Evidencias Enoxaparina 2008

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Enoxaparin Updated 2008 Oct 16 03:54 PM: enoxaparin and unfractionated heparin had similar outcomes in high-risk eldery patients with non-ST-segment elevation acute coronary syndrome (Eur Heart J 2008 Aug) American College of Chest Physicians guidelines (8th Edition) recommendations on parenteral anticoagulants (Chest 2008 Jun) enoxaparin may be more effective than unfractionated heparin for reducing subsequent myocardial infarction (Eur Heart J 2007 Sep) Related Summaries: Anticoagulation overview Low-molecular-weight heparin (LMWH) for treatment of venous thromboembolism Perioperative DVT prophylaxis

Warnings: Spinal/Epidural Hematoma Risk 1. Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concurrent use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture.1 División de Cirugía; Año 2008

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2. Risk increased by use of indwelling epidural catheters for administration of analgesia or by concomitant use of drugs affecting hemostasis (e.g., NSAIAs, platelet inhibitors, other anticoagulants).1 3. Risk also increased by traumatic or repeated epidural or spinal puncture.1 4. Monitor frequently for signs and symptoms of neurological impairment and treat urgently if neurologic compromise noted.1 5. Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for thromboprophylaxis with anticoagulants.1 (See Hematologic Effects and see Neurologic Effects under Cautions.) General Information Description: Anticoagulant; a low molecular weight heparin.1

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Class: Class: Heparins Synonym: Low molecular weight Heparin Abbreviation: LMWH Brand: Lovenox® División de Cirugía; Año 2008

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Uses and Efficacy Uses: Hip-Replacement Surgery: A low-molecular weight heparin recommended by ACCP for prophylaxis of postoperative deep-vein thrombosis and pulmonary embolism in patients undergoing hip-replacement surgery.1 2 3 5 6 7 20 21 22 27 30 34 35 36 37 38 60 104 Consider extended prophylaxis† in patients undergoing hipreplacement surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).104 Hip-Fracture Surgery: Prevention of postoperative deep-vein thrombosis and pulmonary embolism in patients undergoing hip-fracture surgery†. Consider extended prophylaxis† in patients undergoing hipfracture surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).104 Knee-Replacement Surgery: Prophylaxis of deep-vein thrombosis and pulmonary embolism in patients undergoing knee-replacement surgery.1 20 22 30 104 Knee Arthroscopy: A low-molecular weight heparin recommended by ACCP for prophylaxis of venous thromboembolism in high-risk patients undergoing knee arthroscopy† (e.g., those with preexisting División de Cirugía; Año 2008

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thromboembolic risk factors or following a prolonged or complicated procedure); based on limited data.104 General Surgery: Prophylaxis of postoperative venous thromboembolism in patients undergoing general (e.g., abdominal) surgery who are at risk for thromboembolic complications.1 2 3 5 6 7 20 21 22 27 30 34 35 36 37 38 60 104 Early ambulation without specific thromboprophylaxis recommended by ACCP in patients undergoing general surgery who are at low risk for venous thromboembolism (those undergoing minor operations who are <40 years of age and who have no clinical risk factors).30 60 104 Recommended as alternative to fixed low-dose unfractionated heparin in moderate-risk general surgery patients (those undergoing nonmajor surgery who are 40–60 years of age or who have additional risk factors for thromboembolism, patients <40 years of age undergoing major surgery with no additional risk factors, and patients with risk factors who are undergoing minor surgery).23 30 60 104 Recommended as alternative to fixed low-dose unfractionated heparin in patients undergoing general surgery who are at higher risk for thromboembolism (those undergoing major surgery who are ≥40 years of age or who have additional risk factors and patients undergoing nonmajor surgery who are ≥60 years of age or who have additional risk factors).23 30 31 60 104 Recommended as alternative to low-dose unfractionated heparin and in combination with intermittent pneumatic División de Cirugía; Año 2008

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compression or graduated-compression stockings23 30 31 60 in high-risk general surgery patients (those >40 years of age with multiple risk factors such as a history of previous venous thromboembolism, cancer, or a hypercoagulable state)27 90 . Continue therapy with a low molecular weight heparin after hospital discharge in selected high-risk general surgery patients, including those undergoing major cancer surgery.23 31 60 104 Thromboprophylaxis with low-dose unfractionated heparin, low molecular weight heparin, intermittent pneumatic compression, graduated compression stockings, or a combination of these therapies suggested in patients undergoing laparoscopic gynecologic procedures who have additional risk factors for venous thromboembolic events (e.g., malignancy, older age, previous thromboembolism, prior pelvic radiation therapy, use of an abdominal surgical approach).104 Thromboprophylaxis with a low molecular weight heparin recommended as alternative to low-dose unfractionated heparin1 60 104 or intermittent pneumatic compression in patients having major gynecologic surgery for benign disease who do not have additional risk factors for thromboembolism.104 Begin just prior to surgery and continue until hospital discharge or patient is ambulatory.104 Routine prophylaxis with low molecular weight heparin or unfractionated heparin recommended in patients undergoing extensive gynecologic procedures for malignancy and in those with additional risk factors for venous thromboembolic events.104 Alternative regimens include intermittent pneumatic compression continued until hospital discharge, or División de Cirugía; Año 2008

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the combination of low-dose unfractionated heparin or low molecular weight heparin and intermittent pneumatic compression or graduated-compression stockings.104 Continue prophylaxis for 2–4 weeks following hospital discharge in those at particularly high risk for thromboembolism (e.g., previous cancer surgery, ≥60 years of age, history of thromboembolism).104 Thromboprophylaxis with a low molecular weight heparin or low-dose unfractionated heparin recommended in patients undergoing major vascular surgery who have additional risk factors for thromboembolism (e.g., advanced age, limb ischemia, long duration of surgery, intraoperative local trauma).104 Medical Conditions Associated with Thromboembolism: Prophylaxis of venous thromboembolism in medical patients with CHF or severe lung disease or who have severely restricted mobility in conjunction with one or more additional risk factors (e.g., previous venous thromboembolism, sepsis, acute neurologic disease, inflammatory bowel disease).1 2 3 5 6 7 20 21 22 27 30 34 35 36 37 60 104 Deep-Vein Thrombosis and Pulmonary Embolism: Inpatient treatment of acute deep-vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium.128 102 106 Outpatient treatment of acute deep-vein thrombosis without pulmonary embolism when administered in conjunction with warfarin sodium.1 28

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A low molecular weight heparin recommended by ACCP for treatment of suspected deep-vein thrombosis† while awaiting confirmation of diagnosis, provided no contraindications exist.102 103 A low molecular weight heparin preferred over unfractionated heparin for treatment of deep-vein thrombosis and acute nonmassive pulmonary embolism.102 A low molecular weight heparin recommended by ACCP as alternative to oral anticoagulation (e.g., with warfarin) for long-term treatment of deep-vein thrombosis or acute nonmassive pulmonary embolism† in patients in whom oral anticoagulation is contraindicated or inconvenient.102 ACCP recommends that unfractionated heparin be substituted for low molecular weight heparin in patients with severe renal failure.102 Superficial Thrombophlebitis: A low molecular weight heparin suggested by ACCP as an alternative to unfractionated heparin for treatment of superficial thrombophlebitis† .102 Unstable Angina and Non-ST Segment Elevation MI: Reduction in the risk of acute cardiac ischemic events (combined end point of death, MI, or recurrent angina) in patients with unstable angina or non-ST-segment elevation/non-Q-wave MI (i.e., non-ST-segment elevation acute coronary syndromes) when administered concurrently with aspirin.1 40 41 42 43 Considered by ACCP preferable to unfractionated heparin in patients with non-ST-segment elevation acute coronary División de Cirugía; Año 2008

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syndromes who have received a GP IIb/IIIa-receptor inhibitor prior to PCI.111 ST-Segment Elevation Myocardial Infarction: A low molecular weight heparin suggested by the American Heart Association (AHA), American College of Cardiology (ACC), and ACCP as alternative to unfractionated heparin for adjunctive therapy in patients with ST-segment elevation MI† receiving thrombolytic therapy. Additional study and experience recommended before routine use of low molecular weight heparin instead of unfractionated heparin in patients with ST-segment elevation MI. Low molecular weight heparin not recommended in place of unfractionated heparin as adjunctive therapy for patients who are >75 years of age or who have renal dysfunction (serum creatinine >2.5 mg/dL in men or >2 mg/dL in women). Preferred over unfractionated heparin by ACC and AHA in patients with CHF after ST-segment elevation MI who are hospitalized for prolonged periods, nonambulatory, or considered at high risk for deep-vein thrombosis and are not receiving other anticoagulant therapy. Also recommended by ACC and AHA in patients surviving STsegment elevation MI with or without acute ischemic stroke who have cardiac sources of embolism (atrial fibrillation, mural thrombus, akinetic segment) after reperfusion; administer until adequate anticoagulation with warfarin achieved. ACC and AHA suggest as reasonable therapy in patients with ST-segment elevation MI who are not receiving thrombolytic División de Cirugía; Año 2008

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therapy, provided no contraindications to anticoagulation exist. Neurosurgery: A low molecular weight heparin recommended by ACCP as alternative therapy (e.g., instead of intermittent pneumatic compression with or without graduated compression stockings) for thromboprophylaxis in selected patients undergoing intracranial neurologic surgery† .104 Combination of a low molecular weight heparin or low-dose unfractionated heparin with graduated-compression stockings and/or intermittent pneumatic compression recommended in patients with multiple risk factors for venous thromboembolism.104 Elective Spinal Surgery: A low molecular weight heparin recommended by ACCP for prevention of venous thromboembolism in patients undergoing elective spinal surgery† who have additional risk factors (e.g., advanced age, known malignancy, neurologic deficit, previous venous thromboembolic event, anterior surgical approach), as alternative to postoperative low-dose unfractionated heparin or perioperative intermittent pneumatic compression.104 Combine anticoagulant therapy with graduated-compression stockings and/or intermittent pneumatic compression in patients with multiple risk factors for venous thromboembolism.104

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Acute Spinal Cord Injury: A low molecular weight heparin recommended by ACCP as first-line therapy for prophylaxis of thromboembolism in patients with acute spinal cord injury† .104 For prevention of thromboembolism in therehabilitation phase of acute spinal cord injury† , continue therapy, or, alternatively, convert to full-dose oral anticoagulation.104 Trauma: A low molecular weight heparin recommended by ACCP as first-line prophylaxis for thromboembolism in patients with major trauma† .60 Initiate prophylaxis as soon as considered safe to do so and continue until hospital discharge, including during inpatient rehabilitation.30 104 Extended prophylaxis after hospital discharge suggested in patients with major mobility impairment.104 Burns: A low molecular weight heparin recommended by ACCP as alternative to low-dose unfractionated heparin in burn patients who have at least one additional risk factor for venous thromboembolism (e.g., advanced age, morbid obesity, extensive or lower extremity burns, concomitant lower extremity trauma, use of a femoral catheter, or prolonged immobility).104 Initiate prophylaxis as soon the risk of bleeding is no longer high, provided no contraindications exist.104

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Long-Distance Travel: Single prophylactic dose of a low molecular weight heparin may be considered for thromboprophylaxis prior to travel† as alternative to below-knee graduated-compression stockings in those with risk factors for venous thrombosis (e.g., previous deep-vein thrombosis, coagulation disorder, limited mobility, current or recent cancer, large varicose veins, severe obesity).104 Data insufficient to support routine use in any group of travelers.104 Acute Ischemic Stroke: A low molecular weight heparin recommended by ACCP as first-line thromboprophylaxis in patients with acute ischemic stroke† and impaired mobility who have no contraindications.108 Thromboembolism during Pregnancy: A low molecular weight heparin recommended in selected patients for prevention or treatment of thromboembolism during pregnancy† .63 103 Embolism Associated with Atrial Fibrillation/Flutter: A low molecular weight heparin may be initiated at diagnosis to reduce the incidence of embolism in patients undergoing cardioversion for atrial fibrillation/flutter† of <48 hours' duration, provided no contraindications exist.105 A low molecular weight heparin may be substituted for oral anticoagulant (e.g., warfarin) therapy in patients with atrial fibrillation† who require a series of diagnostic or surgical procedures that necessitate interruption of oral anticoagulation† for >1 week or in selected high-risk patients División de Cirugía; Año 2008

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who require interruption of oral anticoagulant therapy for shorter periods.62 Thromboembolism Associated with Prosthetic Heart Valves: Therapy with a low molecular weight heparin has been recommended in selected patients for prophylaxis of thromboembolism associated with prosthetic heart valves† .59 60 62 63 65 105 107 Systemic Venous Thrombosis in Pediatric Patients: A low molecular weight heparin suggested by ACCP for the treatment and prevention of systemic venous thrombosis in neonates and children† ; data insufficient to make strong recommendations.118 Renal Vein Thrombosis: A low molecular weight heparin suggested by ACCP for the treatment of renal vein thrombosis in neonates† ; data limited and use of anticoagulant or thrombolytic therapy controversial in such patients.118 Cerebral Venous Sinus Thrombosis: A low molecular weight heparin recommended by ACCP with follow-up oral anticoagulation (e.g., warfarin) in adults with acute cerebral venous sinus thrombosis† , even in the presence of hemorrhagic venous infarcts.65 108 Not recommended by some clinicians for use in adults with large hemorrhagic venous infarcts and associated hematomas.65 108 Neonates without large ischemic infarction or intracranial hemorrhage: Initial therapy with a low molecular weight División de Cirugía; Año 2008

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heparin or unfractionated heparin suggested, then administer low molecular weight heparin for 3 months.118 Neonates with large infarcts or intracranial hemorrhage: Radiographic monitoring suggested; initiate anticoagulation if extension of thrombus detected.118 Children without major intracranial hemorrhage: Low molecular weight heparin or unfractionated heparin followed by low molecular weight heparin or oral anticoagulation (e.g., with warfarin).118 Spontaneous Aortic Thrombosis: Neonates with spontaneous aortic thrombosis† and evidence of renal ischemia: Urgent, aggressive use of thrombolytic or surgical therapy supported by anticoagulation with a low molecular weight heparin or unfractionated heparin suggested by ACCP.118 Efficacy: Acute coronary syndrome: • enoxaparin is more effective than unfractionated heparin for reducing subsequent myocardial infarction in patients with ST-elevation myocardial infarction (level 1 [likely reliable] evidence) and possibly in patients with non-STelevation acute coronary syndrome (level 2 [midlevel] evidence) o based on systematic review o meta-analysis of 12 randomized trials of enoxaparin vs. unfractionated heparin in 49,088 patients with ST-elevation myocardial infarction División de Cirugía; Año 2008

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(STEMI) (6 trials with 27,131 patients) or non-STelevation acute coronary syndrome (6 trials with 21,945 patients) o 1 trial in STEMI patients meeting all quality criteria showed clear reduction in reinfarction rates, all other trials either had methodologic limitations or did not have statistically significant differences in primary outcomes o most patients with STEMI were treated with aspirin and fibrinolytic therapy o comparing enoxaparin vs. unfractionated heparin at 30 days overall 1. death or nonfatal myocardial infarction in 9.8% vs. 11.4% in analysis of 12 trials with 49,088 patients (p < 0.001, NNT 63) 2. death, nonfatal myocardial infarction or nonfatal major bleeding in 12.5% vs. 13.5% in analysis of 11 trials with 49,075 patients (p = 0.051), but results may be limited by heterogeneity (p = 0.006) 3. mortality in 5 vs. 5.3% in analysis of 12 trials with 49,076 patients (not significant) 4. myocardial infarction in 5.5% vs. 6.9% in analysis of 12 trials with 49,028 patients (p < 0.001, NNT 72) 5. major bleeding in 4.3% vs. 3.4% in analysis of 12 trials with 48,877 patients (p = 0.019, NNH 111) 6. comparing enoxaparin vs. unfractionated heparin at 30 days in subgroup analysis of 27,131 patients with STEMI, based on 6 trials División de Cirugía; Año 2008

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7. myocardial infarction in 3.4% vs. 5.1% (p < 0.001, NNT 59) 8. major bleeding in 2.6% vs. 1.8% (p < 0.001, NNH 125) 9. mortality in 6.6% vs. 7.1% (p = 0.097) • comparing enoxaparin vs. unfractionated heparin at 30 days in subgroup analysis of 21,945 patients with nonST-elevation acute coronary syndrome, based on 6 trials • myocardial infarction in 8% vs. 9.1% (p = 0.005, NNT 91) • no significant differences in mortality or major bleeding Reference - Eur Heart J 2007 Sep;28(17):2077 ST-elevation myocardial infarction: • enoxaparin has lower rate of mortality and reinfarction but higher rate of bleeding than unfractionated heparin in patients with STelevation myocardial infarction treated with fibrinolysis (level 1 [likely reliable] evidence) o based on randomized trial o 20,506 patients with ST-elevation myocardial infarction scheduled to have fibrinolysis were randomized to enoxaparin vs. unfractionated heparin o all patients treated with aspirin (150-325 mg orally or 500 mg intravenously), then oral División de Cirugía; Año 2008

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aspirin 75-325 mg once daily for at least 30 days o enoxaparin (or matching placebo) given based on age and renal function until hospital discharge or for up to 8 days o if age < 75 years, 30 mg intravenous bolus then 15 minutes later 1 mg/kg (maximum 100 mg) subcutaneously every 12 hours o if age 75 years or older, no bolus, 0.75 mg/kg (maximum 75 mg) subcutaneously every 12 hours o if estimated creatinine clearance < 30 mL/minute, dose modified to 1 mg/kg every 24 hours o unfractionated heparin (or matching placebo) given as intravenous 60 units/kg bolus (maximum 4,000 unit) then infusion of 12 units/kg/hour (initial maximum 1,000 units/hour) titrated to maintain aPTT 1.5-2x control for at least 48 hours o 20,479 patients included in intent-to-treat analysis • comparing enoxaparin vs. heparin at 30 days o 9.9% vs. 12% had death or nonfatal recurrent myocardial infarction within 30 days (p < 0.001, NNT 48) o 3% vs. 4.5% had nonfatal reinfartion (p < 0.001, NNT 67) o 6.9% vs. 7.5% died (p = 0.11) División de Cirugía; Año 2008

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o 2.1% vs. 2.8% urgent revascularization (p < 0.001, NNT 143) o 2.1% vs. 1.4% major bleeding (p < 0.001, NNH 142) o 2.6% vs. 1.8% minor bleeding (p < 0.001, NNH 125) o 0.8% vs. 0.7% intracranial hemorrhage (p = 0.14) o 11% vs. 12.8% had death, reinfarction or major bleeding (p < 0.001, NNT 56) Reference - ExTRACT-TIMI 25 trial (N Engl J Med 2006 Apr 6;354(14):1477, editorial can be found in N Engl J Med 2006 Apr 6;354(14):1524, commentary can be found in N Engl J Med 2006 Jun 29;354(26):2830 , ACP J Club 2006 Sep-Oct;145(2):30 o lower rates of mortality and reinfarction with enoxaparin appear independent of fibrinolytic use o comparing enoxaparin vs. unfractionated heparin o 9.8% vs. 12% death or nonfatal recurrent myocardial infarction at 30 days in subgroup of 16,283 patients treated with fibrin-specific agents (p < 0.001, NNT 46) o 10.2% vs. 11.8% death or nonfatal recurrent myocardial infarction at 30 days in subgroup of 4,139 patients treated with streptokinase (p = 0.1) División de Cirugía; Año 2008

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Reference - Eur Heart J 2007 Jul;28(13):1566, commentary can be found in ACP J Club 2007 NovDec;147(3):63 • lower rates of mortality and reinfarction with enoxaparin appear independent of clopidogrel use • comparing enoxaparin vs. unfractionated heparin • 10.8% vs. 13.9% death, recurrent myocardial infarction, myocardial ischemia or stroke in subgroup of 2,173 patients treated with clopidogrel (p = 0.013, NNT 33) • 13.3% vs. 15.3% death, recurrent myocardial infarction, myocardial ischemia or stroke in subgroup of 12,918 patients not treated with clopidogrel (p = 0.003, NNT 50) • 2.7% vs. 1% major bleeding in patients taking clopidogrel (NNH 58) • 2.1% vs. 1.2% major bleeding in patients not taking clopidogrel (NNH 111) Reference - J Am Coll Cardiol 2007 Jun 12;49(23):2256 • lower rates of mortality and reinfarction with enoxaparin reported in subgroup of 4,676 patients who had fibrinolysis followed by percutaneous coronary intervention (J Am Coll Cardiol 2007 Jun 12;49(23):2238) non-ST-elevation acute coronary syndrome: División de Cirugía; Año 2008

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enoxaparin more effective than unfractionated heparin for preventing myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome (level 2 [mid-level] evidence) meta-analysis of 6 randomized trials with 21,946 patients no significant differences in 3% rates of death at 30 days, or risks of major bleeding or blood transfusion at 7 days 10.1% enoxaparin patients vs. 11% unfractionated heparin patients had combined endpoint of death or myocardial infarction at 30 days (NNT 107) Reference - JAMA 2004 Jul 7;292(1):89, editorial can be found in JAMA 2004 Jul 7;292(1):101, commentary can be found in JAMA 2004 Sep 22;292(12):1427, Am Fam Physician 2004 Nov 15;80(10):1976 enoxaparin and unfractionated heparin had similar outcomes in high-risk patients with non-STsegment elevation acute coronary syndrome (level 2 [mid-level] evidence)

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10,027 such patients to be treated with early invasive strategy were randomized to open-label enoxaparin subcutaneously vs. unfractionated heparin IV until no further anticoagulation needed as judged by treating physician, 49 excluded due to randomization error no significant differences in death or myocardial infarction within 30 days (14% vs. 14.5%), ischemic

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events during percutaneous coronary intervention (1.3% vs. 1.7%), unsuccessful percutaneous coronary intervention (3.6% vs. 3.4%), emergency CABG (0.3% vs. 0.3%) enoxaparin associated with more severe bleeding, 9.1% vs. 7.6% by TIMI definitions (p = 0.008, NNH 66), 2.7% vs. 2.2% by GUSTO definition (p = 0.08, NNH 200) Reference - SYNERGY trial (JAMA 2004 Jul 7;292(1):45), editorial can be found in JAMA 2004 Jul 7;292(1):101, commentary can be found in JAMA 2004 Sep 22;292(12):1427, JAMA 2004 Oct 27;292(16):1952 similar outcomes also reported at 6 months and 1 year (JAMA 2005 Nov 23/30;294(20):2594), commentary can be found in Am Fam Physician 2006 Mar 1;73(5):890, JAMA 2006 May 24/31;295(20):2353 similar outcomes for subgroup of 2,450 elderly patients from SYNERGY trial (Eur Heart J 2008 Aug;29(15):1827) enoxaparin reduces ischemic events in patients with unstable coronary syndromes based on smaller trials enoxaparin and aspirin more effective than unfractionated heparin and aspirin in reducing incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction, with increased minor but not major bleeding; study of 3,171 patients with angina at rest or non-Q-wave myocardial infarction given enoxaparin 1 mg/kg subcutaneously every 12 hours vs. continuous IV heparin for 2-8 days, all patients given aspirin 100-325 mg/day; Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary

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Events (ESSENCE) trial performed in 176 hospitals in 10 countries; ischemic event defined as combined endpoint of death, myocardial infarction/reinfarction or recurrent angina; 16.6% vs. 19.8% patients had ischemic event at 14 days, 19.8% vs. 23.3% at 30 days, 27% vs. 32.2% patients needed revascularization at 30 days; 6.5% vs. 7% major bleeding complications, 18.4% vs. 14.2% incidence of any bleeding complications, mainly attributable to ecchymoses at injection sites (N Engl J Med 1997 Aug 14;337(7):447; discussion of related trials can be found in editorial (N Engl J Med 1997 Aug 14;337(7):492; commentary can be found in N Engl J Med 1998 Jan 8;338(2):129; about 30 patients need to be treated with enoxaparin instead of unfractionated heparin to prevent 1 further coronary event, LMWH at least equivalent + perhaps superior to unfractionated heparin (in Evidence-Based Medicine 1998 Mar/Apr;3(2);43); enoxaparin reported as more costeffective than heparin based on this trial (Circulation 1998 May 5;97(17):1702 in Am Fam Physician 1998 Oct 15;58(6):1435 and in Evidence-Based Medicine 1998 Nov/Dec;3(6);193 or in ACP Journal Club 1998 Nov/Dec;129(3):80:34) enoxaparin associated with sustained benefit at 1 year; 1-year follow-up of ESSENCE trial described above, 32% vs. 35.7% reached composite triple endpoint (death or infarction or recurrent angina) (p = 0.022, NNT 27) (J Am Coll Cardiol 2000 Sep;36(3):693 in JAMA 2000 Oct 25;284(16):2037)

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enoxaparin short-term instead of unfractionated heparin has potential to reduce complication rates without increased hemorrhage; 3910 patients with unstable coronary syndromes randomized to enoxaparin vs. unfractionated heparin (placebo as outpatient); at 8 days, 12.4% vs. 14.5% combined outcome of death, MI or urgent revascularization (p < 0.05, NNT 48); at 43 days, similar 17.3% vs. 19.7% complication rates, 2.9% vs. 1.5% major hemorrhage during outpatient treatment (NNH 71); study funded by drug manufacturer (Circulation 1999 Oct 12;100(15):1593 in J Watch 1999 Nov 15;19(22);176) meta-analysis of these 2 trials comparing enoxaparin vs. unfractionated heparin found, at 43 days, 3.3% vs. 3.9% mortality (NNT 167 but significance not reported), 15.6% vs. 18.8% combined endpoint of death/myocardial infarction/urgent revascularization (p = 0.0005, NNT 32), 1.3% vs. 1.1% major bleeding (not significant), 10% vs. 4.3% minor bleeding (p < 0.0001, NNH 17) (Circulation 1999 Oct 12;100(15):1602 in QuickScan Reviews in Fam Pract 2000 Mar;24(12);18), editorial can be found in Circulation 1999 Oct 12;100(15):1586 enoxaparin reported to be cost-effective in analysis based on these 2 trials (BMC Cardiovascular Disorders 2001 Oct 15;1:2) enoxaparin at least as effective as unfractionated heparin in patients with non-STsegment elevation acute coronary syndrome receiving tirofiban and aspirin (level 2 [mid-level]

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evidence); 3,987 such patients randomized to openlabelenoxaparin 1 mg/kg subcutaneously every 12 hours vs. unfractionated heparin IV until no further anticoagulation needed as judged by treating physician, 17 excluded due to incomplete data at 7 days; no significant differences in combined outcome of death, myocardial infarction or refractory ischemia at 7 days (8.4% vs. 9.4%) or TIMI grade bleeding (3% vs. 2.2%); known as A to Z trial (JAMA 2004 Jul 7;292(1):55), editorial can be found in JAMA 2004 Jul 7;292(1):101, correction can be found in JAMA 2004 Sep 8;292(10):1178 enoxaparin reduces rates of myocardial infarction and major bleeding compared to unfractionated heparin in acute coronary syndrome patients receiving eptifibatide and aspirin; 746 patients with non-ST-segment elevation acute coronary syndrome and ischemic pain at rest within 24 hours of onset were randomized to open-label enoxaparin 1 mg/kg subcutaneously twice daily vs. unfractionated heparin (70 units/kg bolus, 15 unit/kg/hour infusion titrated to target aPTT 1.5-2x control) for 48 hours, all patients given aspirin and eptifibatide (180 mcg/kg bolus, 2 mcg/kg/minute infusion); 1.8% enoxaparin vs. 4.6% heparin patients had major non-CABG-related bleeding at 96 hours (p = 0.03, NNT 36), 30.3% vs. 20.8% minor bleeding (NNH 10), 14.3% vs. 25.4% had ischemia on ECG in initial 48 hours (NNT 9), 12.7% vs. 25.9% had ischemia on ECG in subsequent 48 hours (NNT 8), 5% vs. 9% death or myocardial infarction at 30

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days (p = 0.031, NNT 25) (Circulation 2003 Jan 21;107(2):238)

Dosage and Administration General: Evaluate the possibility of an underlying bleeding disorder before initiation of treatment, unless the need for therapy is urgent.1 Since coagulation parameters are insensitive for monitoring enoxaparin activity, routine monitoring of coagulation parameters is not required.1 (For information on populations that require monitoring, see Pregnancy and also Renal Impairment under Cautions and see Hematologic Effects under Cautions.) In patients with unstable angina and non-ST-segment elevation/non-Q-wave myocardial infarction, adhere precisely to intervals recommended between doses to minimize the risk of bleeding.1 Keep vascular access sheath in place for 6– 8 hours following a dose of enoxaparin.1Administer the next scheduled dose no sooner than 6–8 hours after sheath removal.1 Observe procedure site for signs of bleeding or hematoma formation.1 Administration: Administer by deep sub-Q injection; do not give IM.1 Patient should be supine during administration.1 17 To avoid loss of drug when using the 30- or 40-mg prefilled syringes, do not expel air from syringe prior to injection.1 When using single-use ampuls or multiple-dose vials, withdraw the dose using a tuberculin or equivalent syringe.1 Inject drug sub-Q into the left and right anterolateral and posterolateral abdominal wall.1 División de Cirugía; Año 2008

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Alternate injection sites frequently.1 To minimize bruising, do not massage injection sites after injection.1 Insert the entire length of the needle into a skin fold created by the thumb and forefinger; hold the skin fold until the needle is withdrawn.1 Do not mix enoxaparin with other injections or infusions.1 Dosage: Available as enoxaparin sodium; dosage expressed in terms of the salt.100 Dosages for enoxaparin sodium and regular (unfractionated) heparin or other low molecular weight heparins cannot be used interchangeably on a unit-for-unit (or mg-for-mg) basis.1 Enoxaparin has an approximate anti-factor Xa activity of 100 units/mg using the World Health Organization (WHO) First International Low Molecular Weight Heparin Reference Standard.1 Adults: Prevention of Venous Thrombosis and Pulmonary Embolism: General Surgery: Sub-Q: In patients undergoing general (e.g., abdominal, gynecologic, urologic) surgery who are at moderate to very high risk for thromboembolic complications (e.g., those with malignancy, history of deep-vein thrombosis or pulmonary embolism, or obesity, or patients >40 years of age or undergoing major surgery under general anesthesia lasting División de Cirugía; Año 2008

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>30 minutes), 40 mg once daily with the initial dose given 2 hours prior to surgery.1 30 39 60 Usual duration of therapy is 7–10 days, although up to 12 days of treatment has been well tolerated in clinical trials.1 71 Extended prophylaxis: ACCP suggests continuation for 2–3 weeks after hospital discharge in patients at high risk for thromboembolism.23 31 60 104 Hip-Replacement Surgery: Sub-Q: Initially, 30 mg every 12 hours for ≥10 days; begin 12–24 hours after surgery provided hemostasis has been established.1 Alternatively, consider 40 mg once daily, with the initial dose given approximately 12 hours prior to surgery.1 2 10 34 71 Extended prophylaxis: Following the initial phase of thromboprophylaxis, continue 40 mg once daily for 28–35 days.1 35 36 104 Knee-Replacement Surgery: Sub-Q: Initially, 30 mg every 12 hours for >10 days; begin 12–24 hours after surgery provided hemostasis has been established.1 104 Long-Distance Travel: Long-distance travelers at increased risk for thromboembolism: single dose of <34 mg prior to departure.104 Medical Conditions Associated with Thromboembolism: Sub-Q: División de Cirugía; Año 2008

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Acute illness with impaired mobility: 40 mg once daily.1 Usual duration of therapy is 6–11 days; well tolerated up to 14 days in clinical trials.1 Thromboembolism During Pregnancy: Sub-Q: Primary prevention in women with inherited causes of thrombophilia (e.g., antithrombin deficiency, heterozygous genetic mutation of both prothrombin G20210A and factor V Leiden, or homozygous genetic mutation for factor V Leiden or prothrombin G20210A): 1 mg/kg every 12 hours suggested.103 Primary prevention in other patients with confirmed thrombophilia: 40 mg once daily, followed by postpartum oral anticoagulation (e.g., with warfarin) suggested.103 Secondary prevention after a single episode of idiopathic venous thromboembolism with no long-term anticoagulation: 40 mg once daily.103 Secondary prevention after a single episode of venous thromboembolism with risk factors (e.g., confirmed thrombophilia, strong family history of thrombosis) and no long-term anticoagulation: 40 mg once or twice daily, followed by postpartum oral anticoagulation.103 Secondary prevention after >2 episodes of venous thromboembolism: 1 mg/kg twice daily throughout pregnancy followed by postpartum resumption of long-term anticoagulation.103 Secondary prevention in women who require long-term anticoagulation: 1 mg/kg twice daily throughout pregnancy.103 División de Cirugía; Año 2008

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Treatment of Deep-Vein Thrombosis with or without Pulmonary Embolism: Sub-Q: Outpatient treatment at home in patients without pulmonary embolism: 1 mg/kg every 12 hours.1 29 Pregnant women: 1 mg/kg every 12 hours for remainder of pregnancy.103 Inpatient (hospital) treatment in patients with or without pulmonary embolism (not candidates for outpatient treatment): 1 mg/kg every 12 hours or 1.5 mg/kg once daily at the same time every day.1 Average duration of therapy is 7 days, although up to 17 days of treatment has been well tolerated in clinical trials.1 Initiate concurrent warfarin sodium therapy when appropriate, usually within 72 hours of enoxaparin injection.1 39 59 Continue enoxaparin for a minimum of 5 days, until a therapeutic oral anticoagulant effect is achieved.1 39 59 Embolism Associated with Atrial Fibrillation: Sub-Q: Patients with atrial fibrillation duration <48 hours undergoing cardioversion who have no contraindications to anticoagulation: 1 mg/kg every 12 hours.102 103 105 ACCP suggests same regimen for anticoagulation in patients undergoing cardioversion for atrial flutter.105 Unstable Angina and Non-ST-Segment Elevation MI:

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Sub-Q: 1 mg/kg every 12 hours in conjunction with aspirin therapy.1 41 Administer for a minimum of 2 days and continue until clinical stabilization.1 41 Usual duration of treatment is 2–8 days, although up to 12.5 days of treatment has been well tolerated in clinical trials.1 In patients with unstable angina or non-ST-segment elevation MI undergoingPCI, further anticoagulation suggested based on time of last dose of enoxaparin sodium.114 Last dose within 8 hours of PCI: No additional anticoagulation suggested during procedure.114 Last dose administered 8–12 hours before PCI: 0.3 mg/kg given by directIV injection suggested at initiation of PCI.114 Last dose administered >12 hours prior to PCI: Conventional anticoagulation with unfractionated heparin suggested during PCI.114 116 ST-Segment Elevation Myocardial Infarction: IV, then Sub-Q: Loading dose: 30 mg by direct IV injection†. Maintenance dosage: 1 mg/kg sub-Q every 12 hours until hospital discharge. Special Populations: Dosage in Hepatic Impairment: No dosage recommendations.1 No dosage adjustments necessary in patients with mild (Clcr 50–80 mL/minute) or moderate (Clcr 30–50 mL/minute) renal impairment.1 División de Cirugía; Año 2008

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Dosage in Renal Impairment: Use with caution in renally impaired patients.1 3 No dosage adjustments necessary in patients with mild (Clcr 50–80 mL/minute) or moderate (Clcr30–50 mL/minute) renal impairment.1 Venous Thrombosis and Pulmonary Embolism: Prophylaxis in General (e.g., Abdominal) Surgery: Sub-Q: In patients with severe renal impairment (Clcr <30 mL/minute), 30 mg once daily.1 Prophylaxis in Hip or Knee Replacement Surgery: Sub-Q: In patients with severe renal impairment (Clcr <30 mL/minute), 30 mg once daily.1 Prophylaxis in Medical Conditions Associated with Thromboembolism: Sub-Q: In patients with severe renal impairment (Clcr <30 mL/minute), 30 mg once daily.1 Treatment of Deep-Vein Thrombosis with or without Pulmonary Embolism: Sub-Q: In patients with severe renal impairment (Clcr <30 mL/minute), 1 mg/kg once daily, in conjunction with warfarin therapy.1 Unstable Angina and Non-ST Segment Elevation MI: Sub-Q: División de Cirugía; Año 2008

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In patients with severe renal impairment (Clcr <30 mL/minute), 1 mg/kg once daily, in conjunction with aspirin therapy.1 Geriatric Patients: Use with caution.1 3 Low-Weight Patients: Consider adjustment of dosage for low weight (women <45 kg or men <57 kg).1 Cautions and Adverse Effects

• •

Contraindications: Active major bleeding.1 Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of the drug.1 Known hypersensitivity to enoxaparin sodium, heparin, pork products, or any ingredient in the formulation.1 Warnings/Precautions: Warnings: Neurologic Effects: Epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, associated with concurrent use of low molecular weight heparins and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 Frequent monitoring for signs of neurologic impairment recommended.1 (See Boxed Warning.)

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Hematologic Effects: Use with extreme caution in patients with an increased risk of hemorrhage.1 Such patients include those with bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic GI disease, hemorrhagic stroke, or recent brain, spinal, or ophthalmologic surgery.1 Increased risk for hemorrhage in patients treated concomitantly with platelet inhibitors.1 Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension, or a history of recent GI ulceration, diabetic retinopathy, or hemorrhage.1 Carefully monitor patients with low body weight or renal impairment for signs and symptoms of bleeding.1 As with other anticoagulants, bleeding may occur at any site during therapy.1 Major (sometimes fatal) hemorrhages, including retroperitoneal and intracranial bleeding, have been reported.1 Search for bleeding site if an unexplained fall in hematocrit or blood pressure occurs.1 If enoxaparin overdosage occurs, protamine sulfate may be administered.1 Because fatal reactions resembling anaphylaxis have been reported with protamine sulfate administration, use only when resuscitation techniques and treatment for anaphylactic shock are readily available.1 If a thromboembolic event occurs despite enoxaparin prophylaxis, discontinue the drug and initiate appropriate therapy.1 Cases of heparin-induced thrombocytopenia with thrombosis reported, including complications such as organ infarction, limb ischemia, or death.1 División de Cirugía; Año 2008

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Use with extreme caution in patients with a history of heparin-induced thrombocytopenia.1 Monitor thrombocytopenia of any degree closely.1If platelet count falls to <100,000/mm3, discontinue therapy.1 113 Patients with Prosthetic Heart Valves: Valve thrombosis that was potentially fatal and/or required surgical intervention reported during prophylaxis in some patients (including pregnant women) with mechanical prosthetic heart valves.1 68 69 70 71 82 83 85 87 90 Women with mechanical prosthetic heart valves are at higher risk for thromboembolism during pregnancy.1 63 85 If enoxaparin is used, monitor anti-factor Xa concentrations frequently and adjust dosage appropriately to maintain antifactor Xa concentrations at approximately 1–1.2 units/mL.1 83 93 103 General Precautions: Hematologic Effects: Periodic CBCs, including platelet counts, and stool occult blood tests are recommended.1 If abnormal coagulation parameters or bleeding should occur, monitor anti-factor Xa levels.1 If thromboembolic events occur despite prophylaxis, institute appropriate therapy.1 Specific Populations: Pregnancy: Category B.

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No evidence of teratogenicity or fetotoxicity.1 No excess in the incidence of congenital anomalies compared with what would be expected in the general population.1 Maternal and neonatal hemorrhage has occurred.1 Hemorrhage may lead to death of mother and/or fetus.1 Monitor pregnant women carefully for evidence of bleeding or excessive anticoagulation.1 As delivery approaches, consider use of a shorter-acting anticoagulant.1 Increased risk of thromboembolism in pregnant women.1 Greater risk of thromboembolism in women with a history of thromboembolism and certain high-risk pregnancy conditions.1 63 82 83 Such conditions include hereditary or acquired thrombophilias and the presence of a mechanical prosthetic heart valve.1 63 82 83 If used in pregnant women with mechanical prosthetic heart valves, frequently monitor peak and trough anti-Factor Xa levels.1 71 83 93 Adjust dosage to ensure consistent anticoagulation.1 71 83 93 Lactation: Not known whether enoxaparin is distributed into breast milk.1 Use caution in nursing women.1 Pediatric Use: Safety and efficacy in children not established.1

17

Geriatric Use: Increased risk of enoxaparin-associated bleeding with age.1 Pay careful attention to dosing intervals and concomitant medications (especially antiplatelet medications).1 Consider monitoring (i.e., with anti-Factor Xa División de Cirugía; Año 2008

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assay) geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function.1 Renal Impairment: Monitor anti-factor Xa concentrations in patients with appreciable renal impairment.1 (See Renal Impairment under Dosage and Administration.) Common Adverse Effects: Hemorrhage (including at injection site), anemia, ecchymosis, thrombocytopenia, hematuria, fever, nausea, diarrhea, peripheral or unspecified edema, dyspnea, injection site pain, or confusion.1 Additional Adverse Effect Information: •

enoxaparin associated with greater risk of minor (but not major) bleeding compared to unfractionated heparin in subgroup with severe renal insufficiency (creatinine clearance < 20 mL/minute) in retrospective study of 620 hospitalized patients with renal insufficiency (Chest 2004 Mar;125(3):856 in J Watch 2004 Apr 20) spinal or epidural hematoma reported in 43 patients on enoxaparin (N Engl J Med 1998 Jun 11;338(24):1774 Drug Interactions Drugs That Affect Hemostasis: Potential pharmacodynamic effect (increased risk of hemorrhage) with concurrent use of drugs that affect hemostasis (i.e., oral anticoagulants and/or drugs that affect platelet function, including aspirin, salicylate salts, other División de Cirugía; Año 2008

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NSAIAs [including ketorolac tromethamine], dipyridamole, and sulfinpyrazone).1 Discontinue such drugs prior to initiating enoxaparin therapy.1 Monitor carefully if concurrent administration of such drugs and enoxaparin are considered essential.1 Mechanism of Action/Pharmacokinetics

Actions: Less effect on thrombin than unfractionated heparin at a given level of anti-factor Xa activity.1 2 17 Prolongs some global clotting function tests (i.e., thrombin time, activated partial thromboplastin time [aPTT]) by up to 1.8 times the control value.1 At a recommended dosage in a large clinical trial, the aPTT was ≤45 seconds in most treated patients.1 Pharmacokinetics: Absorption: Bioavailability: Mean absolute bioavailability of 92% when given sub-Q (based on anti-Factor Xa activity).1 Onset: Maximum anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities occur 3–5 hours after administration.1 Duration: Substantial anti-Factor Xa activity persists in plasma for about 12 hours following administration (40 mg once daily).1 Distribution: División de Cirugía; Año 2008

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Extent: About 6 L (based on anti-Factor Xa activity).1 Not known whether enoxaparin is distributed into milk.1 Does not appear to cross placenta.1 Elimination: Elimination Route: Excreted mainly in urine.1 Half-life: 4.5 hours (based on anti-Factor Xa activity).1 Special Populations: In patients with severe renal impairment (Clcr <30 mL/minute), the mean apparent clearance of enoxaparin was approximately 30% lower than controls.1 Delayed elimination in patients with renal insufficiency.1 Delayed elimination in geriatric patients.1 3

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Stability and Compatibility Compatible Sodium chloride 0.9% Preparations Enoxaparin Sodium (Porcine) Routes

Dosage Forms

Strengths Brand Names

Parenteral Injection, for 10 mg/0.1 subcutaneous mL (30, use 40, 60, 80, and 100 mg)

Lovenox® (preservative- Aventis free; available as disposable prefilled syringes)

15 mg/0.1 mL (120 and 150 mg)

Lovenox® (preservative- Aventis free; available as disposable prefilled syringes)

300 mg/3 Lovenox® (with benzyl mL alcohol)

Manufacturer

Aventis

Patient Information Advice to Patients: Importance of reporting any unexplained bleeding or bruising to clinicians.1 División de Cirugía; Año 2008

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Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Apprise pregnant women of the potential hazards to the mother and fetus associated with use during pregnancy.1 Importance of informing patients of other important precautionary information.

References for AHFS DI Essentials: 1.Aventis. Lovenox® (enoxaparin sodium) injection prescribing information. Bridgewater, NJ; 2004 Jul. 2.Buckley MM, Sorkin EM. Enoxaparin: A review of its pharmacology and clinical applications in the prevention and treatment of thromboembolic disorders. Drugs. 1992; 44:465-97. [PubMed 1382939] 3.Turpie A. Enoxaparin prophylaxis in elective hip surgery. Acta Chir Scand Suppl. 1990; 556:103-107. [PubMed 1963014] 4.Fareed J, Walenga JM, Lassen M et al. Pharmacologic profile of a low molecular weight heparin (enoxaparin): experimental and clinical validation of the prophylactic antithrombotic effects. Acta Chir Scand Suppl. 1990; 556:75-90. [PubMed 1963021] 5.Hirsh J. From unfractionated heparins to low molecular weight heparins. Acta Chir Scand Suppl. 1990; 556:42-50. [PubMed 1705072] 6.Planes A, Vochelle N, Fagola M et al. Once-daily dosing of enoxaparin (a low molecular weight heparin) in prevention of deepDivisión de Cirugía; Año 2008

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vein thrombosis after total hip replacement. Acta Chir Scand Suppl. 1990; 556:108-15. [PubMed 1963015] 7.Planes A, Vochelle N, Mazas F et al. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost. 1988; 60:40710. [PubMed 2853459] 8.Levine MN, Hirsh J, Gent M et al. Prevention of deep-vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med. 1991; 114:545- 51. [IDIS EBSCOhostFull Text 279488] [PubMed 1848054] 9.Haas S, Flosbach CW. Prevention of post-operative thromboembolism in general surgery with enoxaparin: preliminary findings. Acta Chir Scand Suppl. 1990; 556:96-102. [PubMed 1963023] 10.Spiro TE, Enoxaparin Clinical Trial Group. A randomized trial of enoxaparin administered post operatively for the prevention of deep-vein thrombosis following elective hip replacement surgery. Thromb Haemost. 1991; 65:927. 11.Griffiths MC, ed. USAN 1993: USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1992:238-9. 12.Bara L, Samama M. Pharmacokinetics of low molecular weight heparins. Acta Chir Scand Suppl. 1990; 556:57- 61. [PubMed 1963018]

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13.Fareed J, Walenga JM, Hoppensteadt D et al. Biochemical and pharmacologic inequivalence of low molecular weight heparins. Ann N Y Acad Sci. 1989; 556:333-53. [PubMed 2544128] 14.Hoppensteadt D, Racanelli A, Walenga JM et al. Comparative antithrombotic and hemorrhagic effects of dermatan sulfate, heparan sulfate, and heparin. Semin Thromb Hemost. 1989; 15:378-85. [PubMed 2530633] 15.Fareed J, Walenga JM, Hoppensteadt D et al. Chemical and biological heterogeneity in low molecular weight heparins: implications for clinical use and standardization. Semin Thromb Hemost. 1989; 15:440-63. [PubMed 2554505] 16.Fareed J, Walenga JM, Williamson K et al. Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments.Semin Thromb Hemost. 1985; 11:56-74. [PubMed 3883500] 17.Rhône-Poulenc Rorer, Collegeville, PA: Personal communication. 18.Spiro TE, Colwell CW, Trowbridge AA for the Enoxaparin Clinical Trial Group. A clinical trial comparing the efficacy and safety of enoxaparin, a low molecular weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement surgery. 19.Imperiale TF, Speroff T. A meta-anlysis of methods to prevent venous thromboembolism following total hip replacement. JAMA. 1994; 271:1780-5. [IDIS 330661] [PubMed 7515115] 20.Ledere JR, Geerts WH, Desjardins L et al. Prevention of deepvein thrombosis after major knee surgery—a randomized, doubleblind trial comparing a low molecular weight heparin fragment

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(enoxaparin) to placebo. Thromb Haemost. 1992; 67:41723. [PubMed 1321509] 21.Spiro TE, Colwell CW, Bona RD et al et al. Enoxaparin versus unfractionated heparin for prevention of venous thromboembolic disease after elective knee replacement surgery. Chest. 1994; 106(Suppl 2):48S. 22.Noble S, Peters DH, Goa KL. Enoxaparin: a reappraisal of its pharmacology and clinical applications in the prevention and treatment of thromboembolic disease. Drugs. 1995; 49:388410. [PubMed 7774513] 23.Clagett GP, Anderson FA, Heit J et al. Prevention of venous thromboembolism. Chest. 1995; 108(Suppl):312-34S. 24.Heit JA, Berkowitz SD, Bona R et al. Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Thromb Haemost. 1997; 77:32-8. [IDIS 380054] [PubMed 9031445] 25.Hull R, Raskob G, Pineo G et al. A comparison of subcutaneous low-molecular weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med. 1993; 329:1370-6. [IDIS 322164] [PubMed 8413432] EBSCOhost Full Text 26.Lumpkin MM. Dear health care professional letter regarding reports of epidural or spinal hematomas with concurrent use of low molecular weight heparins or heparinoids and spinal/epidural anesthesia or spinal puncture. Rockville, MD: US Food and Drug Administration; 1997 Dec 15.

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27.ENOXACAN Study Group. Efficacy of enoxaparin versus unfractionated heparin for prevention of deep-vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg. 1997; 84:1099103. [PubMed 9278651] 28.Dolovich LR, Ginsberg JS, Douketis JD et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med. 2000; 160:181-8. [IDIS 442244] [PubMed 10647756] 29.Levine M, Gent M, Hirsch J et al. A comparison of low-molecularweight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996; 334:677-81. [IDIS EBSCOhost Full Text 361075] [PubMed 8594425] 30.Clagett GP, Anderson FA, Geerts W et al. Prevention of venous thromboembolism. Chest. 1998; 114(Suppl. 5S):531S-60. [IDIS 416740][PubMed 9822062] 31.Verstraete M, Prentice CRM, Samama M et al. A European view on the North American Fifth Consensus on Antithrombotic Therapy. Chest. 2000; 117:1755-70. [IDIS 449137] [PubMed 10858413] 32.Pharmacia & Upjohn, Inc. Fragmin® (dalteparin sodium injection) prescribing information. Kalamazoo, MI; 1999 May. 33.Francis CW, Pelligrini VD, Totterman S et al. Prevention of deepvein thrombosis after total hip arthroplasty: comparison of warfarin and dalteparin. J Bone Joint Surg Am. 1997; 79:1365-72. [PubMed 9314399]

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34.Spiro TE, Johnson GJ, Christie MJ et al. Efficacy and safety of enoxaparin to prevent deep-vein thrombosis after hip replacement therapy. Ann Intern Med. 1994; 121:81-9. [IDIS 332861] [PubMed 8017740] EBSCOhost Full Text 35.Planes A, Vochelle N, Darmon JY et al. Efficacy and safety of postdischarge administration of enoxaparin in the prevention of deep venous thrombosis after total hip replacement: a prospective randomised double-blind placebo-controlled trial. Drugs. 1996; 52(Suppl 7):47-54.[PubMed 9042560] 36.Bergqvist D, Benoni G, Bjorgell O et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med. 1996; 335:696-700. [IDIS 371704] [PubMed 8703168] EBSCOhost Full Text 37.Horlocker TT, Heit JA. Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for reginal anesthetic management. Anesth Analg. 1997; 85:874-85. [IDIS 395935] [PubMed 9322474] 38.Davidson BL. Out-of-hospital prophylaxis with low-molecularweight heparin in hip surgery: the Swedish study. Chest. 1998; 114(Suppl 2): 130S-2S. 39.Hyers TM, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 1998; 114(Suppl 5):561S78S. [IDIS 416741] [PubMed 9822063] 40.Eikelboom JW, Anand SA, Malmberg K et al. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet. 2000; 355:1936-42. [IDIS 448634] [PubMed 10859038] EBSCOhost Full Text División de Cirugía; Año 2008

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41.Cohen M, Demers C, Gurfinkel EP et al. A comparison of lowmolecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997; 337:447-52. [IDIS 389816] [PubMed 9250846] EBSCOhost Full Text 42.Antman EM, McCabe CH, Gurfinkel EP et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 11B trial. Circulation. 1999; 100:1593-601. [IDIS 437219][PubMed 10517729] 43.Antman EM, Cohen M, Radley D et al. Asessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction: TIMI 11B-ESSENCE metaanalysis. Circulation. 1999; 100:1602-8. [IDIS 437220] [PubMed 10517730] 44.Armstrong PW. Pursuing progress in acute coronary syndromes. Circulation. 1999; 100:1586-9. [IDIS 437218] [PubMed 10517727] 45.Hull RD, Pineo GF, Francis C et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthoplasty patients: a double-blind, randomized comparison. Arch Intern Med. 2000; 160:2199-207. [IDIS 450825] [PubMed 10904464] 46.Eriksson BI, Kalebo P, Anthymyr BA et al. Prevention of deepvein thrombosis and pulmonary embolism after total hip replacement. Comparions of low-molecular-weight heparin and unfractionated heparin. J Bone Joint Surg Am. 1991; 73:48493. [PubMed 2013587] 47.Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 División de Cirugía; Año 2008

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update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). From http://www.acc.org/clinical/guidelines and http://www.americ anheart.org 48.Antman EM, Fox KM et al. Guidelines for the diagnosis and management of unstable angina and non-Q-wave myocardial infarction: proposed revisions. Am Heart J. 2000; 139:461-75. [IDIS 444999] [PubMed 10689261] 49.Wallentin L. New trials of LMW heparins-light and heavy weight as good on short but what about longer distances? Eur Heart J. 1999; 20:1522-24. 50.Agency for Health Care Policy and Research. Diagnosing and managing unstable angina. 1994. (AHCPR publication no. 94-0603) 51.Cairns JA, Theroux P, Lewis D et al. Antithrombotic agents in coronary artery disease. Chest. 1998; 114(Suppl 5):611S-33S. [IDIS 416745][PubMed 9822067] 52.Kaul S, Shah PK. Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin? J Am Coll Cardiol. 2000; 35:1699-702. 53.Klein W, Buchwald A, Hillis SE et al. Comparison of lowmolecular-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; 96:61-8. [IDIS 389986] [PubMed 9236418]

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54.Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet. 1996; 347:561-8. [IDIS 361634] [PubMed 8596317] EBSCOhost Full Text 55.LeClerc JR, Geerts WH, Desjardins L et al. Prevention of venous thromboembolism after knee arthroplasty: a randomized, doubleblind trial comparing enoxaparin with warfarin. Ann Intern Med. 1996; 124:619-26. [IDIS 362226] [PubMed 8607589] EBSCOhost Full Text 56.RD Heparin Arthroplasty Group. RD Heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. J Bone Joint Surg Am. 1994; 76:1174-85. [PubMed 8056798] 57.Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol. 2000; 36:970-1062. [IDIS 452618] [PubMed 10987629] 58.Gould MK, Dembitzer AD, Doyle RL et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep-vein thombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med. 1999; 130:800-9. [IDIS 424536] [PubMed 10366369] EBSCOhost Full Text 59.Hyers TM, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001; 119(Suppl.):176S93S. [IDIS 459448] [PubMed 11157648] EBSCOhost Full Text

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60.Geerts WH, Heit JA, Clagett GP et al. Prevention of venous thromboembolism. Chest. 2001; 119(Suppl.):132S-75S. [IDIS EBSCOhost Full Text 459447] [PubMed 11157647] 61.Cairns JA, Theroux P, Lewis HD et al. Antithrombotic agents in coronary artery disease. Chest. 2001; 119:228S-52S. [IDIS 459452] [PubMed 11157652] EBSCOhost Full Text 62.Fuster V, Ryden LE, Assinger RW et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology, American Heart Association Task Force on Practice guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol. 2001; 38:1266i-l. 63.Ginsberg JS, Greer I, Hirsch J. Use of antithrombotic agents during pregnancy. Chest. 2001; 119(Suppl.):122S-131S. [IDIS 459446] [PubMed 11157646] EBSCOhost Full Text 64.Bonow RO, Carabello B, de Leon AC et al. ACC/AHA guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol. 1998; 32:1486-588. [IDIS 417155] [PubMed 9809971] 65.Albers GW, Amarenco P, Easton JD et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001; 119(Suppl.):300S-20S. [IDIS 459456] [PubMed 11157656] EBSCOhost Full Text 66.Mcleod RS,, Geerts WH, Sniderman KW et al. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery. Results of the Canadian colorectal DVT prophylaxis trials: a

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