Avoiding Intelligence Failures in the Cardiac Catheterization Laboratory

Review

Avoiding Intelligence Failures in the Cardiac Catheterization Laboratory: Strategies for the Safe and Rational Use of Dalteparin or Enoxaparin during Percutaneous Coronary Intervention

Jonathan D. Marmur, MD, Renee P. Bullock-Palmer, MD, Shyam Poludasu, MD, Erdal Cavusoglu, MD

ABSTRACT: Low-molecular-weight heparin (LMWH) has been a of unstable angina (UA) and non-ST-segment elevation myocardial mainstay for the management of acute coronary syndromes (ACS) for infarction (NSTEMI). The ESSENCE and TIMI 11B trials support almost a decade. However, several recent developments have seriously the use of LMWH over unfractionated heparin (UFH) in acute coro - threatened the prominence of this drug class: (i) the adoption of an nary syndromes managed with a predominantly medical approach early invasive strategy, frequently leading to percutaneous coronary in - 1,2 tervention (PCI) where the dosing and monitoring of LMWH is un - as opposed to an invasive initial strategy. familiar to most operators, (ii) the results of the SYNERGY trial, which Since the publication of the ESSENCE and TIMI 11B trials, not only failed to establish the superiority of enoxaparin over unfrac - the management of acute coronary syndromes (ACS) has tionated heparin with respect to efficacy, but also demonstrated more evolved to favor an early invasive strategy. This evolution is sup - bleeding with LMWH, and (iii) the results of the REPLACE-2 and ported by a number of studies, including the FRISC II and the ACUITY trials, which have demonstrated the advantages of an ACS TACTICS TIMI-18 trials. 3,4 The Superior Yield of the New and PCI treatment strategy based on direct thrombin inhibition with bivalirudin. To confront these challenges, cardiologists committed to Strategy of Enoxaparin, Revascularization and Glycoprotein the continued use of LMWH must develop safe and user-friendly ap - IIb/IIIa Inhibitors (SYNERGY) trial was therefore designed to proaches to transition patients from the noninvasive to invasive set - extend the observations of ESSENCE and TIMI 11B to an in - tings. This review summarizes an approach that takes advantage of the vasively managed population. The SYNERGY trial compared fact that LMWH can be readily monitored with the point-of-care ac - enoxaparin to unfractionated heparin (UFH) in the invasive tivated clotting time (ACT) assay. This assay is inexpensive, available management of ACS patients and demonstrated similar rates in virtually every catheterization laboratory, and familiar to most op - of success post-PCI. 5 However, patients randomized to enoxa - erators who monitor unfractionated heparin (UFH). A key concept 5 that is presented is that the ACT is a more accurate measure of parin in SYNERGY had a higher rate of bleeding. It is note - LMWH-induced anticoagulation than of UFH-induced anticoagula - worthy that in the SYNERGY trial design, monitoring was used tion. Our preliminary work suggests that during PCI operators should for UFH, but not for LMWH. This lack of monitoring of target an ACT of 175 seconds in the presence, and 200 seconds in the enoxaparin reflects the conventional view that LMWH cannot absence, of adjunctive glycoprotein IIb/IIIa inhibition. Sheath removal be readily monitored with bedside assays, such as the activated is recommended at an ACT < 160. These guidelines may facilitate con - clotting time (ACT), and may have contributed to the excessive tinued use of LMWH, which has the potential to reduce cost (less ex - bleeding rate seen in enoxaparin-treated patients. Indeed, one pensive than bivalirudin), diminish the need for intravenous medication (can be administered subcutaneously in the noninvasive of the principal reasons that LMWH is generally not used dur - setting with minimal to no monitoring), and provide an ideal antico - ing PCI is this notion that LMWH cannot be monitored. agulant during PCI (easy to monitor with the ACT, at least partially The notion that LMWH is not amenable to monitoring was reversible with protamine in the event of coronary perforation, effec - derived from studies using a subcutaneous route of administra - tive antithrombin with no platelet activation, thereby potentially re - tion, following which relatively low plasma levels are achieved. ducing the need for routine adjunctive IIb/IIIa inhibition). However, in contrast to the noninvasive setting, LMWH is gen - J INVASIVE CARDIOL 2009;21:653 –664 erally administered as an intravenous (IV) bolus during PCI, Key words: Low molecular weight heparin, Activated clotting time, PCI thereby achieving higher peak plasma concentrations. We have shown that the level of anticoagulation induced by intravenously administered dalteparin can in fact be measured using the standard Low-molecular-weight heparin (LMWH) has been in clinical use ACT test. 6 Later, we reported similar observation with enoxa - for over a decade and has assumed a major role in the management parin. 7 More recently we demonstrated that the dose of dalteparin administered intravenously during PCI can be safely adjusted by From the Division of Cardiology, Department of Medicine, State University monitoring the ACT and could constitute a safe and effective of New York (SUNY) Health Science Center at Brooklyn, New York. The authors report no conflicts of interest regarding the content herein. strategy during PCI. 8 Monitoring of LMWH may be particularly Manuscript submitted January 29, 2009, provisional acceptance given important for those patients undergoing PCI after having already March 12, 2009, final version accepted June 12, 2009. Address for correspondence: Jonathan D. Marmur, MD, Professor of Med - received a dose of subcutaneous (SC) LMWH for the initial man - icine, Director of Cardiac Catheterization and Interventional Cardiology, SUNY agement of their ACS. The ACT is the current standard of care Downstate Medical Center, 450 Clarkson Avenue, Box 1257, Brooklyn, NY 11203-2098. E-mail: [email protected] for the management of anticoagu lation during PCI. The chief

Vol. 21, No. 12, December 2009 653 MARMUR , et al.

Figure 1. Size distribution plot for low-molecular-weight heparin (LMWH) versus unfractionated heparin (UFH). Both LMWH and UFH represent heterogeneous populations with molecular weight distribution of 1,000 to 10,000 Daltons and 3000 to 30,000 Daltons respectively. Note that LMWH is both smaller in molecular size and has a lesser degree of heterogeneity. purpose of this article is to review the LMWH literature as it relates to the issue of monitoring, and to answer key questions Figure 2. Catalysis of antithrombin-mediated inactivation of that may arise in LMWH-treated patients managed with an thrombin or factor Xa by UFH or LMWH. The interaction of un - invasive strategy. fractionated heparin and low-molecular-weight heparins with antithrombin is mediated by the pentasaccharide sequence of the drugs. Binding of either Mechanism of action of Low-Molecular-Weight to antithrombin causes a conformational change at its reactive center that accelerates its interaction with factor Xa. Consequently, both unfraction - Heparins ated heparin and low-molecular-weight heparins catalyze the inactivation LMWH is an indirect thrombin inhibitor formed by de - of factor Xa by antithrombin. In contrast to factor Xa inhibition, catalysis polymerization of heparin using chemical or enzymatic meth - of antithrombin-mediated inactivation of thrombin requires the formation ods. 9 LMWH preparations have a mean molecular weight of of a ternary heparin-antithrombin-thrombin complex. This complex can 4,500 –5,000 Daltons, with a distribution of 1,000 to 10,000 be formed only by chains at least 18 saccharide units long. (Adapted from Daltons. 9 Unfractionated heparin is a more heterogeneous mix - Weitz J. N Engl J Med 1997;337:688 –698.) ture of polysaccharide chains ranging in molecular weight from 3,000 –30,000 Daltons, with an average molecular weight of The binding of LMWH to antithrombin causes less inacti - 15,000. 10 Unlike direct thrombin inhibitors, which consist of vation of coagulation factor IIa (thrombin) when compared a single molecular weight entity, LMWH represents a popula - with that of unfractionated heparin. 9 This is because inactiva - tion of molecules with an average molecular weight lower than tion of factor IIa requires the formation of a ternary complex that of UFH (Figure 1). in which heparin binds to both antithrombin and to a binding The mechanism of action of UFH and LMWH starts with site on factor IIa (Figure 2). 17 This ternary complex is formed the formation of a complex with antithrombin (Figure 2). on pentasaccharide containing chains of at least 18 saccharide LMWH’s catalytic activity then converts antithrombin from units. However, unlike UFH, many of the LMWH do not con - a slow to a rapid inactivator of coagulation factor Xa, acceler - tain sufficient saccharide units to form the ternary complex. 9 ating antithrombin’s interaction with thrombin and Xa by a It has been estimated that 25 –50% of LMWH chains are suf - factor of approximately 1,000. 10 –12 Antithrombin has two ac - ficiently long to bridge antithrombin to factor IIa. 10,17 –20 tive functional sites: the reactive center, Arg 393-Ser 394, and Therefore, a major difference between UFH and LMWH is the LMWH binding site located at the amino terminus of the in their relative inhibitory activity against factor Xa and factor molecule. 13 The binding of LMWH to antithrombin is medi - IIa (Table 1). Any pentasaccharide-containing heparin chain ated by a unique pentasaccharide sequence randomly distrib - can inactivate factor Xa, but a minimum number of saccharide uted along the LMWH chain. 12,14 Approximately one-third of units is required to exert an inhibitory effect on factor IIa. 10 the chains of UFH, but only 15 –25% of the chains of Therefore, LMWH has a greater ratio of factor Xa to factor IIa LMWHs, contain the pentasaccharide sequence. 10 After the inhibitory activity when compared with UFH, which has equiv - LMWH has been bound to the heparin binding site on an - alent activity against these factors. 10 tithrombin, a conformational change in antithrombin occurs, Other antithrombogenic effects of LMWH include its pro - and this significantly accelerates antithrombin’s inactivation motion of the release of tissue factor pathway inhibitor (TFPI) of coagulation factor Xa. 15,16 from vascular endothelium, a reduction in the levels of von

654 The Journal of Invasive Cardiology Safe and Rational Use of Dalteparin or Enoxaparin during PCI

Table 1. Comparison of low-molecular-weight heparin preparations. plasma proteins other than thrombin and its half-life is approxi - mately 25 minutes, assuming normal renal function. However, LMWH Preparation Mean Molecular Anti-Xa: Weight (Daltons) ANTI-IIa Ratio prolongation may occur in patients with moderate (34 mins) or severe (57 mins) renal impairment, with creatinine clearance of ardeparin (Normiﬂo) 6,000 1.9 35 dalteparin (Fragmin) 6,000 2.7 30 –59 ml/min and < 30 ml/min, respectively. Bivalirudin is 36 enoxaparin (Lovenox) 4,200 3.8 eliminated via the renal system and also via proteolytic cleavage. nadroparin (Fraxiparine) 4,500 3.6 Fondaparinux, a pentasaccharide derived from the heparin reviparin (Clivarine) 4,000 3.5 molecule, is an indirect, high-affinity factor Xa reversible in - tinzaparin (Innohep) 4,500 1.9 hibitor. By virtue of its very short chain length, it does not bind nonspecifically to plasma proteins. It also has 100% bioavailabil - Willebrand factor (vWf), the inhibition of the procoagulant effects ity after SC administration, reaching its peak serum concentra - of leukocytes, the promotion of fibrinolysis and the inhibition of tion at 1.7 hours post administration. The half-life of 17 hours monocyte adhesion. 21 Platelet factor 4 recently has been found to is longer than that of LMWH, allowing it to be administered as induce natural killer (NK) cells’ production of inflammatory cy - once-daily dosing. The route of elimination is via the renal system tokine IL-8, which may exert a prothrombotic effect in acute coro - and it is excreted unchanged in the urine, with an elimination nary syndromes (ACS). 21 LMWH is less likely to be bound to half-life of 15 –17 hours. It has not been approved by the FDA platelet factor 4 than UFH, and thus exerts a less prothrombotic for use during PCI. 37 In the Fifth Organization to Assess Strate - and potentially less proinflammatory effect than UFH. 21 gies in Acute Ischemic Syndromes (OASIS-5) trial, among those who underwent invasive strategy, an increased risk of coronary Pharmacokinetics of Low-Molecular-Weight guide-catheter thrombus formation was reported with fonda - Heparins parinux compared with enoxaparin (0.9% vs. 0.4%; p = 0.001). 38 LMWH exhibits less nonspecific binding to plasma pro - It has not been approved by the FDA for use during PCI. 37 teins, endothelial cells and macrophages, and therefore has greater bioavailability than UFH. 10 The diminished binding to Low-Molecular-Weight Heparins versus macrophages results in reduced clearance by hepatic mecha - Unfractionated Heparin nisms; this is one of the reasons why renal clearance mechanisms There are several features of LMWH that support its use dur - are the major determinants of LMWH’s plasma half-life. 10 ing ACS and PCI. The most important advantage of LMWH The pharmacokinetics of LMWH are different from those of versus UFH is that there is less platelet activation with LMWH UFH after both IV and SC administration. The plasma anti-factor (Figures 3 and 4). 39,40 Platelet aggregation requires activation of Xa activity is approximately two to four times longer than that of glycoprotein (GP) IIb/IIIa receptors located on the surface of UFH, and this is regardless of the injected dose of the different platelets, with fibrinogen acting as a cofactor for platelet activa - forms of LMWH. 10 This generally ranges from 2 to 4 hours after tion. Standard UFH with its high molecular weight and longer IV injection and from 4 to 6 hours after SC injection. 10 The factor saccharide chain activates platelet GP IIb/IIIa receptors, thereby Xa inhibitory activity of LMWH persists longer than its inhibitory potentiating platelet aggregation (Figure 5). 41 –47 The lower pro- activity against factor IIa as a result of the more rapid clearance of aggregatory actions of LMWH have been detected in vitro and longer heparin chains. 10 The duration of anti-factor IIa activity of in vivo ,44,47 –55 and appear to decrease with decreasing molecular LMWH is only slightly longer than that of UFH. 22 weight. 52 In fact, LMWHs, with a molecular weight of < 3,000 Because its route of elimination is via the renal system, the half- Daltons did not result in binding of fibrinogen to the platelet life of LMWH increases in patients with renal failure. 9 LMWH surface. 47 This is of particular relevance to PCI, where increased dosing should therefore be reduced by 50% in patients with cre - platelet aggregation may contribute to complications. 21 atinine clearance < 30 ml/min. 23 –25 LMWH is associated with less tissue factor (TF) pathway The pharmacokinetics of LMWH differ substantially from inhibitor depletion, and actually promotes the release of TF two of the newer anticoagulants, bivalirudin and fondaparinux. pathway inhibitors, thereby enhancing LMWH’s anti-factor Xa Bivalirudin is a reversible, direct, pure thrombin inhibitor that activity. 21,56 –58 In contrast, UFH increases the depletion of TF is administered intravenously. It is a synthetic 20 amino-acid pathway inhibitors. 56 –59 As a result, less rebound hypercoagula - polypeptide modeled after hirudin and comprised of an active bility may be seen with LMWH compared to UFH. 60 site-directed peptide linked via a tetraglycine spacer to a dode - Increased circulating levels of von Willebrand factor (vWf) capeptide analogue of the carboxy-terminal of hirudin. 26 There in patients with ACS post PCI have been implicated as a factor have been several trials, including BAT, REPLACE-1, CA CHET, contributing to adverse outcomes. 21 Whereas UFH does not REPLACE-2, ACUITY and HORIZONS-AMI, which have blunt the increased vWf levels seen in patients with ACS, suggested its superiority over UFH during PCI. 27 –32 It has been LMWH does appear to attenuate this increase. 61 recently approved by the U.S. Food and Drug Administration LMWH is associated with a lower incidence of heparin-induced (FDA) for use during PCI. 33 Bivalirudin’s recommended route thrombocytopenia (HIT) when compared to UFH. 9 HIT is an of administration is IV, its onset of action is immediate and du - antibody-mediated adverse reaction to heparin, which unlike other ration of action is approximately 1 hour. 34 It does not bind to drug-induced thrombocytopenias, causes venous and arterial

Vol. 21, No. 12, December 2009 655 MARMUR , et al.

Figure 4. Flow cytometry and platelet activation by unfractionated heparin (UFH) but not by low-molecular-weight heparin (LMWH). PAC-1 is an IgM polyclonal antibody that binds specifically to activated GP IIb/IIIa. Anti-CD62 is a murine monoclonal antibody directed against P- selectin expressed on the platelet surface, an indicator of platelet activation. (Adapted from Xiao and Theroux, Circulation 1998;97:251º256.) Figure 3. Enhanced platelet activation on unfractionated heparin (UFH). An example of platelet aggregation to low concentrations of TRAP before and during an infusion of UFH in a patient with unstable thrombosis rather than bleeding. HIT is a syndrome manifested angina. Inset shows the results of light transmission aggregometry in by HIT antibody formation, a > 50% decrease in platelet count platelet-rich plasma from volunteers after adding saline, UFH, enoxa - or skin lesions at injection sites. 9 HIT is mediated by the HIT parin, or argatroban. Platelet aggregation to low concentrations of ADP antibody recognizing the epitope on the platelet factor 4 (PF4)- and TRAP is significantly increased in the presence of UFH. *p < 0.05, 62 ** p < 0.01 vs. control. Note the absence of platelet activation in the pres - heparin complex as an antigen. The HIT antibody binds to ence of LMWH or the direct thrombin inhibitor argatroban. (Adapted one or more PF4 regions conformationally modified by the in - from Xiao and Theroux, Circulation 1998;97:251 –256.) teraction with heparin. 9 At least 12 –14 saccharide units within the heparin molecule are required to form the antigenic com - plex with PF4. 9 Therefore, the risk of HIT

Photoaffinity cross-linking of heparin to intact platelets Inhibition of heparin-mediated platelet aggregation antibody formation is lower during treat - ment with LMWH than with UFH. 9 A B C The better bioavailability, dose inde - Heparin 1 u/ml PRP was preincubated with GRGDS peptide, a pendent clearance and decreased affinity competitive inhibitor of for heparin-binding proteins make the 200 fibrinogen binding, or GpIIb [ aIIb ] 116 GpIIIa [ ] EDTA or saline control, anticoagulant response to LMWHs more b3 and then exposed to 97.5 GRGDS heparin 1U/mL final predictable than that to UFH. 10 kD 5 mM concentration. 66 Saline EDTA The Methodology of the Activated 44 2mM Clotting Time (ACT) and the No UV UV No UV UV No UV UV Activated Partial Thromboplastin Platelets were incubated with tritiated heparin, and then 1 minute exposed to UV light (or not), and the cross-linked platelets Time (aPTT) washed and solubilized. (A) Coomassie stain of original Translocation of Rap2B in response to heparin aggregation Activated Clotting Time (ACT) . The 6% SDS-PAGE of platelet proteins after electrotransfer. (B) Autoradiography of the same lanes from the Western Heparin 1 u/ml activated clotting time (ACT) is a measure blot. (C) Immunostaining of same blot for aIIb b3. of the overall tendency of the blood to

PBS Control thrombose. It was first described by Hatter - Adapted from Sobel et al. On the left are aggregation tracings of PRP exposed to heparin or PBS control. On the right are Western blots from the detergent insoluble cytoskeletal fraction of the same sley in 1966 and came into clinical use in J Vasc Surg 2001;33:587 –594 platelets, probed for Rap2B. Significantly less Rap2B is visible in the control sample. the mid-1970s to guide the administration Figure 5. Heparin binds and activates platelet GP IIb/IIIa. Left panel: Photoaffinity cross- and reversal of UFH during cardiopul - linking of heparin to intact platelets. Platelets were incubated with tritiated heparin, and then ex - monary bypass. 63 It is also used in point-of- posed to UV light (or not), and the cross-linked platelets washed and solubilized. (A) Coomassie care monitoring of the anticoagulation stain of original 6% SDS-PAGE of platelet proteins after electrotransfer. (B) Autoradiography effect of UFH during cardiac catheteriza - of the same lanes from the Western blot. (C) Immunostaining of same blot for αIIb β3. Right tion and vascular surgery. upper panel: Inhibition of heparin-mediated platelet aggregation. PRP was preincubated with The methodology of the ACT involves GRGDS peptide, a competitive inhibitor of fibrinogen binding, or EDTA or saline control, and then exposed to heparin 1 U/mL final concentration. Right lower panel: Translocation of Rap2B the collection of whole blood into a tube in response to heparin aggregation. On the left are aggregation tracings of PRP exposed to heparin containing a magnet and an activator of co - or PBS control. On the right are Western blots from the detergent insoluble cytoskeletal fraction agulation, diatomaceous earth. 64 This acti - of the same platelets, probed for Rap2B. Significantly less Rap2B, a marker for the early signaling vator stimulates clot formation upon events mediated by the integrin αIIb β3, is visible in the control sample. contact with whole blood via the intrinsic

656 The Journal of Invasive Cardiology Safe and Rational Use of Dalteparin or Enoxaparin during PCI

from a baseline of approximately 110 –130 sec to a post-bivalirudin bolus of 300 –400 sec. In contrast, when using an agent such as LMWH that has a reduced ratio of anti-IIa:anti-Xa activity, the operator must anticipate a reduction in the magnitude of change from baseline values. The target ACT for the LMWH-treated patient is discussed below. The Activated Partial Thromboplastin Time (aPTT) . The activated partial thromboplastin time (aPTT) measures the clotting time from the activation of factor XII to the formation of the fibrin clot, thus measuring the integrity of the intrinsic Figure 6. ACT methodology. Blood is collected into a tube containing a and common pathways of coagulation. 65 The aPTT is usually magnet and diatomaceous earth which activates clot formation via the intrinsic used to monitor therapeutic heparin, hirudin and argatroban pathway. This results in displacement of the magnet followed by alarm acti - anticoagulation. However, as noted before, at high doses of he - vation. Results are read in seconds. Clotted blood, in contrast to unclotted parin, the use of aPTT is not ideal. blood, remains in the well of the tube after inversion (right panel). To measure the aPTT, blood is collected into a tube con - taining kaolin, an intrinsic pathway activator. A reagent of phospholipid is also provided in the aPTT assay; 65 this is in contrast to the ACT assay, in which the platelets provide phos - pholipids. The measurement of the aPTT is generally per - formed in a hospital’s core laboratory facility, with results obtained within 30 –60 minutes. This delay is an additional rea - son for which the ACT has been traditionally used in the car - diac catheterization laboratory and cardiovascular operating room settings where immediate results are often needed. Point-of-Care Monitoring Devices. There are point-of-care devices which have been developed to monitor both the ACT and the aPTT. These include The Hemochron ® System (International Technidyne Corp.) , which include the Hemochron Jr., Hemochron 801 and Hemochron 400 and Hemochron Jr. LR. 67 –71 Medtronic, Inc. (Minneapolis, Minnesota) has also developed point-of-care mon - Figure 7. Composite figure of dose-response of the ACT as a func - itoring devices, which include the HemoTec and the Medtronic tion of increasing concentrations of anticoagulant in whole blood. ACT II devices. 72 –74 There are other similar devices available such Solid lines derived from healthy volunteer blood samples spiked with increasing as Celite i-STAT ACT and the Hepcon/HMS devices. 75 –78 doses of either UFH (•) or dalteparin (g). Stippled lines represent theoretic correlations derived from studies referenced in parentheses. Because the ACT These devices are generally cartridge- or cuvette-based, al - is most sensitive to thrombin inhibition, the slope of the line increases for drugs lowing for less blood drawing and potentially greater repro - with greater anti-IIa properties. ducibility of results as operator variables such as the shaking of tubes no longer comes into play. pathway. 65 The tube is placed in a coagulation analyzer ( e.g., He - Use of Low-Molecular-Weight Heparins during mochron ®, International Technidyne Corp., Edison, New Jersey) .65 Percutaneous Coronary Intervention The magnet at the bottom of the tube is displaced once a clot is Anticoagulation during PCI is used to prevent thrombotic formed, activating the alarm on the analyzer (Figure 6). 64 An ad - complications, including abrupt or subacute closure of the vantage of the ACT in comparison to the aPTT is that at high coronary vasculature and myocardial necrosis. LMWH offers doses of heparin, the dose-response relationship remains linear theoretic advantages over UFH as an anticoagulant to prevent for the ACT. The aPTT usually becomes prolonged beyond thrombotic arterial complications. However, UFH remains the measurable levels at heparin concentrations > 1 U/ml. This most commonly used anticoagulant in PCI, in part because it makes the aPTT unsuitable for monitoring heparin dosage dur - is familiar and can be monitored easily. LMWH has seen in - ing angioplasty and bypass surgery, as patients may require he - creased use in the medical treatment of ACS, including patients parin levels > 1U/ml. The ACT has a graded response to heparin with STEMI. A significant number of patients currently present concentrations in the range of 1 U –5 U/ml. As a result, moni - to the cardiac catheterization laboratory for PCI already having toring of heparin with the ACT may be more useful. 66 received at least one, and occasionally several, doses of LMWH. Although it is used to monitor agents that possess both anti-IIa Such patients pose several challenges and questions to the in - and anti-Xa activities, the ACT (and aPTT) are influenced pre - terventionist, such as: 1) Is there any value in using LMWH, dominantly by anti-IIa activity (Figure 7). Thus, if the ACT is used as opposed to UFH, in PCI? 2) Can the LMWH that was ad - to monitor bivalirudin, one would expect a dramatic in crease, e.g., ministered prior to the patient’s arrival to the cath lab, or any

Vol. 21, No. 12, December 2009 657 MARMUR , et al. additionally administered LMWH given in the cath lab be mon - itored using a bedside assay? 3) If so, what ACT value should be targeted? These questions and concerns have become all the more relevant and urgent given the emerging consensus, based on the SYNERGY trial, that switching antithrombotic agents appears to be associated with an increase in adverse events. Question 1. Is there any value in using LMWH, as op - posed to UFH, in PCI? Theoretic advantages of LMWH versus UFH in PCI: LMWH demonstrates less platelet activation and less platelet endothelial interactions when compared with UFH (Figures 3 –5). 39,40 Al - though not proven, the propensity of UFH to activate platelets may have important clinical implications. For example, in the Figure 8. Results of the ASSENT 3 trial showing greater probability of ASSENT III trial, over 6,000 acute MI patients were random - death, reinfarction or refractory ischemia in the unfractionated heparin group. (Adapted from ASSENT 3 Investigators. Lancet 2001;358:605 –613.) ized to one of three arms: (i) full-dose fibrinolysis with UFH; (ii) half-dose fibrinolysis with UFH plus GP IIb/IIIa inhibition (abciximab); or (iii) full-dose fibrinolysis with LMWH (but no effective when administered in conjunction with a standard abciximab), and the composite endpoint to 30 days of death, dose of abciximab. 82 reinfarction and refractory ischemia was examined. The worst The SYNERGY trial. The SYNERGY trial was designed to outcomes were seen in the group of patients treated with full- be the definitive investigation for establishing the superiority dose tenecteplase (TNK) administered with UFH. Both combi - of LMWH over UFH in the context of ACS managed inva - nation therapy of half-dose TNK and abciximab, as well as the sively. 5 Approximately 10,000 ACS patients were randomized regimen of TNK with enoxaparin, showed a significant reduction to anticoagulation with either enoxaparin or UFH prior to un - in event rates (Figure 8). 79 Thus, the beneficial effects of GP dergoing PCI. There were no significant differences in the pri - IIb/IIIa inhibition appear to be replicated by the use of LMWH, mary composite endpoint of death and myocardial infarction or seen from another perspective, the platelet activating effects (MI) at 30 days, and the rate of successful PCI was similar be - of UFH require coadministration of GP IIb/IIIa inhibition to tween the two groups. However, bleeding complications were achieve results that could be achieved by using an antithrombin significantly greater in the LMWH group compared with UFH agent that does not activate platelets in the first place. This raises (Table 2). With respect to the increased bleeding in the enoxa - the question as to whether better antithrombins might reduce, parin arm, it is noteworthy that the UFH group was monitored or even eliminate, the need for adjunctive anti-GP IIb/IIIa ther - using the ACT, while the LMWH group was not (Table 3). The apy, as suggested by the results of the RE PLACE-2 trial. 30 failure to include monitoring of enoxaparin in the SYNERGY Use of LMWH in elective and/or urgent PCI. Several studies study design reflects the unsubstantiated conventional view that have been conducted to evaluate the safety and efficacy of LMWH LMWH cannot be readily monitored with bedside assays, such alone or in combination with GP IIb/IIIa inhibitors in PCI. The as the activated clotting time (ACT), and may have contributed National Investigators Collaborating on Enoxaparin (NICE) group to the excessive bleeding rate seen in enoxaparin-treated pa - conducted two separate studies: NICE 1 and NICE 4. Patients in tients. Indeed, one of the principal reasons that LMWH is gen - NICE 1 were administered IV enoxaparin alone at a dose of 1 erally not used during PCI is this notion that LMWH cannot mg/kg during PCI, while the NICE 4 group of patients were ad - be monitored. However, as discussed below, we have shown that ministered a reduced dose 0.75 mg/kg of IV enoxaparin, along the level of anticoagulation induced by intravenously adminis - with a standard dose of abciximab during PCI. In both groups of tered dalteparin and enoxaparin can in fact be measured using patients, bleeding complications and ischemic outcomes in hos - the standard ACT test. 6,7 pital and at 30 days post PCI were infrequent. Thus, enoxaparin The Safety and Efficacy of Enoxaparin in Percutaneous Coro - appears to be a safe and effective anticoagulant during PCI, both nary Intervention Patients (STEEPLE) Trial. 83 The STEEPLE when administered alone and in combination with abciximab. 80 trial is the most important trial to address the potential role of Bhatt et al assessed the use of enoxaparin in combination with ep - LMWH in PCI. It is the first large ( n = 3,528 patients), multi - tifibatide during PCI. The study was conducted on 261 PCI pa - center ( n = 124 sites), prospective, randomized trial of LMWH tients randomized to either LMWH plus eptifibatide, or UFH versus UFH in PCI. STEEPLE randomized patients to one of plus eptifibatide. There were no significant differences in the rates two doses of IV enoxaparin (0.5 mg/kg or 0.75 mg/kg) or IV of bleeding nor in the rates of death, myocardial infarction or ur - UFH, with GP IIb/IIIa inhibition use at the discretion of the gent target revascularization at 48 hours or 30 days. 81 operator. The primary endpoint of the study was non-coronary Another study by Kereiakes et al was conducted to assess the artery bypass graft surgery (CABG) major and minor bleeding anticoagulant effect and clinical safety of dalteparin adminis - at 48 hours. Secondary endpoints included various combina - tered in combination with abciximab during PCI. This study tions of non -CABG major bleeds at 48 hours, death, nonfatal concluded that IV dalteparin 60 IU/kg appeared to be safe and MI, or urgent target vessel revascularization at 30 days. The

658 The Journal of Invasive Cardiology Safe and Rational Use of Dalteparin or Enoxaparin during PCI

Table 2. Bleeding rates in the SYNERGY trial. not en tirely in the control of operators ( e.g., medication dos - ing errors and drug administration errors; this latter point Bleeding Deﬁnition Enoxaparin Unfractionated p-Value (%) Heparin (%) may be particularly relevant in cath labs where enoxaparin or dalteparin are administered from small preloaded syringes GUSTO severe bleeding 2.7 2.2 0.08 designed for SC administration). Decrease in hemoglobin and 15.2 12.5 < 0.001 Meta-analysis. Dumaine et al reported a meta-analysis of hematocrit † TIMI major * bleeding (all) 9.1 7.6 0.008 randomized trials comparing the efficacy and safety of LMWH 84 TIMI major * bleeding 6.8 5.9 0.08 versus UFH as anticoagulants in the setting of PCI. The au - (CABG-related) thors concluded that LMWH use during PCI is associated with TIMI major * bleeding 2.4 1.8 0.03 similar efficacy and significantly reduced major bleeding com - (not CABG-related) plications when compared to UFH. Again, all the studies in - Any Transfusions 0.16 17.0 16.0 cluded in the analysis used a fixed dose of LMWH without CABG = coronary artery bypass grafting; GUSTO = global utilization of streptok - monitoring the anticoagulant effect of LMWH. inase and t-PA for occluded arteries; TIMI = thrombolysis in myocardial infarction Question 2. Can LMWH be monitored readily and * Associated with clinical bleed † At least a 5 g/dL decrease in hemoglobin or at least a 15% decrease in hematocrit accurately with the ACT? The notion that LMWH is not not associated with an overt bleeding event. amenable to monitoring was derived from studies using a SC route of administration, following Table 3. The study drug in the SYNERGY trial and cardiac procedures. which relatively low plasma levels are achieved. Furthermore, these studies Procedure Enoxaparin UFH were conducted in an era during which Catheterization Perform catheterization any time Continue UFH and the default management strategy for after last dose perform catheterization ACS was noninvasive, where accurate PCI < 8 hrs from last No additional Stop UFH infusion and use knowledge of the specific level of anti - subcutaneous dose LMWH IV boluses to achieve ACT coagulation in an individual patient may > 8 hrs from last dose 0.3 mg/kg IV bolus of 250 sec not have been as critical as in today’s era CABG Elective Stop > 8 hrs Stop > 6 hrs of invasive management. Urgent Stop Stop It is our contention that the anticoag - PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting ulant effect of LMWH administered dur - ing PCI can and should be monitored, and that algorithms based on the timing major finding of the study was that the primary end point of from the last administered SC dose, such as those used in the major bleeding was 57% lower in the enoxaparin arms than in SYNERGY trial, are inadequate. 85 First, it is not always possible the UFH arm. There were no significant differences in rates of to determine the timing of the last dose of LMWH; not infre - death, death or MI, or death, MI and urgent target vessel revas - quently, there is inadequate documentation in the chart, par - cularization, suggesting that the reduction in bleeding was not ticularly in the case of patients who may have had therapies achieved at the expense of increased vulnerability to cardiac events. initiated at one institution, and then are transferred to a tertiary The STEEPLE trial provides important data to support the care center for intervention. Second, the timing approach is use of LMWH in elective PCI. However, one limitation of the based on a presumption that the pharmacokinetics of LMWH trial was the failure to monitor the effects of enoxaparin with are always predictable. While this may be true in healthy vol - the ACT. Although some have emphasized the advantage of “no unteers, such is not the case for patients presenting with a va - need to monitor,” many operators remain skeptical about the riety of conditions such as obesity and renal dysfunction, safety of using a strategy that precludes the ability to determine conditions associated with an ever-increasing proportion of pa - to any measurable degree the level of anticoagulation during PCI. tients undergoing PCI. For example, an elderly diabetic patient While the advantage of not monitoring may be appealing in elec - with acute MI and hemodynamic compromise may have altered tive, low risk situations, there are a number of circumstances in absorption from a SC dose because of poor skin perfusion, and which the ability to rapidly assess the anticoagulant status of the altered elimination because of changes in an already compro - patient may be useful, including patients presenting with com - mised glomerular filtration rate. Thus, LMWH-treated patients plex histories ( e.g., a chronic renal failure patient who had recently most in need of accurate levels of anticoagulation are likely to received SC enoxaparin, thrombolytic therapy and now arrives be the most at risk for inaccurate dosing and excessive bleeding. at the cath lab with skin hypoperfusion due to cardiogenic These issues are likely to have contributed to the disappointing shock), patients in whom the implications of thrombosis could results of the SYNERGY trial. be life-threatening ( e.g., unprotected left main stenting), patients The ability to monitor UFH with the ACT or aPTT is deter - who initially were deemed low-risk who become high-risk in mined predominantly by its anti-IIa activity, rather than by its the course of their PCI ( e.g., the unexpected appearance of in - anti-Xa activity (Figure 7). Thus, agents that are mainly anti-IIa, traluminal thrombus), and finally, in circum stances that are such as bivalirudin result in very high levels of ACT ( i.e., 300 –400

Vol. 21, No. 12, December 2009 659 MARMUR , et al. seconds range). 29 In contrast, an agent such as pen tasaccharide, which is almost exclusively anti-Xa, has very little influence on the ACT or aPTT. 86 UFH, like LMWH, lies somewhere be - tween these extremes, possessing both anti-IIa and anti-Xa ac - tivities (Figure 7). Among the LMWH agents, each agent has a relatively pre - dictable and measurable anti-IIa activity. Because the ACT cor - relates with the anti-IIa activity, ACT is a reasonable measure of each drug concentration and is dependent on the anti-IIa in - hibitory activity of that particular agent. Thus ACT should be a good guide to monitor the degree of anticoagulation and min - imize bleeding risk provided that the operator recognizes that Figure 9. Strategies for sheath management in low-molecular-weight he - each agent impacts ACT to a variable but predictable level. parin-treated patients. An activated clotting time-based approach eliminates The anti-IIa activity of UFH is determined by the formation some of the complexities associated with the non-monitored, timing-based of a ternary complex which requires at least 18 saccharide sheath management strategy used in the SYNERGY trial. units. 9 Because most UFH molecules contain at least 18 sac - charide units, UFH has an anti-Xa to anti-IIa ratio that approx - changes in ACT, aPTT and anti-Xa levels. 7 Both enoxaparin imates unity. 9 LMWHs, by virtue of their lower molecular and dalteparin induced a significant rise in the ACT and aPTT weight and fewer saccharide units, have less anti-IIa activity and (Figure 11), with an ACT dose-response approximately one-half therefore a decreased ability to form the required ternary com - the magnitude of that obtained using UFH. The elevation in plex. The anti-Xa:anti-IIa ratio of several forms of commercially the ACT was both significant and rapidly detectable; for exam - available LMWH range between 2 and 4, depending on the ple, within minutes of receiving IV enoxaparin 0.5 mg/kg, the molecular weight distribution (Table 1). 9 ACT increased on average 41 seconds. The time course of We have previously reported that the ACT can be used to changes in the ACT and aPTT after administration of enoxa - monitor dalteparin administered intravenously at the time of parin and dalteparin was virtually identical, with a return to PCI. 6 Five minutes after 60 IU/kg of IV dalteparin, the ACT baseline at approximately 2 hours, suggesting a return to hemo - increased from levels of 120 –130 sec to levels of 170 –180 sec static competence that is as rapid as that seen using bivalirudin. (and aPTT increased from 25 –30 sec to 55 –70 sec). Approxi - An additional strategy for monitoring LMWH, specifically mately 1 hour after the bolus dose, a decrease in the ACT and enoxaparin, is based on a bedside anti-Xa assay (ENOX test). anti-IIa and anti-Xa levels was observed. This time course is fa - Moliterno et al studied the Enox test in the ELECT study to vorable in the current era of stenting, where procedures are often determine a target range of anticoagulation for enoxaparin dur - completed within a half-hour, and raises the question as to ing PCI. 88 This study was a prospective multicenter trial involv - whether the ACT could be used not only to determine the dos - ing 445 patients receiving SC or IV enoxaparin. The rate of ing of LMWH, but also to determine the timing of sheath re - ischemic events was lowest in the mid-range of Enox times, and moval (Figure 9). In addition, the rapid decline in LMWH bleeding events increased with increasing Enox times. concentration after IV bolus administration provides an antico - Lawrence et al studied the effect of IV enoxaparin on both agulant profile that is more similar to bivalirudin, where hemo - the ACT and the Enox test in the setting of PCI. 89 Sixty-seven static competence is rapidly restored after cessation of drug consecutive patients undergoing PCI were given either 1 mg/kg infusion, thereby reducing bleeding complications. 30 of IV enoxaparin alone, or 0.75 mg/kg of IV enoxaparin plus An additional previously reported observation is that al - eptifibatide. The ACT was measured before and 5 minutes fol - though UFH induced a greater increase in the ACT compared lowing enoxaparin administration. The mean increase in the with dalteparin, there was a corresponding greater degree of ACT was 77 ± 26 seconds in the 1 mg/kg group, and 69 ± 23 variability in the response of the ACT to UFH compared with sec in the 0.75 mg/kg group ( p < 0.0001). There was a signifi - dalteparin. 4 The tighter distribution of dalteparin-induced (in cant correlation between the ACT and the Enox test ( r = 0.86). comparison to UFH-induced) peak ACT values has been con - The study had concluded that enoxaparin at clinically relevant firmed in a recent randomized trial of PCI 87 (Figure 10). This doses increases the ACT, further supporting the idea that point- suggests that once a target ACT is reached, the corresponding of-care monitoring of enoxaparin during PCI may be achieved blood levels of anticoagulant may be more reliably predicted by measuring the ACT. Finally, it is noteworthy that because than had UFH been administered. the ACT correlates with the more costly Enox test, it may not To extend our observations to enoxaparin, we performed ad - be necessary to use the Enox, or other anti-Xa assays altogether. ditional monitoring studies using doses that more closely reflect Most operators, in fact, have not embraced this assay, which those used in the STEEPLE trial. Specifically, in a population has led to its withdrawal from the market. of 130 patients undergoing cardiac catheterization, the effects Question 3. If LMWH can be monitored in the cath lab, of intravenously administered enoxaparin 0.5 mg/kg, dalteparin what ACT value should be targeted? The in vitro and in vivo 50 IU/kg, and UFH 50 units/kg were assessed with respect to dose response of the ACT following IV LMWH is characterized

660 The Journal of Invasive Cardiology Safe and Rational Use of Dalteparin or Enoxaparin during PCI

curve will yield a corresponding target ACT on the y-axis (Figure 12). 6 Based on these observations, we propose a minimum target ACT of 175 sec for patients receiving LMWH with GP IIb/IIIa inhi bition, and a minimum of 200 sec for patients receiving LMWH alone ( i.e., no adjunctive GP IIb/IIIa inhibition) dur - ing PCI (Figure 12). These targets are supported by previously published observations on an ACT-guided strategy to safely ad - just the dose of dalteparin during PCI, 8 and those of Kereiakes et al where patients treated with dalteparin 40 IU/kg achieved a maximum mean ACT of < 175 sec, and experienced a higher rate of thrombotic complications compared with patients treated with 60 IU/kg who had achieved levels of ACT > 175 sec. 82 In our study on an ACT-guided strategy, all patients ( n = 104) received an initial IV bolus of 50 IU/kg of dalteparin. A Figure 10. Distribution of activated clotting time (ACT) levels during per - bolus dose of GP IIb/IIIa inhibitors was administered at the cutaneous coronary intervention. The distribution of peak ACT levels meas - discretion of the operator. No infusion of GP IIb/IIIa inhibitors ured at 30 minutes after a randomized bolus administration of either unfractionated heparin or dalteparin. (Adapted from Natarajan MJ, et al. was administered following the bolus dose, as per routine man - Am Heart J 2006;151:175. agement at our institution. 93,94 As mentioned previously, the minimum target ACT was 175 sec for patients who received GP IIb/IIIa inhibitors and 200 sec for patients who were not given GP IIb/IIIa inhibitors. Patients who did not achieve the target ACT after the initial 50 IU/kg were given supplemental boluses of dalteparin, with a rule-of-thumb that for every 10 IU/kg of dalteparin IV, the ACT will increase by approximately 10 sec. The mean baseline ACT was 138 ± 41 sec; after the ini - tial bolus of dalteparin 50 IU/kg, this value rose to 231 ± 78 sec. In the 68 patients who achieved the target ACT after the initial bolus of d alteparin, the mean ACT was 261 ± 76 sec. In Figure 11. Time course of the activated clotting time (ACT) and acti - the 36 patients who required a supplemental bolus to achieve vated partial prothrombin time (aPTT). After obtaining baseline blood the target ACT, the mean initial post-dalteparin bolus ACT samples, enoxaparin (triangles) and dalteparin (squares) were administered in - value was 188 ± 59 sec. The mean supplemental dose adminis - travenously as 2 boluses 5 minutes apart to a total dose of 0.5 mg/kg and 50 tered was 14 ± 6 IU/kg of dalteparin. The mean ACT after the IU/kg, respectively. The ACT and aPTT responded similarly to the two forms of low-molecular-weight heparin and approached baseline values at 2 hours. Fol - supplemental dose was 239 ± 79 sec. The incidence of ischemic lowing the administration of each of the boluses, there was a statistically significant endpoints in our study was comparable to the ischemic end - change in the ACT at all time points compared to baseline, with the exception points reported in the SYNERGY 5 and STEEPLE trials. 83 of dalteparin at 2 hours (*). Data presented as mean ± SEM. (Adapted from However, bleeding complications in our study appeared to be Cavusoglu E, et al. J Invasive Cardiol 2005;17:416 –421.) lower than those reported in the LMWH arms of these trials possibly due to the close monitoring of the anticoagulant ac - by a slope that is approximately one-half the magnitude of tivity of dalteparin, nevertheless this finding could be entirely UFH (Figure 12). This relationship provides an opportunity to due to small sample size in our study. Based on our clinical ex - derive a theoretic LMWH ACT target value based on the gen - perience, a convenient rule of thumb for achieving a target erally accepted UFH ACT target values. Although the ideal tar - ACT level is that for every 0.1 mg/kg of enoxaparin IV or for get ACT for UFH has not been defined, in current every 10 IU/kg of dalteparin IV, the operator can anticipate a interventional practice there is an apparent consensus that op - rise in the ACT of approximately 10 sec. 8 Using doses from the erators should achieve a minimal value of 200 sec in the presence STEEPLE trial 83 and other published reports, 80 a starting dose of adjunctive GP IIb/IIIa inhibition, and 300 sec in its ab - of enoxaparin 0.5 mg/kg IV or dalteparin 50 IU/kg appears sence. 90 –92 In order to convert these UFH targets of 200 and 300 reasonable, and will yield an elevation in the ACT of approxi - seconds to theoretic values appropriate for enoxaparin or dal - mately 50 sec. teparin, one must take into account the more blunted dose-re - Finally, our earlier study with dalteparin demonstrated that sponse of the ACT following LMWH administration. A vertical the increase in the ACT was sustained for a period of time rel - line perpendicular to the x-axis (drug concentration) is drawn evant to current interventional practice. Using IV LMWH, the from the 300 (or 200) second intercept for UFH. Assuming ACT is elevated for 40 –60 min, with a decline in values at ap - similar levels of drug concentration (dalteparin 40 U/kg yields proximately 90 min. 6 This raises the possibility that a decline similar anti-IIa levels to that achieved with 40 units/kg of UFH), in the ACT to a target level, for example < 160 sec, could be the intersection of this line with the LMWH dose-response used to determine the timing of sheath removal, a potentially

Vol. 21, No. 12, December 2009 661 MARMUR , et al.

and, when appropriate, percutaneous coronary intervention (PCI). The results of SYNERGY demonstrate that enoxaparin- treated patients may undergo PCI with a similar rate of success compared to UFH-treated patients. However, patients who were randomized to enoxaparin suffered a significantly greater rate of hemorrhagic complication. It is noteworthy that a major distinction between the two groups was that monitoring was used in the UFH-treated patients, but not in the LMWH- treated group. This failure to include monitoring in the trial design reflects an unsubstantiated bias that LMWH-treated pa - tients are not amenable to monitoring with a readily available bedside assay such as the ACT. Arguably, the reluctance of PCI operators to embrace LMWH, despite a number of theoretic and practical advantages ( e.g., less thrombocytopenia, dimin - ished platelet activation, low cost, partial reversibility with pro - tamine), is related in a large part to the perceived inability to monitor LMWH. Our earlier studies and more recent observations have Figure 12. A composite of the dose-response of the activated clotting time demonstrated that, in fact, both dalteparin and enoxaparin can (ACT) following intravenous administration of low-molecular-weight he - be monitored with the ACT. Based on these preliminary ob - parin, characterized by a slope that is approximately one-half the magnitude servations, we have proposed a minimum target ACT of 175 of unfractionated heparin (UFH). Using the UFH ACT targets of 200 and sec for LMWH in PCI performed with GP IIb/IIIa inhibition 300 seconds (for patients with and without adjunctive GP IIb/IIIa inhibition, and a minimum target ACT of 200 sec for LMWH in PCI respectively), a vertical line started at the drug concentration that is associated without GP IIb/IIIa inhibition, which are supported by our with the target ACT for UFH can be extrapolated to intersect with the dose previous observation and others (Figure 13). We have also a response slope for LMWH. The point of intersection with the LMWH dose response slope would then represent the target LMWH ACT. Based on study proposed a target ACT value of < 160 sec for sheath removal. observations and these calculations, we have proposed a minimum target ACT of 175 sec for patients receiving LMWH with GP IIb/IIIa inhibition, and a References minimum of 200 sec for patients receiving LMWH alone (without GP 1. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy IIb/IIIa inhibition) during percutaneous coronary intervention. and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337:447 –452. 2. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and car - diac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999;100:1593 –1601. 3. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascular - isation during InStability in Coronary artery disease Investigators. Lancet 1999;354:708 –715. 4. Cannon CP, Weintraub WS, Demopoulos LA, et al, the TACTICS-Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of Early Invasive and Con - servative Strategies in Patients with Unstable Coronary Syndromes Treated with the Glycoprotein IIb/IIIa Inhibitor Tirofiban 10.1056/NEJM200106213442501. N Engl J Med 2001;344:1879 –1887. 5. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes man - aged with an intended early invasive strategy: Primary results of the SYNERGY ran - Figure 13. Algorithm for the use of low-molelcular-weight heparin during domized trial. JAMA 2004;292:45 –54. 6. Marmur JD, Anand SX, Bagga RS, et al. The activated clotting time can be used to percutaneous coronary intervention in use at SUNY Downstate Medical monitor the low molecular weight heparin dalteparin after intravenous administra - Center, Brooklyn, New York. tion. J Am Coll Cardiol 2003;41:394 –402. 7. Cavusoglu E, Lakhani M, Marmur JD. The activated clotting time (ACT) can be used to monitor enoxaparin and dalteparin after intravenous administration. J Inva - sive Cardiol 2005;17:416 –421. simpler approach compared to one based on calculating the 8. Marmur JD, Poludasu S, Feit A, et al. Activated clotting time (ACT)-guided intra - venous dalteparin dosing during percutaneous coronary intervention. J Invasive Car - time from the last dose administered (Figure 9). diol 2008;20:323 –327. 9. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and Summary safety. Chest 2001;119:64S –94S. LMWH has been in use for over a decade and appears to be 10. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688 –698. 11. Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to anticoagulant therapy: Heparin: superior to unfractionated heparin in the non-invasive treatment A statement for healthcare professionals from the American Heart Association. Cir - of patients with acute coronary syndromes (ACS). The SYN - culation 2001;103:2994 –3018. 12. Hirsh J, Warkentin TE, Raschke R, et al. Heparin and low-molecular-weight heparin: ERGY trial was designed to extend the indication of LMWH to Mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, include ACS patients managed with an early inva sive ap proach and safety. Chest 1998;114:489S –510S.

662 The Journal of Invasive Cardiology Safe and Rational Use of Dalteparin or Enoxaparin during PCI

13. Perry DJ. Antithrombin and its inherited deficiencies. Blood Rev 1994;8:37 –55. not hirudin stimulate platelet aggregation in whole blood from acetylsalicylic acid 14. Choay J, Petitou M, Lormeau JC, et al. Structure-activity relationship in heparin: A treated healthy volunteers. Thromb Res 1991;63:319 –329. synthetic pentasaccharide with high affinity for antithrombin III and eliciting high 47. Heinrich D, Gorg T, Schulz M. Effects of unfractionated and fractionated heparin anti-factor Xa activity. Biochem Biophys Res Commun 1983;116:492 –499. on platelet function. Haemostasis 1988;18(Suppl 3):48 –54. 15. Marcum JA, McKenney JB, Rosenberg RD. Acceleration of thrombin-antithrombin 48. Dunn FW, Soria C, Thomaidis A, et al. Interactions of platelets with standard heparin complex formation in rat hindquarters via heparinlike molecules bound to the en - and low molecular weight fractions. Nouv Rev Fr Hematol 1984;26:249 –253. dothelium. J Clin Invest 1984;74:341 –350. 49. Mikhailidis DP, Barradas MA, Mikhailidis AM, et al. Comparison of the effect of a 16. Klein B, Faridi A, von Tempelhoff GF, et al. A whole blood flow cytometric deter - conventional heparin and a low molecular weight heparinoid on platelet function. mination of platelet activation by unfractionated and low molecular weight heparin Br J Clin Pharmacol 1984;17:43 –48. in vitro. Thromb Res 2002;108:291 –296. 50. Kawano K, Ikeda Y, Handa M, et al. Enhancing effect by heparin on shear-induced 17. Danielsson A, Raub E, Lindahl U, Bjork I. Role of ternary complexes, in which he - platelet aggregation. Semin Thromb Hemost 1990;16(Suppl):60 –65. parin binds both antithrombin and proteinase, in the acceleration of the reactions 51. Mastacchi R, Stanzani L, Barbanti M, et al. Interaction of heparin and heparin frac - between antithrombin and thrombin or factor Xa. J Biol Chem tions with human platelets. Thromb Res 1982;28:275 –280. 1986;261:15467 –15473. 52. Brace LD, Fareed J. Heparin-induced platelet aggregation: Dose/response relation - 18. Anderson W, Harthill JE. Molecular weight dependence of heparin anti-factor Xa ships for a low molecular weight heparin derivative (PK 10169) and its subfractions. activity: Influence of method. Thromb Res 1981;21:557 –564. Thromb Res 1986;42:769 –782. 19. Rosenberg RD, Jordan RE, Favreau LV, Lam LH. Highly active heparin species with 53. Westwick J, Scully MF, Poll C, Kakkar VV. Comparison of the effects of low molec - multiple binding sites for antithrombin. Biochem Biophys Res Commun ular weight heparin and unfractionated heparin on activation of human platelets in 1979;86:1319 –1324. vitro. Thromb Res 1986;42:435 –447. 20. Jordan RE, Favreau LV, Braswell EH, Rosenberg RD. Heparin with two binding sites 54. Mastacchi R, Barbanti M, Bianchini P, Osima B. Interaction of a new low molecular for antithrombin or platelet factor 4. J Biol Chem 1982;257:400 –406. weight heparin (OP/LMWH) with human platelets. Agents Actions 21. Selwyn AP. Prothrombotic and antithrombotic pathways in acute coronary syn - 1986;17:512 –514. dromes. Am J Cardiol 2003;91:3H –11H. 55. Cella G, Scattolo N, Luzzatto G, Girolami A. Effects of low-molecular-weight he - 22. Bara L, Samama M. Pharmacokinetics of low molecular weight heparins. Acta Chir parin on platelets as compared with commercial heparin. Res Exp Med (Berl) Scand Suppl 1990;556:57 –61. 1984;184:227 –229. 23. Caranobe C, Barret A, Gabaig AM, et al. Disappearance of circulating anti-Xa activity 56. Hansen JB, Sandset PM. Differential effects of low molecular weight heparin and after intravenous injection of standard heparin and of a low molecular weight heparin unfractionated heparin on circulating levels of antithrombin and tissue factor path - (CY 216) in normal and nephrectomized rabbits. Thromb Res 1985;40:129 –133. way inhibitor (TFPI): A possible mechanism for difference in therapeutic efficacy. 24. Palm M, Mattsson C. Pharmacokinetics of heparin and low molecular weight heparin Thromb Res 1998;91:177 –181. fragment (fragmin) in rabbits with impaired renal or metabolic clearance. Thromb 57. Hansen JB, Sandset PM, Huseby KR, et al. Differential effect of unfractionated he - Haemost 1987;58:932 –935. parin and low molecular weight heparin on intravascular tissue factor pathway in - 25. Collet JP, Montalescot G, Choussat R, et al. Enoxaparin in unstable angina patients hibitor: Evidence for a difference in antithrombotic action. Br J Haematol with renal failure. Int J Cardiol 2001;80:81 –82. 1998;101:638 –646. 26. Maraganore JM, Bourdon P, Jablonski J, et al. Design and characterization of hiru - 58. Hansen JB, Naalsund T, Sandset PM, Svensson B. Rebound activation of coagulation logs: A novel class of bivalent peptide inhibitors of thrombin. Biochemistry after treatment with unfractionated heparin and not with low molecular weight he - 1990;29:7095 –7101. parin is associated with partial depletion of tissue factor pathway inhibitor and an - 27. Bittl JA, Chaitman BR, Feit F, et al. Bivalirudin versus heparin during coronary an - tithrombin. Thromb Res 2000;100:413 –417. gioplasty for unstable or postinfarction angina: Final report reanalysis of the bi - 59. Sandset PM, Bendz B, Hansen JB. Physiological function of tissue factor pathway valirudin angioplasty study. Am Heart J 2001;142:952 –959. inhibitor and interaction with heparins. Haemostasis 2000;30(Suppl 2):48 –56. 28. Lincoff AM, Bittl JA, Kleiman NS, et al. The REPLACE 1 trial: A pilot study of bi - 60. Wong GC, Giugliano RP, Antman EM. Use of low-molecular-weight heparins in valirudin versus heparin during percutaneous coronary intervention with stenting the management of acute coronary artery syndromes and percutaneous coronary in - and GP IIb/IIIa blockade. J Am Coll Cardiol 2002;39:16 –17. tervention. JAMA 2003;289:331 –342. 29. Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned or 61. Montalescot G, Philippe F, Ankri A, et al. Early increase of von Willebrand factor provisional abciximab versus low-dose heparin and abciximab during percutaneous predicts adverse outcome in unstable coronary artery disease: Beneficial effects of coronary revascularization: Results of the Comparison of Abciximab Complications enoxaparin. French Investigators of the ESSENCE Trial. Circulation with Hirulog for Ischemic Events Trial (CACHET). Am Heart J 2002;143:847 –853. 1998;98:294 –299. 30. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein 62. Chong BH. Heparin-induced thrombocytopenia. J Thromb Haemost 2003;1:1471 –1478. IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade 63. Bowers J, Ferguson JJ. Use of the activated clotting time in anticoagulation moni - during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA toring of intravascular procedures. Tex Heart Inst J 1993;20:258 –263. 2003;289:853 –863. 64. Marmur JD. Low molecular weight heparin in the cardiac catheterization laboratory: 31. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary CD-ROM 2002. syndromes. N Engl J Med 2006;355:2203 –2216. 65. Van Cott EM, Laposta M. Coagulation. In: Jacobs DS, et al (eds). The Laboratory 32. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in Test Handbook, 5th Edition . Cleveland: Lexi-Comp. 2001, pp.327 –358. acute myocardial infarction. N Engl J Med 2008;358:2218 –2230. 66. Hirsh J, Raschke R, Warkentin TE, et al. Heparin: Mechanism of action, pharma - 33. Leung LL. New anticoagulants. In: Date UT, ed., 2005. cokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 34. Bivalirudin — Drug information. In: Online UTD (ed). Lexi-Corp, Inc Online, 1995;108:258S –275S. 2005. 67. Fitch JC, Mirto GP, Geary KL, et al. Point-of-care and standard laboratory coagula - 35. Maraganore JM, Adelman BA. Hirulog: A direct thrombin inhibitor for management tion testing during cardiovascular surgery: Balancing reliability and timeliness. J Clin of acute coronary syndromes. Coron Artery Dis 1996;7:438 –448. Monit Comput 1999;15:197 –204. 36. Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and 68. Searles B, Nasrallah F, Graham S, Tozer M. Electronic data management for the He - pharmacodynamics: Effect of renal function, dose and gender. Clin Pharmacol Ther mochron Jr. Signature coagulation analyzer. J Extra Corpor Technol 2002;34:182 –184. 2002;71:433 –439. 69. Jaryno S, Bennett K, Loder C, et al. Validation of a new whole blood coagulation 37. Bauer KA. Clinical use of fondaparinux. Up to date. 2004 Online 12.1. monitoring system. J Extra Corpor Technol 2002;34:271 –275. 38. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxa - 70. Uden DL, Seay RE, Kriesmer PJ, et al. The effect of heparin on three whole blood parin in acute coronary syndromes. N Engl J Med 2006;354:1464 –1476. activated clotting tests and thrombin time. ASAIO Trans 1991;37:88 –91. 39. Cella G, Girolami A, Sasahara AA. Platelet activation with unfractionated heparin 71. Colby CE, Sheehan A, Benitz W, et al. Maintaining adequate anticoagulation on ex - at therapeutic concentrations and comparison with low-molecular-weight heparin tracorporeal membrane oxygenation therapy: Hemochron Junior Low Range versus and with a direct thrombin inhibitor. Circulation 1999;99:3323. Hemochron 400. J Extra Corpor Technol 2003;35:35 –38. 40. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic 72. Avendano A, Ferguson JJ. Comparison of Hemochron and HemoTec activated co - concentrations and comparisons with a low-molecular-weight heparin and with a di - agulation time target values during percutaneous transluminal coronary angioplasty. rect thrombin inhibitor. Circulation 1998;97:251 –256. J Am Coll Cardiol 1994;23:907 –910. 41. Sobel M, Fish WR, Toma N, et al. Heparin modulates integrin function in human 73. Cohen M. Monitoring Anticoagulation during percutaneous coronary interventions. platelets. J Vasc Surg 2001;33:587 –594. J Thromb Thrombolysis 1995;1:285 –288. 42. Komarnicki M, Kazmierczak M, Haertle D. Standard heparin and low molecular 74. Koster A, Despotis G, Gruendel M, et al. The plasma supplemented modified acti - weight heparin effect on spontaneous platelet aggregation measured in whole blood vated clotting time for monitoring of heparinization during cardiopulmonary by - and in platelet-rich plasma. Acta Haematol Pol 1993;24:263 –265. pass: A pilot investigation. Anesth Analg 2002;95:26 –30, Table of contents. 43. Eika C. Platelet refractory state induced by heparin. Scand J Haemato l 1972;9:665 –672. 75. Paniccia R, Fedi S, Carbonetto F, et al. Evaluation of a new point-of-care celite-ac - 44. Salzman EW, Rosenberg RD, Smith MH, et al. Effect of heparin and heparin frac - tivated clotting time analyzer in different clinical settings. The i-STAT celite-acti - tions on platelet aggregation. J Clin Invest 1980;65:64 –73. vated clotting time test. Anesthesiology 2003;99:54 –59. 45. Chong BH, Ismail F. The mechanism of heparin-induced platelet aggregation. Eur 76. Raymond PD, Ray MJ, Callen SN, Marsh NA. Heparin monitoring during cardiac J Haematol 1989;43:245 –251. surgery. Part 1: Validation of whole-blood heparin concentration and activated clot - 46. Chen JH, Karlberg KE, Sylven C. Heparin and low molecular weight heparin but ting time. Perfusion 2003;18:269 –276.

Vol. 21, No. 12, December 2009 663 MARMUR , et al.

77. Murray DJ, Brosnahan WJ, Pennell B, et al. Heparin detection by the activated co - a pure factor Xa inhibitor, as an antithrombotic agent — A pilot study in the setting agulation time: A comparison of the sensitivity of coagulation tests and heparin as - of coronary angioplasty. Thromb Haemost 1999;81:214 –220. says. J Cardiothorac Vasc Anesth 1997;11:24 –28. 87. Natarajan MK, Velianou JL, Turpie AG, et al. A randomized pilot study of dalteparin 78. Iqbal O, Ahmad S, Lewis BE, et al. Monitoring of argatroban in ARG310 study: versus unfractionated heparin during percutaneous coronary interventions. Am Heart Po tential recommendations for its use in interventional cardiology. Clin Appl Thromb J 2006;151:175. Hemost 2002;8:217 –224. 88. Moliterno DJ, Hermiller JB, Kereiakes DJ, et al. A novel point-of-care enoxaparin 79. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or monitor for use during percutaneous coronary intervention. Results of the Evaluating unfractionated heparin: The ASSENT-3 randomised trial in acute myocardial infarc - Enoxaparin Clotting Times (ELECT) study. J Am Coll Cardiol 2003;42:1132 –1139. tion. Lancet 2001;358:605 –613. 89. Lawrence M, Mixon TA, Cross D, et al. Assessment of anticoagulation using activated 80. Kereiakes DJ, Grines C, Fry E, et al. Enoxaparin and abciximab adjunctive pharma - clotting times in patients receiving intravenous enoxaparin during percutaneous coro - cotherapy during percutaneous coronary intervention. J Invasive Cardiol nary intervention. Catheter Cardiovasc Interv 2004;61:52 –55. 2001;13:272 –278. 90. Chew DP, Bhatt DL, Lincoff AM, et al. Defining the optimal activated clotting 81. Bhatt DL, Lee BI, Casterella PJ, et al. Safety of concomitant therapy with eptifibatide time during percutaneous coronary intervention: Aggregate results from 6 random - and enoxaparin in patients undergoing percutaneous coronary intervention: Results ized, controlled trials. Circulation 2001;103:961 –966. of the Coronary Revascularization Using Integrilin and Single bolus Enoxaparin 91. Brener SJ, Moliterno DJ, Lincoff AM, et al. Relationship between activated clotting study. J Am Coll Cardiol 2003;41:20 –25. time and ischemic or hemorrhagic complications: Analysis of 4 recent randomized 82. Kereiakes DJ, Kleiman NS, Fry E, et al. Dalteparin in combination with abciximab clinical trials of percutaneous coronary intervention. Circulation 2004;110:994 –998. during percutaneous coronary intervention. Am Heart J 2001;141:348 –352. 92. Valgimigli M, Percoco G, Barbieri D, et al. The additive value of tirofiban admin - 83. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin istered with the high-dose bolus in the prevention of ischemic complications during in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006 –1017. high-risk coronary angioplasty: The ADVANCE Trial. J Am Coll Cardiol 84. Dumaine R, Borentain M, Bertel O, et al. Intravenous low-molecular-weight he - 2004;44:14 –19. parins compared with unfractionated heparin in percutaneous coronary intervention: 93. Marmur JD, Poludasu S, Agarwal A, et al. Bolus-only platelet glycoprotein IIb-IIIa Quantitative review of randomized trials. Arch Intern Med 2007;167:2423 –2430. inhibition during percutaneous coronary intervention. J Invasive Cardiol 85. Kereiakes DJ, Montalescot G, Antman EM, et al. Low-molecular-weight heparin 2006;18:521 –526. therapy for non-ST-elevation acute coronary syndromes and during percutaneous 94. Marmur JD, Poludasu S, Agarwal A, et al. High-dose tirofiban administered as coronary intervention: An expert consensus. Am Heart J 2002;144:615 –624. bolus-only during percutaneous coronary intervention. J Invasive Cardiol 86. Vuillemenot A, Schiele F, Meneveau N, et al. Efficacy of a synthetic pentasaccharide, 2008;20:53 –58.

664 The Journal of Invasive Cardiology