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

Peter J. Zed, PharmD; James E. Tisdale, PharmD; Steven Borzak, MD

cute coronary syndromes (unstable and non–Q-wave ) are caused by the rupture of an atherosclerotic plaque, activation, and fibrin deposition resulting in . and unfractionated have tradi- tionally been the treatments of choice for patients with acute coronary syndromes. ALow-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 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 . Arch Intern Med. 1999;159:1849-1857

The initiating event of the acute coro- available literature on the use of LMWHs nary syndromes (unstable angina and non– in the management of acute coronary syn- Q-wave myocardial infarction) involves the dromes and to provide recommenda- rupture of an atherosclerotic plaque re- tions for their role in therapy. sulting in the platelet activation and fi- brin deposition that leads to thrombo- UNFRACTIONATED HEPARIN sis.1 Evidence that both platelet activation and generation are involved in Unfractionated heparin is a hetero- the thrombotic process provides a rationale geneous polydispersed mixture of sul- for the use of both aspirin and unfraction- fated polysaccharides ranging in molecu- ated heparin (UFH) in the management of lar weight from 5000 to 30 000 d (average acute coronary syndromes. There has been molecular weight, 12 000-15 000 d).9 Its much research and debate in the past de- major effect is attributed to cade on the value of these agents alone or a unique pentasaccharide sequence with in combination.2-8 Aspirin and UFH have high affinity for III (ATIII).9 become the standard practice for treat- Binding of heparin to ATIII produces a ment of patients presenting with un- conformational change in this protein, ac- stable angina or non–Q-wave myocardial celerating the ability to inactivate the co- infarction. Low-molecular-weight hepa- agulation enzymes thrombin (factor IIa), rins (LMWHs) have recently been mar- factor Xa, and factor IXa. Of these 3 en- keted in North America and offer poten- zymes, thrombin is the most sensitive to tial advantages over UFH. The purpose of inhibition by the heparin/ATIII com- this article is to review and evaluate the plex.10-13 Unfractionated heparin acceler- ates the inactivation of thrombin by ATIII by acting as a template to which both the From CSU Pharmaceutical Sciences, Vancouver Hospital and Health Sciences Center, and the Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver enzyme and the inhibitor bind to form a (Dr Zed); and the Department of Practice, College of Pharmacy and Allied ternary complex. In contrast, the inacti- Health Professions, Wayne State University and Department of Pharmacy Services vation of factor Xa does not require a ter- (Dr Tisdale), and the Cardiac Intensive Care Unit, Division of Cardiovascular nary complex and is achieved by binding (Dr Borzak), Henry Ford Hospital, Detroit, Mich. directly to ATIII.14 The ability of UFH to

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 1. Characteristics of Available Low-Molecular-Weight Heparins (LMWHs)29-31

Mean Molecular Anti-Xa/Anti-lla LMWH Method of Preparation Weight, d Ratio Half-life, h* Availability Enoxaparin (Lovenox) Benzylation and alkaline depolymerization 4200 3.8:1 2.2-6.0 Canada/United States Dalteparin (Fragmin) Nitrous acid depolymerization 6000 2.7:1 2.0-5.0 Canada/United States Tinzaparin (Innohep) Heparinase digestion 4500 1.9:1 1.4-1.9 Canada Ardeparin (Normiflo) Peroxidative depolymerization 6000 1.9:1 3.0 United States Nadroparin (Fraxiparine) Nitrous acid depolymerization 4500 3.6:1 2.2-3.5 Canada

*Based on plasma antifactor Xa activity.

lation, impairing platelet function, Table 2. Comparison of Unfractionated Heparin (UFH) and 29,30 and increasing permeabil- Low-Molecular-Weight Heparins (LMWHs) ity.9 Heparin-induced thrombocyto- penia occurs in approximately 3% to Drug Characteristic UFH LMWH 4% of heparin-treated patients.20-22 It Mean molecular weight (range), d 15 000 (5000-30 000) 4500 (3000-6000) is an immunoglobulin-mediated ad- Anti-Xa/anti-lla ratio 1:1 2:1-4:1 verse drug reaction associated with , % 30 90 Peak onset, min 20-30 4-6 h a high risk for thrombotic complica- Plasma half-life, min 60-150 3-6 h tions. The pathogenic antibody, usu- Elimination Reticuloendothelial and renal systems Renal system ally IgG, recognizes a multimolecu- lar complex of heparin and platelet factor 4 resulting in platelet activa- inhibit thrombin is dependent on nonsaturable mechanism. The con- tion.22-23 Finally, osteoporosis has saccharide chain length and ulti- centration-dependent mechanism re- been associated with high-dose, long- mately molecular weight. Thus, UFH sults from UFH binding to macro- term UFH therapy.24-27 molecules that contain fewer than 18 phages and endothelial cells. saccharide units are unable to bind Clearance through the much slower LOW-MOLECULAR-WEIGHT thrombin and ATIII simultaneously nonsaturable mechanism is par- HEPARINS and therefore are unable to acceler- tially through renal excretion. The ap- ate the inactivation of thrombin. parent biological half-life of UFH is Low-molecular-weight heparins are However, they do retain their abil- dose dependent, increasing from 30 produced by enzymatic or chemi- ity to catalyze the inactivation of fac- minutes with an IV bolus of 25 U/kg, cal depolymerization of UFH to yield tor Xa.14-15 to 60 minutes with an IV bolus of 100 chains with molecular weights rang- Unfractionated heparin is not U/kg, to 150 minutes with an IV bo- ing from 4000 to 6500 d, with an av- absorbed following oral administra- lus of 400 U/kg.18,19 erage molecular weight of 5000 d (15 tion and therefore must be given by The anticoagulant effect of UFH saccharide units)28-30 (Table 1). intravenous (IV) or subcutaneous is traditionally monitored by the ac- Owing to their small molecular size, (SC) injection. The efficacy and safety tivated partial thromboplastin time LMWHs have a reduced ability to of UFH when administered by ei- (aPTT), which is sensitive to the in- catalyze the inactivation of throm- ther continuous IV infusion or by the hibitory effect of UFH on throm- bin relative to their ability to cata- SC route are comparable provided bin, factor Xa, and factor IXa. Thera- lyze the inactivation of factor Xa. that the doses are adequate.16 Fol- peutic ranges are typically 1.5 to 2.5 Thus, compared with UFH, which lowing its injection and passage into times baseline aPTT.9 Alterna- has an antifactor Xa–antifactor IIa the bloodstream, UFH binds to a tively, UFH treatment can be moni- ratio of 1:1, LMWHs have an anti- number of plasma proteins includ- tored by a chromatographic antifac- factor Xa–antifactor IIa ratio of be- ing histidine-rich glycoprotein, plate- tor Xa heparin assay with a targeted tween 4:1 and 2:1 (Table 2). The let factor 4, vitronectin, fibronectin, range of 0.3 to 0.7 U/mL.9 relative importance of inhibition of and von Willebrand factor.9 The Administration of UFH is asso- factor Xa and thrombin in mediat- binding of UFH to these proteins re- ciated with some disadvantages. The ing the effect of sults in reduced bioavailability, vari- interpatient variability of anticoagu- UFH and LMWHs is unclear, but able anticoagulant response, and the lant response is thought to be due to there is evidence that they are both phenomenon known as heparin re- the interindividual differences in con- necessary.11,12,32 In addition, the re- sistance.17 Unfractionated heparin centrations of heparin-neutralizing duced protein binding of LMWHs also binds to and en- plasma proteins, as well as variable improves their pharmacokinetic dothelial cells, another reason for its elevations of factor VIII as part of the properties, and a minimal inter- complicated . Un- acute-phase reaction response to is- action with could be fractionated heparin is cleared chemia.9 is the most com- responsible for the reduced micro- through the combination of a rapid, mon complication of UFH therapy; vascular bleeding and lower inci- concentration-dependent (satu- UFH has the potential to induce dence of heparin-induced throm- rable) mechanism and a much slower bleeding by inhibiting blood coagu- bocytopenia.28,29

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 The bioavailability of LMWHs bleeding observed in early experi- in the aspirin group and 7.9% in the after SC injection is approximately mental animal models has not been aspirin plus UFH group (P = .06). 90% compared with 30% for UFH.29 as obvious in clinical studies. However, the confidence interval This difference may be explained by Results from clinical trials and was wide, and included a 56% re- the lower binding affinity of LMWHs meta-analyses show a similar or duction as well as a 2% excess of for plasma proteins such as histidine- lower incidence of bleeding with events. These statistically marginal rich glycoproteins, fibronectin, and LMWHs46-52; however, other stud- benefits may have been a result of platelet factor 4.33-35 This lower rate ies have shown higher bleeding limitations of UFH rather than the of protein binding of LMWHs com- rates with LMWHs.53,54 Evidence lack of importance of thrombin in- pared with UFH explains the more from recent clinical trials indicates hibition in reducing ischemic events. predictable anticoagulant response that the risk of major bleeding The limited number of patients stud- that can be obtained at a given dose complications with LMWHs is ied may also have affected the re- of LMWHs. The half-life of 2 to 4 similar to that of UFH55-57; how- sults. hours following IV administration ever, minor bleeding complications To identify and evaluate the use and 3 to 6 hours following SC in- have been higher in the LMWH tri- of LMWHs in the management of jection is longer than the average 90- als primarily as a result of injection- acute coronary syndromes, we con- minute half-life of UFH.31,36,37 In ad- site ecchymosis.56,57 Overall, it ducted a qualitative systematic re- dition, while UFH is eliminated in seems that the theoretical advan- view of the English-language litera- 2 phases, LMWHs are eliminated al- tage of reduced bleeding complica- ture from 1966 to December 1998 most entirely by the renal route tions with LMWHs has not been using MEDLINE. Key terms used in (Table 2).18,38 Overall, the combina- demonstrated clinically, and if any- the literature search included un- tion of predictable anticoagulant re- thing, the risk of minor bleeding stable angina, myocardial infarc- sponse, high bioavailability, and long complications is greater than it is tion, heparin, and low-molecular- half-life of LMWHs means that an with UFH. weight heparin. In addition, the adequate and predictable anticoagu- Low-molecular-weight hepa- references from relevant literature lant response can be achieved with rins are as safe and effective as UFH were reviewed to collect reports not 1 or 2 daily SC injections at fixed or for the treatment of venous throm- identified in the MEDLINE search. weight-adjusted doses.28,29 In addi- boembolism46-48,55,56,58 and pulmo- Finally, we contacted experts in the tion, because LMWHs do not affect nary .59 In addition, they field to obtain information on un- the aPTT, routine laboratory moni- are as safe and effective for preven- published results and conference ab- toring to assess the anticoagulant ef- tion of venous thromboembolism stracts. We included all controlled fect is not necessary. Although an an- following abdominal ,60 or- clinical trials using LMWHs in un- tifactor Xa assay is available, it is not thopedic surgery,61,62 spinal sur- stable angina or non–Q-wave myo- routinely used owing to its expense gery,63,64 multiple trauma,65 and other cardial infarction that reported ei- and the lack of a clinically defined general medical conditions.66,67 Tri- ther efficacy or safety outcomes. All therapeutic range. als are currently under way evalu- trials were evaluated indepen- Treatment with LMWHs in ani- ating the role of LMWHs for indi- dently by each of us for inclusion in mal models results in less bleeding cations that are currently treated the review as well as for scientific than UFH treatment.39,40 This de- with UFH.29 validity. creased incidence of bleeding may There have been 6 prospec- be explained by the following: (1) CLINICAL TRIALS IN ACUTE tive, randomized, controlled clini- LMWHs have a lower affinity for CORONARY SYNDROMES cal trials and 1 open-labeled dose- platelets, thus inhibiting their func- ranging study completed evaluating tion less than UFH41,42; (2) unlike The efficacy of aspirin in the acute the role of LMWHs in patients with UFH, LMWHs do not increase mi- phase of unstable angina has been unstable angina and non–Q-wave crovascular permeability43; and (3) demonstrated in a number of ran- myocardial infarction (Table 3). because of their lower affinity for en- domized, controlled clinical tri- Gurfinkel et al71 randomized 219 pa- dothelial cells, von Willebrand fac- als.2,3,68,69 The addition of UFH to as- tients with unstable angina to re- tor, and platelets, LMWHs are less pirin may further improve survival ceive 214 U of nadroparin by SC in- likely to interfere with the prothrom- and prevent progression to nonfa- jection twice daily or 5000 U of UFH botic interaction between platelets tal myocardial infarction.2-4,7,8 Oler by IV bolus followed by a continu- and the vessel wall.40,44,45 As a re- et al70 recently conducted a meta- ous infusion or matching placebo for sult of less interaction with plate- analysis of 6 randomized con- 5 to 7 days (Table 3). There was a lets, heparin-induced thrombocyto- trolled trials involving 1353 pa- significant reduction in the num- penia is less common with LMWHs tients comparing aspirin plus UFH ber of patients reaching the pri- than with UFH.21-23 with aspirin alone to estimate the ef- mary end point of recurrent an- While there is a suggestion fect on subsequent myocardial in- gina, nonfatal myocardial infarction, that the risk of bleeding is lower farction and death in patients with urgent revascularization, or death in with LMWHs than with UFH in unstable angina. At 30 days, the ad- the nadroparin group compared with certain patient groups, this favor- dition of UFH to aspirin was asso- the UFH and placebo groups, re- able result does not occur in all ciated with a 33% reduction in death spectively (Table 4). Patients re- studies. The reduction in the risk of or myocardial infarction, or 10.4% ceiving nadroparin had signifi-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 3. Clinical Trials of Low-Molecular-Weight Heparins in Patients With Unstable Angina or Non–Q-Wave Myocardial Infarction*

Trial (No. of Patients) Characteristic(s) Treatment Control Primary End Point(s) Gurfinkel et al71 Unstable angina Nadroparin, 214 U/kg, SC BID for 5-7 d (n = 68) UFH/placebo Total events at 7 d; (n = 219) vs heparin, 5000 U, IV bolus followed by 400 recurrent angina at 7 d; U/kg/d to keep aPTT 2 ϫ baseline for 5-7 d acute MI at 7 d; (n = 70) vs placebo for 5-7 d (n = 73) revascularization at 7 d; death at 7 d FRISC72 (n = 1506) Unstable angina Dalteparin, 120 U/kg, SC BID for 6 d followed by Placebo Death/MI at 6 d Non–Q-wave 7500 U SC daily for 35-45 d (n = 760) vs MI placebo (n = 746) FRIC73 (n = 1482) Unstable angina Dalteparin, 120 U/kg, SC BID on days 1-6 UFH Death/MI/angina at 6-45 d Non–Q-wave (acute phase) (n = 751) followed by 7500 U MI SC daily on days 6-45 (chronic phase) (n = 567) vs heparin, 5000 U, IV bolus followed by 1000 U/h to keep aPTT 1.5 ϫ baseline on days 1-6 (n = 731) followed by placebo on days 6-45 (n = 565) TIMI 11A74 (n = 630) Unstable angina Enoxaparin, 1.0 mg/kg, SC BID (n = 309) vs Open label Major hemorrhage at 14 d Non–Q-wave enoxaparin, 1.25 mg/kg, SC BID (n = 321) MI (in the hospital for at least 48 h followed by 40-60 mg SC BID on discharge to complete 14 d of therapy) ESSENCE57 (n = 3171) Unstable angina Enoxaparin, 1.0 mg/kg, SC BID (n = 1607) vs UFH Death/MI/angina at 14 d Non–Q-wave heparin, 5000 U, IV bolus followed by MI infusion to keep aPTT at 55-85 s (n = 1564) TIMI 11B75 (n = 3910) Unstable angina Enoxaparin 30 mg IV bolus then 1.0 mg/kg UFH Death/MI/urgent Non–Q-wave SC BID for at least 72 h and up to 8 d revascularization at 8 d MI (acute phase) (n = 1938) followed by 40-60 mg SC BID to complete 43 d of treatment (chronic phase) (n = 1179) vs heparin 70 U/kg IV bolus followed by 15 U/kg per hour infusion to keep aPTT 1.5-2.5 ϫ baseline for at least 72 h (n = 1936) followed by placebo to complete 43 d of treatment (n = 1185) FRAXIS76 (n = 3468) Unstable angina Nadroparin 0.1 mL/10 kg SC BID for 6 d UFH Cardiovascular death/MI/ Non–Q-wave (n = 1166) vs nadroparin 0.1 mL/10 kg SC refractory angina at 14 d MI BID for 14 d (n = 1151) vs heparin IV bolus followed by infusion for6d(n=1151)

*All patients received aspirin as well as antianginal therapy (␤-blockers, calcium channel blockers, or nitrates) alone or in combination. SC indicates subcutaneously; BID, twice daily; IV, intravenous; aPTT, activated partial thromboplastin time; UFH, unfractionated heparin; MI, myocardial infarction; FRISC, Fragmin during Instability in Coronary Disease Study; FRIC, Fragmin in Unstable Coronary Artery Disease Study; TIMI, in Acute Myocardial Infarction Study; ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study; and FRAXIS, Fraxiparine in Ischemic Syndromes Trial.

cantly less recurrent angina than the dalteparin by SC injection twice daily dalteparin is more effective than pla- patients in the UFH or placebo for 6 days followed by 7500 U sub- cebo in patients with unstable an- groups. There was no significant dif- cutaneously once daily for an addi- gina or non–Q-wave myocardial ference in major bleeding compli- tional 35 to 45 days or matching pla- infarction. However, long-term ben- cations (Figure 1); however, more cebo. Results after 6 days indicated efits of dalteparin were not estab- patients in the UFH group experi- a 63% reduction in the primary end lished in this trial. enced minor bleeding (Figure 2). point of death or myocardial infarc- The Fragmin in Unstable Coro- There was a trend toward favorable tion in the dalteparin group com- nary Artery Disease Study (FRIC)73 results using nadroparin to prevent pared with the placebo group (Table was a prospective, 2-phase trial in myocardial infarction and the need 4). The absolute risk reduction of 3% 1482 patients with unstable angina for revascularization, but the sample correlates to 1 death or myocardial or non–Q-wave myocardial infarc- size was insufficient to conclu- infarction prevented at 6 days for ev- tion (Table 3). During the acute sively evaluate this end point. ery 34 dalteparin-treated patients. phase, patients were randomized The Fragmin during Instabil- The difference between the 2 groups within 72 hours of the onset of chest ity in Coronary Artery Disease was not significant when evaluated pain in an open-labeled fashion to (FRISC) Study Group72 evaluated the at 40 and 150 days. The dalteparin- receive 120 U/kg of dalteparin by SC use of dalteparin in 1506 patients treated groups experienced more mi- injection twice daily or 5000 U of with unstable angina or non–Q- nor bleeding complications (Fig- UFH by IV bolus followed by a con- wave myocardial infarction (Table ure 2). The results of the acute phase tinuous infusion. After treatment of 3). Patients presenting within 72 of this trial are similar to trials con- the acute condition, patients were hours of the onset of were ducted comparing UFH with pla- randomized into a chronic phase randomized to receive 120 U/kg of cebo.2-5 Therefore, it appears that group in a double-blinded manner

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 4. Results of Clinical Trials*

Results†

Trial End Points LMWH Control P Gurfinkel et al71 Nadroparin Heparin Total events at 7 d‡ 15 (22) 44 (63) <.001 Recurrent angina at 7 d 12 (21) 31 (44) .002 Acute MI at 7 d 0 (0) 4 (6) NS Revascularization at 7 d 1 (1.5) 7 (10) NS Death at 7 d 0 (0) 0 (0) NS FRISC72 Dalteparin Placebo Death/MI at 6 d‡ 13 (1.8) 36 (4.8) .001 Death/MI at 40 d 59 (8.0) 81 (10.7) NS Death/MI at 150 d 102 (14.0) 116 (15.5) NS Revascularization at 150 d 229 (32.9) 254 (35.5) NS FRIC73 Dalteparin Heparin Death/MI/angina at 6-45 d‡ 69 (12.3) 69 (12.3) NS Death/MI/angina at 6 d 69 (9.3) 55 (7.6) NS Revascularization at 6-45 d 76 (14.2) 76 (14.3) NS TIMI 11A74 Enoxaparin, 1.25 mg/kg Enoxaparin, 1.0 mg/kg Death at 14 d 7 (2.2) 2 (0.6) NS MI at 14 d 7 (2.2) 9 (2.9) NS Recurrent at 14 d 4 (1.2) 5 (1.6) NS ESSENCE57 Enoxaparin Heparin Death/MI/angina 14 d‡ 266 (16.6) 309 (19.8) .02 48 h 99 (5.2) 115 (7.4) NS 30 d 318 (19.8) 364 (23.3) .02 TIMI 11B77 Enoxaparin Heparin Death/MI/urgent revascularization 8 d 240 (12.4) 281 (14.5) .048 14 d 275 (14.2) 324 (16.7) .029 43 d 335 (17.3) 382 (19.7) .048

*LMWH indicates low-molecular-weight heparin; MI, myocardial infarction; NS, not significant; FRISC, Fragmin during Instability in Coronary Artery Disease Study; FRIC, Fragmin in Unstable Coronary Artery Disease Study; TIMI, Thrombolysis in Acute Myocardial Infarction Study; and ESSENCE, Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study. †Data are given as number (percentage) of events. ‡Primary end point.

to receive 7500 U of dalteparin by term therapy with aspirin alone. The receiving 1.25 mg/kg of enoxapa- SC injection daily or matching pla- trial was not powered to detect a dif- rin than in the 1.0-mg/kg group (Fig- cebo on days 6 through 45. Be- ference in death, myocardial infarc- ure 1). No difference was found in tween days 6 and 45 the propor- tion, or recurrent angina during the any of the secondary end points of tion of patients reaching the primary acute phase. death, myocardial infarction, or re- end point of death, nonfatal myo- The Thrombolysis in Acute current ischemia requiring revascu- cardial infarction, or recurrent an- Myocardial Infarction (TIMI) 11A larization (Table 4). Since this trial gina was 12.3% in both the daltepa- Trial investigators74 conducted an was an unblinded dose-ranging rin and UFH groups (Table 4). At 6 open-labeled, dose-ranging study us- study, no definitive conclusions days, there was no significant dif- ing enoxaparin in patients with un- could be made about the efficacy of ference between the 2 groups in stable angina and non–Q-wave myo- enoxaparin in unstable angina. reaching the same composite triple cardial infarction (Table 3). During The Efficacy and Safety of Sub- end point. The proportion of revas- the acute phase, patients were treated cutaneous Enoxaparin in Non–Q- cularizations at 45 days did not dif- with 1.0 mg/kg of enoxaparin by SC Wave Coronary Events Study Group fer between the 2 groups. There was injection twice daily or 1.25 mg/kg (ESSENCE)57 conducted one of the no difference in major and minor of enoxaparin by SC injection twice largest trials comparing the use of bleeding complications between the daily for a minimum of 48 hours. Af- LMWHs to UFH in acute coronary 2 groups (Figures 1 and 2). The au- ter the acute treatment, patients were syndromes (Table 3). This trial en- thors concluded that dalteparin discharged and received 40 to 60 mg rolled 3171 patients with unstable seemed to be equivalent to UFH in of enoxaparin by SC injection twice angina or non–Q-wave myocardial the acute phase of unstable angina daily to complete 14 days of therapy. infarction. Patients were random- or non–Q-wave myocardial infarc- The primary end point was major ized to receive 1.0 mg/kg of enoxa- tion, and that prolonged adminis- hemorrhage occurring within 2 parin subcutaneously twice daily or tration of a reduced dose of daltepa- weeks of enrollment, which oc- 5000 U of UFH by IV bolus fol- rin offered no advantage over long- curred more frequently in patients lowed by a continuous infusion.

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 efit of enoxaparin in the primary end LMWH UFH Placebo point was maintained (32% for 7 enoxaparin vs 35.7% for UFH; P= .02).78 The difference between the 6 2 groups was primarily the result of less recurrent angina in the enoxa- 5 parin group, which composed 75% of events. There was no difference 4 between groups in major bleeding ∗ complications (Figure 1); how- 3 ever, more patients in the enoxapa- rin groups experienced minor bleed- 2 ing (Figure 2). One limitation of this Major Bleeding Complications, % trial was the fixed rather than 1 weight-adjusted UFH nomogram. Only 46% of patients had therapeu- 0 tic levels of UFH at 24 hours, which Gurfinkel et al71 FRISC72 FRIC73 ESSENCE57 TIMI 11B77 TIMI 11B (Acute) (Chronic) improved to only 51.3% at 48 hours. Although a weight-adjusted hepa- Figure 1. Major bleeding complications. Gurfinkel et al 71 indicate a fall in hemoglobin level of more than rin nomogram may achieve a thera- 20 g/L (Ͼ2 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 (Ͼ2 g/dL) associated with signs peutic aPTT more rapidly in patients and symptoms, intracranial bleeding, or bleeding leading to transfusion, interruption of treatment, or with venous thromboembolism, death; the Fragmin in Unstable Coronary Artery Disease Study (FRIC),73 a fall in hemoglobin level of more the importance of weight-adjusted than 20 g/L (Ͼ2 g/dL), a required transfusion, intracranial hemorrhage, or death or cessation of therapy; nomograms in patients with an- 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 (Ͼ3 g/dL), bleeding resulting in death, gina has not been thoroughly stud- transfusion of at least2Uofblood, or a retroperitoneal, intracranial, or intraocular hemorrhage; and the ied.79,80 Thrombolysis in Acute Myocardial Infarction Trial (TIMI) 11B,77 at least 1 of the following: (1) clinically The Thrombolysis in Myocar- overt hemorrhage resulting in a fall in hemoglobin level of more than 30 g/L (Ͼ3g/dL), and/or (2) a retroperitoneal, intracranial, or intraocular hemorrhage. LMWH indicates low-molecular-weight heparin; dial Infarction (TIMI) 11B Trial in- 75 UFH, unfractionated heparin; and asterisk, P = .02. vestigators conducted a second study comparing 1.0 mg/kg of LMWH UFH Placebo enoxaparin by SC injection twice daily with UFH using a weight- ∗ 14 adjusted UFH nomogram for the treatment of unstable angina and † 12 non–Q-wave myocardial infarction (Table 3). During the acute phase, 10 patients received treatment for a minimum of 72 hours and up to 8 8 days. Following acute treatment, pa- tients initially randomized to enoxa- 6 parin continued to receive enoxa- parin for an additional 35 days at a 4 weight-adjusted reduced dose of 40 Minor Bleeding Complications, % to 60 mg SC twice daily. Patients ran- 2 domized to UFH received placebo during the chronic phase. Results 0 were presented at the 71st Scien- Gurfinkel et al71 FRISC72 FRIC73 ESSENCE57 tific Sessions of the American Heart Association in Dallas, Tex, and in- Figure 2. Minor bleeding complications. LMWH indicates low-molecular-weight heparin; UFH, unfractionated heparin; FRISC, Fragmin during Instability in Coronary Artery Disease Study 72; dicate that fewer enoxaparin- FRIC, Fragmin in Unstable Coronary Artery Disease Study;73 ESSENCE, Efficacy and Safety of treated patients reached the pri- Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events Study 57; asterisk, P = .01; and dagger, mary end points of death, nonfatal PϽ.001. myocardial infarction, and severe re- current ischemia requiring revascu- Treatment continued for a period of nificant difference was maintained larization during the acute phase at least 48 hours and for as long as at 30 days. There was no difference (Table 4).77 This initial benefit was 8 days. At the conclusion of the trial, between groups at 48 hours, nor was maintained at 43 days; however, no significantly fewer enoxaparin- there a difference in the combina- relative reduction in events oc- treated patients reached the pri- tion end point of death or myocar- curred during the chronic phase. Su- mary end point of death, nonfatal dial infarction at 14 and 30 days. Re- periority of enoxaparin in the acute myocardial infarction, or recurrent sults after 1 year of follow-up have phase was not associated with any angina at 14 days (Table 4). This sig- been presented, and the early ben- increase in major bleeding (Figure

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 1); however, there was an increase sults of the cost analysis demon- farction. Prolonged therapy with in major hemorrhage during the strated that the improved clinical lower doses of LMWHs may not of- chronic phase. outcomes for patients treated with fer any advantage over aspirin in the Combined analysis of the re- enoxaparin were associated with a prevention of coronary events or sults of ESSENCE and TIMI 11B cost saving. Despite the US $75 in- death. Major bleeding complica- showed a consistent reduction in the cremental drug cost of administer- tions are similar for LMWHs and odds of the triple end point of death, ing enoxaparin rather than UFH, UFH, but minor bleeding compli- myocardial infarction, or urgent re- cost savings of US $763 were real- cations are more common with vascularization at 8, 14, and 43 days ized at hospital discharge and US LMWHs primarily because of injec- after randomization. Overall, there $1172 at 30 days. The most substan- tion-site hematomas. Finally, was a relative 20% reduction at 43 tial resource effect of enoxaparin was LMWHs appear to be cost-effective days (odds ratio, 0.80; 95% confi- a reduction in the use of coronary compared with UFH based on phar- dence interval, 0.71-0.91). This re- angioplasty, which was a result of the macoeconomic analyses con- duction was also evident when the clinical reduction of recurrent is- ducted in Canada and the United double end point of death or myo- chemic events. Additional savings re- States based on the ESSENCE study cardial infarction was evaluated at 43 sulted from the estimated reduc- results. Taken together, the use of days (odds ratio, 0.82; 95% confi- tion in the cost of IV therapy, tubing LMWHs for the treatment of un- dence interval, 0.69-0.98).77 and appliances, and aPTT monitor- stable angina or non–Q-wave myo- Preliminary results from the ing. This analysis did not evaluate cardial infarction should be fa- Fraxiparine in Ischemic Syndromes cost of outpatient care or indirect vored over UFH. (FRAXIS) trial were presented at the costs related to lost productivity. The Several questions regarding 20th Congress of the European So- authors concluded that the clinical LMWHs remain unresolved. First, ciety of meetings (Table as well as economic advantages of are all LMWH agents comparable? 3).76 This trial enrolled 3468 pa- using enoxaparin over UFH made it Although the biochemical distinc- tients presenting with either un- a dominant strategy in the manage- tions between agents may be mi- stable angina or non–Q-wave myo- ment of acute coronary syndromes. nor, few data define whether impor- cardial infarction. Patients were A Canadian cost-effectiveness tant clinical differences between randomized to receive 1 of 3 treat- analysis has also been conducted agents result. Evidence from FRIC ments: 0.1 mL/10 kg of nadroparin based on the 30-day end point of the and FRAXIS failed to demonstrate by SC injection every 12 hours for 6 ESSENCE trial.82 Based on costs of increased efficacy of LMWHs over days; 0.1 mL/10 kg of nadroparin by medical care in Canada, the aver- UFH by using dalteparin and nadro- SC injection every 12 hours for 14 age cost per patient for enoxaparin parin, respectively.73,76 As a result, days; or UFH for 6 days. Results in- was determined to be Can $848 vs the effective dose of these agents re- dicated no significant difference in the Can $892 for UFH. (At the time of mains uncertain. Alternatively, data primary end point between the 3 this analysis, Can $1.00 was equiva- from ESSENCE and TIMI 11B show treatment groups for cardiovascular lent to US $0.66.) As with the US the greatest benefits and demon- death, myocardial infarction, or re- economic analysis, enoxaparin was strate superiority over UFH using fractory or recurrent angina at 14 considered the dominant antithrom- enoxaparin.57,75,77 Thus, based on the days, with event rates of 17.8%, botic pharmacotherapeutic strat- best available evidence, a class ef- 20.0%, and 18.1%, respectively. Ma- egy for patients with unstable coro- fect of LMWH preparations should jor bleeding was similar between the nary artery disease. not be assumed, and enoxaparin groups when evaluated at 6 days; should be the preferred LMWH however, a higher major bleeding rate CONCLUSIONS agent for patients with unstable an- occurred in the 14-day nadroparin gina or non–Q-wave myocardial in- arm compared with the 6-day nadro- The data evaluating the use of farction. Enoxaparin, 1.0 mg/kg, parin and UFH groups (3.5%, 1.5%, LMWHs in the management of acute subcutaneously twice daily should and 1.6%, respectively) when evalu- coronary syndromes continue to ac- be continued for at least 72 hours, ated at 14 days. cumulate. Despite the encouraging but not beyond the hospital phase. results, the variation in Other unanswered questions PHARMACOECONOMICS study designs and trial end points include the use of LMWHs with complicates a quantitative systematic other antiplatelet agents such as the The positive clinical results demon- comparison of all these data. How- IV and oral glycoprotein IIb/IIIa re- strated in the ESSENCE trial were ever, evidence from TIMI 11B and ceptor antagonists or direct throm- supplemented with a pharmacoeco- ESSENCEinvolvingover7000patients bin inhibitors. Results of large, ran- nomic analysis comparing LMWHs is sufficient to allow recommending domized, controlled trials using and UFH in acute coronary syn- the use of LMWHs in the management glycoprotein IIb/IIIa receptor an- dromes. Mark et al81 conducted a of acute coronary syndromes. tagonists for acute coronary syn- prospective economic assessment Low-molecular-weight hepa- dromes are encouraging.83-86 Unfor- of 936 patients enrolled in the rins are superior to placebo and UFH tunately, it may be many years before ESSENCE trial. These patients rep- in reducing ischemic events or death these agents are evaluated in com- resented 85% of all the patients in the acute phase of unstable an- bination with LMWHs. To date, enrolled from the United States. Re- gina or non–Q-wave myocardial in- clinical experience with direct

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