Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention FREE

The inciting event in an acute coronary syndrome (ACS) typically involves disruption of a vulnerable atherosclerotic plaque with superimposed thrombosis, leading to varying degrees of occlusion of the culprit artery.^1- 3 ST-elevation myocardial infarction (STEMI) is usually associated with complete thrombotic occlusion of the culprit artery,⁴ while nonocclusive thrombus is the typical finding associated with unstable angina/non–ST-elevation myocardial infarction (UA/NSTEMI).^5- 6 Tissue factor exposed following plaque rupture leads to activation of the coagulation cascade and generation of factor Xa (Figure 1).⁷ Thrombin is formed, which leads to fibrin deposition, platelet activation, and ultimately the formation of a stable clot.⁸

Given the central role of thrombin in the pathogenesis of ACSs, an antithrombotic agent is an important element in therapy, regardless of whether ST elevation is present. However, there are important limitations associated with unfractionated heparin (currently the most commonly used antithrombotic agent), which has prompted a search for alternative compounds.⁹ One promising class of agents is the low-molecular-weight heparins (LMWHs), which offer potential advantages in terms of clinical efficacy, safety, and ease of use in the setting of ACS.

Studies for this review were identified using MEDLINE searches, reviewing reference lists, and conferring with experts and pharmaceutical companies. The medical subject headings used were heparin, enoxaparin, dalteparin, nadroparin, tinzaparin, low molecular weight heparin, myocardial infarction, unstable angina, coronary angioplasty, thrombolytic therapy, reperfusion,, and drug therapy, combination. In addition, relevant abstracts from the annual meetings of the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology were reviewed. We selected for review randomized clinical trials that compared a LMWH with either unfractionated heparin or placebo for the treatment of STEMI and UA/NSTEMI. We also included nonrandomized trials and registries of LMWH that examined clinical outcomes, and/or pharmacokinetics and phamacodynamics in the setting of percutaneous coronary intervention (PCI). Data quality was determined by publication in a peer-reviewed journal or presentation at an official cardiology society–sponsored meeting. Of 39 studies identified, 31 fulfilled criteria for analysis.

Understanding of the pharmacological characteristics of LMWHs has evolved since previous reviews.^10- 11 The LMWHs act more proximally on the coagulation cascade than unfractionated heparin and more effectively inhibit thrombin generation (Figure 1). Increasing evidence also suggests that LMWHs may differ from unfractionated heparin in other thrombin-dependent and thrombin-independent mechanisms (Table 1). These differences may explain the different pharmacological profiles of LMWH and unfractionated heparin in the setting of ACSs and PCI.

Although anti-Xa monitoring is not commonly performed nor recommended in routine clinical practice,^12- 13 it has been suggested that monitoring of LMWH activity may be of benefit in certain high-risk patient subgroups in which the optimal dose of LMWH has not been established.¹⁴ These include patients at weight extremes, patients with renal insufficiency (prolongation of anti-Xa activity),¹⁵ and patients who are pregnant (lower than normal anti-Xa activity for a given LMWH).¹⁶

The LMWHs have been compared with unfractionated heparin for the treatment of UA/NSTEMI in 4 large, prospective randomized trials.^17- 20 Several meta-analyses comparing unfractionated heparin with LMWH have already demonstrated the superiority of LMWH over placebo^21- 23 and the superiority of enoxaparin over unfractionated heparin^21- 22 (Figure 2).

Key differences in clinical trial design, patient selection, and characteristics of the preparations make comparisons among LMWHs difficult. Only 1 trial has compared 2 LMWH preparations in the setting of UA/NSTEMI. The Enoxaparin Versus Tinzaparin (EVET) trial randomized 438 patients presenting with UA/NSTEMI to either enoxaparin (subcutaneous injection of 1 mg/kg twice daily; n = 220) or tinzaparin (subcutaneous injection of 175 IU/kg daily; n = 318).²⁴ The composite primary end point (death, reinfarction, or recurrent angina) was lower with enoxaparin compared with tinzaparin at day 7 (12.3% vs 21.1%; P = .02). This difference, which persisted to 30 days, was driven almost entirely by a reduction in recurrent angina (at 7 days: 11.8% vs 19.3% [P = .03]; at 30 days: 17.3% vs 26.1% [P = .02]). Major bleeding was uncommon and not statistically different between the enoxaparin and tinzaparin groups (3.6% vs 3.2%).

The combination of enoxaparin and tirofiban resulted in a trend toward a greater proportion of patients achieving more than 70% inhibition of platelet aggregation compared with the combination of unfractionated heparin and tirofiban in the Antithrombotic Combination Using Tirofiban and Enoxaparin (ACUTE I) trial (84% vs 65%),²⁵ suggesting a possible synergistic effect on platelet inhibition from LMWH and glycoprotein IIb/IIIa inhibitors. This combination has since been evaluated in 5 trials of initial medical therapy for UA/NSTEMI (Table 2 and Table 3). The major finding was that major hemorrhage occurred rarely in the LMWH and glycoprotein IIb/IIIa inhibitor arms (0.3%-1.8%). These rates compare favorably with the overall 2.4% rate of major bleeding calculated in a meta-analysis of glycoprotein IIb/IIIa inhibitors and unfractionated heparin for the treatment of ACSs.²⁶ Furthermore, no increase in bleeding was noted among UA/NSTEMI patients who proceeded to PCI. Although not powered to detect differences in clinical events, rates of ischemic events in these trials were noted to be similar between the LMWH and unfractionated heparin groups.

The combination of tirofiban and enoxaparin was studied in 1224 patients presenting with STEMI in the Treatment of Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) trial. Patients ineligible for fibrinolysis were randomized in a 2 × 2 fashion to receive either enoxaparin (intravenous 30-mg bolus and subcutaneous injection of 1 mg/kg twice daily) or unfractionated heparin (intravenous 70 U/kg bolus and 15 U/kg per hour infusion) with or without tirofiban (intravenous 10-µg/kg bolus and 0.1-µg/kg per minute infusion) for 2 to 8 days.²⁷ There were no differences noted in the primary efficacy end point between either enoxaparin and unfractionated heparin monotherapy groups (15.4% vs 17.3%) or between enoxaparin and unfractionated heparin combination groups (16.1% vs 17.2%). Major bleeding was rare and not statistically different among all 4 groups.

Evidence suggests that the prothrombotic state associated with an ACS may persist for several months following the index event,^28- 30 providing a biologically plausible rationale for prolonged antithrombotic therapy in this setting. The LMWHs are attractive as long-term antithrombotic agents by virtue of their safety profile and ease of use, prompting several trials to evaluate their use in the outpatient setting following an acute coronary event.^18- 20,31

Although the clinical benefit of inhospital LMWH therapy is maintained up to 1 year following the index event³² (hazard ratio, 0.88; 95% confidence interval, 0.81-0.97; P = .008 for the combined end point of death, MI, or urgent revascularization), no additional benefit from use of LMWH beyond hospital discharge has been convincingly demonstrated among UA/NSTEMI patients.^{17- 18,31,33} In addition, an increase in bleeding with prolonged LMWH treatment has been noted.¹⁷

Prolonged treatment with subcutaneous injections of dalteparin in Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II) did significantly lower the overall risk of death, MI, and revascularization at 30 days compared with placebo (3.1% vs 5.9%; P = .002).³³ However, this benefit was not sustained at 6 months. Because this difference was observed only in patients randomized to the conservative arm of FRISC II,³⁴ the investigators suggested that prolonged antithrombotic therapy may offer benefit as a medical bridge to PCI in patients for whom invasive procedures are delayed.

A statistically significant benefit of prolonged dalteparin treatment compared with placebo was demonstrated in the subgroup of patients in FRISC and FRISC II who presented with elevated baseline troponin-T levels.^35- 36 Moreover, an analysis of Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non–Q-Wave MI/Thrombolysis in MI (ESSENCE/TIMI 11B) demonstrated that compared with unfractionated heparin, enoxaparin blunted the increase in event rates associated with higher baseline risk,³⁷ and among those who underwent invasive therapy.³⁸ However, the effects of early mechanical revascularization may minimize any early differences attributable to prolonged antithrombotic therapy.³⁴

Necessity for Adjunctive Antithrombotic Therapy in Thrombolytic Regimens. The effectiveness of pharmacological reperfusion for STEMI depends on the balance between fibrinolytic and prothrombotic activity. Fibrinolysis enhances the prothrombotic state associated with STEMI by promoting the generation and release of thrombin following successful clot lysis,^39- 41 and activating the coagulation cascade, leading to further platelet activation.^42- 44 Therefore, there is sound theoretical rationale to support the use of concurrent antithrombotic therapy to enhance the process of fibrinolysis in STEMI.

Results of Randomized Clinical Trials of LMWH in STEMI. To date, 8 phase 2 trials and 2 large exploratory clinical trials have been completed that evaluate LMWH with fibrinolytic therapy in STEMI (Table 4 and Table 5). Infarct-related arterial patency following fibrinolysis has been evaluated in 3 trials with enoxaparin (Acute MI-Streptokinase [AMI-SK],⁴⁵ second trial of Heparin and Aspirin Reperfusion Therapy [HART II⁴⁶], and Enoxaparin Antithrombin Therapy for ST-Elevation Thrombolysis in MI [ENTIRE-TIMI 23⁴⁷]) and 1 trial with dalteparin (second trial of Biochemical Markers in ACSs [BIOMACS II⁴⁸]). Use of adjunctive LMWH resulted in improved late coronary artery patency rates (3%-16% absolute improvement in TIMI 2 flow^45- 47 and TIMI 3 flow⁴⁹) and a tendency toward higher TIMI 3 flow rates (1%-17% absolute improvement^45- 49) compared with unfractionated heparin (Table 5). Adjunctive LMWH may also be associated with improved tissue level perfusion following fibrinolysis assessed using ST-segment resolution and other noninvasive composite measurements of reperfusion seen with enoxaparin in the AMI-SK⁴⁵ and Accelerated Streptokinase and Enoxaparin (ASENOX⁵⁰) trials, respectively. Rates of other significant clinical events such late infarct-related arterial reocclusion^45- 46,49 and recurrent ischemia^47- 48,51 were reduced with LMWH compared with unfractionated heparin. Finally, similar bleeding rates were found with LMWH compared with unfractionated heparin in the majority of completed trials (Table 5).

However, preliminary results presented at the AHA 2002 Scientific Sessions from the third Assessment of the Safety and Efficacy of a New Thrombolytic PLUS (ASSENT 3 PLUS) underscore the need for continued evaluation of the safety of LMWH as an adjunct to fibrinolysis.⁵² Among 1639 patients with STEMI receiving tenecteplase and either enoxaparin or unfractionated heparin in a prehospital setting, higher rates of both major bleeding (4.0% vs 2.8%) and intracranial hemorrhage (2.2% vs 1.0%; P = .05) were seen in the enoxaparin group compared with the unfractionated heparin group. There was a significant interaction between patient age and risk of bleeding because almost all cases of intracerebral hemorrhage were confined to patients older than 75 years.

This safety concern of enoxaparin among elderly patients will be addressed in the ongoing (ExTRACT-TIMI 25) trial. This double-blind, parallel group trial is randomizing approximately 21 000 fibrinolysis-eligible STEMI patients in a 1:1 fashion to receive either adjunctive unfractionated heparin (intravenous 60-IU/kg bolus and 12-IU/kg infusion per hour) or enoxaparin (intravenous 30-mg bolus and a subcutaneous injection of 1 mg/kg twice daily). Of note, patients older than 75 years will not receive the intravenous bolus of enoxaparin and will receive only 75% of the subcutaneous injection dose. The primary end point is a composite of all-cause mortality and nonfatal reinfarction within 30 days of randomization.

The issue of LMWH treatment in combination with PCI is becoming increasingly relevant given the results of several studies demonstrating the superiority of an invasive approach for the management of both UA/NSTEMI^34,53 and STEMI.⁵⁴ Compared with the large amount of literature evaluating LMWHs for the medical management of UA/NSTEMI, there are fewer data evaluating LMWHs in the invasive setting. Accordingly, while the ACC, AHA, European Society of Cardiology, and the American College of Chest Physicians have all acknowledged the safety and potential pharmacological advantages of LMWH over unfractionated heparin,^55- 57 none of these organizations have endorsed the use of LMWH as the preferred antithrombotic agent in the invasive management of UA/NSTEMI. Nevertheless, data suggest that LMWH monotherapy is safe and efficacious in the setting of elective and urgent PCI (Table 6 and Table 7). In addition, several trials have also demonstrated the safety and efficacy using LMWH in combination with a glycoprotein IIb/IIIa inhibitor (Table 8 and Table 9).

Unfractionated heparin retains several attractive properties compared with LMWH in the invasive setting, including low cost, complete reversibility with protamine, and the availability of an easily interpretable and standardized point-of-care test (activated clotting time).⁵⁸ In contrast, protamine is able to fully reverse the effect of LMWH on thrombin, but only 60% of its anti-Xa activity.⁵⁹ It remains controversial whether routine monitoring of anticoagulation is needed with LMWH in the catheterization laboratory.^12- 13,60 Moreover, the optimal level of anticoagulation for LMWH during invasive cardiac procedures has not been prospectively defined.

Since LMWH does not appreciably affect either the activated partial thromboplastin time or activated clotting time, clinical trials have focused on the anti-Xa activity as a surrogate to assess the level of anticoagulation. Although now commercially available, routine monitoring of anticoagulation with LMWH has not been universally adopted. The currently accepted therapeutic activity of LMWH in PCI (anti-Xa, >0.5-1.8 IU/mL) is based primarily on clinical data from the deep venous thrombosis literature⁶⁰ and dose-ranging studies in UA/NSTEMI.⁶¹ In TIMI 11A, enoxaparin administered as an intravenous 30-mg bolus followed by a subcutaneous injection of 1 mg/kg twice daily generated trough anti-Xa activity of 0.5 IU/mL and peak activity of 1.1 IU/mL, with a low rate (2.7%) of major hemorrhage among patients undergoing PCI.⁶¹ Several trials have demonstrated that reliable levels of anti-Xa activity consistently greater than the 0.5 IU/mL threshold may be obtained using various doses of LMWH when administered several days or immediately before PCI (Table 10).

From the available data, 2 strategies have emerged guiding the use of LMWH (with or without concomitant glycoprotein IIb/IIIa inhibition) for PCI. First, unfractionated heparin has been substituted for LMWH prior to angiography and coronary intervention if the last LMWH dose was given more than 8 to 12 hours before the procedure.^{34,38,62- 63} Second, a number of pilot trials have evaluated the use of LMWH as the sole anticoagulant throughout angiography and intervention without changing to unfractionated heparin.^25,64- 73 However, these 2 strategies have not been directly compared. With the limited data available, both approaches appear to be safe and efficacious, with bleeding and clinical event rates similar to historical controls (Table 7 and Table 9). Ongoing large trials (ie, A to Z,⁷⁴ SYNERGY⁷⁵) will yield additional information on the safety and efficacy of enoxaparin and glycoprotein IIb/IIIa inhibition in the PCI setting.

Unstable Angina/Non–ST-Elevation MI. Based on the available evidence, the 2002 ACC and AHA guidelines list the use of either LMWH or unfractionated heparin as a class I recommendation for the treatment of UA/NSTEMI (level of evidence, A).⁵⁷ In addition, use of enoxaparin is preferred over unfractionated heparin (class IIA; level of evidence, A), except if coronary artery bypass graft surgery is anticipated within 24 hours.⁵⁷

ST-Elevation MI. Completed trials of adjunctive LMWH compared with either placebo or unfractionated heparin in the setting of STEMI have demonstrated lower rates of late ischemic events and improved rates of late coronary artery patency. The increased bleeding seen with prehospital enoxaparin in ASSENT-3 PLUS requires further study and possible dose modification in elderly patients, although it appears LMWHs are safe among patients younger than 75 years. ExTRACT-TIMI 25, ADVANCE-MI, and FINESSE will be able to provide more definitive data regarding the utility of enoxaparin in modern reperfusion regimens in all age groups.

Although an expert consensus statement has been published with recommendations of LMWH in the setting of PCI,⁶⁰ the most recent guidelines from the ACC and AHA do not discuss the use of LMWH as the sole anticoagulant in the setting of PCI.⁷⁶ Moreover, the optimal level of anticoagulation has not been prospectively validated, although similar efficacy and safety outcomes with LMWH compared with unfractionated heparin (with and without concomitant glycoprotein IIb/IIIa inhibitors) have been shown with a target anti-Xa level of higher than 0.5 IU/mL.

Low-molecular-weight heparin may be used as the sole anticoagulant during PCI. Dalteparin should be given at a dose of 120 IU/kg subcutaneously twice daily provided PCI is performed within 8 hours.³⁴ If PCI is to be performed more than 8 to 12 hours following the last subcutaneous injection dose, patients should be given an additional 60-IU/kg intravenous bolus of dalteparin.⁷⁰ Enoxaparin may be given subcutaneously at a dose of 1 mg/kg twice daily without the need for further supplementation if PCI is performed within 8 hours.^38,67- 68 An additional 0.3-mg/kg intravenous bolus should be given if PCI is performed between 8 and 12 hours after the last subcutaneous dose.^71- 72 Subcutaneous enoxaparin should be reduced for patients with severe renal insufficiency (creatinine clearance <30 mL/min [<0.501 mL/s]). A single 0.5-mg/kg intravenous dose of enoxaparin without further subcutaneous dosing may be safe and efficacious in the setting of moderate-to-severe renal failure.⁷³ Alternatively, unfractionated heparin may be substituted for enoxaparin if PCI is to be performed more than 8 to 12 hours following the last subcutaneous dose of enoxaparin.³⁸

Low-molecular-weight heparin can also be used in conjunction with glycoprotein IIb/IIIa inhibitors. Data from several clinical trials suggest that the combination of enoxaparin with various glycoprotein IIb/IIIa inhibitors^{66,68- 69,77} and dalteparin with abciximab⁷⁰ are safe in the setting of PCI. More definitive information will be forthcoming about the combination of enoxaparin and glycoprotein IIb/IIIa inhibitors during PCI.^74- 75

The use of LMWH has been established as a first-line choice in the treatment of UA/NSTEMI, and increasing evidence suggests that it may supplant unfractionated heparin as an anticoagulant in the setting of PCI and STEMI. However, more clinical data regarding the safety of these agents in elderly patients and in combination with potent platelet inhibitors such as thienopyridines and glycoprotein IIb/IIIa inhibitors are needed before their routine adoption in the setting of STEMI and PCI.