Low-Molecular-Weight Heparins in the Treatment of Acute Coronary Syndromes

REVIEW ARTICLE Low-Molecular-Weight Heparins in the Treatment of Acute Coronary Syndromes

Alexander G. G. Turpie, MD; Elliott M. Antman, MD

latelet aggregation and activation of coagulation are key events in the development of acute coronary syndromes. Patients with an acute coronary syndrome are at high risk of death or myocardial infarction, and hence there is a strong rationale for the use of antithrombotic agents. Heparin has been shown to reduce the risk of death or myocar- Pdial infarction in aspirin-treated patients with acute coronary syndromes, but it has a number of limitations, including the need for regular monitoring and the risk of hemorrhage and thrombocytopenia. Low-molecular-weight heparins offer a number of practical and clinical advantages over unfractionated heparin, such as higher bioavailability and administration by subcutaneous injection. Several low-molecular-weight heparins are available that differ in their biochemical and pharmacologic properties, and it is not possible to predict their clinical efficacy from their pharmacologic profile. The decision regarding the use of a specific low-molecular-weight heparin should be based on the efficacy and safety data available for each product. In clinical trials comparing low- molecular-weight heparin with heparin, only enoxaparin sodium has been shown to reduce the risk of coronary events in patients with non–ST segment elevation acute coronary ischemia. Arch Intern Med. 2001;161:1484-1490

Clinical and pathologic studies have high- gina and non–Q wave MI indicates that the lighted the importance of plaque rupture culprit artery is only partially or intermit- and platelet aggregation in the pathogen- tently occluded or that a rich collateral cir- esis of the acute coronary syndromes (ACS) culation exists. Nonocclusive intracoro- of Q wave myocardial infarction (MI), nary thrombi are present in 85% or more non–Q wave MI, and unstable angina.1,2 Fol- of patients with non–ST segment elevation lowing rupture of an atherosclerotic plaque, ACS,1 and autopsy studies in such patients tissue factor in the lipid core is exposed to suggest that vascular occlusion that leads to circulating factor VIIa, resulting in the for- MI or sudden death results from repeated mation of a tissue factor–factor VIIa com- episodes of plaque fissure and mural throm- plex and generation of factor Xa.3,4 This leads bosis.2,7 Such lesions are often not stabi- ultimately to the formation of large amounts lized by therapy focused only on symptom of thrombin, resulting in fibrin deposition relief, but continue to progress and cause and platelet activation.5,6 Electrocardio- ischemic events throughout several graphic evidence of ST segment elevation months.8,9 As a result, patients with ACS are indicates that the culprit artery is com- at increased risk of death and MI. Death or pletely occluded and that the patient will MI occurs in 9% to 11% of patients with most likely subsequently develop ST seg- non–ST segment elevation ACS within 4 to ment elevation MI. The absence of ST seg- 6 weeks after the onset of symptoms,10,11 and ment elevation in patients with unstable an- recurrent angina occurs in up to 64% of patients who are hospitalized.12 From the Department of Medicine, McMaster University, Hamilton, Ontario The key roles of thrombin genera- (Dr Turpie), and Cardiovascular Division, Department of Medicine, Brigham and tion and platelet activation in the patho- Women’s Hospital, Boston, Mass (Dr Antman). genesis of ACS create a strong rationale for

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 the use of antithrombotic agents in need to be continuously adjusted that a number of other actions con- the management of these condi- according to the activated partial tribute to the antithrombotic effects tions. Current management guide- thromboplastin time, and even with of these agents. Indeed, it is now rec- lines13 recommend that patients with adjustment dosing is often subthera- ognized that up to 70% to 80% of the unstable angina should receive as- peutic, making long-term treat- material contained in a dose of pirin, at doses between 75 and 325 ment impractical.21 This is an im- LMWH acts via mechanisms that are mg, unless clear contraindications portant issue because long-term independent of antithrombin.28,29 are present. These guidelines are treatment may be beneficial in pa- Such mechanisms include the fol- supported by a 1983 study14 in which tients with ACS: the risk of ische- lowing: release of tissue factor path- the incidence of death or MI in men mic events remains significant for way inhibitor (TFPI), interaction with unstable angina who were several weeks after the initial epi- with heparin cofactor II, inhibition treated with 325 mg/d of aspirin sode,21 and the coagulation system of procoagulant effects of leuko- compared with placebo was re- can remain activated for several cytes, promotion of fibrinolysis, produced by 51% (P=.0005). The risk months.22,23 Furthermore, UFH treat- tein binding, and effects on vascu- of nonfatal MI was also signifi- ment is associated with significant lar endothelium (receptor mediated cantly lower in aspirin-treated pa- complications, including hemor- and receptor independent). In par- tients than in the placebo group and rhage,19 reactivation of the thrombotic ticular, the effects of LMWHs on mortality was reduced, although not process within hours of discontinu- TFPI have attracted increasing at- significantly. Subsequently, several ing treatment,24 heparin-induced tention. Tissue factor pathway in- large controlled trials in patients with thrombocytopenia,25 and a rebound hibitor is a glycoprotein that inhib- unstable angina treated with aspi- increase in thrombotic activity and its the factor VIIa–tissue factor rin at daily doses between 75 and clinical events after discontinuation complex by forming a quaternary 325 mg demonstrated a significant of treatment.22,26 complex with the factor VIIa– reduction in death, MI, or both.15-18 Low-molecular-weight hepa- tissue factor complex and factor Xa.30 Unfractionated heparin (UFH) rins (LMWHs) offer a number of po- In addition, it inhibits factor Xa by has also been used, alone or in com- tential advantages over UFH in the binding at or near the active site30 bination with aspirin, in patients management of ACS. They have a and has a variety of other antithrom- with unstable angina, since it inhib- higher ratio of anti-Xa–anti-IIa ac- botic effects, which include the fol- its thrombin-induced platelet aggre- tivity than UFH (thereby offering a lowing: inhibition of tissue factor– gation and fibrin formation and thus potentially greater antithrombotic ef- mediated activation of platelets and prevents propagation of an estab- fect), and as a result of the cascad- macrophages, inhibition of factor Xa lished thrombus. Indeed, combina- ing nature of the coagulation sys- and elastase, multidomain inhibitor tion treatment with aspirin and UFH tem, inhibition of a small quantity of protease generation, interactions has previously been recommended of factor Xa prevents the formation with low-density lipoproteins, inter- for patients with unstable angina or of considerably larger amounts of actions with vascular endothelium, non–ST segment elevation MI be- thrombin.6 Other potential advan- modulation of endogenous gly- cause of the accumulating trial evi- tages include a high bioavailability cosaminoglycans, neutralization of dence showing the benefit of such after subcutaneous administration; endogenous tissue factor, and pos- treatment.13 In an early clinical trial, more predictable anticoagulant ef- sible regulatory functions.29 Both UFH treatment with UFH was associ- fect, which avoids the need for thera- and LMWHs release TFPI from the ated with reduced incidences of MI peutic monitoring; and decreased vascular endothelium.30,31 and refractory angina, compared sensitivity to platelet factor 4.6 Al- The LMWHs are prepared by a with placebo, and UFH tended to re- though these features are common variety of chemical and enzymatic duce the incidence of MI to a greater to all LMWHs, it is important to note depolymerization techniques, re- extent than aspirin.17 In a subse- that LMWHs are a heterogeneous sulting in marked differences in their quent extension of this study, the in- group of compounds that differ physical and biochemical proper- cidence of MI was significantly lower markedly in their physical and phar- ties.27,28,32 Such variations in biologi- in UFH-treated patients than in pa- macologic properties. Thus, each cal activity among LMWHs include tients receiving aspirin (0.8% vs LMWH must be tested in each clini- the following: variations in affinity 3.7%; P=.035).19 A meta-analysis of cal indication and the results ob- for coagulation proteins (eg, anti- published trials found that the risk tained with one LMWH do not ap- thrombin, platelet factor 4, fibrino- of death or MI was reduced by 33% ply to another. gen, protamine, factor VIII), differ- in patients with unstable angina who ences in binding to endothelial cells received both aspirin and UFH, com- LMWHs IN ACS: and blood cells, differences in pro- pared with those who received as- PHARMACOLOGIC tease inhibition, and differences in pirin alone, which suggests that the CONSIDERATIONS bioavailability and pharmacokinet- addition of heparin provides fur- ics. Typically, LMWHs have mo- ther benefit in aspirin-treated pa- The potency of LMWH is normally lecular weights between 4000 and tients.20 However, the use of UFH is expressed in terms of the anti-Xa ac- 8000 kd, but the available prepara- associated with significant disad- tivity.27,28 However, with increasing tions differ in their molecular weight vantages. The anticoagulant effect understanding of the mechanisms of distribution: some show a wide dis- produced is unpredictable and doses action of LMWHs, it has become clear tribution of low- and high-molecu-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 lar-weight components, whereas be magnified, are required for the the observed reduction was not sta- with others the distribution is much prevention of ischemic events in tistically significant between the narrower.32 Because the antithrom- patients with ACS, and thus differ- groups after 3 months. The inci- botic effects of LMWHs depend on ences in efficacy and safety may dence of death or MI at 6 months the relative distribution of me- become clinically evident in these was 13.3% in the dalteparin group dium- (Ͼ9500 kd) and low- (Ͻ3500 situations. The efficacy of a given and 13.1% in the placebo group, and kd) molecular-weight compo- LMWH in ACS depends on interac- long-term dalteparin treatment was nents,32 this variation has impor- tions between numerous biological associated with an increased risk of tant implications for the biological activities that are complex and not major bleeding complications, com- activity of LMWHs. Furthermore, yet completely understood, includ- pared with that in the placebo group chemical depolymerization pro- ing anti-Xa and anti-IIa activities, re- (3.3% vs 1.5%, respectively). cesses tend to reduce antithrombin lease of TFPI, and effects on the vas- binding activity, contributing to the cular endothelium. As a result, it is Comparisons With UFH variation in anti-Xa activity among currently not possible to predict the products.27,28 clinical effect of LMWHs from their Dalteparin. In the Fragmin in Un- Differences in biological activ- pharmacologic profiles in labora- stable Coronary Artery Disease ity among LMWHs have been docu- tory studies. Hence, the use of a (FRIC) study, 1482 patients re- mented in a series of studies.27-29 In given LMWH in ACS must be based ceived either dalteparin, 120 IU/kg anticoagulant assays, the specific ac- on firm evidence from well-de- twice daily, or adjusted doses of UFH tivity ranges from 35 to 45 anti-IIa signed clinical trials. for 6 days, after which they were ran- U/mg or 80 to 120 anti-Xa U/mg,28 domly assigned dalteparin, 7500 IU and the ratios of anti-Xa to anti-IIa LMWHs IN ACS: A REVIEW OF once daily, or placebo for a further activities also differ; enoxaparin so- THE CLINICAL EVIDENCE 39 days.37 The incidence of death, dium and nadroparin calcium, for MI, or recurrent angina during the example, have anti-Xa–anti-IIa ra- A number of controlled clinical tri- first 6 days was 7.6% in patients re- tios of approximately 3:1, whereas als have investigated the use of ceiving UFH and 9.3% in dalteparin- dalteparin sodium has a ratio of ap- LMWHs in patients with ACS.11,34-39 treated patients; during the double- proximately 2:1.29 Similarly, the an- Details of these trials are summa- blind treatment period, the incidence tithrombotic effect of different prod- rized in the Table. of this composite end point was ucts varies markedly. In a rabbit 12.3% in both the placebo and model of venous thrombosis, for ex- Placebo-Controlled Trials dalteparin groups. Thus, treatment ample, enoxaparin and nadroparin of ACS with dalteparin did not show were found to be more effective than The Fragmin during Instability in long-term benefits. dalteparin and logiparin.27 More- Coronary Artery Disease (FRISC) over, LMWHs also differ in their study,11 which was the only large pla- Nadroparin. In clinical trials of the ability to release endogenous TFPI; cebo-controlled trial we found, com- LMWH nadroparin, inconsistent re- following intravenous administra- pared the effects of subcutaneous sults have been reported. For ex- tion of 100-U/kg doses in primates, dalteparin and placebo in 1506 as- ample, in the recent Fraxiparine in circulating TFPI concentrations pirin-treated patients with un- Ischemic Syndrome (FRAXIS) study ranged from 110 (dalteparin) to 150 stable angina or non–Q wave MI. (N=3468), the incidence of coro- ng/mL (logiparin).27 During the first 6 days, the inci- nary events (death, MI, refractory Such findings raise the question dence of death or MI was signifi- angina, or recurrence of unstable an- of whether differences in pharmaco- cantly lower in dalteparin-treated pa- gina) in patients receiving nadropa- logic properties among LMWHs tients than in the placebo group rin, 86 anti-Xa U/kg twice daily, for are clinically relevant. In laboratory (1.8% vs 4.8%; P=.001). However, 5 to 7 days or for 14 days was com- studies,theantithromboticandbleed- during long-term treatment for 35 parable with that in patients treated ing effects of a given LMWH de- to 45 days with a lower dosage of with UFH at doses adjusted accord- pend on a number of factors, includ- dalteparin (7500 IU/d), there was an ing to the activated partial throm- ing the animal model used and the apparent reactivation of disease, and boplastin time.35 By contrast, in a route of administration32; thus, the therefore the incidence of death or previous smaller study of just 219 clinical significance of such differ- MI at 40 days did not differ signifi- patients,36 the incidence of coro- ences is difficult to assess. Differ- cantly between the groups. In the nary events in patients receiving as- ences in efficacy and safety between subsequent FRISC II study,34 pa- pirin plus a high dosage of nadro- LMWHs have been considered to be tients received open-label daltepa- parin (214 Institut Choay units per small in clinical practice.28,33 How- rin for at least 5 days, they were then kilogram twice daily) was signifi- ever, most comparisons between dif- randomly assigned either invasive or cantly lower than in patients treated ferent agents have been made on the noninvasive treatment, and they with aspirin plus UFH or aspirin basis of the clinical experience ob- were randomly allocated treatment alone. tained with the low doses required with dalteparin or placebo for 3 for the prophylaxis of deep vein months. The risk of death or MI was Enoxaparin. Two recent studies with thrombosis.28 Higher doses, where reduced by 47% (P=.002) in daltepa- enoxaparin38,39 have independently any pharmacologic differences may rin-treated patients at 30 days, but shown that this agent is more effec-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Clinical Trials With Low-Molecular-Weight Heparins in Patients With Acute Coronary Syndromes*

Trial Patients Treatment Outcome Placebo-Controlled Trials FRISC11 1506 Patients with unstable angina or Placebo or dalteparin, 120 IU/kg twice 63% Reduction in risk of death or MI non–Q wave MI daily, for 6 d, then 7500 IU once daily during first6d(P= .001); 25% for 35-45 d reduction (not significant) at day 40 FRISC II34 2267 Patients with ischemic symptoms Open-label phase: dalteparin, 120 IU/kg 47% Reduction (P = .002) in risk of at rest or increasing in frequency twice daily for at least 5 d death or MI at 30 d; no significant Double-blind phase: placebo or difference at 3 mo dalteparin, 7500 IU twice daily (5000 IU in men weighing Ͻ70 kg or women weighing Ͻ80 kg), for 3 mo Comparisons With UFH Gurfinkel et al36 219 Patients with unstable angina Aspirin, 200 mg/d, alone or with UFH, Nadroparin treatment was associated 400 IU/kg titrated according to aPTT, with lower incidences of recurrent or nadroparin, 214 UIC/kg every 12 h, angina, MI, or urgent for 5-7 d revascularization compared with aspirin plus UFH FRAXIS35 3468 Patients with unstable angina or Nadroparin, 86–anti-Xa U/kg bolus No significant difference between the non–Q wave MI followed by 86–anti-Xa U/kg twice groups in incidence of death, MI, daily for6±2or14d,orUFH, refractory angina, or recurrence of 5000-IU bolus followed by infusion at unstable angina doses adjusted according to aPTT FRIC37 1482 Patients with unstable angina or Open phase: dalteparin, 120 IU/kg twice No significant difference between non–Q wave MI daily, or UFH for 6 d dalteparin and UFH in risk of death, Double-blind phase: dalteparin, 7500 IU MI, or recurrent angina at day once daily or placebo 6 (7.6% vs 9.3%, respectively); no difference between dalteparin and placebo groups at day 45 (incidence, 12.3% in both groups) ESSENCE38 3171 Patients with unstable angina or Enoxaparin, 1 mg/kg twice daily, or UFH, 20% Reduction (P = .02) in risk of non–Q wave MI adjusted according to aPTT, for 2-8 d death, MI, or recurrent angina at 14 d; 19% reduction (P = .02) at 30 d; 10% risk reduction at1y(P= .022) TIMI 11B39 3910 Patients with unstable angina or Acute phase: enoxaparin, 30-mg bolus 17% Reduction (P = .048) in death, MI, non–Q wave MI followed by 1 mg/kg twice daily, or or urgent revascularization at day 8; UFH, adjusted according to aPTT, for 15% reduction (P = .048) at day 43 28 d Outpatient phase: enoxaparin, 60 mg twice daily (40 mg twice daily for patients weighing Ͻ65 kg) or placebo (in patients originally assigned to UFH) until day 43

*FRISC indicates Fragmin during Instability in Coronary Artery Disease; MI, myocardial infarction; UFH, unfractionated heparin; aPTT, activated partial thromboplastin time; FRAXIS, Fraxiparine in Ischemic Syndrome; FRIC, Fragmin in Unstable Coronary Artery Disease; ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events; TIMI 11B, Thrombolysis in Myocardial Infarction 11B; and UIC, Institut Choay units. Dalteparin was given as dalteparin sodium, nadroparin as nadroparin calcium, and enoxaparin as enoxaparin sodium.

tive than UFH in preventing coro- reduction of 20% (P=.019). The re- largely ecchymosis at the injection nary events in patients with ACS. duction in the incidence of the com- sites. In the Efficacy and Safety of Sub- posite end point was maintained and The Thrombolysis in Myocar- cutaneous Enoxaparin in Non–Q was significantly lower in the enoxa- dial Infarction (TIMI) 11B study39 Wave Coronary Events (ESSENCE) parin group at 30 days (19.8% vs (N=3910) was similar in design to study,38 3171 patients with angina 23.3%, respectively; P=.016). The the ESSENCE study, except that at rest or non–Q wave MI were ran- proportion of patients requiring enoxaparin was given as an initial domly assigned either enoxaparin, coronary revascularization was also 30-mg intravenous bolus, followed 1 mg/kg (100 anti-Xa U/mg) every significantly lower in the enoxapa- by injections of 1 mg/kg every 12 12 hours, or adjusted doses of UFH rin group at this time (27% vs 32.2%; hours, and the short-term treat- for up to 8 days; in addition, all pa- P =.001). Long-term follow-up ment phase was followed by a tients received oral aspirin at daily showed that the beneficial effect of 5-week outpatient placebo compari- doses between 100 and 325 mg. Af- enoxaparin was still evident after 1 son using a lower dose of enoxapa- ter 14 days, death, MI, or recurrent year.40 There was no significant dif- rin. After 8 days, the composite end angina had occurred in 19.8% of pa- ference in the incidence of serious point of death, MI, or urgent revas- tients receiving UFH, compared with hemorrhagic complications be- cularization had occurred in 14.5% 16.6% of patients in the enoxapa- tween the 2 groups, but there was of patients receiving UFH and 12.4% rin group; this corresponds to a risk an increase in minor hemorrhage, of enoxaparin-treated patients, which

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 corresponds to a risk reduction of examine differences in efficacy at just cal end points may also have con- 17% (P=.048). The corresponding 72 hours; to do so would have ne- tributed to the differences between figures at 14 days for the same com- cessitated a much larger trial be- individual trial results.45 posite end point were 16.7% and cause of the low number of events 14.2%, respectively (P=.029). At the at this early time point. It is no- Differences in Study Populations end of the outpatient phase on day 43, table, however, that when the data the beneficial effects of enoxaparin from TIMI 11B and ESSENCE are Differences in the patient popula- seen during the short-term phase were combined, there is a strong trend to- tions studied may have contrib- maintained during 7 weeks of long- ward a benefit of enoxaparin for the uted to the variation in outcome, term treatment (although continued composite end point of death and MI since there is some evidence that pa- treatment provided no additional ben- (enoxaparin, 1.9%, vs UFH, 2.5%; tients at the highest risk of coro- efit); the composite end point had odds ratio, 0.77; 95% confidence in- nary events derive even greater ben- occurred in 19.7% of UFH-treated terval, 0.56-1.01) and a significant efit from treatment with LMWH patients and 17.3% of enoxaparin- benefit in the composite end point compared with UFH therapy. In the treated patients (P=.048). As in the of death, MI, and recurrent angina FRISC II study, treatment with ESSENCE study, there was no sig- requiring urgent revascularization dalteparin was associated with a re- nificant difference in the rates of ma- (enoxaparin, 6.4%, vs UFH, 8.1%; duced incidence of death or MI at 3 jor bleeding complications during the odds ratio, 0.78; 95% confidence in- months in patients with elevated tro- initial hospitalization between treat- terval, 0.65-0.94). ponin T concentrations at baseline, ment groups. However, during the Economic analysis of the data but not in patients with normal tro- outpatient phase, major hemor- from the ESSENCE trial has shown ponin T concentrations.34 In the rhages occurred in 2.9% of enoxapa- that the added treatment benefits of ESSENCE and TIMI 11B studies, for rin-treated patients and 1.5% of pla- enoxaparin and the reduction in example, although there was a rela- cebo-treated patients (P=.021). hospital costs due to the ease of use tive reduction in coronary events The data from the TIMI 11B and lack of need for coagulation achieved with enoxaparin in all pa- and ESSENCE studies were com- monitoring result in cost benefits tients compared with UFH, the ben- bined in a prospectively planned of using enoxaparin in place of efit was greater in patients with risk meta-analysis to provide statisti- UFH.44 factors such as ST-segment depres- cally robust estimates of the effects sion or electrocardiographic changes of enoxaparin on specific end VARIATION IN EFFICACY at baseline or a previous history of points.41,42 This analysis showed that OF LMWHs IN ACS: FACT aspirin use.38,41 Similarly, in trials the incidence of death or MI was sig- OR ARTIFACT? with glycoprotein IIb/IIIa inhibi- nificantly reduced in enoxaparin- tors, patients at highest risk have treated patients from day 8 to day 43; Although the differing results ob- derived the greatest treatment similarly, the incidence of death, MI, tained in clinical trials with differ- benefit.46 Differences in study de- or urgent revascularization was con- ent LMWHs in ACS would be con- signs, however, do not preclude sistently about 20% lower in enoxa- sistent with the heterogeneous genuine differences in efficacy parin-treated patients than in pa- nature of this group of agents, it is among LMWHs. tients treated with UFH from day 2 necessary to consider the possibil- to day 43. The pooled incidence of ity that these discrepancies are at- POTENTIAL BIOCHEMICAL major hemorrhagic complications tributable to differences in study de- BASIS FOR PRODUCT during short-term treatment was signs or study populations rather DIFFERENCES 1.3% in the enoxaparin group than true differences in efficacy and 1.1% in the UFH group (P=.35). among the LMWHs. The LMWHs show considerable The incidence of minor hemor- variation in their biochemical prop- rhages during the short-term phase Differences in Study Designs erties, and it is this variation that may was 10.0% and 4.3%, respectively underlie the differing results seen in (PϽ.001). A recently published The doses of LMWH and UFH used clinical trials focusing on ACS. meta-analysis by Eikelboom et al43 in these studies differed, as did the commented that the pooled LMWH duration of treatment and the tim- Anti-Xa Activity trial data did not show a benefit of ing of the first dose after the onset LMWH over UFH in unstable an- of symptoms. In the study by Gur- Although the anti-Xa activity of a gina and non–ST segment eleva- finkel et al,36 the ESSENCE study,38 LMWH does not directly predict an- tion MI. The article highlighted that and the TIMI 11B study,39 for ex- tithrombotic activity,29 it is note- in the TIMI 11B and ESSENCE stud- ample, patients were allocated treat- worthy that there were marked varies, at 72 hours (when the treatment within 24 hours of the onset iations in the anti-Xa activities and ment durations of both UFH and of chest pain, whereas in the the anti-Xa–anti-IIa ratios of the enoxaparin were equal in most pa- FRISC,11 FRISC II,34 and FRAXIS35 LMWHs used in different trials. tients) there was no real benefit of studies, patients were randomly as- Enoxaparin has a higher anti-Xa– enoxaparin over UFH in the “hard signed treatment up to 48 or 72 anti-IIa ratio than LMWHs, such as end point” of death and MI. Nei- hours after the onset of symptoms. dalteparin, which have not shown ther of these trials were powered to Differences in the definitions of clini- consistently favorable results in clini-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 cal trials, although the anti-Xa–anti- hours after admission with ACS and chemical bases for differences in ef- IIa ratio of nadroparin is similar to that the magnitude of this increase ficacy among LMWHs, but direct enoxaparin and the clinical study re- was predictive of a poor outcome. In comparisons among the LMWHs are sults to date with nadroparin have addition, vWF mediates platelet ad- required to determine the superior- not shown a consistent treatment hesion to the vascular endothelium ity of one over another. benefit.6,35,36 Moreover, the trough and thus plays a key role in throm- anti-Xa activities reported with bus formation. In enoxaparin- Accepted for publication January 9, dalteparin in the FRIC study37 (0.35- treated patients, the increase in vWF 2001. 0.37 anti-Xa IU/mL) were lower than concentrations was significantly at- This study was supported by a those obtained with the enoxapa- tenuated (mean increase of 8.7% grant from Aventis Pharma, Parsip- rin dose used in the ESSENCE and compared with 93.9% in patients re- pany, NJ. TIMI 11B studies (0.5-0.6 anti-Xa ceiving UFH, PϽ.001).49 The reduc- Corresponding author and re- IU/mL).47 The finding in the FRIC tion in vWF concentrations seen in prints: Alexander G. G. Turpie, MD, study that long-term treatment with the ESSENCE substudy may there- HHSC-General Division, 237 Barton dalteparin did not reduce the inci- fore contribute to the antithrom- St E, Hamilton, Ontario, Canada L8L dence of coronary events suggests botic effect of enoxaparin. This re- 2X2 (e-mail: [email protected]). that the dose of dalteparin may have duction may be a result of the been too low or the interval be- binding of enoxaparin to the hepa- REFERENCES tween doses too long to provide ef- rin-binding domain of vWF, result- 37 fective anticoagulant cover. Im- ing in impaired binding of vWF to 1. Davies MJ, Thomas AC. Plaque fissuring: the cause portantly, the higher anti-Xa platelets, or to a decrease in throm- of acute myocardial infarction, sudden ischemic activities obtained with enoxaparin bin-induced release of vWF.6 Re- death, and crescendo angina. Br Heart J. 1985; in ESSENCE and TIMI 11B were not cently, a small study50 of vWF in 53:363-373. 2. Fuster V, Badimon L, Badimon JJ, Chesebro JH. associated with an increased risk of 154 patients with ACS revealed The pathogenesis of coronary artery disease and major bleeding. that patients treated with enoxapa- the acute coronary syndromes. 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Effects of tissue plas- minogen activator and a comparison of early in- basis for the different clinical ben- use of a given LMWH should be vasive and conservative strategies in unstable an- efits of these compounds. based on the efficacy and safety data gina and non–Q-wave myocardial infarction: available for each specific product. results of the TIMI IIIB trial. Circulation. 1994;89: von Willebrand Factor The LMWHs have been shown to be 1545-1556. 11. Fragmin during Instability in Coronary Artery Dis- effective in reducing ischemic out- ease (FRISC) Study Group. Low-molecular- 49 A recent substudy of the ESSENCE comes in ACS. weight heparin during instability in coronary ar- trial has highlighted another poten- The LMWH enoxaparin has tery disease. Lancet. 1996;347:561-568. tial mechanism by which enoxapa- been shown to reduce the risk of 12. van Miltenburg-van Zijl AJ, Simoons ML, Veer- rin may exert its beneficial effect in acute coronary events and the need hoek RJ, Bossuyt PM. 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