A Potential Role for EnoxaparinABSTRACT: Unfractionated heparin (UFH) is currently given as the standard anticoagulant therapy in ST-elevation myocardial infarction (STEMI) patients, including those undergoing percutaneous coronary intervention (PCI). Recent data, however, have shown lower rates of death or recurrent myocardial infarction (MI) with the low-molecular-weight heparin (LMWH) enoxaparin compared with UFH in STEMI patients treated with thrombolytics, offsetting an increase in major bleeding. This review compares the use of enoxaparin with UFH in STEMI patients undergoing PCI, within the context of available evidence for other anticoagulant drugs. Evidence is accumulating for the preferential use of enoxaparin in STEMI patients undergoing PCI. J INVASIVE CARDIOL 2008;20:615–621 Antithrombotic therapy has become the standard-of-care in the treatment of acute coronary syndromes (ACS). With regard to non-ST-segment elevation myocardial infarction (NSTEMI), unfractionated heparin (UFH), the low-molecular-weight heparin (LMWH) enoxaparin, and fondaparinux are the anticoagulant options for any treatment strategy, while bivalirudin is an option for an invasive strategy.1 More specifically, the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for NSTEMI recommend the use of either enoxaparin or fondaparinux in preference to UFH for an initial conservative strategy unless coronary artery bypass grafting is planned within the next 24 hours.1 In the acute management of ST-elevation myocardial infraction (STEMI), the 2008 ACC/AHA guidelines state that in patients undergoing reperfusion with fibrinolytics, treatment should include aspirin and administration of enoxaparin (level of evidence: A), fondaparinux (level of evidence: B) or UFH (level of evidence: C).2 Recently, the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction-25 (ExTRACT-TIMI 25) trial showed that enoxaparin was associated with a lower rate of death or recurrent myocardial infarction (MI) than UFH in STEMI patients, but with a higher rate of major bleeding.3 The benefit of the reduced rate of death or recurrent MI, however, outweighed the increase in major bleeding, resulting in a net clinical benefit of enoxaparin over UFH. Therefore, there is a need to consider whether enoxaparin should be the preferred agent in the routine care of STEMI patients treated with thrombolytics. Approximately half of all STEMI patients will require reperfusion with percutaneous coronary intervention (PCI) at some point during their care pathway.4 PCI may be performed as a primary intervention (primary PCI), after thrombolysis when the infarct artery has not been successfully recanalized (rescue PCI), or after thrombolytics have successfully recanalized the infarct-related artery, but residual stenosis remains. Because anticoagulants are indispensable in the setting of any coronary intervention, UFH has been given as the standard anticoagulant therapy in STEMI patients undergoing PCI, even though no placebo-controlled trials have been performed.5,6 Using the available data, this review compares the use of enoxaparin with that of UFH in STEMI patients undergoing PCI in the context of available evidence for other anticoagulant drugs. Methods Studies for consideration were identified by multiple Medline searches performed for all years up to September 2007. Drugs included in the search criteria were ardeparin, tinzaparin, dalteparin, enoxaparin, reviparin, fondaparinux, bivalirudin, desirudin, argatroban, and dabigatran. Searches for articles on STEMI PCI or clinical trials/randomized, controlled trials in STEMI or PCI were performed for each drug. Articles were excluded from the review if an abstract was not available, the article was not published in English, or the content was not relevant to the topic. The reference lists of key articles were also searched for potentially relevant article citations. Publications that included trials in STEMI patients were examined for data on patients undergoing PCI, and subgroups of STEMI patients were sought within trial publications on PCI. Use of Anticoagulant Drugs in STEMI PCI Few large-scale clinical trials have been published that assess the use of anticoagulant drugs only in STEMI patients undergoing PCI. Information is available from subgroup data from STEMI trials and from a number of small-scale studies (Table 1, Figure 1). Consequently, the revised, recently published 2008 ACC/AHA guidelines for patients with STEMI have updated recommendations for patients undergoing PCI.2 Enoxaparin in STEMI patients treated with thrombolytics and proceeding to PCI. A number of studies have been published on the use of enoxaparin in STEMI patients treated with thrombolytics, including patients who subsequently underwent PCI. PCI was performed in 28–48% of the patients in the study populations (Table 1). Although not all of these studies reported separate results for the subgroup of PCI patients,7,8,11 a number of subgroup analyses are available.10,20,21 In the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-TIMI-28 study of nearly 3,000 STEMI patients, LMWH therapy was compared with UFH, each as an adjunct to standard fibrinolytic treatment, aspirin and clopidogrel. Although the use and type of LMWH were at the discretion of the treating physician, 85% of the patients treated with a LMWH were given enoxaparin. Before angiography, the patients receiving LMWH had a 13.5% incidence of the composite endpoint of occluded infarct-related artery, death or recurrent MI, which was lower compared with 22.5% in those receiving UFH (p = 0.027). Within the subgroup of 55% of patients undergoing PCI, a lower rate of cardiovascular death or MI was found with LMWH than with UFH (adjusted odds ratio [OR], 0.60; 95% confidence interval [CI], 0.40–0.91). Thrombolysis in myocardial infarction (TIMI) major bleeding rates, however, were similar (0.8% in the LMWH group and 1.7% in the UFH group [p = 0.12]), as were the rates of intracranial hemorrhage (0.6% versus 0.8%; p = 0.50).21 In the Assessment of the Safety and Efficacy of a New Thrombolytic regimen- 3 (ASSENT-3) study, the use of enoxaparin (initial 30 mg intravenous [IV] bolus followed by 1.0 mg/kg q12h up to 7 days) and IV UFH (for 48 h) was compared in 4,078 STEMI patients treated with tenecteplase. Almost 30% of the patients underwent subsequent PCI.9 Subanalyses of the data of patients undergoing PCI showed no significant difference between patients given enoxaparin and those receiving UFH in the primary composite endpoint of 30-day mortality, in-hospital reinfarction or in-hospital refractory ischemia, irrespective of whether the PCI was planned, urgent or performed early.10 In the planned PCI group, the primary composite end point occurred in 1.44% of the patients treated with enoxaparin and in 2.12% of those treated with UFH (hazard ratio [HR], 0.70; 95% CI, 0.22–2.21). Protocol-defined bleeding complications were similar between the two groups (enoxaparin, 1.72%; UFH, 1.81%; HR, 0.81; 95% CI, 0.25–2.66). Fewer of the patients who received enoxaparin required urgent PCI (11.9%) compared with those given UFH (14.3%) (p Other Anticoagulants for PCI in STEMI Patients. LMWHs. Evidence related to the use of LMWHs other than enoxaparin in STEMI PCI is limited (Table 1). In the ASSENT-Plus study of 439 STEMI patients, 21% of the dalteparin-treated (120 IU/kg SC q12h) patients underwent PCI after thrombolysis with alteplase. Data on these patients, however, were not reported separately.15 In the large-scale Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation (CREATE), the LMWH reviparin was compared with placebo therapy in 15,570 patients with STEMI or new left bundle-branch block. Patients who weighed less than 50 kg received 3,436 IU SC q12h reviparin, those who weighed 50–75 kg received 5,153 IU SC q12h, and those who weighed more than 75 kg received 6,871 IU SC q12h. Data on the 949 (6.1%) patients who underwent primary PCI did not demonstrate significant efficacy benefit with reviparin treatment compared with placebo (HR, 0.79; 95% CI, 0.48–1.31). Bleeding data were not reported for the PCI subgroup16 (Table 1, Figure 1). Fondaparinux. In the recently published large-scale, international Organization to Assess Strategies for Ischaemic Syndromes-6 (OASIS-6) study, 12,092 STEMI patients were randomized to receive either 2.5 mg fondaparinux or usual care, which could include UFH for up to 48 hours as antithrombotic therapy.17 Around 30% of the patients underwent primary PCI (Table 1, Figure 1). In the PCI subgroup, fondaparinux was associated with a 6.1% rate of death or reinfarction compared with 5.1% in the UFH group (p = 0.19) and 16 versus 9 occurrences of protocol-defined major bleeding (no p-value was given). Thus, compared with UFH, fondaparinux does not appear to be more effective in STEMI patients undergoing primary PCI.17 Moreover, PCI patients in the fondaparinux group had higher rates of coronary complications such as guiding catheter thrombosis (22 versus 0 cases; p Practical Matters in the use of Enoxaparin in STEMI PCI Monitoring and HIT. Laboratory monitoring of activated partial thromboplastin time (aPTT) is essential when using UFH to ensure that the treatment provides adequate anticoagulation without undue risk of bleeding. In contrast, LMWHs have more predictable pharmacokinetic and pharmacodynamic properties and can be dosed without the need for therapeutic monitoring.28 A further advantage of LMWH over UFH is the much lower rate of heparin-induced thrombocytopenia (HIT). A meta-analysis calculated that the risk of HIT is ten times lower for LMWHs such as enoxaparin than for UFH (OR, 0.10; 95% CI, 0.01–0.2).29 The Global Registry of Acute Coronary Events (GRACE) reported the relative risk of HIT to be 0.15 (95% CI, 0.07–0.32) when LMWH is administered to ACS patients compared with UFH.30 Note, however, that neither UFH nor LMWH should be used in patients with HIT.28 Administration and dosing. According to the ExTRACT-TIMI-25 study, the standard enoxaparin regimen for STEMI patients receiving thrombolytics is an initial 30 mg IV bolus with subsequent SC injections of 1.0 mg/kg q12h3,31 (Table 3). Patients proceeding to PCI are then given an additional 0.3 mg/kg IV bolus if the last dose of enoxaparin was given 8–12 h previously.31,32 For elderly patients (≥ 75 years of age), the initial IV bolus was eliminated and SC dosing was reduced to 75% of normal dosing. For patients with severe renal impairment, defined as an estimated creatinine clearance (CrCl) of less than 30 mL/min, the dose was modified to 1.0 mg/kg SC every 24 h.3 The revised 2008 ACC/AHA guidelines include these dosing specifications for enoxaparin in STEMI patients undergoing PCI (level of evidence: A) In one analysis of the ExTRACT-TIMI-25 trial measuring patient renal function, death or MI occurred in 33.0% of the patients with CrCl 0.05). Major bleeding rates were 5.7% and 2.8%, respectively (p > 0.05). The net clinical endpoints of death, MI and major bleeding were similar between enoxaparin (34.9%) and UFH (37.7%) (p > 0.05).33 A number of studies have used different dosing regimens (Table 2). For example, a regimen of enoxaparin 0.5 mg/kg IV followed by 1.0 mg/kg SC reliably reached target anti-Xa levels (0.5–1.5 IU/mL).12 However, if an initial single SC enoxaparin dose of 1.0 mg/kg is used, it should be combined with IV enoxaparin 0.3–0.5 mg/kg prior to PCI.23 In elective PCI, enoxaparin 0.5 or 0.75 mg/kg IV reliably achieved target anticoagulation levels in the Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients, an International Randomized Evaluation (STEEPLE) trial.34 Ease of administration and predictable pharmacokinetics of enoxaparin allow for rapid initiation of treatment. Conclusion Clinical evidence from the largest STEMI PCI population to date supports the preferential use of enoxaparin over UFH in STEMI patients treated with thrombolytics and proceeding to PCI. Furthermore, evidence is accumulating for the prehospital use of enoxaparin before primary PCI and for facilitated PCI. Large-scale randomized clinical trials in over 50,000 patients conducted over a decade have consistently shown that enoxaparin is more effective than UFH, with a good safety profile and easier use in ACS patients including those undergoing PCI. Thus, there is strong support for using enoxaparin across the continuum of treatment for ACS patients, including STEMI patients undergoing PCI.
1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction): Developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148‚Äì304.
2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008;117:296‚Äì329.
3. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477‚Äì1488.
4. Fox KA, Anderson FA Jr, Dabbous OH, et al. Intervention in acute coronary syndromes: Do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE). Heart 2007;93:177‚Äì182.
5. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005;26:804‚Äì847.
6. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006;113:e166‚Äìe286.
7. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003;108:135‚Äì142.
8. Simoons M, Krzemi√±ska-Pakula M, Alonso A, et al. Improved reperfusion and clinical outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myocardial infarction. The AMI-SK study. Eur Heart J 2002;23:1282‚Äì1290.
9. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605‚Äì613.
10. Dubois CL, Belmans A, Granger CB, et al. Outcome of urgent and elective percutaneous coronary interventions after pharmacologic reperfusion with tenecteplase combined with unfractionated heparin, enoxaparin, or abciximab. J Am Coll Cardiol 2003;42:1178‚Äì1185.
11. Antman EM, Louwerenburg HW, Baars HF, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: Results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Circulation 2002;105:1642‚Äì1649.
12. Lab√®que JN, Ja√Øs C, Dubos O, et al. Prehospital administration of enoxaparin before primary angioplasty for ST-elevation acute myocardial infarction. Catheter Cardiovasc Interv 2006;67:207‚Äì213.
13. Svensson L, Aasa M, Dellborg M, et al. Comparison of very early treatment with either fibrinolysis or percutaneous coronary intervention facilitated with abciximab with respect to ST recovery and infarct-related artery epicardial flow in patients with acute ST-segment elevation myocardial infarction: The Swedish Early Decision (SWEDES) reperfusion trial. Am Heart J 2006;151:798.e1‚Äìe7.
14. Armstrong PW; WEST Steering Committee. A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: The WEST (Which Early ST-elevation myocardial infarction Therapy) study. Eur Heart J 2006;27:1530‚Äì1538.
15. Wallentin L, Bergstrand L, Dellborg M, et al. Low molecular weight heparin (dalteparin) compared to unfractionated heparin as an adjunct to rt-PA (alteplase) for improvement of coronary artery patency in acute myocardial infarction ‚Äî The ASSENT Plus study. Eur Heart J 2003;24:897‚Äì908.
16. Yusuf S, Mehta SR, Xie C, et al. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA 2005;293:427‚Äì435.
17. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: The OASIS-6 randomized trial. JAMA 2006;295:1519‚Äì1530.
18. White H; Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: The HERO-2 randomised trial. Lancet 2001;358:1855‚Äì1863.
19. Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J Am Coll Cardiol 1994;23:993‚Äì1003.
20. Gibson CM, Murphy SA, Montalescot G, et al. Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol 2007;49:2238‚Äì2246.
21. Sabatine MS, Morrow DA, Montalescot G, et al. Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Angiographic and clinical outcomes in patients receiving low-molecular-weight heparin versus unfractionated heparin in ST-elevation myocardial infarction treated with fibrinolytics in the CLARITY-TIMI 28 Trial. Circulation 2005;112:3846‚Äì3854.
22. Buller CE, Pate GE, Armstrong PW, et al. Catheter thrombosis during primary percutaneous coronary intervention for acute ST elevation myocardial infarction despite SC low-molecular-weight heparin, acetylsalicylic acid, clopidogrel and abciximab pretreatment. Can J Cardiol 2006;22:511‚Äì515.
23. Welsh RC, Gordon P, Westerhout CM, et al. A novel enoxaparin regime for ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: A WEST sub-study. Catheter Cardiovasc Interv 2007;70:341‚Äì348.
24. Fern√°ndez-Avil√©s F, Alonso JJ, Pe√±a G, et al. Primary angioplasty vs. early routine post-fibrinolysis angioplasty for acute myocardial infarction with ST-segment elevation: The GRACIA-2 non-inferiority, randomized, controlled trial. Eur Heart J 2007;28:949‚Äì960.
25. ADVANCE MI Investigators. Facilitated percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: Results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE MI) trial. Am Heart J 2005;150:116‚Äì122.
26. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial. Lancet 2006;367:569‚Äì578.
27. Stone GW, Witzenbichler B, Guagliumi G, et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218‚Äì2230.
28. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(Suppl 3):188S‚Äì203S.
29. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: A meta-analysis. Blood 2005;106:2710‚Äì2715.
30. Gore JM, Granger CB. Incidence of heparin-induced thrombocytopenia lower than expected in patients with acute coronary syndromes. The Global Registry of Acute Coronary Events. AHA Scientific Sessions 2006. Circulation 2006. Abstract 4014.
31. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin as antithrombin therapy in patients receiving fibrinolysis for ST-elevation myocardial infarction. Design and rationale for the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25). Am Heart J 2005;149:217‚Äì226.
32. D√≠ez JG, Cheong BY, O‚ÄôMeallie LP, Alt EU. Monitoring of enoxaparin level using citrated clotting time during percutaneous coronary intervention. J Intervent Cardiol 2004;17:307‚Äì313.
33. Fox KA, Antman EM, Montalescot G, et al. The impact of renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol 2007;49:2249‚Äì2255.
34. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006‚Äì1017.