Low-Molecular-Weight Heparins

Last Updated

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • April 2022; March 2020; March 2018; May 2017; April 2015; Feb. 2015; May 2013; June 2011; Jan. 2009; Aug. 2003; July 2002; July 2001; Aug. 2000. 
  • Initially developed
    • Aug. 1999

1.1. Adults

Low-molecular-weight heparins (LMWH) are FDA-approved in adults to prevent deep vein thrombosis (DVT) in patients undergoing abdominal surgery, hip replacement surgery, as well as those medical patients with acute illness and severely limited mobility, and prevent ischemic complications of unstable angina and non-Q-wave myocardial infarction1-4. Enoxaparin is also indicated to prevent DVT in patients requiring knee replacement surgery, treat inpatient DVT with or without pulmonary embolism (PE), treat outpatient acute DVT without PE, and treat acute ST-segment elevation myocardial infarction (STEMI) in patients managed medically or with subsequent percutaneous coronary intervention, while dalteparin is FDA-approved to treat venous thromboembolism (VTE) to reduce recurrence in cancer patients1-4. However, dalteparin is not FDA-approved to treat acute venous thromboembolism in adults1,2,4. Adult dosages are dependent upon therapeutic diagnosis, body weight, and renal function and are summarized in Table 1. In some circumstances (e.g., weight-based dosages), maximum daily dosages are not readily identifiable.

Table 1. Adult LMWH Recommended Dosages1-4
Treatment Indication Drug Name Maximum Recommended Dosage - Standard Maximum Recommended Dosage - Severe Renal Impairment (CrCl less than 30 ml/min)
Deep vein thrombosis (DVT)/pulmonary embolus (PE) prophylaxis for hip replacement surgery Enoxaparin (Lovenox®) 30 mg SC every 12 hours or 40 mg subcutaneously (SC) once daily 30 mg SC once daily
Deep vein thrombosis (DVT)/pulmonary embolus (PE) prophylaxis for hip replacement surgery Dalteparin (Fragmin®) 5000 IU SC once daily ---
DVT/PE prophylaxis for knee replacement surgery Enoxaparin 30 mg SC every 12 hours 30 mg SC once daily
DVT/PE prophylaxis for abdominal surgery Enoxaparin 40 mg SC once daily 30 mg SC once daily
DVT/PE prophylaxis for abdominal surgery Dalteparin

moderate risk: 2500 IU SC once daily

high risk: 5000 IU SC once daily

 ---
DVT prophylaxis for acute illness and significantly limited mobility Enoxaparin 40 mg SC once daily 30 mg SC once daily
DVT prophylaxis for acute illness and significantly limited mobility Dalteparin 5000 IU SC once daily ---
Outpatient DVT treatment without PE, co-administered with warfarin Enoxaparin 1 mg/kg SC every 12 hours 1 mg/kg SC once daily
DVT/PE treatment in cancer patients Dalteparin

month 1:  200 IU/kg SC once daily

month 2-6:  150 IU/kg SC once daily

(maximum total daily dose = 18,000 IU)

 ---*
Inpatient DVT treatment with or without PE, co-administered with warfarin Enoxaparin 1 mg/kg SC every 12 hours or 1.5 mg/kg SC daily 1 mg/kg SC once daily
Unstable angina/non-Q-wave myocardial infarction (MI), when co-administered with aspirin Enoxaparin 1 mg/kg SC every 12 hours 1 mg/kg SC once daily
Unstable angina/non-Q-wave myocardial infarction (MI), when co-administered with aspirin Dalteparin 120 IU/kg SC every 12 hours (maximum single dose = 10,000 units) ---
Acute STEMI Enoxaparin Less than 75 years:  30 mg IV bolus x 1 + 1 mg/kg SC, followed by 1 mg/kg SC every 12 hours with aspirin 30 mg IV bolus x1 + 1 mg/kg SC, followed by 1 mg/kg SC once daily with aspirin
Acute STEMI Enoxaparin Greater than or equal to 75 years:  0.75 mg/kg SC every 12 hours with aspirin (no bolus) 1 mg/kg SC once daily with aspirin (no bolus)

Legend:

  • * In severe renal impairment in cancer patients, monitor anti-Xa levels to determine dalteparin dose necessary to achieve anti-Xa levels in the range of 0.5 to 1.5 IU/ml.

1.2. Pediatrics

Safety and efficacy of enoxaparin for use in children younger than 18 years of age have not been established1-3. Dalteparin is FDA approved to treat VTE to reduce VTE recurrence in pediatric patients greater than or equal to 1 month of age1,2,4. Dalteparin pediatric dosages are summarized in Table 2. Dosages exceeding these recommendations will be reviewed.

Table 2. Pediatric LMWH Recommended Dosages1,2,4
Treatment Indication Drug Name Maximum Recommended Dosage
Venous thromboembolism treatment Dalteparin
  • 4 weeks to less than 2 years:
    • 150 IU/kg twice daily as starting dose; adjust to maintain anti-Xa level between 0.5-1 IU/mL
  • 2 years to less than 8 years:
    • 125 IU/kg twice daily as starting dose; adjust to maintain anti-Xa level between 0.5-1 IU/mL
  • 8 years to less than 17 years:
    • 100 IU/kg twice daily as starting dose; adjust to maintain anti-Xa level between 0.5-1 IU/mL

2.1. Adults

When prescribed as preventive therapy, LMWH should be administered until the risk of deep venous thrombosis has diminished. When utilized in the management of DVT and pulmonary embolism, warfarin therapy is typically initiated within 72 hours of enoxaparin therapy. Enoxaparin is continued until a therapeutic anticoagulant effect with warfarin has been achieved1-3 . If using Direct-Acting Oral Anticoagulant (DOAC) therapy, then LMWH is typically discontinued upon initiation of DOAC therapy1,2,5-8. LMWH treatment duration varies with respect to therapeutic indication and is summarized in Table 3.

Table 3. LMWH Recommended Treatment Duration (Adults)1-4, 9-15
Treatment Indication Drug Name Treatment Duration Range Maximum Treatment Duration
DVT/PE prophylaxis for hip replacement surgery Enoxaparin 7 to 10 days^ 21 days^
DVT/PE prophylaxis for hip replacement surgery Dalteparin 5 to 10 days 14 days^ 
DVT/PE prophylaxis for knee replacement surgery Enoxaparin 7 to 10 days 14 days^
DVT/PE prophylaxis for abdominal surgery Enoxaparin 7 to 10 days 12 days
DVT/PE prophylaxis for abdominal surgery Dalteparin 5 to 10 days 10 days 
DVT/PE prophylaxis for acute illness and significantly limited mobility Enoxaparin 6 to 11 days 14 days
DVT/PE prophylaxis for acute illness and significantly limited mobility Dalteparin 12 to 14 days 14 days
DVT/PE treatment in cancer patients Dalteparin 6 months 6 months
Outpatient DVT treatment without pulmonary embolus (PE) Enoxaparin 7 days 17 days
Inpatient DVT treatment with or without PE Enoxaparin 7 days 17 days
Unstable angina/non-Q-wave myocardial infarction (MI) Enoxaparin 2 to 8 days 12.5 days
Unstable angina/non-Q-wave myocardial infarction (MI) Dalteparin 5 to 8 daysup to 8 days or hospital discharge, whichever is first 8 days
Acute STEMI Enoxaparin   not determined

Legend:

  • ^In patients undergoing orthopedic surgery, dalteparin and enoxaparin may be continued for 28 to 35 days13.

2.2. Pediatrics

Although treatment durations have not been solidified, experts recommend that dalteparin therapy should be continued for less than or equal to 3 months in pediatric patients with provoked DVT or PE and up to 12 months (range, 6 to 12 months) in pediatric patients with unprovoked DVT or PE15. Dalteparin treatment recommendations for pediatric patients are summarized in Table 4.

Table 4. LMWH Recommended Treatment Duration (Pediatric Patients) 1,2,4,15
Treatment Indication Drug Name Treatment Duration Range Maximum Treatment Duration
Venous thromboembolism treatment Dalteparin 3 to 12 months 12 months

 

3. Duplicative Therapy

Concurrent administration of multiple LMWH products does not provide additional therapeutic benefit and is not recommended. Patient profiles containing concomitant prescriptions for two or more LMWH products will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for LMWHs are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 5. LMWH Drug-Drug Interactions1-4
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
LMWHs defibrotide enhances LMWH pharmacologic effects, increasing bleeding risk avoid concurrent use contraindicated (DrugReax); 1-severe (CP)
LMWHs drugs affecting hemostasis (e.g., anticoagulants, NSAIDs) combined use may produce additive prolongation of bleeding time and increased bleeding risk, including gastrointestinal bleeding; prolonged bleeding risk may persist for several days following LMWH discontinuation; spinal, epidural hematomas reported with enoxaparin use in patients receiving spinal or epidural anesthesia (many also receiving drugs that affect hemostasis like NSAIDs) avoid combination, if possible; discontinue drugs that affect hemostasis prior to initiating LMWH therapy; non-acetylated salicylate may be administered in conjunction with LMWH to avoid antiplatelet activity; acetaminophen, narcotic analgesics additional alternative analgesics for use in patients without inflammatory pain requiring LMWH therapy; if coadministration necessary, monitor closely for clinical, laboratory bleeding complications major (DrugReax) apixaban: 1-severe (CP); other DOACs: 2- major (CP)
LMWHs SSRIs, SNRIs combined use may increase bleeding event risk (e.g., ecchymosis, epistaxis, hematoma, petechiae, life-threatening hemorrhages) as SSRIs and SNRIs may mechanistically interfere with platelet function since serotonin contributes to hemostasis patients requiring adjunctive therapy should be closely monitored for bleeding, with treatment adjustments as necessary, when doses are modified or therapy is initiated or discontinued major (DrugReax); 2-major (CP)

Legend:

  • +CP = Clinical Pharmacology
  • DOACs = direct oral anticoagulants
  • LMWHs = low-molecular-weight heparins
  • NSAIDs = nonsteroidal anti-inflammatory drugs
  • SNRIs = serotonin-norepinephrine reuptake inhibitors
    • SSRIs = selective serotonin reuptake inhibitors

5. References

  1. DRUGDEX® System (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: March 17, 2022).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: https://www-clinicalkey-com.ezproxy.lib.utexas.edu/pharmacology/.  Accessed March 17, 2022.
  3. Enoxaparin subcutaneous/intravenous injection (Lovenox®) package insert. Sanofi-Aventis, December 2021.
  4. Dalteparin subcutaneous injection (Fragmin®) package insert. Pfizer, September 2021.
  5. Edoxaban oral tablets (Savaysa®) package insert. Daiichi Sankyo Inc., September 2021.
  6. Dabigatran oral capsules (Pradaxa®) package insert. Boehringer Ingelheim Pharmaceuticals Inc., June 2021.
  7. Rivaroxaban oral tablets (Xarelto®) package insert. Janssen Pharmaceuticals, Inc., January 2022.
  8. Apixaban oral tablets (Eliquis®) package insert. E.R. Squibb & Sons, LLC., September 2021.
  9. Hong J, Ahn SY, Lee YJ, et al. Updated recommendations for the treatment of venous thromboembolism. Blood Res. 2021;56(1):6-16.
  10. Gary H. Lyman, Marc Carrier, Cihan Ay, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021; 5 (4): 927–974.
  11. Holger J. Schünemann, Mary Cushman, Allison E. Burnett, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2 (22): 3198–3225.
  12. Stevens SM, Woller SC, Kreuziger LB, et al. Executive summary: antithrombotic therapy for vte disease: second update of the chest guideline and expert panel report. CHEST. 2021;160(6):2247-2259.
  13. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e278S-e325S.
  14. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease. CHEST guideline and expert panel report. Chest. 2016;149(2):315-52.
  15. Monagle P, Cuello CA, Augustine C, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Adv. 2018;2(22):3292-316.