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Review Article |

Low-Molecular-Weight Heparins in the Management of Acute Coronary Syndromes FREE

Peter J. Zed, PharmD; James E. Tisdale, PharmD; Steven Borzak, MD
[+] Author Affiliations

From CSU Pharmaceutical Sciences, Vancouver Hospital and Health Sciences Center, and the Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver (Dr Zed); and the Department of Pharmacy Practice, College of Pharmacy and Allied Health Professions, Wayne State University and Department of Pharmacy Services (Dr Tisdale), and the Cardiac Intensive Care Unit, Division of Cardiovascular Medicine (Dr Borzak), Henry Ford Hospital, Detroit, Mich.


Arch Intern Med. 1999;159(16):1849-1857. doi:10.1001/archinte.159.16.1849.
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Acute coronary syndromes (unstable angina and non–Q-wave myocardial infarction) are caused by the rupture of an atherosclerotic plaque, platelet activation, and fibrin deposition resulting in thrombosis. Aspirin and unfractionated heparin have traditionally been the treatments of choice for patients with acute coronary syndromes. Low-molecular-weight heparins offer potential advantages over unfractionated heparin, having proven equally effective for the treatment and prevention of many thromboembolic processes. Recently, a number of randomized controlled trials have been conducted to evaluate the role of low-molecular-weight heparins in the management of patients with unstable angina or non–Q-wave myocardial infarction. The purpose of this article is to review and evaluate the available literature on the use of low-molecular-weight heparins in the management of acute coronary syndromes to establish their role in therapy.

Figures in this Article

The initiating event of the acute coronary syndromes (unstable angina and non–Q-wave myocardial infarction) involves the rupture of an atherosclerotic plaque resulting in the platelet activation and fibrin deposition that leads to thrombosis.1 Evidence that both platelet activation and thrombin generation are involved in the thrombotic process provides a rationale for the use of both aspirin and unfractionated heparin (UFH) in the management of acute coronary syndromes. There has been much research and debate in the past decade on the value of these agents alone or in combination.28 Aspirin and UFH have become the standard practice for treatment of patients presenting with unstable angina or non–Q-wave myocardial infarction. Low-molecular-weight heparins (LMWHs) have recently been marketed in North America and offer potential advantages over UFH. The purpose of this article is to review and evaluate the available literature on the use of LMWHs in the management of acute coronary syndromes and to provide recommendations for their role in therapy.

Unfractionated heparin is a heterogeneous polydispersed mixture of sulfated polysaccharides ranging in molecular weight from 5000 to 30,000 d (average molecular weight, 12,000-15,000 d).9 Its major anticoagulant effect is attributed to a unique pentasaccharide sequence with high affinity for antithrombin III (ATIII).9 Binding of heparin to ATIII produces a conformational change in this protein, accelerating the ability to inactivate the coagulation enzymes thrombin (factor IIa), factor Xa, and factor IXa. Of these 3 enzymes, thrombin is the most sensitive to inhibition by the heparin/ATIII complex.1013 Unfractionated heparin accelerates the inactivation of thrombin by ATIII by acting as a template to which both the enzyme and the inhibitor bind to form a ternary complex. In contrast, the inactivation of factor Xa does not require a ternary complex and is achieved by binding directly to ATIII.14 The ability of UFH to inhibit thrombin is dependent on saccharide chain length and ultimately molecular weight. Thus, UFH molecules that contain fewer than 18 saccharide units are unable to bind thrombin and ATIII simultaneously and therefore are unable to accelerate the inactivation of thrombin. However, they do retain their ability to catalyze the inactivation of factor Xa.14,15

Unfractionated heparin is not absorbed following oral administration and therefore must be given by intravenous (IV) or subcutaneous (SC) injection. The efficacy and safety of UFH when administered by either continuous IV infusion or by the SC route are comparable provided that the doses are adequate.16 Following its injection and passage into the bloodstream, UFH binds to a number of plasma proteins including histidine-rich glycoprotein, platelet factor 4, vitronectin, fibronectin, and von Willebrand factor.9 The binding of UFH to these proteins results in reduced bioavailability, variable anticoagulant response, and the phenomenon known as heparin resistance.17 Unfractionated heparin also binds to macrophages and endothelial cells, another reason for its complicated pharmacokinetics. Unfractionated heparin is cleared through the combination of a rapid, concentration-dependent (saturable) mechanism and a much slower nonsaturable mechanism. The concentration-dependent mechanism results from UFH binding to macrophages and endothelial cells. Clearance through the much slower nonsaturable mechanism is partially through renal excretion. The apparent biological half-life of UFH is dose dependent, increasing from 30 minutes with an IV bolus of 25 U/kg, to 60 minutes with an IV bolus of 100 U/kg, to 150 minutes with an IV bolus of 400 U/kg.18,19

The anticoagulant effect of UFH is traditionally monitored by the activated partial thromboplastin time (aPTT), which is sensitive to the inhibitory effect of UFH on thrombin, factor Xa, and factor IXa. Therapeutic ranges are typically 1.5 to 2.5 times baseline aPTT.9 Alternatively, UFH treatment can be monitored by a chromatographic antifactor Xa heparin assay with a targeted range of 0.3 to 0.7 U/mL.9

Administration of UFH is associated with some disadvantages. The interpatient variability of anticoagulant response is thought to be due to the interindividual differences in concentrations of heparin-neutralizing plasma proteins, as well as variable elevations of factor VIII as part of the acute-phase reaction response to ischemia.9 Bleeding is the most common complication of UFH therapy; UFH has the potential to induce bleeding by inhibiting blood coagulation, impairing platelet function, and increasing capillary permeability.9 Heparin-induced thrombocytopenia occurs in approximately 3% to 4% of heparin-treated patients.2022 It is an immunoglobulin-mediated adverse drug reaction associated with a high risk for thrombotic complications. The pathogenic antibody, usually IgG, recognizes a multimolecular complex of heparin and platelet factor 4 resulting in platelet activation.22,23 Finally, osteoporosis has been associated with high-dose, long-term UFH therapy.2427

Low-molecular-weight heparins are produced by enzymatic or chemical depolymerization of UFH to yield chains with molecular weights ranging from 4000 to 6500 d, with an average molecular weight of 5000 d (15 saccharide units)2830 (Table 1). Owing to their small molecular size, LMWHs have a reduced ability to catalyze the inactivation of thrombin relative to their ability to catalyze the inactivation of factor Xa. Thus, compared with UFH, which has an antifactor Xa–antifactor IIa ratio of 1:1, LMWHs have an antifactor Xa–antifactor IIa ratio of between 4:1 and 2:1 (Table 2). The relative importance of inhibition of factor Xa and thrombin in mediating the antithrombotic effect of UFH and LMWHs is unclear, but there is evidence that they are both necessary.11,12,32 In addition, the reduced protein binding of LMWHs improves their pharmacokinetic properties, and a minimal interaction with platelets could be responsible for the reduced microvascular bleeding and lower incidence of heparin-induced thrombocytopenia.28,29

Table Graphic Jump LocationTable 1. Characteristics of Available Low-Molecular-Weight Heparins (LMWHs)
Table Graphic Jump LocationTable 2. Comparison of Unfractionated Heparin (UFH) and Low-Molecular-Weight Heparins (LMWHs)

The bioavailability of LMWHs after SC injection is approximately 90% compared with 30% for UFH.29 This difference may be explained by the lower binding affinity of LMWHs for plasma proteins such as histidine-rich glycoproteins, fibronectin, and platelet factor 4.3335 This lower rate of protein binding of LMWHs compared with UFH explains the more predictable anticoagulant response that can be obtained at a given dose of LMWHs. The half-life of 2 to 4 hours following IV administration and 3 to 6 hours following SC injection is longer than the average 90-minute half-life of UFH.31,36,37 In addition, while UFH is eliminated in 2 phases, LMWHs are eliminated almost entirely by the renal route (Table 2).18,38 Overall, the combination of predictable anticoagulant response, high bioavailability, and long half-life of LMWHs means that an adequate and predictable anticoagulant response can be achieved with 1 or 2 daily SC injections at fixed or weight-adjusted doses.28,29 In addition, because LMWHs do not affect the aPTT, routine laboratory monitoring to assess the anticoagulant effect is not necessary. Although an antifactor Xa assay is available, it is not routinely used owing to its expense and the lack of a clinically defined therapeutic range.

Treatment with LMWHs in animal models results in less bleeding than UFH treatment.39,40 This decreased incidence of bleeding may be explained by the following: (1) LMWHs have a lower affinity for platelets, thus inhibiting their function less than UFH41,42; (2) unlike UFH, LMWHs do not increase microvascular permeability43; and (3) because of their lower affinity for endothelial cells, von Willebrand factor, and platelets, LMWHs are less likely to interfere with the prothrombotic interaction between platelets and the vessel wall.40,44,45 As a result of less interaction with platelets, heparin-induced thrombocytopenia is less common with LMWHs than with UFH.2123

While there is a suggestion that the risk of bleeding is lower with LMWHs than with UFH in certain patient groups, this favorable result does not occur in all studies. The reduction in the risk of bleeding observed in early experimental animal models has not been as obvious in clinical studies. Results from clinical trials and meta-analyses show a similar or lower incidence of bleeding with LMWHs4652; however, other studies have shown higher bleeding rates with LMWHs.53,54 Evidence from recent clinical trials indicates that the risk of major bleeding complications with LMWHs is similar to that of UFH5557; however, minor bleeding complications have been higher in the LMWH trials primarily as a result of injection-site ecchymosis.56,57 Overall, it seems that the theoretical advantage of reduced bleeding complications with LMWHs has not been demonstrated clinically, and if anything, the risk of minor bleeding complications is greater than it is with UFH.

Low-molecular-weight heparins are as safe and effective as UFH for the treatment of venous thromboembolism4648,55,56,58 and pulmonary embolism.59 In addition, they are as safe and effective for prevention of venous thromboembolism following abdominal surgery,60 orthopedic surgery,61,62 spinal surgery,63,64 multiple trauma,65 and other general medical conditions.66,67 Trials are currently under way evaluating the role of LMWHs for indications that are currently treated with UFH.29

The efficacy of aspirin in the acute phase of unstable angina has been demonstrated in a number of randomized, controlled clinical trials.2,3,68,69 The addition of UFH to aspirin may further improve survival and prevent progression to nonfatal myocardial infarction.24,7,8 Oler et al70 recently conducted a meta-analysis of 6 randomized controlled trials involving 1353 patients comparing aspirin plus UFH with aspirin alone to estimate the effect on subsequent myocardial infarction and death in patients with unstable angina. At 30 days, the addition of UFH to aspirin was associated with a 33% reduction in death or myocardial infarction, or 10.4% in the aspirin group and 7.9% in the aspirin plus UFH group (P=.06). However, the confidence interval was wide, and included a 56% reduction as well as a 2% excess of events. These statistically marginal benefits may have been a result of limitations of UFH rather than the lack of importance of thrombin inhibition in reducing ischemic events. The limited number of patients studied may also have affected the results.

To identify and evaluate the use of LMWHs in the management of acute coronary syndromes, we conducted a qualitative systematic review of the English-language literature from 1966 to December 1998 using MEDLINE. Key terms used in the literature search included unstable angina, myocardial infarction, heparin, and low-molecular-weight heparin. In addition, the references from relevant literature were reviewed to collect reports not identified in the MEDLINE search. Finally, we contacted experts in the field to obtain information on unpublished results and conference abstracts. We included all controlled clinical trials using LMWHs in unstable angina or non–Q-wave myocardial infarction that reported either efficacy or safety outcomes. All trials were evaluated independently by each of us for inclusion in the review as well as for scientific validity.

There have been 6 prospective, randomized, controlled clinical trials and 1 open-labeled dose-ranging study completed evaluating the role of LMWHs in patients with unstable angina and non–Q-wave myocardial infarction (Table 3). Gurfinkel et al71 randomized 219 patients with unstable angina to receive 214 U of nadroparin by SC injection twice daily or 5000 U of UFH by IV bolus followed by a continuous infusion or matching placebo for 5 to 7 days (Table 3). There was a significant reduction in the number of patients reaching the primary end point of recurrent angina, nonfatal myocardial infarction, urgent revascularization, or death in the nadroparin group compared with the UFH and placebo groups, respectively (Table 4). Patients receiving nadroparin had significantly less recurrent angina than the patients in the UFH or placebo groups. There was no significant difference in major bleeding complications (Figure 1); however, more patients in the UFH group experienced minor bleeding (Figure 2). There was a trend toward favorable results using nadroparin to prevent myocardial infarction and the need for revascularization, but the sample size was insufficient to conclusively evaluate this end point.

Table Graphic Jump LocationTable 3. Clinical Trials of Low-Molecular-Weight Heparins in Patients With Unstable Angina or Non–Q-Wave Myocardial Infarction*
Table Graphic Jump LocationTable 4. Results of Clinical Trials*
Place holder to copy figure label and caption
Figure 1.

Major bleeding complications. Gurfinkel et al71 indicate a fall in hemoglobin level of more than 20 g/L (>2 g/dL), a need for transfusion, or both; the Fragmin during Instability in Coronary Artery Disease Study (FRISC),72 a fall in hemoglobin level of more than 20 g/L (>2 g/dL) associated with signs and symptoms, intracranial bleeding, or bleeding leading to transfusion, interruption of treatment, or death; the Fragmin in Unstable Coronary Artery Disease Study (FRIC),73 a fall in hemoglobin level of more than 20 g/L (>2 g/dL), a required transfusion, intracranial hemorrhage, or death or cessation of therapy; the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study (ESSENCE),57 a fall in hemoglobin level of more than 30 g/L (>3 g/dL), bleeding resulting in death, transfusion of at least 2 U of blood, or a retroperitoneal, intracranial, or intraocular hemorrhage; and the Thrombolysis in Acute Myocardial Infarction Trial (TIMI) 11B,77 at least 1 of the following: (1) clinically overt hemorrhage resulting in a fall in hemoglobin level of more than 30 g/L (>3g/dL), and/or (2) a retroperitoneal, intracranial, or intraocular hemorrhage. LMWH indicates low-molecular-weight heparin; UFH, unfractionated heparin; and asterisk, P=.02.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Minor bleeding complications. LMWH indicates low-molecular-weight heparin; UFH, unfractionated heparin; FRISC, Fragmin during Instability in Coronary Artery Disease Study72; FRIC, Fragmin in Unstable Coronary Artery Disease Study;73 ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study57; asterisk, P=.01; and dagger, P<.001.

Graphic Jump Location

The Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group72 evaluated the use of dalteparin in 1506 patients with unstable angina or non–Q-wave myocardial infarction (Table 3). Patients presenting within 72 hours of the onset of chest pain were randomized to receive 120 U/kg of dalteparin by SC injection twice daily for 6 days followed by 7500 U subcutaneously once daily for an additional 35 to 45 days or matching placebo. Results after 6 days indicated a 63% reduction in the primary end point of death or myocardial infarction in the dalteparin group compared with the placebo group (Table 4). The absolute risk reduction of 3% correlates to 1 death or myocardial infarction prevented at 6 days for every 34 dalteparin-treated patients. The difference between the 2 groups was not significant when evaluated at 40 and 150 days. The dalteparin-treated groups experienced more minor bleeding complications (Figure 2). The results of the acute phase of this trial are similar to trials conducted comparing UFH with placebo.25 Therefore, it appears that dalteparin is more effective than placebo in patients with unstable angina or non–Q-wave myocardial infarction. However, long-term benefits of dalteparin were not established in this trial.

The Fragmin in Unstable Coronary Artery Disease Study (FRIC)73 was a prospective, 2-phase trial in 1482 patients with unstable angina or non–Q-wave myocardial infarction (Table 3). During the acute phase, patients were randomized within 72 hours of the onset of chest pain in an open-labeled fashion to receive 120 U/kg of dalteparin by SC injection twice daily or 5000 U of UFH by IV bolus followed by a continuous infusion. After treatment of the acute condition, patients were randomized into a chronic phase group in a double-blinded manner to receive 7500 U of dalteparin by SC injection daily or matching placebo on days 6 through 45. Between days 6 and 45 the proportion of patients reaching the primary end point of death, nonfatal myocardial infarction, or recurrent angina was 12.3% in both the dalteparin and UFH groups (Table 4). At 6 days, there was no significant difference between the 2 groups in reaching the same composite triple end point. The proportion of revascularizations at 45 days did not differ between the 2 groups. There was no difference in major and minor bleeding complications between the 2 groups (Figure 1 and Figure 2). The authors concluded that dalteparin seemed to be equivalent to UFH in the acute phase of unstable angina or non–Q-wave myocardial infarction, and that prolonged administration of a reduced dose of dalteparin offered no advantage over long-term therapy with aspirin alone. The trial was not powered to detect a difference in death, myocardial infarction, or recurrent angina during the acute phase.

The Thrombolysis in Acute Myocardial Infarction (TIMI) 11A Trial investigators74 conducted an open-labeled, dose-ranging study using enoxaparin in patients with unstable angina and non–Q-wave myocardial infarction (Table 3). During the acute phase, patients were treated with 1.0 mg/kg of enoxaparin by SC injection twice daily or 1.25 mg/kg of enoxaparin by SC injection twice daily for a minimum of 48 hours. After the acute treatment, patients were discharged and received 40 to 60 mg of enoxaparin by SC injection twice daily to complete 14 days of therapy. The primary end point was major hemorrhage occurring within 2 weeks of enrollment, which occurred more frequently in patients receiving 1.25 mg/kg of enoxaparin than in the 1.0-mg/kg group (Figure 1). No difference was found in any of the secondary end points of death, myocardial infarction, or recurrent ischemia requiring revascularization (Table 4). Since this trial was an unblinded dose-ranging study, no definitive conclusions could be made about the efficacy of enoxaparin in unstable angina.

The Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study Group (ESSENCE)57 conducted one of the largest trials comparing the use of LMWHs to UFH in acute coronary syndromes (Table 3). This trial enrolled 3171 patients with unstable angina or non–Q-wave myocardial infarction. Patients were randomized to receive 1.0 mg/kg of enoxaparin subcutaneously twice daily or 5000 U of UFH by IV bolus followed by a continuous infusion. Treatment continued for a period of at least 48 hours and for as long as 8 days. At the conclusion of the trial, significantly fewer enoxaparin-treated patients reached the primary end point of death, nonfatal myocardial infarction, or recurrent angina at 14 days (Table 4). This significant difference was maintained at 30 days. There was no difference between groups at 48 hours, nor was there a difference in the combination end point of death or myocardial infarction at 14 and 30 days. Results after 1 year of follow-up have been presented, and the early benefit of enoxaparin in the primary end point was maintained (32% for enoxaparin vs 35.7% for UFH; P=.02).78 The difference between the 2 groups was primarily the result of less recurrent angina in the enoxaparin group, which composed 75% of events. There was no difference between groups in major bleeding complications (Figure 1); however, more patients in the enoxaparin groups experienced minor bleeding (Figure 2). One limitation of this trial was the fixed rather than weight-adjusted UFH nomogram. Only 46% of patients had therapeutic levels of UFH at 24 hours, which improved to only 51.3% at 48 hours. Although a weight-adjusted heparin nomogram may achieve a therapeutic aPTT more rapidly in patients with venous thromboembolism, the importance of weight-adjusted nomograms in patients with angina has not been thoroughly studied.79,80

The Thrombolysis in Myocardial Infarction (TIMI) 11B Trial investigators75 conducted a second study comparing 1.0 mg/kg of enoxaparin by SC injection twice daily with UFH using a weight-adjusted UFH nomogram for the treatment of unstable angina and non–Q-wave myocardial infarction (Table 3). During the acute phase, patients received treatment for a minimum of 72 hours and up to 8 days. Following acute treatment, patients initially randomized to enoxaparin continued to receive enoxaparin for an additional 35 days at a weight-adjusted reduced dose of 40 to 60 mg SC twice daily. Patients randomized to UFH received placebo during the chronic phase. Results were presented at the 71st Scientific Sessions of the American Heart Association in Dallas, Tex, and indicate that fewer enoxaparin-treated patients reached the primary end points of death, nonfatal myocardial infarction, and severe recurrent ischemia requiring revascularization during the acute phase (Table 4).77 This initial benefit was maintained at 43 days; however, no relative reduction in events occurred during the chronic phase. Superiority of enoxaparin in the acute phase was not associated with any increase in major bleeding (Figure 1); however, there was an increase in major hemorrhage during the chronic phase.

Combined analysis of the results of ESSENCE and TIMI 11B showed a consistent reduction in the odds of the triple end point of death, myocardial infarction, or urgent revascularization at 8, 14, and 43 days after randomization. Overall, there was a relative 20% reduction at 43 days (odds ratio, 0.80; 95% confidence interval, 0.71-0.91). This reduction was also evident when the double end point of death or myocardial infarction was evaluated at 43 days (odds ratio, 0.82; 95% confidence interval, 0.69-0.98).77

Preliminary results from the Fraxiparine in Ischemic Syndromes (FRAXIS) trial were presented at the 20th Congress of the European Society of Cardiology meetings (Table 3).76 This trial enrolled 3468 patients presenting with either unstable angina or non–Q-wave myocardial infarction. Patients were randomized to receive 1 of 3 treatments: 0.1 mL/10 kg of nadroparin by SC injection every 12 hours for 6 days; 0.1 mL/10 kg of nadroparin by SC injection every 12 hours for 14 days; or UFH for 6 days. Results indicated no significant difference in the primary end point between the 3 treatment groups for cardiovascular death, myocardial infarction, or refractory or recurrent angina at 14 days, with event rates of 17.8%, 20.0%, and 18.1%, respectively. Major bleeding was similar between the groups when evaluated at 6 days; however, a higher major bleeding rate occurred in the 14-day nadroparin arm compared with the 6-day nadroparin and UFH groups (3.5%, 1.5%, and 1.6%, respectively) when evaluated at 14 days.

The positive clinical results demonstrated in the ESSENCE trial were supplemented with a pharmacoeconomic analysis comparing LMWHs and UFH in acute coronary syndromes. Mark et al81 conducted a prospective economic assessment of 936 patients enrolled in the ESSENCE trial. These patients represented 85% of all the patients enrolled from the United States. Results of the cost analysis demonstrated that the improved clinical outcomes for patients treated with enoxaparin were associated with a cost saving. Despite the US $75 incremental drug cost of administering enoxaparin rather than UFH, cost savings of US $763 were realized at hospital discharge and US $1172 at 30 days. The most substantial resource effect of enoxaparin was a reduction in the use of coronary angioplasty, which was a result of the clinical reduction of recurrent ischemic events. Additional savings resulted from the estimated reduction in the cost of IV therapy, tubing and appliances, and aPTT monitoring. This analysis did not evaluate cost of outpatient care or indirect costs related to lost productivity. The authors concluded that the clinical as well as economic advantages of using enoxaparin over UFH made it a dominant strategy in the management of acute coronary syndromes.

A Canadian cost-effectiveness analysis has also been conducted based on the 30-day end point of the ESSENCE trial.82 Based on costs of medical care in Canada, the average cost per patient for enoxaparin was determined to be Can $848 vs Can $892 for UFH. (At the time of this analysis, Can $1.00 was equivalent to US $0.66.) As with the US economic analysis, enoxaparin was considered the dominant antithrombotic pharmacotherapeutic strategy for patients with unstable coronary artery disease.

The data evaluating the use of LMWHs in the management of acute coronary syndromes continue to accumulate. Despite the encouraging clinical trial results, the variation in study designs and trial end points complicates a quantitative systematic comparison of all these data. However, evidence from TIMI 11B and ESSENCE involving over 7000 patients is sufficient to allow recommending the use of LMWHs in the management of acute coronary syndromes.

Low-molecular-weight heparins are superior to placebo and UFH in reducing ischemic events or death in the acute phase of unstable angina or non–Q-wave myocardial infarction. Prolonged therapy with lower doses of LMWHs may not offer any advantage over aspirin in the prevention of coronary events or death. Major bleeding complications are similar for LMWHs and UFH, but minor bleeding complications are more common with LMWHs primarily because of injection-site hematomas. Finally, LMWHs appear to be cost-effective compared with UFH based on pharmacoeconomic analyses conducted in Canada and the United States based on the ESSENCE study results. Taken together, the use of LMWHs for the treatment of unstable angina or non–Q-wave myocardial infarction should be favored over UFH.

Several questions regarding LMWHs remain unresolved. First, are all LMWH agents comparable? Although the biochemical distinctions between agents may be minor, few data define whether important clinical differences between agents result. Evidence from FRIC and FRAXIS failed to demonstrate increased efficacy of LMWHs over UFH by using dalteparin and nadroparin, respectively.73,76 As a result, the effective dose of these agents remains uncertain. Alternatively, data from ESSENCE and TIMI 11B show the greatest benefits and demonstrate superiority over UFH using enoxaparin.57,75,77 Thus, based on the best available evidence, a class effect of LMWH preparations should not be assumed, and enoxaparin should be the preferred LMWH agent for patients with unstable angina or non–Q-wave myocardial infarction. Enoxaparin, 1.0 mg/kg, subcutaneously twice daily should be continued for at least 72 hours, but not beyond the hospital phase.

Other unanswered questions include the use of LMWHs with other antiplatelet agents such as the IV and oral glycoprotein IIb/IIIa receptor antagonists or direct thrombin inhibitors. Results of large, randomized, controlled trials using glycoprotein IIb/IIIa receptor antagonists for acute coronary syndromes are encouraging.8386 Unfortunately, it may be many years before these agents are evaluated in combination with LMWHs. To date, clinical experience with direct thrombin inhibitors has been disappointing, with no clear evidence of clinical efficacy and potential increased bleeding risk.87,88 Promising results from the Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators demonstrated an improved outcomes compared with UFH; however, the benefit in combination with or compared with LMWHs remains unknown.89 Research will continue in an attempt to improve outcomes for patients with cardiovascular disease. In the meantime, LMWHs appear to be a major advance in the management of unstable angina and non–Q-wave myocardial infarction.

Accepted for publication January 26, 1999.

Dr Tisdale has received lecture honoraria from Hoechst-Marion Roussel Inc, Kansas City, Mo; Wyeth-Ayerst Laboratories, Cranbury, NJ; Merck & Co, Whitehouse Station, NJ; Boehringer-Mannheim, now merged with Roche Pharmaceuticals, Nutley, NJ; and G. D. Searle & Co, Skokie, Ill. He has received research grants from Hoechst-Marion Roussel Inc and Merck & Co. He has been a consultant for Hoechst-Marion Roussel Inc; Wyeth-Ayerst Laboratories; Rhone-Poulenc-Rorer Pharmaceuticals, Collegeville, Pa; Roche Pharmaceuticals; Parke-Davis, Morris Plains, NJ; Cor Therapeutics, San Francisco, Calif; and 3M Pharmaceuticals, St Paul, Minn. Dr Borzak has served on the speakers' bureau and received grants from Rhone-Poulenc-Rorer.

Corresponding author: Peter J. Zed, PharmD, CSU Pharmaceutical Sciences, Vancouver Hospital and Health Sciences Center, 855 W 12th Ave, Vancouver, British Columbia, Canada, V5Z 1M9 (e-mail: zed@interchange.ubc.ca).

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Warkentin  TELevine  MNHirsh  J  et al.  Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;3321330- 1335
Link to Article
Warkentin  TE Heparin-induced thrombocytopenia: pathogenesis, frequency, avoidance and management. Drug Saf. 1997;17325- 341
Link to Article
Brieger  DBMak  KHKottke-Marchant  KTopol  EJ Heparin-induced thrombocytopenia. J Am Coll Cardiol. 1998;311449- 1459
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Griffith  CCNichols  GAsher  JDFlanagan  B Heparin osteoporosis. JAMA. 1965;19385- 88
Link to Article
Howell  RFidler  JLetsky  Ede Swiet  M The risks of antenatal subcutaneous heparin prophylaxis: a controlled-trial. Br J Obstet Gynaecol. 1983;901124- 1128
Link to Article
Dahlman  TLindvall  NHellgren  M Osteopenia in pregnancy during long-term heparin treatment: a radiological study post-partum. Br J Obstet Gynaecol. 1990;97221- 228
Link to Article
Ginsberg  JSKowalchuck  GHirsh  J  et al.  Heparin effect on bone density. Thromb Haemost. 1990;64286- 289
Hirsh  JLevine  MN Low molecular weight heparin. Blood. 1992;791- 17
Weitz  JI Low-molecular-weight heparins. N Engl J Med. 1997;337688- 698
Link to Article
Turpie  AGG Pharmacology of the low-molecular-weight heparins. Am Heart J. 1998;135S329- S335
Link to Article
Martineau  PTawil  N Low-molecular-weight heparins in the treatment of deep-vein thrombosis. Ann Pharmacother. 1998;32588- 601
Link to Article
Barrowcliffe  TWMerton  REHavercroft  SJThunberg  LLindahl  UThomas  DP Low-affinity heparin potentiates the action of high-affinity heparin oligosaccharides. Thromb Res. 1984;34125- 133
Link to Article
Lane  DAPejler  GFlynn  AMThompson  EALindahl  U Neutralization of heparin-related saccharides by histidine-rich glycoprotein and platelet factor 4. J Biol Chem. 1986;2613980- 3986
Young  EWells  PHolloway  SWeitz  JHirsh  J Ex-vivo and in-vitro evidence that low-molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost. 1994;71300- 304
Young  ECosmi  BWeitz  JHirsch  J Comparison of the non-specific binding of unfractionated heparin and low molecular weight heparin (enoxaparin) to plasma proteins. Thromb Haemost. 1993;70625- 630
Harenberg  J Pharmacology of low molecular weight heparins. Semin Thromb Hemost. 1990;16(suppl)12- 18
Matzsch  TBergquist  DHedner  UOstergaard  P Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers. Thromb Haemost. 1987;5797- 101
Boneu  BCaranobe  CCadroy  Y  et al.  Pharmacokinetic studies of standard unfractionated heparin, and low molecular weight heparins in the rabbit. Semin Thromb Hemost. 1988;1418- 27
Link to Article
Bergqvist  DNilsson  BHedner  UPederson  PCOstergaard  PB The effects of heparin fragments of different molecular weights on experimental thrombosis and haemostasis. Thromb Res. 1985;38589- 601
Link to Article
Carter  CJKelton  JGHirsch  JCerskus  ASantos  AVGent  M The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparins in rabbits. Blood. 1982;591339- 1345
Salzman  EWRosenberg  RDSmith  MHLindon  JNFavreau  L Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest. 1980;6564- 73
Link to Article
Horne  MK  IIIChao  ES The effect of molecular weight on heparin binding to platelets. Br J Haematol. 1990;74306- 312
Link to Article
Blajchman  MAYoung  EOfosu  FA Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits. Ann N Y Acad Sci. 1989;556245- 254
Link to Article
Sobel  MMcNeill  PMCarlson  PL  et al.  Heparin inhibition of von Willebrand factor–dependent platelet function in vitro and in vivo. J Clin Invest. 1991;871787- 1793
Link to Article
de Romeuf  CMazurier  C Heparin binding assay of von Willebrand factor (vWF) in plasma milieu: evidence of the importance of the mutimerization degree of vWF. Thromb Haemost. 1993;69436- 440
Leizororovicz  ASimonneau  GDecousis  HBoissel  JP Comparison of efficacy and safety of low-molecular-weight heparins and unfractionated heparin in initial treatment of venous thrombosis: a meta-analysis. BMJ. 1994;309299- 304
Link to Article
Siragusa  SCosmi  BPiovella  FHirsh  JGinsberg  JS Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med. 1996;100269- 277
Link to Article
Lensing  AWAPrins  MHDavidson  BLHirsch  J Treatment of deep-vein thrombosis with low molecular-weight-heparins: a meta-analysis. Arch Intern Med. 1995;155601- 607
Link to Article
Anderson  DRO'Brien  BJLevine  MNRoberts  RWells  PSHirsh  J Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep-vein thrombosis after total hip arthroplasty. Ann Intern Med. 1993;1191105- 1112
Link to Article
Lassen  MRBorris  LCChristiansen  HM  et al.  Clinical trials with low molecular weight heparins in the prevention of postoperative thromboembolic complications: a meta-analysis. Semin Thromb Hemost. 1991;17(suppl 3)284- 290
Nuromohamed  MTRosendaal  FRBuller  HR  et al.  Low-molecular-weight heparin versus standard heparin in general and orthopedic surgery: a meta-analysis. Lancet. 1992;340152- 156
Link to Article
Hull  RDRaskob  GEPineo  GF  et al.  Subcutaneous low molecular weight heparin compared with continuous intravenous heparin in the treatment of proximal vein thrombosis. N Engl J Med. 1992;326975- 982
Link to Article
Bergqvist  DBurmark  USFrisell  J  et al.  Thromboprophylactic effect of low molecular weight heparin started in the evening before elective general abdominal surgery: a comparison with low-dose heparin. Semin Thromb Hemost. 1990;16(suppl)19- 24
Bergqvist  DBurmark  USFrisell  J  et al.  Prospective double-blind comparison between Fragmin and conventional low-dose heparin: thromboprophylactic effect and bleeding complications. Haemostasis. 1986;16(suppl 2)11- 18
Levine  MGent  MHirsch  J  et al.  A comparison of low-molecular weight heparin administered primarily at home with unfractionated heparin in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334677- 681
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Koopman  MMPrandoni  PPiovella  F  et al.  Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared to subcutaneous low-molecular-weight heparin administered at home. N Engl J Med. 1996;334682- 687
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Cohen  MDemers  CGurfinkel  EP  et al.  A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337447- 452
Link to Article
The Columbus Investigators, Low-molecular weight heparin in the treatment of patients with venous thromboembolism. N Eng J Med. 1997;337657- 662
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Simonneau  GSors  HCharbonnier  B  et al.  A comparison of low-molecular weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med. 1997;337663- 669
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Kakker  WCohen  ATEdmonson  RA  et al.  Low molecular weight heparin versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. Lancet. 1993;341259- 265
Link to Article
Turpie  AGGLevine  MNHirsch  J  et al.  A randomized controlled trial of a low-molecular weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med. 1986;315925- 929
Link to Article
Leclerc  JRGeerts  WHDesjardins  L  et al.  Prevention of venous thromboembolism after knee arthroplasty: a randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med. 1996;124619- 626
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Green  D Prophylaxis of thromboembolism in spinal-cord injured patients. Chest. 1994;102(suppl A)649S- 651S
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Green  DLee  YIto  VY  et al.  Fixed- vs. adjusted-dose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA. 1988;2601255- 1258
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Geerts  WHJay  RMCode  KI  et al.  A comparison of low-dose heparin with low-molecular weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996;335701- 707
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Bergmann  JFNeuhart  E A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute illness. Thromb Haemost. 1996;76529- 534
Harenberg  JKallenbach  BMartin  U  et al.  Randomized controlled study of heparin and low molecular weight heparin for prevention of deep-vein thrombosis in medical patients. Thromb Res. 1990;59639- 650
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Cairns  JAGent  MSinger  J  et al.  Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med. 1985;3131369- 1375
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Lewis  H  JrDavis  JWArchibald  DG  et al.  Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study. N Engl J Med. 1983;309396- 403
Link to Article
Oler  AWhooley  MAOler  JGrady  D Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA. 1996;276811- 815
Link to Article
Gurfinkel  EPManos  EJMejail  RI  et al.  Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol. 1995;26313- 318
Link to Article
Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group, Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996;347561- 568
Link to Article
Klein  WBuchwald  AHillis  SE  et al.  Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation. 1997;9661- 68
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The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators, Dose ranging trial of enoxaparin for unstable angina: results of TIMI 11A. J Am Coll Cardiol. 1997;291474- 1482
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Antman  EMThrombolyis in Myocardial Infarction (TIMI) Investigators, TIMI 11B, Enoxaparin versus unfractionated heparin for unstable angina or non–Q-wave myocardial infarction: a double-blind, placebo-controlled, parallel-group, multicenter trial: rationale, study design, and methods. Am Heart J. 1998;135S353- S360
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Leizorovicz  A The FRAXIS study: optimal duration of treatment of unstable angina in the acute phase—preliminary results [abstract].  Presented at: 20th Congress of the European Society of Cardiology August 22-26, 1998 Vienna, Austria
Antman  EMMcCabe  CHPremmereur  J  et al.  Enoxaparin for the acute and chronic management of unstable angina/non–Q wave myocardial infarction: results of TIMI 11B [abstract]. Circulation. 1998;98(suppl I)I- 504
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Ferguson  JJ Meeting highlights: 47th annual scientific sessions of the American College of Cardiology. Circulation. 1998;972377- 2381
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Raschke  RAReilly  RMGuidry  JRFontana  JRSrinivas  S The weight based heparin nomogram compared with a "standard care" nomogram: a randomized controlled trial. Ann Intern Med. 1993;119874- 881
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Becker  RCBall  SPEisenberg  P  et al.  A randomized trial of weight-adjusted intravenous heparin dose titrationand point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease. Am Heart J. 1999;13759- 71
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Mark  DBCowper  PABerkowitz  SD  et al.  Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients: results from the ESSENCE randomized trial. Circulation. 1998;971702- 1707
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Balen  RMMarra  CAZed  PJCohen  MFrighetto  L Cost-effectiveness analysis of enoxaparin versus unfractionated heparin for acute coronary syndromes: a Canadian hospital perspective. Pharmacoeconomics. In press.
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators, Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction. N Engl J Med. 1998;3381488- 1497
Link to Article
The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators, A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med. 1998;3381498- 1505
Link to Article
The PARAGON Investigators, International, randomized, controlled trial of lamifiban (a glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina. Circulation. 1998;972386- 2395
Link to Article
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators, Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes without persistent ST-segment elevation. N Engl J Med. 1998;339436- 443
Link to Article
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators, A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med. 1996;335775- 782
Link to Article
Antman  EMTIMI 9B Investigators, Hirudin in acute myocardial infarction: thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9B trial. Circulation. 1996;94911- 921
Link to Article
Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators, Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Lancet. 1999;353429- 438
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Major bleeding complications. Gurfinkel et al71 indicate a fall in hemoglobin level of more than 20 g/L (>2 g/dL), a need for transfusion, or both; the Fragmin during Instability in Coronary Artery Disease Study (FRISC),72 a fall in hemoglobin level of more than 20 g/L (>2 g/dL) associated with signs and symptoms, intracranial bleeding, or bleeding leading to transfusion, interruption of treatment, or death; the Fragmin in Unstable Coronary Artery Disease Study (FRIC),73 a fall in hemoglobin level of more than 20 g/L (>2 g/dL), a required transfusion, intracranial hemorrhage, or death or cessation of therapy; the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study (ESSENCE),57 a fall in hemoglobin level of more than 30 g/L (>3 g/dL), bleeding resulting in death, transfusion of at least 2 U of blood, or a retroperitoneal, intracranial, or intraocular hemorrhage; and the Thrombolysis in Acute Myocardial Infarction Trial (TIMI) 11B,77 at least 1 of the following: (1) clinically overt hemorrhage resulting in a fall in hemoglobin level of more than 30 g/L (>3g/dL), and/or (2) a retroperitoneal, intracranial, or intraocular hemorrhage. LMWH indicates low-molecular-weight heparin; UFH, unfractionated heparin; and asterisk, P=.02.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Minor bleeding complications. LMWH indicates low-molecular-weight heparin; UFH, unfractionated heparin; FRISC, Fragmin during Instability in Coronary Artery Disease Study72; FRIC, Fragmin in Unstable Coronary Artery Disease Study;73 ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study57; asterisk, P=.01; and dagger, P<.001.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of Available Low-Molecular-Weight Heparins (LMWHs)
Table Graphic Jump LocationTable 2. Comparison of Unfractionated Heparin (UFH) and Low-Molecular-Weight Heparins (LMWHs)
Table Graphic Jump LocationTable 3. Clinical Trials of Low-Molecular-Weight Heparins in Patients With Unstable Angina or Non–Q-Wave Myocardial Infarction*
Table Graphic Jump LocationTable 4. Results of Clinical Trials*

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Young  EWells  PHolloway  SWeitz  JHirsh  J Ex-vivo and in-vitro evidence that low-molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost. 1994;71300- 304
Young  ECosmi  BWeitz  JHirsch  J Comparison of the non-specific binding of unfractionated heparin and low molecular weight heparin (enoxaparin) to plasma proteins. Thromb Haemost. 1993;70625- 630
Harenberg  J Pharmacology of low molecular weight heparins. Semin Thromb Hemost. 1990;16(suppl)12- 18
Matzsch  TBergquist  DHedner  UOstergaard  P Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers. Thromb Haemost. 1987;5797- 101
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Link to Article
Bergqvist  DNilsson  BHedner  UPederson  PCOstergaard  PB The effects of heparin fragments of different molecular weights on experimental thrombosis and haemostasis. Thromb Res. 1985;38589- 601
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Link to Article
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Link to Article
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Link to Article
Lensing  AWAPrins  MHDavidson  BLHirsch  J Treatment of deep-vein thrombosis with low molecular-weight-heparins: a meta-analysis. Arch Intern Med. 1995;155601- 607
Link to Article
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