein (GP) IIb/IIIa antagonist: Case-control studies. Heparin is widely used in the PCI setting despite a dearth of information from well-controlled randomized trials. After decades of use and a large volume of clinical experience, the optimal dose for heparin in PCI remains unclear. Two small randomized studies compared low versus high doses of heparin for anticoagulation during elective PCI.^48,49 Although lacking consistency, data from these studies support the perception that UFH’s ability to prevent thrombosis is dose dependent, i.e., that higher plasma levels of heparin achieve higher ACTs, and that these higher heparin concentrations are more likely to be protective against ischemic complications. However, this protection appears to be associated with an increased risk of hemorrhage. Although there have been no trials in which patients were randomized to undergo PCI at different ACT values, data from three case-controlled studies provide evidence that patients with higher ACT or aPTT values had fewer ischemic events compared to patients with lower ACT or aPTT values (Table 2).^50–52 When these data are pooled, the combined odds ratio for death or ischemic complications was 0.25 [95% confidence interval (CI), 0.17–0.37; p 50 The inverse relation between the initial ACT and the probability of adverse clinical outcomes was statistically linear, and persisted throughout the observed range of ACT values. Thus, the probability of ischemic events continued to decrease progressively with increasing ACT, with no evidence of a threshold value above which a further increase in degree of anticoagulation would not be associated with a further reduction in the probability of an ischemic event.⁵⁰ Continued on next page