Unfractionated heparin (UFH) is a glycosaminoglycan, composed of a heterogeneous mixture of molecules of different molecular weights. The anticoagulant action of UFH
is derived from the binding of approximately one-third of UFH molecules to antithrombin III (AT-III), leading to a conformational change that markedly enhances the affinity of the UFH AT-III complex for activated thrombin (1). UFH avidly binds to endothelial cells, macrophages, and plasma proteins, which results in two distinct clearance phases from the body. An initial rapid equilibration phase is followed by a slower, saturable elimination phase (2). The binding capacity for UFH varies by individual, because heparin-binding proteins are largely acute-phase reactants. Thus, the half-life of UFH is both variable and dose dependent (1). Natural inhibitors of UFH (platelet factor 4 [PF4]) may be released from platelet-rich thrombus and may further alter the UFH dose-response relationship, especially when large amounts of thrombus are present (1).

Controversy exists with regard to the appropriate periprocedural dosing and strategies to monitor procedural UFH therapy in clinical practice. The three main tests used to monitor UFH anticoagulation have been the whole blood clotting time, the activated clotting time (ACT), and the activated partial thromboplastin time (aPTT) (3, 4, 5). The term activated refers to the use of agents that activate factor XII during performance of the assay. The whole blood clotting time may be less reproducible and is more dependent on the degree of contact activation (3, 4, 5, 6). The aPTT traditionally has been used to monitor UFH therapy but has limited responsiveness to changes in UFH concentration, especially at higher levels of anticoagulation (7, 8, 9, 10). In addition, the use of a platelet-poor preparation during the measurement of the aPTT ignores the potential UFHneutralizing effects of PF4 (1). These concerns are less applicable to measurement of the ACT. The added appeal of a rapidly available “point-of-care” assay has contributed to making the ACT the standard for assessing UFH anticoagulation in catheterization laboratories (11,12).

Guidelines for UFH use during PCI have been the subject of discussion and controversy (13, 14, 15, 16). Initially, empirically derived intravenous (IV) bolus doses of 5,000 to 10,000 units of UFH prior to PCI were utilized widely. The variable adequacy of anticoagulation with this regimen led to the subsequent formation of weight-adjusted bolus dose regimens and to dose adjustment based on close monitoring of in-laboratory ACT values (11,17). Early recommendations for UFH dosing during PCI came from studies demonstrating that an ACT of more than 300 to 400 seconds is required to prevent fibrin deposition within the extracorporeal circuit in patients undergoing cardiopulmonary bypass (18). Retrospective analyses of clinical series demonstrated an inverse relationship between the intensity of UFH anticoagulation during PCI, as reflected by the ACT, and the occurrence of ischemic complications including abrupt vessel closure, emergency bypass surgery, and death (19, 20, 21, 22, 23, 24, 25, 26). However, the risk of serious bleeding complications also increased at progressively higher ACT levels (20,24,27,28). Although an optimal “target” or threshold for ACT could not be identified from these data, the consensus recommendation was made for achieving an ACT level ≥300 seconds during PCI.

Recently, a meta-analysis that combined data from six randomized controlled trials was performed to determine the relationship of periprocedural ACT with clinical outcomes (29). This analysis included 6,146 patients derived from studies of novel adjunctive antithrombotic regimens, in which UFH constituted the control arm and ACT data were available on 5,216 patients. An ACT of 350 to 375 seconds during PCI was associated with the lowest composite event rate (death, myocardial infarction [MI], revascularization) to 7 days follow-up (6.6%) (29). The lowest incidence of major or minor bleeding events was observed for ACTs in the range of 300 to 325 seconds (8.6%), and progressively
increased at 350 to 375 seconds (12.4%) (Fig. 47.1A,B). This analysis concluded that, contrary to prior reports, the optimal suppression of ischemic events with UFH therapy in patients undergoing PCI requires ACT levels substantially higher than previously appreciated. These data suggest that the optimal level of periprocedural ACT is in the range of 350 to 375 seconds for preventing ischemic complications while minimizing bleeding complications during PCI.

The dose of UFH should be reduced using a weight-adjusted algorithm if concomitant platelet glycoprotein (GP) IIb/IIIa receptor inhibitor therapy is administered. Through an interaction at the level of the GP IIb/IIIa receptor, GP IIb/IIIa blocking agents further prolong the ACT in the presence of UFH (30,31). In the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial, markedly elevated ACT levels were observed following the administration of non-weight-adjusted UFH in combination with abciximab and were associated with frequent major bleeding complications and transfusion requirements (32). Subsequent utilization of a reduced-dose weight-adjusted UFH regimen in conjunction with early vascular access sheath removal resulted in a marked reduction in both bleeding and transfusion events for abciximab-treated patients (33). The safety and efficacy of this reduced-dose UFH regimen (70 U/kg bolus) in combination with abciximab was subsequently confirmed in a large, multicenter randomized trial (Evaluation of PTCA to Improve Long-Term Outcome by c7E3 GP IIb/IIIa Receptor Blockade [EPILOG]) (34). Mean and median maximum in-laboratory ACT values observed with this regimen were 270 and 299 seconds, respectively. Although subsequent clinical trials and empirical clinical experience have suggested enhanced safety (fewer bleeding complications) with maintenance of efficacy at even lower doses of weight-adjusted UFH without concomitant GP IIb/IIIa blockade (65 U/kg or 60 U/kg UFH) (35,36) or with concomitant GP IIb/IIIa blockade (50 U/kg or less [≤1,000 units] UFH) (37,38) to target ACT values of 200 seconds during PCI, these regimens have not been compared in large-scale randomized trials. Most recently, a pooled analysis involving data from four randomized controlled trials of adjunctive pharmacotherapy for PCI involving a high prevalence (89%) of platelet GP IIb/IIIa receptor blockade and bivalirudin use observed no relationship between ACT prolongation and clinical ischemic events. Interestingly, although no relationship between ACT and major bleeding events was observed, the composite occurrence of major and minor bleeding events was increased in the highest (3rd and 4th) quartiles of periprocedural ACT (39).

The Organization to Assess Strategies for Ischemic Syndromes (OASIS) investigators recently examined the relationship between aPTT, recurrent cardiovascular events, and bleeding among 5,058 patients receiving UFH during ACS (40). There was an increase in relative risk of cardiovascular events (1.54, 95% CI 1.10 to 2.15; p = 0.01) among patients with subtherapeutic (<60 seconds) aPTT values, while higher aPTT values were associated with increased bleeding; for every 10-second increase in aPTT, the probability of major bleeding was increased 7% (95% CI 3% to 11%; p = 0.0004) (40). These results justify the practice of regularly monitoring UFH and substantiate the difficulty in maintaining therapeutic levels with this anticoagulant. The administration of an LMWH may provide a more reliable and safe means of antithrombin therapy during ACS and PCI.

LMWHs are produced by enzymatic or chemical depolymerization of UFH and have saccharide chains with molecular weights of 4,000 to 6,500 Daltons (average 5,000 D or 15 saccharide units) (41, 42, 43). Due to their relatively small molecular size, LMWHs have a greater capacity for inactivating factor Xa, relative to thrombin (factor IIa). Thus, compared with UFH, which has a ratio for factor Xa to IIa inactivation of 1:1, LMWHs exhibit antifactor Xa to IIa ratios of between 2 and 4:1 (43). Because early (“upstream”) events are greatly magnified during the coagulation cascade, factor Xa likely contributes more to the procoagulant activity of thrombus in situ than does thrombin (IIa). Furthermore, inhibition of factor Xa may be of greater importance in ACS and during PCI.

Unlike UFH, LMWHs have little nonspecific plasma protein and cellular binding, which contributes to a more predictable dose response and a longer pharmacologic half-life. Furthermore, the bioavailability of LMWH following subcutaneous (SQ) injection approximates 90% (versus 30% for UFH) (43). This combination of more predictable anticoagulant response, high bioavailability, and long half-life suggests that a reliable anticoagulant response can be achieved following twice-daily SQ injections using a weight-adjusted dose regimen in the absence of routine laboratory monitoring. In addition, animal models of thrombosis have shown LMWH to be associated with less bleeding (enhanced safety), which may in part be explained by a lower affinity for platelets and less consequent inhibition of platelet function (43). Heparin-induced thrombocytopenia also occurs less commonly with LMWH than UFH. The incidence of antiplatelet factor 4/heparin antibody induction in patients undergoing PCI with UFH is higher than previously recognized (44). These potential advantages (Table 47.1) of LMWH over UFH in terms of clinical efficacy, safety, and ease of use in the setting of ACS and PCI have prompted evaluation in numerous studies.