Low-Molecular-Weight Heparins and Thrombin Inhibitors

Number: 0346

Policy

  1. Aetna considers the use of low-molecular-weight heparins (LMWHs) medically necessary in certain clinical settings in which they have been found to offer an improved efficacy/safety ratio over standard unfractionated heparins (UFHs).  Consistent with the Medical/Scientific Statements of the American Heart Association and the American Society of Clinical Oncology, Aetna considers LMWHs medically necessary for the following indications:
     
    1. For the prevention of venous thromboembolism for any of the following:
       
      • Hip surgery including replacement and hip fracture surgery (for up to 35 days post-operatively); or
      • Knee surgery including replacement surgery (for up to 2 weeks post-operatively); or
      • Persons who are at risk of thromboembolic complications due to severely restricted mobility during acute illness (e.g., acute multiple trauma, acute spinal cord injury, acute thrombotic stroke, leg immobilization from ankle or foot trauma); or
      • Persons undergoing major thoracic surgery who are at high-risk for VTE due to presence of a malignancy or a history of deep venous thrombosis or pulmonary embolism (for up to 2 weeks post-operatively); or
      • Persons undergoing abdominal-pelvic surgery at moderate to high risk of VTE (for up to two weeks postoperatively, with extended duration of 4 weeks in persons with high risk of VTE undergoing surgery for cancer).
    2. For the inpatient treatment of venous thrombosis with or without pulmonary embolism; or
    3. For the outpatient treatment of venous thrombosis and prophylaxis of the extension of venous thrombosis and/or the prevention of thromboembolism when inpatient care can be diverted to the home setting by using LMWHs since they require less monitoring and less complicated delivery systems;
    4. In accordance with American College of Obstetricians and Gynecologists' Committee Opinion, for thromboprophylaxis in pregnant women with thrombophilic disorders, and for treatment in pregnant women with VTE (i.e., venous thrombosis, pulmonary embolism);
    5. Anti-coagulation of pregnant women with a prosthetic heart valve;
    6. Persons with mechanical heart valves until stable on vitamin K antagonists or novel oral anticoagulants (NOACs);
    7. For prevention of ischemic complications of unstable angina and non-Q-wave myocardial infarction;
    8. For treatment of acute myocardial infarction;
    9. For children 2 months of age or older who meet any of the following: 
       
      1. For short-term prophylaxis anti-coagulation in high-risk situations such as immobility, significant surgery, or trauma; or
      2. For long-term management of congenital pre-thrombotic states (e.g., congenital anti-thrombin deficiency, congenital homozygous protein C and S deficiency with measurable plasma concentration, etc.); or
      3. When long-term oral anti-coagulant therapy becomes problematic;
    10. When used as short-term therapy pre-operatively when a member on oral anti-coagulation needs to be put on parenteral therapy prior to surgery or as treatment post-operatively as a transition to oral anti-coagulation (See CPB 0200 - Coumadin (Warfarin) to Heparin Conversion Before and After Elective Surgery).
    11. For the initial (5 to 10 days) and continuing (at least 6 months) treatment of cancer patients with established VTE.  (Note: after 6 months, indefinite anti-coagulation therapy should be considered for selected members with active cancer, such as those with metastatic disease and those receiving chemotherapy).
    12. For thromboprophylaxis in persons with multiple myeloma receiving thalidomide or lenalidomide who are at high-risk of VTE (see Appendix).
  2. Aetna considers LMWHs experimental and investigational for all other indications, including in any of the following clinical settings, because the current medical literature does not provide enough scientific evidence that their use is associated with better health outcomes as compared to UFHs:

    • Arterial thrombosis; or
    • Femoral-popliteal graft patency; or
    • Members requiring anti-coagulation for hemodialysis; or
    • Members undergoing cerebral, ocular, or spinal surgery (intermittent pneumatic compression of the legs is indicated); or
    • Members with relatively low-risk for VTE undergoing general surgical procedures; or
    • Metastatic breast cancer, treatment (using LMWH-based nanoparticles); or
    • Metastatic synovial sarcoma, treatment; or
    • Prevention of preeclampsia; or
    • Prevention of proliferative vitreo-retinopathy following retinal re-attachment surgery); or
    • Prevention of re-stenosis following coronary angioplasty; or
    • Raynaud's phenomenon; or
    • Recurrent miscarriage; or
    • Remission induction in persons with ulcerative colitis; or
    • Sepsis/septic shock; or
    • Treatment of acute heparin-induced thrombocytopenia; or
    • Treatment of vaso-occlusive crises in members with sickle cell disease.
  3. Aetna considers argatroban (Argatroban Injection) in the outpatient setting medically necessary for prophylaxis of cerebral thrombosis, and thrombosis in individuals with heparin-induced thrombocytopenia (HIT), and treatment of cerebral thrombosis, and thrombosis in individuals with HIT.

  4. Aetna considers argatroban experimental and investigational for the following indications (not an all-inclusive list):

    1. Anticoagulation of percutaneous ventricular assist device
    2. Inhibition of breast cancer metastasis to bone
    3. Management of acute penetrating artery infarction
    4. Management of acute superior mesenteric venous thrombosis not meeting medical necessity criteria above
    5. Management of persons in whom long-term warfarin treatment is generally indicated and appropriate and where either LMWH has not been shown to improve health outcomes compared to warfarin, or who do not exhibit intolerance or have contraindications to warfarin and have not developed recurrent VTE while on therapeutic doses of warfarin
    6. Management of persons with acute coronary syndrome
    7. Management of persons with acute respiratory distress syndrome undergoing extracorporeal lung support
    8. Management of persons with stroke
    9. Prevention of in-stent re-stenosis after extra-cranial artery stenting
    10. Prevention of thrombosis related to long-term indwelling central venous lines in individuals with cancer.

See also Pharmacy Clinical Policy Bulletin on “LMWH”.  Available at: Aetna Non-Medicare Prescription Drug Plan.

Dosing Recommendations

Low-Molecular Weight Heparins (LMWH)

Arixtra (fondaparinux) 

Available as: Single-dose, prefilled syringes containing 2.5 mg, 5 mg, 7.5 mg, or 10 mg of fondaparinux sodium.

Prophylaxis of deep vein thrombosis: Arixtra 2.5 mg subcutaneously once daily after hemostasis has been established. The initial dose should be given no earlier than 6 to 8 hours after surgery and continued for 5 to 9 days.

For persons undergoing hip fracture surgery, extended prophylaxis up to 24 additional days is recommended. 

Treatment of deep vein thrombosis and pulmonary embolism: Arixtra 5 mg (body weight <50 kg), 7.5 mg (50 to 100 kg), or 10 mg (>100 kg) subcutaneously once daily. Treatment should continue for at least 5 days until INR 2 to 3 achieved with warfarin sodium.

Source: Mylan, 2019

Fragmin (dalteparin)

Available as: Injection: 2,500 IU/ 0.2 mL, 5,000 IU/ 0.2 mL, 7,500 IU/ 0.3 mL, 12,500 IU/ 0.5 mL, 15,000 IU/ 0.6 mL, and 18,000 IU/ 0.72 mL single-dose prefilled syringes. Injection: 10,000 IU/ mL single-dose graduated syringes. Injection: 95,000 IU/ 3.8 mL (25,000 IU/mL) multiple-dose vials.

Table: Fragmin Dosing

Indication

Dosing Regimen

Unstable angina and non-Q-wave MI

120 IU/kg subcutaneous every 12 hours (with aspirin) 

DVT prophylaxis in abdominal surgery

2,500 IU subcutaneous once daily or

5,000 IU subcutaneous once daily or

2,500 IU subcutaneous followed by 2,500 IU subcutaneous 12 hours later and then 5,000 IU subcutaneous once daily

DVT prophylaxis in hip replacement surgery

Postoperative start - 2,500 IU subcutaneous 4 to 8 hours after surgery, then 5,000 IU subcutaneous once daily, or

Preoperative start - day of surgery 2,500 IU subcutaneous 2 hours before surgery followed by 2,500 IU subcutaneous 4 to 8 hours after surgery, then 5,000 IU subcutaneous once daily. 

Preoperative start - Evening Before Surgery 5,000 IU subcutaneous followed by 5,000 IU subcutaneous 4 to 8 hours after surgery.

DVT prophylaxis in medical patients per labeling

5,000 IU subcutaneous once daily

Extended treatment of VTE in adult patients with cancer

Month 1: 200 IU/kg subcutaneous once daily 

Months 2 - 6: 150 IU/kg subcutaneous once daily

Treatment of VTE in pediatrics see full prescribing information

Age Group                                                        Starting Dose

4 Weeks to less than 2 Years                           150 IU/kg twice daily

2 Years to less than 8 Years                             125 IU/kg twice daily

8 Years to less than 17 Years                           100 IU/kg twice daily

Source: Pfizer, 2019

Lovenox (enoxaparin)

Available as: 

  • 100 mg/mL concentration: prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL; graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL; multiple-dose vial: 300 mg/3 mL 
  • 150 mg/mL concentration: graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL.
Table: Lovenox Dosing

Indication

Dosing Regimen

DVT prophylaxis in abdominal surgery

40 mg SC once daily (with the initial dose given 2 hours prior to surgery) in persons undergoing abdominal surgery who are at risk for thromboembolic complications. The usual duration of administration is 7 to 10 days.

DVT prophylaxis in knee replacement surgery

30 mg SC every 12 hours. Administer the initial dose 12 to 24 hours after surgery, provided that hemostasis has been established. The usual duration of  administration is 7 to 10 days.

DVT prophylaxis in hip replacement surgery

30 mg SC every 12 hours. Administer the initial dose 12 to 24 hours after surgery, provided that hemostasis has been established. The usual duration of administration is 7 to 10 days. A dose of 40 mg once a day SC may be considered for up to 3 weeks. Administer the initial dose 12 (±3) hours prior to surgery.

DVT prophylaxis in medical patients

40 mg SC once daily. The usual duration of administration is 6 to 11 days.

Inpatient treatment of acute DVT with or without pulmonary embolism

1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily; initiate warfarin therapy when appropriate (usually within 72 hours of Lovenox). Continue Lovenox for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (INR 2 to 3). The average duration of administration is 7 days.

Outpatient treatment of acute DVT without pulmonary embolism

1 mg/kg SC every 12 hours; initiate warfarin therapy when appropriate (usually within 72 hours of Lovenox). Continue Lovenox for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (INR 2 to 3). The  average duration of administration is 7 days.

Unstable angina and non-Q-wave MI

1 mg/kg SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily) in persons with unstable angina or non–Q-wave myocardial infarction. Treat with Lovenox for a minimum of 2 days and continue until clinical stabilization. The usual duration of treatment is 2 to 8 days. 

Acute STEMI in persons <75 years of age

30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours  (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses) in persons with acute ST-segment elevation myocardial infarction. Unless contraindicated, administer aspirin as soon as they are identified as having STEMI and continue dosing with 75 to 325 mg once daily. When administered in conjunction with a thrombolytic (fibrin specific or non–fibrin specific), administer Lovenox between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. The usual duration of Lovenox therapy is 8 days or until hospital discharge. 

For persons managed with percutaneous coronary intervention (PCI), if the last Lovenox subcutaneous administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last Lovenox subcutaneous administration was given more than 8 hours before balloon inflation, administer an intravenous bolus of 0.3 mg/kg of Lovenox.

Acute STEMI in persons ≥75 years of age

0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses). Unless contraindicated, administer aspirin as soon as they are identified as having STEMI and continue dosing with 75 to 325 mg once daily. When administered in conjunction with a thrombolytic (fibrin specific or non–fibrin specific), administer Lovenox between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. The usual duration of Lovenox therapy is 8 days or until hospital discharge. 

Source: Sanofi-Aventis, 2018

Note: Innohep (tinzarparin) and Orgaran (danaparoid) have been discontinued in the U.S.

Direct Thrombin Inhibitors

Angiomax (bivalirudin)

Available for injection as: 250 mg of bivalirudin in a single-dose vial for reconstitution.

For persons who do not have HIT/HITTS: PCI/PTCA: 0.75 mg/kg intravenous (IV) bolus dose followed immediately by a 1.75 mg/kg/h IV infusion for the duration of the procedure. See Full Prescribing Information for remainder of monitoring and dosing information.

For persons who have HIT/HITTS: PCI: 0.75 mg/kg IV bolus dose followed immediately by a 1.75 mg/kg/h IV infusion for the duration of the procedure. See Full Prescribing Information for remainder of monitoring and dosing information.

For persons with STEMI: Consider extending duration of infusion post-procedure up to 4 hours.

Source: The Medicines Company, 2016

Argatroban

Available as: 250 mg/2.5 mL single-dose vial. Argatroban Injection must be diluted 100-fold by mixing with 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer's Injection to a final concentration of 1 mg/mL.  

Heparin-Induced Thrombocytopenia: The dose without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion.  

Percutaneous Coronary Intervention (PCI): The dose with or at risk for heparin-induced thrombocytopenia undergoing PCI is started at 25 mcg/kg/min and a bolus of 350 mcg/kg administered via a large bore intravenous line over 3 to 5 minutes.

Source: Hospira, 2019

Pradaxa (dabigatran)

Available as: capsules for oral use: 75 mg, 110 mg and 150 mg.

Non-valvular Atrial Fibrillation: For persons with CrCl >30 mL/min: 150 mg orally, twice daily; For persons with CrCl 15-30 mL/min: 75 mg orally, twice daily

Treatment of DVT and PE: For persons with CrCl >30 mL/min: 150 mg orally, twice daily after 5-10 days of parenteral anticoagulation.

Reduction in the Risk of Recurrence of DVT and PE: For persons with CrCl >30 mL/min: 150 mg orally, twice daily after previous treatment.

Prophylaxis of DVT and PE Following Hip Replacement Surgery: For persons with CrCl >30 mL/min: 110 mg orally first day, then 220 mg once daily.

Source: Boehringer Ingelheim, 2019

Note: Refludan (lepirudin) and Iprivask (desirudin) have been discontinued in the U.S.

Background

Low-Molecular-Weight Heparins

Low molecular weight heparins are fragments or fractions of conventional (unfractionated) heparin that produce anticoagulation when administered subcutaneously. The products are prepared using a wide variety of methods. Chromatographic techniques have been employed to separate various fractions from unfractionated heparin. These techniques include molecular exclusion, stearic exclusion, ion exchange, and affinity chromatography. Chromatographic methods of fractionation are effective but give a minimal yield. Chemical or enzymatic depolymerization of heparin produces much higher yields and is more commercially acceptable.

Low molecular weight heparin fractions may contain between four and 25 distinct molecular fragments. Most low molecular weight heparin fractions have a molecular weight between 4000 and 9000 daltons. Each heparin fragment may be comprised of two to 50 monosaccharide units and each exhibits a varying degree of activity.

Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep), fondaparinux (Arixtra), and danaparoid (Orgaran) are the low-molecular-weight heparins (LMWHs)/low-molecular weight heparinoid currently in use. While technically not a LMWH, Arixtra (fondaparinux) also exhibits similar anti‐Factor Xa activity.

Lovenox (enoxaparin sodium) is a low molecular weight heparin which has anti‐Factor Xa and anti‐thrombin (anti‐Factor IIa) activities.

Fragmin (dalteparin sodium) is a low molecular weight heparin. It has antithrombotic properties which inhibits coagulation Factor Xa and thrombin by means of antithrombin, while it slightly affects activated partial thromboplastin time.

Innohep (tinzaparin sodium) is a low molecular weight heparin which exhibits antithrombotic properties. It inhibits reactions through plasma protease inhibitor, antithrombin, which is responsible for blood clotting including fibrin clots formation. It also acts as a potent co‐inhibitor of coagulation factors such as Factors Xa and IIa (thrombin). In December 2008, Celgene issued a Dear Healthcare Professional letter describing a controlled clinical study suggesting that Innohep may increase the risk for death, compared to UFH when used to treat elderly patients with renal insufficiency.  It recommended consideration of alternatives to Innohep when treating these patients for deep vein thrombosis (DVT) with or without pulmonary embolism (PE). In 2011, LEO Pharma Inc voluntarily recalled Innohep. Based on the limited quantity delivered to the US market, LEO Pharma Inc. decided to discontinue marketing innohep 20,000 IU/ml multidose vials in the US effective February 10, 2011.

Orgaran (danaparoid) was a LMWH that was discontinued in August 2002 by the manufacturer (Drugs.com, 2019).

Arixtra (fondaparinux sodium) is an antithrombotic drug that selectively binds to antithrombin III (ATIII); thus, potentiating the neutralization of Factor Xa. Neutralization of Factor Xa disrupts the blood coagulation cascade, which inhibits thrombin formation and thrombus development. Arixtra is technically not a LMWH.

While LMWHs should replace unfractionated heparin (UFH) for preventing thromboembolism in certain clinical settings, some unresolved issues remain to be addressed in specific trials before LMWHs can generally replace UFH for all indications.  Clinical trials have enabled the evaluation of the principal roles that standard UFHs or LMWHs play in clinical practice.  Although the anti-thrombotic efficacy and safety of LMWHs are at least equal to that of UFHs, the medical literature supports their use over UFHs only in certain clinical settings.

Standard UFHs are preferable for the prevention and treatment of venous thrombosis and the prevention of venous thromboembolism in low-risk patients, and for maintaining coronary patency after thrombolytic treatment for acute myocardial infarction.  There is no convincing evidence that LMWHs have an improved benefit to risk ratio over standard UFHs in patients with arterial thrombosis or with symptomatic pulmonary embolism.  The most significant advantage of LMWHs is that they raise the possibility that selected patients with venous thrombosis might be suitable candidates for treatment at home, an advance that would reduce cost and improve patient convenience.

In pregnancy, LMWH provides distinct advantages over UFH.  Studies have shown that LMWH does not cross the placenta, has no teratogenic effects, and is as effective as traditional heparin.  Preliminary evidence suggests that there is no greater risk of bone demineralization, and that LMWH decreases risks of thrombocytopenia and hemorrhagic complications.

Patients with unstable angina and non-Q wave myocardial infarction may sustain a small amount of myocardial loss but have significant amounts of viable, yet ischemic, myocardium, placing them at high-risk for future cardiac events.  The limitations of conventional treatment with UFH in these patients are demonstrated by the 7 to 9 % rate of serious complications (infarction and/or death) at 30 days.  The benefit of LMWHs in acute coronary syndromes has been validated in several clinical trials.  The results of the TIMI trial indicate that LMWHs are effective in reducing major ischemic outcomes in patients with unstable angina and non-Q wave myocardial infarction.  The ESSENCE study showed that combination anti-thrombotic therapy with enoxaparin plus aspirin is more effective than UFH plus aspirin in decreasing ischemic outcomes in patients with unstable angina or non-Q-wave myocardial infarction in the early (30 days) phase, and that the lower recurrent ischemic event rate seen with the LMWH is achieved without an increase in major bleeding.  The subcutaneous administration, the lack of a need for laboratory tests, better predictability of the anticoagulant effect and better tolerance are powerful arguments favoring LMWH for use in unstable angina and infarction without Q wave.  The requirement for prolonged oral anti-platelet or LMWH treatment in ambulatory patients after an acute coronary event remains to be evaluated.  Trials of longer-term therapy with LMWHs are in progress.

The 6th (2000) ACCP Consensus Conference on Antithrombotic Therapy stated that available evidence indicates that enoxaparin is ineffective in preventing restenosis following coronary angioplasty.  Furthermore, LMWH is not recommended for the treatment of acute heparin-induced thrombocytopenia (Hirsh et al, 2001).

In an article on unsolved issues in the treatment of PE, Goldhaber (2001) stated that the current Food and Drug Administration recommendation for patients with symptomatic PE is to administer intravenous UFH as a bridge to therapeutic warfarin.

The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy (Bates et al, 2004) made the following recommendations for women with prosthetic heart valves: adjusted-dose bid LMWH throughout pregnancy, aggressive adjusted-dose UFH throughout pregnancy, or UFH or LMWH until the 13th week and then change to warfarin until the middle of the 3rd trimester before restarting UFH or LMWH.  In high-risk women with prosthetic heart valves, the 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy also suggested the addition of low-dose aspirin, 75 to 162 mg/day.

In the initial treatment of venous thromboembolism, LMWH is administered once- or twice-daily.  A once-daily treatment regimen is more convenient for the patient and may optimize home treatment.  However, it is not clear whether a once-daily treatment regimen is as safe and effective as a twice-daily treatment regimen.  In a Cochrane review, van Dougen et al (2005) reported that once-daily treatment with LMWH is as effective and safe as twice-daily treatment with LMWH.  However, the 95 % confidence interval (CI) implies that there is a possibility that the risk of recurrent venous thromboembolism might be higher when people are treated once-daily.  Thus, the decision to treat a person with a once-daily regimen will depend on the evaluated balance between increased convenience and the potential for a lower efficacy.

On behalf of the American Society of Clinical Oncology (ASCO), a panel of experts (Lyman et al, 2007) performed a comprehensive systematic review of the medical literature on the prevention and treatment of venous thrombo-embolism (VTE) in cancer patients.  Following discussion of the results, the panel drafted recommendations for the use of anti-coagulation in patients with malignant disease.  Recommendations of the American Society of Clinical Oncology VTE Guideline Panel included
  1. all hospitalized cancer patients should be considered for VTE prophylaxis with anti-coagulants in the absence of bleeding or other contraindications;
  2. routine prophylaxis of ambulatory cancer patients with anti-coagulation is not recommended, with the exception of patients receiving thalidomide or lenalidomide;
  3. patients undergoing major surgery for malignant disease should be considered for pharmacologic thromboprophylaxis;
  4. LMWH represents the preferred agent for both the initial and continuing treatment of cancer patients with established VTE; and
  5. the impact of anti-coagulants on cancer patient survival requires additional study and can not be recommended at present.

Key and colleagues (2019) performed a comprehensive systematic review of the medical literature on behalf of the ASCO in order to provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. Changes to previous recommendations now state that clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or LMWH to selected high-risk outpatients with cancer; rivaroxaban and edoxaban have been added as options for VTE treatment; patients with brain metastases are now addressed in the VTE treatment section; and the recommendation regarding long-term postoperative LMWH has been expanded. Extended prophylaxis with LMWH for up to 4 weeks postoperatively is recommended for patients undergoing major open or laparoscopic abdominal or pelvic surgery for cancer who have high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. In lower-risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis (Type: evidence based; Evidence quality: high; Strength of recommendation: moderate to strong). For patients with cancer with established VTE to prevent recurrence, and for long-term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred because of improved efficacy over vitamin K antagonists (VKAs). VKAs are inferior but may be used if LMWH or direct oral anticoagulants (DOACs) are not accessible. There is an increase in major bleeding risk with DOACs, particularly observed in GI and potentially genitourinary malignancies. Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding. Drug-drug interaction should be checked prior to using a DOAC. Anticoagulation with LMWH, DOACs, or VKAs beyond the initial 6 months should be offered to select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. Anticoagulation beyond 6 months needs to be assessed on an intermittent basis to ensure a continued favorable risk-benefit profile (Type: informal consensus; Evidence quality: low; Strength of recommendation: weak to moderate). Notes regarding off-label use in guideline recommendations: Apixaban, rivaroxaban, and LMWH have not been US Food and Drug Administration–approved for thromboprophylaxis in outpatients with cancer. Dalteparin is the only LMWH with US Food and Drug Administration approval for extended therapy to prevent recurrent thrombosis in patients with cancer.

Re-affirmed recommendations from ASCO (2019) include most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for all outpatients with cancer. Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Patients with cancer should be periodically assessed for VTE risk, and oncology professionals should provide patient education about the signs and symptoms of VTE (Key et al, 2019).

Camporese et al (2008) stated that knee arthroscopy is associated with a definite risk for DVT; however, post-surgical thromboprophylaxis is not routinely recommended.  In an assessor-blind, randomized, controlled study, these investigators examined if LMWH better prevents DVT and does not cause more complications than graduated compression stockings in adults undergoing knee arthroscopy.  A total of 1,761 consecutive patients were included in this trial.  Patients were randomly assigned to wear full-length graduated compression stocking for 7 days (n = 660) or to receive a once-daily subcutaneous injection of LMWH (nadroparin, 3,800 anti-Xa IU) for 7 days (n = 657) or 14 days (n = 444).  The data and safety monitoring board prematurely stopped the 14-day heparin group after the second interim analysis.  Combined incidence of asymptomatic proximal DVT, symptomatic VTE, and all-cause mortality (primary efficacy end point) and combined incidence of major and clinically relevant bleeding events (primary safety end point) were recorded.  All patients had bilateral whole-leg ultrasonography at the end of the allocated prophylactic regimen or earlier if indicated.  All patients with normal findings were followed for 3 months, and none was lost to follow-up.  The 3-month cumulative incidence of asymptomatic proximal DVT, symptomatic VTE, and all-cause mortality was 3.2 % (21 of 660 patients) in the stockings group, 0.9 % (6 of 657 patients) in the 7-day LMWH group (absolute difference, 2.3 percentage points [95 % CI: 0.7 to 4.0 percentage points]; p = 0.005), and 0.9 % (4 of 444 patients) in the prematurely stopped 14-day LMWH group.  The cumulative incidence of major or clinically relevant bleeding events was 0.3 % (2 of 660 patients) in the stockings group, 0.9 % (6 of 657 patients) in the 7-day LMWH group (absolute difference, -0.6 percentage point [CI: -1.5 to 0.2 percentage points]), and 0.5 % (2 of 444 patients) in the 14-day LMWH group.  The authors concluded that in patients undergoing knee arthroscopy, prophylactic LMWH for 1 week reduced a composite end point of asymptomatic proximal DVT, symptomatic VTE, and all-cause mortality more than did graduated compression stockings.  This treatment effect was mainly evident in patients having meniscectomy-related procedures.

In an editorial that accompanied the afore-mention paper, Hull (2008) stated that the findings by Camporese et al encourages the use of LMWH thromboprophylaxis in knee arthroscopy patients undergoing meniscectomy.  The aggregate evidence supports this recommendation.  Hull noted that a clear answer regarding thromboprophylaxis in non-meniscectomy patients, which includes diagnostic arthroscopy patients, awaits further investigations to precisely define the incidence of DVT according to the type of arthroscopic procedure.

In a review on prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma, the International Myeloma Working Group (Palumbo et al, 2008) noted that the incidence of VTE is more than 1 in 1,000 annually in the general population and increases further in cancer patients.  The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy.  Various VTE prophylaxis strategies, such as LMWH, warfarin or aspirin, have been investigated in small, uncontrolled clinical studies.  This review summarized the available evidence and recommends a prophylaxis strategy according to a risk-assessment model.  Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, co-morbidities (e.g., infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia.  Myeloma-related risk factors include diagnosis and hyper-viscosity.  Venous thrombo-embolism is very high in patients who receive high-dose dexamethasone, doxorubicin or multi-agent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib.  The panel recommended aspirin for patients with less than or equal to 1 risk factor for VTE.  Low-molecular-weight heparins (equivalent to enoxaparin 40 mg/day) is recommended for those with 2 or more individual/myeloma-related risk factors.  Low-molecular-weight heparins is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin.  Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy.

Klein and colleagues (2009) stated that the immunomodulatory drugs thalidomide and lenalidomide have enhanced activity in patients with MM.  Their efficacy is increased with the addition of dexamethasone, but significant rates of VTE are a severe side effect.  Based on this evidence, it is recommended that VTE prophylaxis be prescribed in these patients.  However, the optimal prophylaxis remains controversial.  These researchers analyzed 45 patients with relapsed MM who were treated with lenalidomide and dexamethasone at their center.  The 45 patients received a total number of 192 cycles, respectively a median of 3 cycles; the median dosage of dexamethasone was 240 mg/cycle.  All patients received prophylactic anti-coagulation with low LMWH.  Moreover, 86.6 % of patients had at least 1 additional VTE risk factor beside the myeloma-related risk.  One out of 45 patients developed a DVT and PE.  None of the other 44 patients had clinical signs of thrombosis or embolism and none of all patients experienced complications or side effects due to anti-coagulation.  These findings indicated that prophylactic anti-coagulation with LMWH is safe and effective.  Thus, these investigators proposed that LMWH should be used in patients being treated with lenalidomide and dexamethasone at least for the first 3 months of treatment until randomized trials have proven the equality of other pharmacological prophylaxis.

Kaandorp et al (2010) noted that aspirin and LMWH are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs.  In this randomized trial, these investigators enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant.  They then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2,850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo.  The primary outcome measure was the live-birth rate.  Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events.  Live-birth rates did not differ significantly among the 3 study groups.  The proportions of women who gave birth to a live infant were 54.5 % in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8 % in the aspirin-only group, and 57.0 % in the placebo group (absolute difference in live-birth rate: combination therapy versus placebo, -2.6 percentage points; 95 % CI: -15.0 to 9.9; aspirin only versus placebo, -6.2 percentage points; 95 % CI: -18.8 to 6.4).  Among 299 women who became pregnant, the live-birth rates were 69.1 % in the combination-therapy group, 61.6 % in the aspirin-only group, and 67.0 % in the placebo group (absolute difference in live-birth rate: combination therapy versus placebo, 2.1 percentage points; 95 % CI: -10.8 to 15.0; aspirin alone versus placebo -5.4 percentage points; 95 % CI: -18.6 to 7.8).  An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other 2 study groups.  The authors concluded that neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage.

In an editorial that accompanied the afore-mentioned study, Greer (2010) stated that the findings of Kaandorp et al and other available data provide good evidence that anti-thrombotic intervention should not be advocated for unexplained recurrent miscarriage, although more data are needed in women with thrombophilia or with 3 or more miscarriages.  The editorialist noted that the widespread use of anti-thrombotic interventions for women with 2 or more miscarriages appears to be no more than another false start in the race to identify an effective intervention for this distressing condition that affects so many women.  Furthermore, in a systematic review and meta-analysis on heparin treatment in anti-phospholipid syndrome with recurrent pregnancy loss, Ziakas and colleagues (2010) stated that the effectiveness of LMWH plus aspirin remains unproven, highlighting the urgent need for large controlled trials.

In a Cochrane review, Chande et al (2010) reviewed randomized trials examining the efficacy of UFH or LMWH for remission induction in patients with ulcerative colitis (UC).  The MEDLINE (PUBMED), and EMBASE databases, the Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on UC, and references from identified papers were searched up to June 2010 in an effort to identify all randomized trials studying UFH or LMWH use in patients with UC.  Abstracts from major gastro-enterological meetings were searched to identify research published in abstract form only.  Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above.  The Cochrane Risk of Bias tool was used to assess study quality.  Studies published in abstract form only were included if the authors could be contacted for further information.  A data extraction form was developed and used to extract data from included studies.  At least 2 authors independently extracted data.  Any disagreements were resolved by consensus.  Data were analyzed on an intention-to-treat basis.  The primary outcome was induction of remission, as defined by the studies.  Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy).  Low-molecular-weight heparin administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement.  High-dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (odd ratio [OR] 2.73; 95 % CI: 1.32 to 5.67; p = 0.007), clinical improvement (OR 2.99; 95 % CI: 1.30 to 6.87; p = 0.01), and endoscopic improvement (OR 2.25; 95 % CI: 1.01 to 5.01; p = 0.05) but not endoscopic remission or histologic improvement.  Low-molecular-weight heparin was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement.  Low-molecular-weight heparin was well-tolerated but provided no significant benefit for quality of life.  One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement.  More patients assigned to UFH had rectal hemorrhage as an adverse event.  The authors concluded that there is evidence to suggest that LMWH may be effective for the treatment of active UC.  When administered by extended colon-release tablets, LMWH was more effective than placebo for treating out-patients with mild-to-moderate disease.  The authors stated that this benefit needs to be confirmed by further randomized controlled studies.  The same benefits were not seen when LMWH was administered subcutaneously at lower doses.  There is no evidence to support the use of UFH for the treatment of active UC.

Scoble et al (2011) stated that anti-phospholipid syndrome (APS) is an autoimmune prothrombotic disorder characterised by the predisposition to venous and/or arterial thrombosis and obstetric morbidity.  Management of APS centers on attenuating the procoagulant state while balancing the risks of anti-coagulant therapy.  Cases of recurrent thromboses and obstetric complications occur despite optimum therapy.  Alternative therapies for refractory cases are subject to disparity among clinicians due to the current lack of clinical evidence present.  This review addressed the current management strategies for refractory thrombotic and obstetric cases and future therapeutic interventions.  The role and current clinical evidence of using long-term LMWH as an alternative to warfarin therapy for refractory thromboses was evaluated.  Potential alternatives for thromboses including statins, hydroxychloroquine, rituximab were reviewed as well as the additional avenues to target in the future as the pathogenic mechanisms of APS were unveiled.  The optimal management for refractory obstetric APS cases is subject to controversy.  This review focused and assessed the current evidence for the uses of low-dose prednisolone, intravenous immunoglobulin and hydroxycholoroquine in obstetric cases.  The authors concluded that the treatment modalities for the management of refractory APS require further clinical evidence.

O'Carroll et al (2011) current evidence regarding the safety of low-dose LMWH in the prevention of VTE complications in patients with acute intra-cerebral hemorrhage (ICH).  The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions.  Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular and hospital neurology.  A recent quasi-randomized controlled trial was selected for critical appraisal.  This trial assigned 75 ICH patients to subcutaneous LMWH or long compression stockings for DVT and PE prophylaxis.  In patients who received low-dose LMWH, there was no hematoma enlargement at 72 hours, day 7, or day 21 compared with the compression stocking group.  There was hematoma enlargement in 9 patients at 24 hours, 6 of which were in the LMWH group, but this was before the initiation of the LMWH, which occurred at 48 hours.  Adverse events were VTE complications in 4 of 39 patients in the LMWH group and in 3 of 36 patients in the long compression stocking group.  The authors concluded that initiation of low-dose LMWH in spontaneous ICH patients for the purpose of VTE prophylaxis is likely safe.  However, a clinical decision based solely on the results of this study can not be made due to numerous methodological and design shortcomings.  They stated that a well-designed randomized controlled trial is still needed to answer this clinical question.

In a Cochrane review, Bhutia and Wong (2013) compared the safety and effectiveness of once-daily versus twice-daily administration of LMWH.  For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013) and CENTRAL (2013, Issue 4).  Randomized clinical trials in which LMWH given once-daily is compared with LMWH given twice-daily for the initial treatment of VTE were selected for analysis.  Two review authors assessed trials for inclusion and extracted data independently.  A total of 5 studies were included with a total of 1,508 participants.  The pooled data showed no statistically significant difference in recurrent VTE between the 2 treatment regimens (OR 0.82, 0.49 to 1.39; p = 0.47).  A comparison of major hemorrhagic events (OR 0.77, 0.40 to 1.45; p = 0.41), improvement of thrombus size (OR 1.41, 0.66 to 3.01; p = 0.38) and mortality (OR 1.14, 0.62 to 2.08; p = 0.68) also showed no statistically significant differences between the 2 treatment regimens.  None of the 5 included studies reported data on post-thrombotic syndrome.  The authors concluded that once-daily treatment with LMWH is as effective and safe as twice-daily treatment with LMWH.

In a Cochrane review, Chen et al (2013) examined if subcutaneous LMWH treatment improves the salvage rate of the digits in patients with digital replantation after traumatic amputation.  The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (October 2012), CENTRAL (2012, Issue 10) and trials databases.  In addition, the authors searched PubMed, CNKI (China National Knowledge Infrastructure) and CEPS (Chinese Electronic Periodical Services), and sought additional trials from reference lists of relevant publications.  They selected randomized or quasi-randomized controlled trials of LMWH in patients who received digital replantation.  Two review authors independently extracted data and assessed the risk of bias of the included trials.  Disagreements were resolved by discussion.  Two randomized trials involving 114 patients with at least 122 replanted digits met the inclusion criteria and were included.  Both trials compared the safety and effectiveness of LMWH with UFH.  They found no trials comparing LMWH with placebo or other anti-coagulants.  The data from the 2 included studies were insufficient for meta-analysis.  The overall success rate of replantation did not differ between the LMWH and UFH groups, 92.3 % versus 89.2 % in 1 trial (risk ratio (RR) 1.03; 95 % CI: 0.87 to 1.22) and 94.3 % versus 94.15 % in the other trial (RR 1.00; 95 % CI: 0.89 to 1.13).  The incidence of both post-operative arterial and venous insufficiency were reported in 1 trial and did not significantly differ between the LMWH and UFH groups (RR 1.08; 95 % CI: 0.16 to 7.10 and RR 0.81; 95 % CI: 0.20 to 3.27, respectively).  Direct and indirect causes of microvascular insufficiency were not reported in the trials.  Different methods were used to monitor the adverse effects related to anti-coagulation in the 2 trials.  Bleeding tendency was monitored for the LMWH and UFH groups in 1 trial and was reported by the incidence of wound hemorrhage (11.5 % versus 17.9 %; RR 0.65; 95 % CI: 0.17 to 2.44), ecchymoses (3.8 % versus 10.7 %; RR 0.36; 95 % CI: 0.04 to 3.24), hematuria (3.8 % versus 7.1 %; RR 0.54; 95 % CI: 0.05 to 5.59), nasal bleeding (0 % versus 7.1 %; RR 0.21; 95 % CI: 0.01 to 4.28), gingival bleeding (0 % versus 10.7 %; RR 0.15, 95 % CI: 0.01 to 2.83) and fecal occult blood (0 % versus 3.6 %; RR 0.36; 95 % CI: 0.02 to 8.42).  The bleeding tendency was increased in the UFH group but this was not statistically significant.  This trial also monitored coagulability changes using parameters such as anti-thrombin activity, factor Xa activity, bleeding time, clotting time and activated partial thromboplastin time (aPTT).  No comparison was made between the LMWH and UFH groups but all data consistently showed that coagulability was reduced more in the UFH group than in the LMWH group.  The other trial reported a post-operative decrease in platelet count in the UFH group (pre-operative 278.4 ± 18.7 x 10(9)/L, post-operative 194.3 ± 26.5 x 10(9)/L; p < 0.05) but not in the LMWH group (pre-operative 260.8 ± 32.5 x 10(9)/L, post-operative 252.4 ± 29.1 x 10(9)/L; p > 0.05).  The authors concluded that current limited evidence based on 2 small-scaled low-to-medium quality randomized trials found no differences in the success rate of replantation between LMWH and UFH, but a lower risk of post-operative bleeding and hypo-coagulability after the use of LMWH.  Moreover, they stated that further well-designed and adequately powered clinical trials are needed.

In a Cochrane review, Sundaram et al (2013) compared the use of intra-vitreal LMWH alone or with 5-fluorouracil (5-FU) versus placebo, as an adjunct in the prevention of proliferative vitreo-retinopathy (PVR) following retinal re-attachment surgery.  These investigators searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 9), MEDLINE (January 1950 to October 2012), EMBASE (January 1980 to October 2012), the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). They did not use any date or language restrictions in the electronic searches for trials.  They last searched the electronic databases on October 15, 2012.  These researchers only included randomized controlled trials (RCTs) that compared intra-vitreal LMWH alone or with 5-FU, versus placebo for the prevention of post-operative PVR in patients undergoing primary vitrectomy for rhegmatogenous retinal detachment repair.  Two review authors independently assessed trial quality and extracted data.  The review authors contacted study authors for additional information.  These investigators included 2RCTs (with a total of 789 participants) comparing LMWH with 5-FU infusion and placebo.  However, they did not perform a meta-analysis because of significant heterogeneity between these studies.  One study found a significant beneficial effect of LMWH with 5-FU in reducing post-operative PVR compared to placebo (RR: 0.48, 95 % CI: 0.25 to 0.92), in 174 patients who were viewed at high-risk of developing post-operative PVR.  The other study included 615 unselected cases of rhegmatogenous retinal detachment and could not show a difference between LMWH with 5-FU infusion and placebo in reducing PVR rates (RR: 1.45, 95 % CI: 0.76 to 2.76).  The authors concluded that results from this review indicated that there is inconsistent evidence from 2 studies on patients at different risk of PVR on the effect of LMWH and 5-FU used during vitrectomy to prevent PVR.  Moreover, they stated that future research should be conducted on high-risk patients only, until a benefit is confirmed at least in this patient subgroup.

In a Cochrane review, van Zuuren and Fedorowicz (2013) evaluated the effects of LMWHs for managing vaso-occlusive crises in people with sickle cell disease.  These investigators searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches.  They also searched abstract books of conference proceedings and several online trials registries for ongoing trials.  Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register was December 6, 2012.  Randomized controlled clinical trials and controlled clinical trials that assessed the effects of LMWHs in the management of vaso-occlusive crises in people with sickle cell disease were selected for analysis.  Study selection, data extraction, assessment of risk of bias and analyses were carried out independently by the 2 review authors.  One study (with an overall unclear to high risk of bias) comprising 253 participants was included.  This study, with limited data, reported that pain severity at day 2 and day 3 was lower in the tinzaparin group than in the placebo group (p < 0.01, analysis of variance (ANOVA)) and additionally at day 4 (p < 0.05 (ANOVA)).  Thus, tinzaparin resulted in more rapid resolution of pain, as measured with a numerical pain scale.  The mean difference in duration of painful crises was statistically significant at -1.78 days in favor of the tinzaparin group (95 % CI: -1.94 to -1.62).  Participants treated with tinzaparin had statistically significantly fewer hospitalization days than participants in the group treated with placebo, with a mean difference of -4.98 days (95 % CI: -5.48 to -4.48).  Two minor bleeding events were reported as adverse events in the tinzaparin group, and none was reported in the placebo group.  The authors concluded that based on the results of 1 study, evidence is incomplete to support or refute the effectiveness of LMWHs in people with sickle cell disease.  They stated that vaso-occlusive crises are extremely debilitating for sufferers of sickle cell disease; therefore well-designed placebo-controlled studies with other types of LMWHs, and in participants with different genotypes of sickle cell disease, still need to be carried out to confirm or dismiss the results of this single study.

Also, an UpToDate review on “Therapeutic use of heparin and low molecular weight heparin” (valentine and Hull, 2014) does not mention the use of LMWHs for the management of vaso-occlusive crises in patients with sickle cell disease.

Roger et al (2014) reported the case of a 35-year old woman with recurrent severe placenta-mediated pregnancy complications in her 2 pregnancies.  These researchers ascertained if LMWH would help prevent recurrent placenta-mediated pregnancy complications in the next pregnancy.   They performed a meta-analysis of RCTs comparing LMWH versus no LMWH for the prevention of recurrent placenta-mediated pregnancy complications.  They identified 6 RCTs that included a total of 848 pregnant women with prior placenta-mediated pregnancy complications.  The primary outcome was a composite of pre-eclampsia (PE), birth of a small-for-gestational-age (SGA) newborn (less than 10th percentile), placental abruption, or pregnancy loss greater than 20 weeks.  Overall, 67 (18.7 %) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications compared with 127 (42.9 %) of 296 women with no LMWH (relative risk reduction, 0.52; 95 % CI: 0.32 to 0.86; p = 0.01; I(2), 69 %, indicating moderate heterogeneity).  These investigators identified similar relative risk reductions with LMWH for individual outcomes, including any PE, severe PE, SGA less than 10th percentile, SGA less than 5th percentile, preterm delivery less than 37 weeks, and preterm delivery less than 34 weeks with minimal heterogeneity.  The authors concluded that LMWH may be a promising therapy for recurrent, especially severe, placenta-mediated pregnancy complications, but further research needed.

Caldeira et al (2014) stated that LMWHs are not approved for patients with mechanical heart valves (MHVs).  However, in several guidelines, temporary LMWH off-label use in this clinical setting is considered to be a valid treatment option.  These investigators reviewed the safety and effectiveness of LMWHs in patients with MHVs.  Medline and Central databases were searched from inception to June 2013.  Review articles and references were also searched.  These researchers included experimental and observational studies that compared LMWHs with UFH or VKAs.  Data were analyzed and pooled to estimate ORs with 95 % CIs for thromboembolic and major bleeding events.  Statistical heterogeneity was evaluated with the I(2)-test.  A total of 9 studies were included: 1 RCT and 8 observational studies, with a total of 1,042 patients.  No differences were found between LMWHs and UFH/VKAs in the risk of thromboembolic events (OR 0.67; 95 % CI: 0.27 to 1.68; I(2) = 9 %) or major bleeding events (OR 0.66; 95 % CI: 0.36 to 1.19; I(2) = 0 %).  The authors concluded that the best evidence available might support the temporary use of LMWHs as a prophylactic treatment option in patients with MHVs.  However, they noted that conclusions are mostly based on observational data (with large CIs), and an adequately powered RCT is urgently needed in this clinical setting.

Low-Molecular Weight Heparin for Lower-Leg Immobilization

Testroote and colleagues (2014) stated that immobilization of the lower leg is associated with VTE; LMWH is an anti-coagulant treatment that might be used in adult patients with lower-leg immobilization to prevent DVT and its complications.  In a Cochrane review, these investigators evaluated the effectiveness of LMWH for the prevention of VTE in patients with lower-leg immobilization in an ambulant setting.  The Cochrane Peripheral Vascular Diseases Group Trials Search Coordinator searched the Specialized Register (last searched June 2013) and CENTRAL (2013, Issue 5).  Selection criteria included RCTs and controlled clinical trials (CCTs) that described thromboprophylaxis by means of LMWH compared with no prophylaxis or placebo in adult patients with lower-leg immobilization.  Immobilization was by means of a plaster cast or brace.  Two authors independently assessed trial quality and extracted data.  The review authors contacted the trial authors for additional information if required.  Statistical analysis was carried out using Review Manager (RevMan 5).  These researchers included 6 RCTs fulfilling the above criteria with a total of 1,490 patients.  they found an incidence of VTE ranging from 4.3 % to 40 % in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least 1 week and who received no prophylaxis, or placebo.  This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization (event rates ranging from 0 % to 37 %; OR 0.49; fixed 95 % CI: 0.34 to 0.72; with minimal evidence of heterogeneity with an I(2) of 20 %, p = 0. 29).  Comparable results were observed in the following sub-categories: operated patients, conservatively treated patients, patients with fractures, patients with soft-tissue injuries, patients with proximal thrombosis, patients with distal thrombosis and patients with below-knee casts.  Complications of major bleeding events were extremely rare (0.3 %) and there were no reports of heparin-induced thrombocytopenia.  The authors concluded that the use of LMWH in out-patients significantly reduced VTE when immobilization of the lower leg was needed.

Zee and co-workers (2017) updated 2014 Cochrane review by Testroote et al.  For this update, the Cochrane Vascular Information Specialist searched the Specialized Register, CENTRAL, and 3 trials registers (April 2017); RCTs and CCTs that described thromboprophylaxis by means of LMWH compared with no prophylaxis or placebo in adult patients with lower-limb immobilization were selected for analysis.  Immobilization was by means of a plaster cast or brace.  Two review authors independently selected trials, assessed risk of bias and extracted data.  The review authors contacted the trial authors for additional information if required.  Statistical analysis was carried out using Review Manager 5.  These researchers included 8 RCTs that fulfilled the selection criteria, with a total of 3,680 participants.  The quality of evidence, according GRADE, varied by outcome and ranged from low-to-moderate.  They found an incidence of DVT ranging from 4.3 % to 40 % in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least 1 week, and who received no prophylaxis, or placebo.  This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization, with event rates ranging from 0 % to 37 % (OR 0.45, 95 % CI: 0.33 to 0.61; with minimal evidence of heterogeneity: I² = 26 %, p = 0.23; 7 studies; 1,676 participants, moderate-quality evidence).  Comparable results were observed in the following groups of participants: patients with below-knee casts, conservatively treated patients (non-operated patients), operated patients, patients with fractures, patients with soft-tissue injuries, and patients with distal or proximal thrombosis.  No clear differences were found between the LMWH and control groups for PE (OR 0.50, 95 % CI: 0.17 to 1.47; with no evidence of heterogeneity: I² = 0 %, p = 0.56; 5 studies, 2,517 participants; low-quality evidence).  The studies also showed less symptomatic VTE in the LMWH groups compared with the control groups (OR 0.40, 95 % CI: 0.21 to 0.76; with minimal evidence of heterogeneity: I² = 16 %, p = 0.31; 6 studies; 2,924 participants; low-quality evidence); 1 death was reported in the included studies, but no deaths due to PE  were reported.  Complications of major adverse events (AEs) were rare, with minor bleedings were the main AEs reported.  The authors concluded that moderate-quality evidence showed that the use of LMWH in out-patients reduced DVT when immobilization of the lower limb was needed, when compared with no prophylaxis or placebo.  The quality of the evidence was reduced to moderate because of risk of selection and attrition bias in the included studies.  Low-quality evidence showed no clear differences in PE between the LMWH and control groups, but less symptomatic VTE in the LMWH groups.  The quality of the evidence was down-graded due to risk of bias and imprecision.

In a systematic review and meta-analysis, Hickey and associates (2018) examined the evidence for thromboprophylaxis for prevention of symptomatic VTE in adults with foot or ankle trauma treated with below knee cast or splint; the secondary objective was to report major bleeding events.  Medline and Embase databases were searched for RCTs from inception to June 1, 2015.  A total of 7 studies were included.  All focused on LMWH.  None found a statistically significant symptomatic DVT reduction individually.  In meta-analysis, LMWH was protective against symptomatic DVT (OR 0.29, 95 % CI: 0.09 to 0.95); symptomatic PE affected 3/692 (0.43 %); none were fatal.  A total of 86 patients required LMWH thromboprophylaxis to prevent 1e symptomatic DVT event.  The overall incidence of major bleeding was 1 in 886 (0.11 %).  The authors concluded that LMWH reduced the incidence of symptomatic VTE in adult patients with foot or ankle trauma treated with below knee cast or splint.

Low-Molecular Weight Heparin for Metastatic Synovial Sarcoma

Cassinelli and co-workers (2018) noted that synovial sarcoma (SS) is an aggressive tumor with propensity for lung metastases that significantly impact patients' prognosis.  New therapeutic approaches are needed to improve treatment outcome.  Targeting the heparanase/heparan sulfate proteoglycan system by heparin derivatives which act as heparanase inhibitors/heparan sulfate mimetics is emerging as a therapeutic approach that can sensitize the tumor response to chemotherapy.  These researchers examined the therapeutic potential of a super-sulfated LMWH (ssLMWH) in pre-clinical models of SS; ssLMWH showed a potent anti-heparanase activity, dose-dependently inhibited SS colony growth and cell invasion, and down-regulated the activation of receptor tyrosine kinases including IGF1R and IR.  The combination of ssLMWH and the IGF1R/IR inhibitor BMS754807 synergistically inhibited proliferation of cells exhibiting IGF1R hyper-activation, also abrogating cell motility and promoting apoptosis in association with PI3K/AKT pathway inhibition.  The drug combination strongly enhanced the anti-tumor effect against the CME-1 model, as compared to single agent treatment, abrogating orthotopic tumor growth and significantly repressing spontaneous lung metastatic dissemination in treated mice.  The authors concluded that these findings provided a strong pre-clinical rationale for developing drug regimens combining heparanase inhibitors/HS mimetics with IGF1R antagonists for treatment of metastatic SS.

Low-Molecular Weight Heparin for Preeclampsia Prevention

In an open-label, RCT, Groom and associates (2017) evaluated the effectiveness of enoxaparin in addition to high-risk care for the prevention of preeclampsia and small-for-gestational-age (SGA) pregnancy in women with a history of these conditions.  This trial was carried out in 5 tertiary-care centers in 3 countries.  Women with a viable singleton pregnancy were invited to participate between greater than 6+0 and less than 16+0 weeks if deemed to be at high-risk of preeclampsia and/or SGA based on their obstetric history.  Eligible participants were randomly assigned in a 1-to-1 ratio to standard high-risk care or standard high-risk care plus enoxaparin 40 mg (4,000 IU) by subcutaneous injection daily from recruitment until 36+0 weeks or delivery, whichever occurred sooner.  Standard high-risk care was defined as care co-ordinated by a high-risk antenatal clinic service, aspirin 100 mg daily until 36+0 weeks, and for women with prior preeclampsia-calcium 1,000 to 1,500 mg daily until 36+0 weeks.  In a subgroup of participants serum samples were taken at recruitment and at 20 and 30 weeks' gestation and later analyzed for soluble fms-like tyrosine kinase-1, soluble endoglin, endothelin-1, placental growth factor, and soluble vascular cell adhesion molecule 1.  The primary outcome was a composite of preeclampsia and/or SGA of less than 5th customized birth-weight percentile.  All data were analyzed on an intention-to-treat basis.  Between July 26, 2010, and October 28, 2015, a total of 156 participants were enrolled and included in the analysis.  In all, 149 participants were included in the outcome analysis (72 receiving standard high-risk care plus enoxaparin and 77 receiving standard high-risk care only); 7 women who miscarried less than 16 weeks' gestation were excluded.  The majority of participants (151/156, 97 %) received aspirin.  The addition of enoxaparin had no effect on the rate of preeclampsia and/or SGA of less than 5th customized birth-weight percentile: enoxaparin 18/72 (25 %) versus no enoxaparin 17/77 (22.1 %) (OR, 1.19; 95 % CI: 0.53 to 2.64).  There was also no difference in any of the secondary outcome measures.  Levels of soluble fms-like tyrosine kinase-1 and soluble endoglin increased among those who developed preeclampsia, but there was no difference in levels of these antiangiogenic factors (nor any of the other serum analytes measured) among those treated with enoxaparin compared to those receiving standard high-risk care only.  The authors concluded that the use of enoxaparin in addition to standard high-risk care did not reduce the risk of recurrence of preeclampsia and SGA infants in a subsequent pregnancy.

McLaughlin and colleagues (2018) stated that LMWH has been extensively evaluated for the prevention of preeclampsia in high-risk pregnant women; however, the results from these trials have been conflicting.  This review discussed the potential mechanisms of action of LMWH for the prevention of severe preeclampsia, how to optimize the selection of high-risk women for participation in future trials, and the importance of trial standardization.  The authors concluded that in order to conclusively determine any benefit of LMWH, a standardized, well-powered trial investigating LMWH for prevention of early-onset preeclampsia in diligently selected women at the highest risk of this disease is needed.

Lecarpentier and co-workers (2018) examined if daily LMWH prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction.  This was a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation) . In the parent study, all women were treated with aspirin and then randomized to receive LMWH or aspirin alone . In this study, these researchers measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10 to 13 6/7 weeks, 14 to 17 6/7 weeks, 18 to 21 6/7 weeks, 22 to 25 6/7 weeks, 26 to 29 6/7 weeks, 30 to 33 6/7 weeks, and 34 to 37 6/7 weeks.  Samples were available from 185 patients: LMWH + aspirin (n = 92) and aspirin alone (n = 93).  The 2 groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0 %] compared with 36/93 [38.7 %]; p = 0.92).  There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMWH and aspirin compared with those who received aspirin alone regardless of gestational age period.  Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10 to 13 6/7 weeks that was most dramatic 6 to 8 weeks preceding delivery.  The authors concluded that prophylactic LMWH therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy was not associated with an improved angiogenic profile; this may provide a molecular explanation for the lack of clinical benefit noted in recent trials.

Low-Molecular Weight Heparin for Splanchnic Vein Thrombosis Associated with Acute Pancreatitis

Riva and colleagues (2012) noted that splanchnic vein thrombosis (SVT) is an unusual manifestation of VTE that involves 1 or more abdominal veins (portal, splenic, mesenteric and supra-hepatic veins).  SVT may be associated with different underlying disorders, either local (abdominal cancer, liver cirrhosis, intra-abdominal inflammation or surgery) or systemic (hormonal treatment, thrombophilic conditions).  In the last decades, myeloproliferative neoplasm (MPN) emerged as the leading systemic cause of SVT.  JAK2 mutation, even in the absence of known MPN, showed a strong association with the development of SVT, and SVT was suggested to be the first clinical manifestation of MPN.  Recently, an association between SVT, in particular supra-hepatic vein thrombosis, and paroxysmal nocturnal hemoglobinuria has also been reported.  SVT occurs with heterogeneous clinical presentations, ranging from incidentally detected events to extensive thrombosis associated with overt gastro-intestinal (GI) bleeding, thus representing a clinical challenge for treatment decisions.  In the absence of major contraindications, anticoagulant therapy (AT) is generally recommended for all patients presenting with acute symptomatic SVT, but there is no consensus regarding the use of anticoagulant drugs in chronic or incidentally detected SVT.  The authors stated that high quality evidence on the acute and long-term management was substantially lacking and the risk to benefit-ratio of AT in SVT still needs to be better assessed.

In a retrospective, single-center study, Harris and co-workers (2013) examined outcomes of SVT in hospitalized patients with acute pancreatitis (AP).  Over the last decade, 1.8 % (45/2454) of patients with AP with a mean (SD) age of 58 (15) years were diagnosed with SVT.  Splenic vein thrombosis was the most common form of SVT (30/45 patients, 67 %); 17 patients were anticoagulated with heparin, when the SVT was diagnosed in the acute stage followed by oral anticoagulation (AC).  The thrombosis that was most commonly anticoagulated was portal vein thrombosis in 11 (65 %) of 17 patients.  Of 17 patients in the AC group, 2 (12 %) showed re-canalization as compared with 3 (11 %) of 28 patients in the non-AC group (p > 0.05).  The mortality was 3 (7 %) of 45 (2 from the AC group versus 1 in the non-AC group, p > 0.05); 2 of these died of multi-organ failure, and the other, from septic shock.  None of the deaths was due to bleeding complications.  The authors concluded that SVT occurred in 1.8 % patients of AP; and the use of AC was reasonably safe with no fatal bleeding complications.  However, there was no significant difference in the re-canalization rates in those with and without AC.

Qiu and colleagues (2019) stated that the effects of LMWH on severe AP (SAP) have been controversial.  In a systematic review and meta-analysis, these researchers examined the efficacy of LMWH on prognosis of SAP.  They searched relevant studies published up to March 2019 in five databases (Medline/PubMed, Embase, the Cochrane Central Register of Controlled Trials in Cochrane Library, China National Knowledge Infrastructure, and the Chinese Journal of Science and Technology of VIP database).  A total of 16 RCTs with 1,625 patients were included in the final analysis.  Most studies were from China.  In analysis of laboratory parameters and clinical scores, SAP patients receiving LMWH treatment had lower white blood cell (WBC) counts, C-reactive protein (CRP) level, Acute Physiology and Chronic Health Evaluation II score, and computed tomography severity index . In clinical outcomes, SAP patients who received LMWH treatment had shorter hospital stay (pooled mean difference (MD) [95 % CI: -8.79 [-11.18 to -6.40], p < 0.01), lower mortality (pooled RR [95 % CI: 0.33 [0.24 to 0.44], p < 0.01), lower incidences of multiple organ failure (pooled RR [95 % CI: 0.34 [0.23 to 0.52], p < 0.01), pancreatic pseudocyst (pooled RR [95 % CI: 0.49 [0.27 to 0.90], p = 0.02), and operation rate (pooled RR [95 % CI]: 0.39 [0.31 to 0.50], p < 0.01).  The authors concluded that LMWH could improve the prognosis of SAP, and has a potential role in reducing hospital stay, mortality, incidences of multi-organ failure, pancreatic pseudocyst, and operation rate.

Valeriani and associates (2019) noted that SVT including portal, mesenteric, splenic vein thrombosis and the Budd-Chiari syndrome, is a manifestation of unusual site VTE.  SVT presents with a lower incidence than DVT of the lower limbs and PE, with portal vein thrombosis and Budd-Chiari syndrome being respectively the most and the least common presentations of SVT.  SVT is classified as provoked if secondary to a local or systemic risk factor, or unprovoked if the causative trigger cannot be identified.  Diagnostic evaluation is often affected by the lack of specificity of clinical manifestations: the presence of 1 or more risk factors in a patient with a high clinical suspicion may suggest the execution of diagnostic tests.  Doppler ultrasonography (US) represents the 1st-line diagnostic tool because of its accuracy and wide availability.  Further investigations, such as computed tomography and magnetic resonance angiography, should be executed in case of suspected thrombosis of the mesenteric veins, suspicion of SVT-related complications, or to complete information after Doppler US.  Once SVT diagnosis is established, a careful patient evaluation should be performed in order to assess the risks and benefits of the AT and to drive the optimal treatment intensity.  Due to the low quality and large heterogeneity of published data, guidance documents and expert opinion could direct therapeutic decision, suggesting which patients to treat, which anticoagulant to use and the duration of treatment.  The authors concluded that great scientific effort has been made in the past years trying to clarify some of the challenges associated with SVT.  However, future studies are needed to strengthen some areas of uncertainty including both the diagnostic (e.g., identification of new underlying diagnostic and prognostic risk factors) and therapeutic approaches (e.g., identification of which patients to treat, which anticoagulant to use and the duration of treatment) to SVT.

Pagliari and associates (2020) noted that SVT is a possible complication of AP.  There are no precise guidelines on the use of AT in these patients.  These researchers examined the safety and the efficacy of AT in AP-associated SVT.  A total of 221 patients were retrospectively and consecutively enrolled from the Pancreatic Outpatient Clinic of the "A. Gemelli" hospital.  Patients had a diagnosis of AP and a diagnostic imaging to evaluate whether they had or not SVT; 27 out of 221 AP patients had SVT (12.21 %) and AT therapy was administered to 16 patients (59.3 %), for 5.2 ± 2.2 months.  A therapeutic dose of LMWH was administered (100 UI/kg b.i.d.) at the diagnosis, with fondaparinux 7.5 mg/day, or vitamin K antagonist, or the novel direct oral anti-coagulants (DOAC), upon discharge.  The presence of SVT resulted significantly associated to male sex (p = 0.002).  The re-canalization rates were 11/16 (68.7 %) in patients who received AT, and 3/11 (27.3 %) in patients who did not receive it.  There was a significant difference between the re-canalization rates with and without AT (p = 0.03, OR 5.87).  No SVT recurrence was registered during follow-up.  No treated patient developed hemorrhagic complications following AT.  No deaths were recorded, either in the group undergoing AT or in the one that was not.  The authors concluded that AT in AP-associated SVT appeared to be safe and effective; yet prospective clinical trials are needed to confirm these findings.

Furthermore, an UpToDate review on “Management of acute pancreatitis” (Vege, 2020) does not mention LMWH as a management option.

Low-Molecular Weight Heparin-Based Nanoparticles for Metastatic Breast Cancer

Sun and colleagues (2018) stated that tumor metastasis is the primary obstacle in cancer treatment and is always the leading cause of death; and heparin and its derivatives are potential anti-metastatic agents with good biocompatibility.  In this study, LMWH-based LMWH-Cholesterol (LHC) conjugates were prepared for intravenous delivery of doxorubicin (DOX).  The DOX/LHC nanoparticles (DOX/LHC NPs) exhibited a spherical shape with a mean diameter of 135.5 ± 2.2 nm and had a longer circulation time than that of DOX.  The in-vitro results confirmed that the DOX/LHC NPs was more effectively taken up by 4T1 cells and showed a stronger anti-metastatic effect by cell invasion and cell migration compared with DOX.  Meanwhile, DOX/LHC NPs also exhibited superior anti-metastatic effects in the pulmonary metastasis model compared with other groups.  The reason may be account for the synergistic effect between the cytotoxic drug of DOX and its drug carrier of LMWH-based nanoparticles, which is capable of anti-metastatic and anti-angiogenic efficiency.  The authors concluded that DOX/LHC nanoparticles could be a promising anti-metastatic drug delivery system for post-operative chemotherapy.

Acute Penetrating Artery Infarction

Nishi and colleagues (2016) noted that treatment to prevent progressive neurological deficits in acute penetrating artery infarction (API) is clinically important, but has not yet been established.  In a pilot study, these researchers examined the safety and effectiveness of argatroban, aspirin, and clopidogrel combination therapy for API.  Patients with API (lacunar infarcts or branch atheromatous disease) admitted within 48 hours after onset were enrolled.  These investigators assigned subjects to argatroban, aspirin, and clopidogrel (AAC) group or argatroban and aspirin (AA) group.  In both groups, blood pressure was controlled to near or below 180/105 mmHg in the admission period.  They defined progressing stroke as a worsening of 2 or more points in the National Institutes of Health Stroke Scale score on the 7th day of admission.  A total of 54 patients were enrolled.  These researchers assigned 28 patients to the AAC group, and 26 patients to the AA group.  There were no significant differences in background factors between the 2 groups.  The incidence of progressing stroke was significantly higher in the AA group (p < 0.05).  Intra-cranial hemorrhage or any other bleeding was not seen in the admission period in either group.  The authors concluded that these findings suggested that the AAC combination therapy may positively affect progressive neurological deficits in API patients.  This was a small pilot study, and its findings were confounded by the combinational use of argatroban, aspirin, and clopidogrel.

Anticoagulation of Percutaneous Ventricular Assist Device

Blum and colleagues (2018) noted that Impella devices are percutaneously inserted ventricular assist devices (VADs), which require a continuous purge solution that contains heparin to prevent pump thrombosis and device failure.  These researchers described 2 patients with HIT supported with an Impella device utilizing an argatroban-based purge solution.  Case 1 involved an 83-year old woman with bi-ventricular failure that resulted in right ventricle Impella support.  The purge solution was changed to include argatroban due to concern of device clotting in the setting of HIT.  Case 2 involved a 55-year old man with worsening cardiogenic shock which resulted in left ventricle Impella support.  Due to decreased purge flow rates and concerns for clotting, argatroban was added to the purge solution.  Both patients' total argatroban regimens were monitored and adjusted by pharmacy, resulting in therapeutic anticoagulation without any major bleeding or thrombotic events.  Subsequently, a protocol was designed and implemented.  The authors concluded that these case reports appeared to demonstrate the safe and effective use of argatroban purge solutions for the necessary anticoagulation with an Impella device.  Moreover, they stated that further studies are needed to confirm these findings and determine the optimal dosing regimen.

Management of Acute Superior Mesenteric Venous Thrombosis

Zeng and colleagues (2017) stated that acute superior mesenteric venous thrombosis (ASMVT) is an intractable disease with poor prognosis.  Argatroban may be a novel anticoagulant method in the therapy of ASMVT.  In a retrospective study, these researchers evaluated the safety and efficacy of early argatroban therapy in ASMVT patients.  This trial reviewed a consecutive series of ASMVT patients receiving early argatroban therapy during hospitalization between March 2013 and April 2014, with 18 ASMVT patients included in the study.  Of these, 16 patients without hepatic dysfunction underwent anticoagulant therapy with argatroban with a mean dose of 1.57 ± 0.34 µg/kg/min and a mean duration of 12.2 ± 3.7 days, while their aPTT was elevated to 1.95 ± 0.26 times the baseline value.  In addition, 2 hepatic dysfunction patients received therapy with a dose of 0.41 µg/kg/min and 0.46 µg/kg/min, and with aPTT of 1.68 and 1.62 times the baseline value, respectively.  Overall, 94 % (n = 17) of the patients presented clinical improvement, while 88 % (n = 16) of patients presented partially or completely dissolved thrombus in contrast-enhanced computed tomography images.  The incidence of surgery and bowel resection was 6 % (excluding 1 case with intestinal necrosis detected on admission).  Furthermore, 11 % (n = 2) of patients experienced a bleeding episode, however no major bleeding or mortality occurred during hospitalization.  During the follow-up, the mortality and the recurrence rate were 6 % and 11 %, respectively.  The authors concluded that argatroban therapy was safe and effective in patients with ASMVT.  It may be another feasible anticoagulant in ASMVT therapy, which is beneficial in that it can rapidly improve symptoms, with low incidence of bowel resection or bleeding complication, and a low mortality rate.  However, they stated that RCTs on the use of argatroban and other anticoagulants or interventional treatment are needed.  In addition, the optimal dose, course and target value of argatroban need to be further researched.

The authors stated that this study had a major drawbacks.  First, the study did not provide an answer to the question of whether argatroban is a better option for ASMVT patients due to the absence of a control group, such as a group receiving interventional treatment or anticoagulant therapy with another medicine.  A single-center randomized clinical trial on argatroban and LMWH in ASMVT therapy is currently conducted.  Second, as a result of the retrospective and cross-sectional nature, and the small number of patients (n = 16 in the argatroban group) included in the current study, the dosage, course and target value of argatroban therapy remains unknown.

Management of Persons with Acute Respiratory Distress Syndrome undergoing Extracorporeal Lung Support

Menk and associates (2017) stated that extracorporeal membrane oxygenation (ECMO) or pump-less extracorporeal lung assist (pECLA) requires effective anticoagulation.  Knowledge on the use of argatroban in patients with acute respiratory distress syndrome (ARDS) undergoing ECMO or pECLA is limited.  In a retrospective study, these investigators evaluated the feasibility, safety and efficacy of argatroban in critically ill ARDS patients undergoing extracorporeal lung support.  This analysis included ARDS patients on extracorporeal lung support who received argatroban between 2007 and 2014 in a single ARDS referral center.  As controls, patients who received heparin were matched for age, sex, body mass index (BMI) and severity of illness scores.  Major and minor bleeding complications, thromboembolic events, administered number of erythrocyte concentrates, thrombocytes and fresh-frozen plasmas were assessed.  The number of extracorporeal circuit systems and extracorporeal lung support cannulas needed due to clotting was recorded.  Also assessed was the efficacy to reach the targeted aPTT in the first consecutive 14 days of therapy, and the controllability of aPTT values was within a therapeutic range of 50 to 75 s.  Fisher's exact test, Mann-Whitney U tests, Friedman tests and multi-variate non-parametric analyses for longitudinal data (MANOVA; Brunner's analysis) were applied where appropriate.  Of the 535 patients who met the inclusion criteria, 39 receiving argatroban and 39 matched patients receiving heparin (controls) were included.  Baseline characteristics were similar between the 2 groups, including severity of illness and organ failure scores.  There were no significant differences in major and minor bleeding complications.  Rates of thromboembolic events were generally low and were similar between the 2 groups, as were the rates of transfusions required and device-associated complications.  The controllability of both argatroban and heparin improved over time, with a significantly increasing probability to reach the targeted aPTT corridor over the first days (p < 0.001).  Over time, there were significantly fewer aPTT values below the targeted aPTT goal in the argatroban group than in the heparin group (p < 0.05).  Both argatroban and heparin reached therapeutic aPTT values for adequate application of extracorporeal lung support.  The authors concluded that argatroban appeared to be a feasible, effective and safe anticoagulant for critically ill ARDS patients undergoing extracorporeal lung support.

The authors stated that this study had several drawbacks.  First, it was retrospective and, although it was one of the largest studies on this topic, the sample size was relatively small (n = 39 for the argatroban group).  Thus, the study may be under-powered to detect significant differences in mortality, bleeding outcomes or transfusion.  Therefore, generalization of these results to other patients undergoing extracorporeal lung support required considerable caution.  Also, in this study the indication for extracorporeal lung support was lung failure.  Extracorporeal lung support was primarily cannulated veno-venously, and the results may not allow conclusions to be drawn in the case of a veno-arterial scenario.  The patients of this study had very high severity scores.  Thus, there might be different results or thresholds in other patient populations.  Another major drawback was that bleeding episodes and thromboembolic events were manually extracted from the patients’ files, which could result in under-estimation of the overall incidence.  There may be residual confounding that was not captured, such as confounding by indication or indicator.  Finally, an additional drawback of the present study was the absence of other parameters of anticoagulation used.

Raynaud's Phenomenon

In a pilot study, Denton and colleagues (2000) examined the tolerability and effectiveness of LMWH therapy in patients with severe Raynaud's phenomenon.  This study compared patients receiving regular subcutaneous LMWM (n = 16) with a matched control group (n = 14); end-points were change in Raynaud's attack severity, non-invasive vascular studies or serum levels of circulating soluble adhesion molecules.  There was overall improvement in Raynaud's attack severity during heparin therapy (p = 0.0002).  This was observed after 4 weeks, and was maximal by 20 weeks.  Mean finger blood flow recovery time improved, and serum levels of circulating ICAM-1, VCAM-1 and E-selectin were lower at completion of LMWH therapy, but changes did not reach statistical significance.  This authors concluded that the results of this study suggested that LMWH therapy was well-tolerated, and potentially beneficial, in patients with severe Raynaud's phenomenon, and justified further evaluation.

In a review on “Raynaud's phenomenon”, Wigley and Flavahan (2016) stated that “Long-term anticoagulation in the absence of a hypercoagulable state is not recommended”.

Furthermore, an UpToDate review on “Treatment of the Raynaud phenomenon resistant to initial therapy” (Wigley, 2017) stated that “Anticoagulation with heparin may be used for short periods during a crisis.  Long-term therapy with LMWH in a small placebo-controlled study was associated with a reduction in the severity of RP after 4 and 20 weeks of LMWH; further study of this approach is needed”.

Recurrent Pregnancy Loss

In a multi-center RCT, Schleussner et al (2015) examined if LMWH increases ongoing pregnancy and live-birth rates in women with unexplained recurrent pregnancy loss (RPL).  A total of 449 women with at least 2 consecutive early miscarriages or 1 late miscarriage were included during 5 to 8 weeks' gestation after a viable pregnancy was confirmed by ultrasonography.  Women in the control group received multi-vitamin pills, and the intervention group received vitamins and 5,000 IU of dalteparin-sodium for up to 24 weeks' gestation.  Primary outcome was ongoing pregnancy at 24 weeks' gestation; secondary outcomes included the live-birth rate and late pregnancy complications.  At 24 weeks' gestation, 191 of 220 pregnancies (86.8 %) and 188 of 214 pregnancies (87.9 %) were intact in the intervention and control groups, respectively (absolute difference, -1.1 percentage points [95 % CI: -7.4 to 5.3 percentage points]).  The live-birth rates were 86.0 % (185 of 215 women) and 86.7 % (183 of 211 women) in the intervention and control groups, respectively (absolute difference, -0.7 percentage point [95 % CI: -7.3 to 5.9 percentage points]).  There were 3 intra-uterine fetal deaths (1 woman had used LMWH); 9 cases of preeclampsia or the hemolysis, elevated liver enzyme level, and low platelet count (HELLP) syndrome (3 women had used LMWH); and 11 cases of intra-uterine growth restriction or placental insufficiency (5 women had used LMWH).  The authors concluded that daily LMWH injections did not increase ongoing pregnancy or live-birth rates in women with unexplained RPL.  They stated that given the burden of the injections, they are not recommended for preventing miscarriage.

Furthermore, an UpToDate review on “Management of couples with recurrent pregnancy loss” (Tulandi and Al-Fozan, 2016) list LMWH as one of the “Ineffective or Unproven Therapies”.

Areia and associates (2016) determined in women with hereditary thrombophilia whether the use of the combination of LMWH and aspirin (ASA) is better than ASA alone.  These investigators performed a meta-analysis of RCTs evaluating LMWH + ASA compared to ASA in pregnant women with hereditary thrombophilia in order to improve live-birth rate.  A systematic literature search was conducted in 5 databases (PubMed, Cochrane Controlled Trials Register, Embase, Scopus and ISI Web of Knowledge).  Trial selection, data extraction, and quality assessment were performed independently by 2 authors.  The main outcome measure was live-birth rate.  Secondary outcomes included rates of 1st-trimester miscarriage, prematurity, pre-eclampsia, and low birth weight for gestational age babies.  A total of 4 trials were included in the quantitative synthesis in a total of 222 randomized women.  Effect of LMWH + ASA versus ASA with regard to live-births was evaluable in all 4 RCTs with a similar overall treatment effect for the therapies OR 1.7 (95  % CI: 0.72 to 4.0) and without heterogeneity (I (2) = 0 %).  No significant differences or heterogeneity were observed between groups for secondary outcomes, namely 1st-trimester miscarriages OR 0.69 (0.22 to 2.16), prematurity OR 0.99 (0.4 to 2.08), pre-eclampsia OR 1.49 (0.63 to 3.5), and small for gestational age babies OR 2.08 (0.96 to 4.47).  The authors concluded that there were no significant differences in live-birth weight and other pregnancy outcomes between LMWH + ASA versus ASA.  Thus, there is no evidence to support any incremental benefit of adding LMWH to ASA alone in women with inherited thrombophilia.

Skeith and colleagues (2016) performed a meta-analysis of RCTs comparing LMWH versus no LMWH in women with inherited thrombophilia and prior late (greater than or equal to 10 weeks) or recurrent early (less than 10 weeks) pregnancy loss.  A total of 8 trials and 483 patients met inclusion criteria.  There was no significant difference in live-birth rates with the use of LMWH compared with no LMWH (RR, 0.81; 95 % CI: 0.55 to 1.19; p = 0.28), suggesting no benefit of LMWH in preventing recurrent pregnancy loss in women with inherited thrombophilia.

Sepsis/Septic Shock

In a systematic review and meta-analysis, Zarychanski et al (2015) evaluated the safety and effectiveness of heparin in patients with sepsis, septic shock, or disseminated intravascular coagulation associated with infection.  Data sources included RCTs  from MEDLINE, EMBASE, CENTRAL, Global Health, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to April 2014), conference proceedings, and reference lists of relevant articles.  Two reviewers independently identified and extracted trial-level data from randomized trials investigating UFH or LMWH administered to patients with sepsis, severe sepsis, septic shock, or disseminated intravascular coagulation associated with infection.  Internal validity was assessed in duplicate using the Risk of Bias tool.  The strength of evidence was assessed in duplicate using Grading of Recommendations Assessment, Development, and Evaluation methodology.  Primary outcome was mortality; safety outcomes included hemorrhage, transfusion, and thrombocytopenia.  These researchers included 9 trials enrolling 2,637 patients; 8 trials were of unclear risk of bias and 1 was classified as having low risk of bias.  In trials comparing heparin to placebo or usual care, the RR for death associated with heparin was 0.88 (95 % CI: 0.77 to 1.00; I2 = 0 %; 2,477 patients; 6 trials; moderate strength of evidence).  In trials comparing heparin to other anticoagulants, the RR for death was 1.30 (95 % CI: 0.78 to 2.18; I2 = 0 %; 160 patients; 3 trials; low strength of evidence).  In trials comparing heparin to placebo or usual care, major hemorrhage was not statistically significantly increased (RR, 0.79; 95 % CI: 0.53 to 1.17; I2 = 0 %; 2,392 patients; 3 trials).  In 1 small trial of heparin compared with other anti-coagulants, the risk of major hemorrhage was significantly increased (2.14; 95 % CI: 1.07 to 4.30; 48 patients).  Important secondary and safety outcomes, including minor bleeding, were sparsely reported.  The authors concluded that heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain.  Safety outcomes have been under-reported and require further study.  Increased major bleeding with heparin administration cannot be excluded.  They stated that large rigorous RCT are needed to evaluate more carefully the safety and effectiveness of heparin in patients with sepsis, severe sepsis, and septic shock.

Furthermore, an UpToDate review on “Evaluation and management of severe sepsis and septic shock in adults” (Schmidt and Mandel, 2016) does not mention heparin as a therapeutic option.

Stroke

Wada and associates (2016) performed a nationwide Japanese study to examine if argatroban improved early stroke outcomes in patients with acute athero-thrombotic stroke.  This retrospective observational study used the Diagnosis Procedure Combination database in Japan, included patients who were hospitalized from July 1, 2010, to March 31, 2012, with a diagnosis of athero-thrombotic stroke within 1 day of stroke onset.  Patients were divided into 2 groups:
  1. those receiving argatroban on admission (argatroban group), and
  2. those who did not receive argatroban during hospitalization (control group).  
To balance the baseline characteristics and concomitant treatments during hospitalization between the 2 groups, 1-to-1 propensity-score matching analyses were performed.  The main outcomes were the modified Rankin Scale score at discharge and the occurrence of hemorrhagic complications during hospitalization.  An ordinal logistic regression analysis evaluated the association between argatroban use and modified Rankin Scale at discharge.  After propensity-score matching, 2,289 pairs of patients were analyzed.  There were no significant differences in modified Rankin Scale at discharge between the argatroban and the control groups (adjusted OR, 1.01; 95 % CI: 0.88 to 1.16).  The occurrence of hemorrhagic complications did not differ significantly between the argatroban and the control groups (3.5 % versus 3.8 %; p = 0.58).  The authors concluded that the findings of this study suggested that argatroban was safe, but had no added benefit in early outcomes after acute athero-thrombotic stroke.

Barreto and co-workers (2017) carried out a randomized exploratory study to examine the safety and probability of a favorable outcome with adjunctive argatroban administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients.  Participants treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 μg/kg per minute (low-dose) or 3 μg/kg per minute (high-dose) for 48 hours.  The main safety measure was incidence of symptomatic ICH.  Probability of clinical benefit (modified Rankin Scale [mRS] score of 0 to 1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95 % CI: 0.33 to 3.0).  A total of 90 patients were randomized: 29 to r-tPA alone, 30 to r-tPA + low-dose argatroban, and 31 to r-tPA + high-dose argatroban.  Rates of symptomatic ICH were similar among control, low-dose, and high-dose arms: 3/29 (10 %), 4/30 (13 %), and 2/31 (7 %), respectively.  At 90 days, 6 (21 %) r-tPA alone, 9 (30 %) low-dose, and 10 (32 %) high-dose patients were with mRS score of 0 to 1.  The relative risks (95 % CI) for mRS score of 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57 to 2.37), 1.27 (0.63 to 2.53), and 1.34 (0.68 to 2.76), respectively.  The probability that adjunctive argatroban was superior to r-tPA alone was 67 %, 74 %, and 79 % for low, high, and low or high dose, respectively.  The authors concluded that in patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic ICH and provided evidence that a definitive effectiveness trial is indicated.

Argatroban (Argatroban Injection)

Argatroban is indicated as an anti-coagulant for
  1. prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia, and
  2. in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI). 

According to Drug Information on Argatroban from UpToDate (2013), argatroban is indicated for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT); and as adjunct to percutaneous coronary intervention (PCI) in patients who have or are at risk of thrombosis associated with HIT.

Argatroban is available as a 250 mg/2.5 mL single use vial. Argatroban Injection must be diluted 100-fold by mixing with 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer’s Injection to a final concentration of 1 mg/mL. Argatroban dosage may be adjusted for Pediatric use.

The dose for heparin-induced thrombocytopenia without hepatic impairment is 2 mcg/kg/min administered as a continuous infusion.

The dose for patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention is started at 25 mcg/kg/min and a bolus of 350 mcg/kg administered via a large bore intravenous line over 3 to 5 minutes.

Cruz-Gonzalez et al (2012) examined the role of argatroban for the treatment of acute coronary syndrome (ACS).  These researchers reviewed the potential use of argatroban for the treatment of ACS and presented the pharmacokinetic data currently available.  These investigators also presented the literature on the pharmacodynamics of argatroban in addition to high-lighting the safety and tolerability of the drug.  Theoretically, argatroban's pharmacokinetics makes it an attractive alternative to heparin.  Pharmacological advantages of argatroban over heparin include a more-predictable anti-coagulant response and the absence of a risk of HIT.  Furthermore, argatroban has a fast and predictable dose-dependent anti-coagulant effect with low inter-individual variability.  It is non-immunogenic, not susceptible to degradation by proteases and it is cleared via the liver.  These characteristics confer argatroban a different profile from other anti-coagulants.  Argatroban is an effective alternative for patients when heparin, lepirudin and bivalirudin cannot be used.  Moreover, they stated that its utility in ACS and PCI in non-HIT patients has been evaluated; but further studies are needed to define its role in this context.

Asanuma et al (2013) noted that breast cancer has the potential to metastasize to bone.  Although many tumor cells have thrombin-generating systems originating from tissue factor (TF), therapy in terms of the coagulation system is not well-established.  These researchers examined the effectiveness of argatroban on bone metastasis.  They investigated TF activation and vascular endothelial growth factor (VEGF) secretion on treatment with thrombin and argatroban.  MDA-231 breast cancer cells were treated with thrombin in presence or absence of argatroban, and TF activity was measured in the form of activated factor X.  Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF concentrations in the medium.  MDA-231 cells were injected into the left heart ventricle of mice, and then argatroban or saline was administered intraperitoneally for 28 days.  After 28 days, incidence of bone metastasis was evaluated in the limbs by radiography.  Tissue factor activity and VEGF secretion were up-regulated by thrombin.  Argatroban inhibited the enhancement of TF activity and VEGF secretion induced by thrombin.  In-vivo analysis revealed that the number of metastasized limbs in the argatroban group was significantly lower compared with the saline group (p < 0.05).  The authors concluded that thrombin not only enhances VEGF secretion but also has a positive feedback mechanism to re-express TF.  These results indicated that inhibition of thrombin is of great value in suppression of tumor metastasis.  They stated that argatroban is a noteworthy and useful thrombin inhibitor because it has already been used in the clinical setting and has anti-metastatic effects in-vivo.  These preliminary findings from a murine model need to be studied in human subjects in well-designed studies.

Ishibashi et al (2013) evaluated the effects of high-dose argatroban therapy in delayed administration for the treatment of stroke, and investigated the mechanism based on the clinical findings.  Argatroban 30 mg was first administered for 15 mins intravenously, and then 90 mg for 60 mins followed by 60 mg for 60 mins were infused continuously.  The change of vascular obstruction caused by the treatment was assessed with magnetic resonance angiography.  In 4 patients studied, high-dose argatroban resulted in 100 % re-canalization of occluded vessels (5/5), even though argatroban was administrated more than 24 hours after onset.  On the other hand, when an inadequate dose of argatroban was administered, a hemorrhage was identified.  This finding supported the hypothesis that high-dose argatroban promotes re-canalization by de-activating thrombin and exerting an anti-coagulant effect on the vascular endothelium.  The authors concluded that high-dose argatroban is an effective treatment for cerebral infarction and offers a novel therapeutic approach for delayed hospitalized patients at greater than 24 hours after onset.  Moreover, they stated that additional studies are needed to identify the cellular and molecular mechanisms and determine the adequate dose in order to reduce risks of complication.

Zhou et al (2014) stated that re-stenosis following extra-cranial artery stenting is a limitation that affects long-term outcomes.  Effective and satisfying pharmacological strategies in preventing re-stenosis have not been established.  In a pilot study, these researchers examined if argatroban could reduce the risk of in-stent re-stenosis after extra-cranial artery stenting.  A total of 114 patients hospitalized between August 2010 and August 2011 were enrolled.  Patients were randomly assigned to argatroban (n = 58) and blank control groups (n = 56).  Patients in the argatroban arm were treated with 10 mg of intravenous argatroban twice-daily 2 days before and 3 days after the stenting procedures.  Patients were followed for 12 months after the procedure.  During follow-up, re-stenosis and target re-vascularization were analyzed.  Recurrent cerebrovascular and cardiovascular events and deaths were also compared between the groups.  One patient in the stenting group withdrew immediately after the procedure due to unsuccessful stenting.  Re-stenosis occurred in 4 patients (7.4 %) in the argatroban group and in 11 patients (21.6 %) in the control group during the 6- to 9-month angiographic follow-up period (p = 0.032).  Nine months after the procedures, argatroban-treated patients had a trend towards a lower incidence of target re-vascularization compared with the controls (5.4 % versus 13.7 %, p = 0.188).  No major bleeding events or other adverse events occurred in the argatroban group.  The authors concluded that this pilot clinical trial is the first that uses argatroban to prevent re-stenosis in ischemic cerebrovascular disease, and suggested that intravenous administration of argatroban is safe and effective in preventing restenosis after extra-cranial artery stenting.  Moreover, they stated that larger RCTs are needed.

Desirudin (Iprivask)

Desirudin, a bi-valent direct thrombin inhibitor (DTI), is modeled after hirudin, a naturally occurring anti-coagulant found in the saliva of medicinal leeches.  It acts by directly inhibiting thrombin (Massart et al, 2009).  Clinical studies have reported that desirudin is significantly more effective than UH and LMWH for preventing VTE in patients undergoing total hip replacement (THR).

Eriksson et al (1997a) compared the safety and effectiveness of desirudin with enoxaparin (a LMWH) for the prevention of thromboembolic complications in patients undergoing primary THR.  Both treatments, which were assigned in a randomized, double-blind manner, were started pre-operatively -- desirudin within 30 mins before the start of surgery, and enoxaparin on the evening before surgery.  The dosage of desirudin was 15 mg subcutaneously twice-daily, and the dosage of enoxaparin was 40 mg subcutaneously once-daily.  The duration of treatment was 8 to 12 days.  Deep vein thrombosis was verified by bilateral venography performed at the end of the treatment period, or earlier if there were clinical signs of DVT.  At 31 centers in 10 European countries, 2,079 eligible patients were randomly assigned to receive desirudin or enoxaparin.  A total of 1,587 patients were included in the primary analysis of effectiveness.  In the desirudin group, as compared with the enoxaparin group, there was a significantly lower rate of proximal DVT (4.5 % versus 7.5 %, p = 0.01; relative reduction in risk, 40.3 %) and a lower overall rate of DVT (18.4 % versus 25.5 %, p = 0.001; relative reduction in risk, 28.0 %).  The safety profiles were similar in the 2 treatment groups.  The authors concluded that when administered 30 mins before THR surgery, desirudin is more effective than enoxaparin in preventing DVT.

Eriksson et al (1997b) compared the safety and effectiveness of desirudin with that of UH (5,000 international units 3 times a day) in patients having a primary elective THR.  The medications were administered subcutaneously, starting pre-operatively and continuing for 8 to 11 days.  The primary end point was a confirmed thromboembolic event during the treatment period.  The presence of DVT was evaluated with bilateral venograms, which were assessed by 2 independent radiologists.  A total of 445 eligible patients were randomized -- 225 to management with desirudin, and 220 to management with UH.  A per-protocol analysis of effectiveness was performed for the 351 patients (79 %) for whom an adequate bilateral venogram had been made within 8 to 11 days after the operation or who had had a proved thromboembolic event.  The prevalence of confirmed DVT was 13 (7 %) of 174 patients who had received desirudin and 41 (23 %) of 177 patients who had received UH, a significant difference (p < 0.0001).  The prevalence of proximal DVT was also significantly reduced (p < 0.0001) by 79 % in the group that had received desirudin (6 [3 %] of 174 patients) compared with in the group that had received UH (29 [16 %] of 177).  There was no confirmed PE or death during the period of prophylaxis.  During a 6-week follow-up period, PE was confirmed in 4 patients, all of whom had received UH.  There was no significant difference between the treatment groups with respect to bleeding variables or bleeding complications.  These data demonstrated that a fixed dose of 15 mg of desirudin, started pre-operatively and administered subcutaneously twice-daily for at least 8 days, provided safe and effective prevention of thromboembolic complications, with no specific requirements for laboratory monitoring in patients who had a THR.

On April 4, 2003, desirudin injection (Iprivask) was approved by the Food and Drug Administration (FDA) for the prevention of DVT, which may lead to PE, in persons undergoing elective hip replacement surgery.  Since desirudin is administered as a fixed subcutaneous dose, it is believed to be easier to use than intravenous DTIs that require dose adjustment; thus providing a safer alternative for DVT prophylaxis.  In patients undergoing hip replacement surgery, the recommended dosage of desirudin is 15 mg every 12 hours administered by subcutaneous injection with the initial dose given up to 5 to 15 mins prior to surgery, but after induction of regional block anesthesia, if used.  Up to 12 days administration (average duration of 9 to 12 days) of desirudin has been well-tolerated in controlled clinical trials.  Adverse reactions associated with the use of desirudin include anaphylaxis, antibody formation, bleeding, injection site reaction/mass, and nausea.  Desirudin is contraindicated in patients with active bleeding and/or irreversible coagulation disorders, or with known hypersensitivity to natural or recombinant hirudins.

Trujillo (2010) discussed the advantages and disadvantages of currently available anti-coagulants, described the characteristics of the ideal anti-coagulant, and compared and contrasted the mechanisms of action, pharmacokinetics, administration, safety, effectiveness, and potential for drug interactions of currently available and emerging anti-coagulants for prevention of VTE.  Despite the proven effectiveness of currently available agents for VTE prevention, several shortcomings exist that may prevent their use under various circumstances.  These include administration by injection, narrow therapeutic index, unpredictable pharmacokinetics and pharmacodynamics, need for laboratory monitoring, risk for bleeding, and drug interactions.  The ideal anti-coagulant would overcome many of these issues; in particular, it would be available as an oral formulation.  Dabigatran, an oral direct thrombin (factor IIa) inhibitor, and apixaban and rivaroxaban, oral direct factor Xa inhibitors, represent new agents for anti-coagulation that may address many of these issues.  While not available as an oral agent, desirudin is an additional option and offers increased flexibility when a non-heparin-based injectable anti-coagulant is desired.  Current literature indicates that these agents generally do not require laboratory monitoring, and are safe and effective for VTE prevention in patients undergoing major orthopedic surgery.

Nafziger and Bertino (2010) noted that desirudin is a renally-eliminated DIT approved for the prevention of VTE.  Empiric dosage adjustment and aPTT monitoring in patients with moderate renal impairment are recommended, but supportive data are lacking.  These investigators evaluated appropriate desirudin dosing in moderate renal impairment and the effect of desirudin on aPTT in moderate renal impairment.  Desirudin plasma concentration and aPTT data were extracted from 6 studies.  Subjects with normal renal function or moderate renal impairment (CrCl 31 to 60 ml/min) were included.  Pharmacokinetic and Monte Carlo simulations were done.  After administration of desirudin 15 mg every 12 hours subcutaneously to steady state, peak desirudin concentrations were 35 and 47 nmol/L in the normal and moderate renal function groups, respectively.  Monte Carlo simulations found median 2-hour C(max) concentrations of 51.7 nmol/L in normal renal function and 52.4 nmol/L in moderate renal impairment.  Desirudin exhibits a linear relationship when the square root of desirudin concentration was plotted versus the aPTT ratio (r(2) = 0.76).  The authors concluded that these findings supported the dosing of desirudin at 15 mg every 12 hours subcutaneously without aPTT monitoring in patients with moderate renal impairment.

In a Cochrane review, Salazar and colleagues (2010) examined the safety and effectiveness of prophylactic anti-coagulation with DTIs versus LMWH or vitamin K antagonists (VKAs) in the prevention of VTE in patients undergoing THR or total knee replacement (TKR).  Three reviewers independently assessed methodological quality and extracted data in pre-designed tables; and reported follow-up events were included.  These investigators included 14 studies (21,642 patients evaluated for effectiveness and 27,360 for safety).  No difference was observed in major VTE in DTIs compared with LMWH in both types of operations (OR 0.91; 95 % CI: 0.69 to 1.19), with high heterogeneity (I(2) 71 %).  No difference was observed with warfarin (OR 0.85; 95 % CI: 0.63 to 1.15) in TKR, with no heterogeneity (I(2) 0 %).  More total bleeding events were observed in the DTI group (in ximelagatran and dabigatran but not in desirudin) in patients subjected to THR (OR 1.40; 95 % CI: 1.06 to 1.85; I(2) 41 %) compared with LMWH.  No difference was observed with warfarin in TKR (OR 1.76; 95 % CI: 0.91 to 3.38; I(2) 0 %).  All-cause mortality was higher in the DTI group when reported follow-up events were included (OR 2.06; 95 % CI: 1.10 to 3.87).  Studies that initiated anti-coagulation before surgery showed less VTE events; those that began anti-coagulation after surgery showed more VTE events in comparison with LMWH.  Therefore, the effect of DTIs compared with LMWH appears to be influenced by the time of initiation of coagulation more than the effect of the drug itself.  The results obtained from sensitivity analysis did not differ from the analyzed results; this strengthens the value of the results.  The authors concluded that DTIs are as effective in the prevention of major VTE in THR or TKR as LMWH and VKAs.  However, they show higher mortality and cause more bleeding than LMWH.  No severe hepatic complications were reported in the analyzed studies.  Use of ximelagatran is not recommended for VTE prevention in patients who have undergone orthopedic surgery.  More studies are necessary regarding dabigatran.

Direct thrombin inhibitors have also been studied in other patient groups including those with acute coronary syndrome (ACS), persons undergoing cardio-thoracic surgery including percutaneous coronary intervention (PCI), persons undergoing elective spine surgery individuals who have or are at risk for heparin-induced thrombocytopenia (HIT), and individuals with mechanical heart valves (Lepor, 2007; Maegdefessel et al, 2009; Rupprecht, 2009; and Sansone et al, 2010).  Lepor (2007) noted that treatment of unstable angina with UH, in addition to aspirin, was introduced into clinical practice in the early 1980s.  Unfractionated heparin was combined with aspirin to suppress thrombin propagation and fibrin formation in patients presenting with ACS or patients undergoing PCI.  However, UH stimulates platelets, leading to both activation and aggregation, which may further promote clot formation.  Clinical trials have demonstrated that newer agents, such as LMWHs, are superior to UH for medical management of unstable angina or non-ST-segment elevation myocardial infarction.  Increasingly, LMWHs have been used as the anti-coagulant of choice for patients presenting with ACS.  For patients undergoing PCI, LMWHs provide no substantial benefit over UH for anti-coagulation; however, DTIs have demonstrated safety and effectiveness in this setting.  Unfractionated heparin is likely to be replaced by more effective and safer anti-thrombin agents, such as DTIs.  Direct thrombin inhibitors have anti-platelet effects, anti-coagulant action, and most do not bind to plasma proteins, thereby providing a more consistent dose-response effect than UH.  The FDA has approved 4 parenteral DTIs for various indications: argatroban, bivalirudin, desirudin, and lepirudin.

Maegdefessel and associates (2009) examined the effectiveness of argatroban and bivalirudin in comparison to UH in preventing thrombus formation on mechanical heart valves.  Blood (230 ml) from healthy young male volunteers was anti-coagulated either by UH, argatroban bolus, argatroban bolus plus continuous infusion, bivalirudin bolus, or bivalirudin bolus plus continuous infusion.  Valve prostheses were placed in a newly developed in-vitro thrombosis tester and exposed to the anti-coagulated blood samples.  To quantify the thrombi, electron microscopy was performed, and each valve was weighed before and after the experiment.  Mean thrombus weight in group 1 (UH) was 117 + 93 mg, in group 2 (argatroban bolus) 722 + 428 mg, in group 3 (bivalirudin bolus) 758 + 323 mg, in group 4 (argatroban bolus plus continuous infusion) 162 + 98 mg, and in group 5 (bivalirudin bolus plus continuous infusion) 166 + 141 mg (p < 0.001).  Electron microscopy showed increased rates of thrombus formation in groups 2 and 3.  Argatroban and bivalirudin were as effective as UH in preventing thrombus formation on valve prostheses in this in-vitro investigation when they were administered continuously.  These investigators hypothesized that continuous infusion of argatroban or bivalirudin are optimal treatment options for patients with HIT after mechanical heart valve replacement for adapting oral to parenteral anti-coagulation or vice versa.

In an editorial that accompanied the afore-mentioned study by Maegdefessel et al, Rupprecht (2009) stated that in clinical settings such as PCI or bypass surgery, replacement of heparins with DTIs as a consequence of HIT revealed promising results, but these data cannot simply be translated to the high-risk situation of patients with mechanical heart valves.  The editorialist noted that it is the merit of Maegdefessel et al to provide solid in-vitro data, indicating equivalency effectiveness of DTI as compared to UH in the high-risk surrounding of artificial heart valve.  This may open an avenue for further clinical evaluation of anti-coagulant regimens in patients who need bridging anti-coagulation and in whom heparin use is restricted.

Sansone and colleagues (2010) the prevalence of thromboembolism as well as the effectiveness and complications of various prophylactic measures in a population of patients who had undergone elective spine surgery.  A meta-analysis and uni-variate logistic regression was performed on selected studies to determine the prevalence of and risk factors for DVT and PE following elective spine surgery.  Studies were included on the basis of the selection criteria (specifically, the inclusion of only patients who underwent spine surgery, or the treatment of patients who underwent spine surgery as an independent cohort; the use of an objective diagnostic modality for the diagnosis of DVT, including Doppler ultrasonography or venography; the use of an objective diagnostic modality for the diagnosis of PE, including computed tomography of the chest or a ventilation-perfusion scan; and a study population of more than 30 patients).  Patients with a known spinal cord injury were excluded.  A total of 14 studies (including a total of 4,383 patients) met selection criteria.  On the basis of the meta-analysis, the prevalence of DVT was 1.09 % (95 % CI: 0.54 % to 1.64 %) and the prevalence of PE was 0.06 % (95 % CI: 0.01 % to 0.12 %) following elective spine surgery.  The use of pharmacologic prophylaxis significantly reduced the prevalence of DVT relative to either mechanical prophylaxis (p = 0.047) or no prophylaxis (p < 0.01).  One fatal PE was reported.  An epidural hematoma requiring surgical evacuation was reported in 8 of 2,071 patients receiving pharmacologic prophylaxis; 3 of these patients had a permanent neurological deficit.  The authors concluded that the risks of DVT and PE are relatively low following elective spine surgery, especially for patients who receive pharmacologic prophylaxis.  Unfortunately, pharmacologic prophylaxis exposes patients to a greater risk of epidural hematoma.  They stated that more evidence is needed prior to establishing a protocol for prophylaxis against VTE in patients undergoing elective spine surgery.  They stated that future prospective studies should seek to define the safety of various prophylactic modalities and to identify specific sub-populations of patients who are at greater risk for VTE.

Iprivask was discontinued in the U.S. (Drugs.com, 2019; Medscape, 2020).

Appendix

Indications for LMWH Prophylaxis in Persons with Multiple Myeloma on Thalidomide or Lenalidomide

  • Concurrent administration of high-dose dexamethasone or doxorubicin; or
  • Presence of 2 or more of the following VTE risk factors:

    • Age greater than 65 years;
    • Central venous catheter;
    • History of venous throboembolism;
    • Hyperviscosity;
    • Immobilization;
    • Inherited thrombophilia;
    • Intravenous drug use;
    • Obesity;
    • Presence of co-morbidities such as infections, diabetes, cardiac disease, or chronic renal disease;
    • Recent (less than 3 months) surgery, trauma or hospital admission; and
    • Recent diagnosis of myeloma.

Source: Palumbo et al, 2008.

Table: Recommendations for Duration of VTE Prophylaxis after Surgery (Based on the American College of Chest Physicians (ACCP) Guideline (8th and 9th edition)
Indication Duration of VTE Prophylaxis  Grade of Evidence 

High risk nonorthopedic general surgery members*

LMWH for up to 28 days *Such as patients who have undergone major pelvic/abdominal cancer surgery or have previously had VTE

1B

Hip fracture surgery

Minimum of 10‐14 days after surgery

 Up to 35 days after surgery

 LMWH

 VKA (Warfarin; INR Goal 2‐3)

 Arixtra (fondaparinux)

1B

2B

1B

2C

2B

Total hip replacement and total knee replacement

Minimum of 10 to 14 days

Suggest up to 35 days after surgery rather than for only 10‐14 days

LMWH

VKA (Warfarin; INR Goal 2‐3)

Arixtra (fondaparinux) 2B

Xarelto (rivaroxaban)

Eliquis (apixaban)

Pradaxa (dabigatran)

1B

2B

1B

2C

2B

2B

2B

2B

1A: Strong recommendation, high‐quality evidence

1B: Strong recommendation, moderate‐quality evidence

2B: Weak recommendation, moderate‐quality evidence

Key: VKA = vitamin K antagonists (i.e., warfarin); LMWH = low molecular weight heparin

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Low-molecular-weight heparins:

Other CPT codes related to the CPB:

27120 Acetabuloplasty; (e.g., Whitman, Colonna, Haygroves, or cup type)
27122 Acetabuloplasty; resection, femoral head (e.g., Girdlestone procedure)
27125 Hemiarthroplasty, hip, partial (e.g., femoral stem prosthesis, bipolar arthroplasty)
27130 Arthroplasty, acetabular and proximal femoral prosthetic replacement (total hip arthroplasty), with or without autograft or allograft
27132 Conversion of previous hip surgery to total hip arthroplasty, with or without autograft or allograft
27134 Revision of total hip arthroplasty; both components, with or without autograft or allograft
27137     acetabular component only, with or without autograft or allograft
27138     femoral component only, with or without allograft
27230 - 27236
27267 - 27269
Treatment of femoral fracture
27447 Arthroplasty, knee, condyle and plateau; medial AND lateral compartments with or without patella resurfacing (total knee arthroplasty)
29880 - 29881 Arthroscopy, knee, surgical; with meniscectomy
30000 - 32999 Respiratory system / surgery
33016 - 37799 Cardiovascular system / surgery
40490 - 49999 Digestive system / Surgery
61000 - 64999 Nervous system / surgery
65091 - 68899 Eye and ocular adnexa / surgery
90935 - 90940 Hemodialysis
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96374 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug
97016 Application of a modality to one or more areas; vasopneumatic devices

HCPCS codes covered if selection criteria are met:

J1645 Injection, dalteparin sodium, per 2500 IU
J1650 Injection, enoxaparin sodium, 10 mg
J1652 Injection, fondaparinux sodium, 0.5 mg
J1655 Injection, tinzaparin sodium, 1000 IU

Other HCPCS codes related to the CPB:

E0650 - E0675 Pneumatic compressor and appliances
J1094 Dexamethasone acetate, IM, 1 mg
J1100 Dexamethasone sodium phosphate, IM, IV, OTH, 1 mg
J7637 Dexamethasone, concentrated form, INH per mg
J7638 Dexamethasone, unit form, INH, per mg
J8540 Dexamethasone, oral, 0.25 mg
J9000 Doxorubicin HCl, IV, 10 mg
Q2050 Injection, doxorubicin hydrochloride, liposomal, not otherwise specified, 10 mg

ICD-10 codes covered if selection criteria are met:

C90.00 - C90.02 Multiple myeloma [recent diagnosis receiving thalidomide or lenalidomide]
D68.51 - D68.62 Primary and other thrombophilia
I20.0 Unstable angina
I21.4, I22.2 Subendocardial infarction
I21.01 - I21.9 Acute myocardial infarction
I26.02 - I26.09 Pulmonary embolism with acute cor pulmonale
I26.92 - I26.99 Pulmonary embolism without acute cor pulmonale
I50.1 - I50.9 Heart failure
I63.30 - I63.39
I63.6
Cerebral infarction due to thrombosis of cerebral arteries and cerebral venous thrombosis
I63.40 - I63.49 Cerebral infarction due to embolism of cerebral arteries
I82.0 - I82.91 Other venous embolism and thrombosis
I87.2
I87.8 - I87.9
I99.8 - I99.9
Other and unspecified disorders of circulatory system
M84.750+ - M84.759+ Atypical femoral fracture
O22.00 - O22.93 Venous complications in pregnancy
O88.011 - O88.019
O88.111 - O88.119
O88.211 - O88.219
O88.311 - O88.319
O88.811 - O88.819
Obstetric embolism in pregnancy
O99.411 - O99.419 Diseases of the circulatory system complicating pregnancy
S14.0xx+ - S14.159+
S24.0xx+ - S24.159+
S34.01x+ - S34.139+
S34.3xx+
Spinal cord injury
S72.001+ - S72.92x+
S79.001+ - S79.199+
Fracture of femur
Z86.711 - Z86.79 Personal history of diseases of the circulatory system
Z95.2 Presence of prosthetic heart valve [for members with mechanical heart valves until stabilized on vitamin K antagonists]
Z96.641 - Z96.659 Presence of artificial hip or knee joint

ICD-10 codes not covered for indications listed in CPB:

A40.00 - A40.9 Streptococcal sepsis
A41.01 - A41.49 Other sepsis
C49.0 - C49.9 Malignant neoplasm of other connective and soft tissue [metastatic synovial sarcoma]
C50.011 - C50.929 Malignant neoplasm of breast
D57.00 - D57.02 Hb-SS disease with crisis
D57.211 - D57.219 Sickle-cell/Hb-C disease with crisis
D57.811 - D57.819 Other sickle-cell disorders with crisis
D69.51 - D69.59 Secondary thrombocytopenia
H33.001 - H33.8 Retinal detachments and breaks
I73.00 - I73.01 Raynaud’s syndrome
I74.01 - I74.9 Arterial embolism and thrombosis
K51.00 - K51.919 Ulcerative Colitis
O15.1 - O15.9 Eclampsia complicating pregnancy [history of preeclampsia]
O26.20 - O26.23 Pregnancy care of habitual aborter
R65.21 Severe sepsis with septic shock
Z98.61 Coronary angioplasty status

LMWM-based nanoparticles - no specific code:

ICD-10 codes not covered for indications listed in CPB:

C50.011 - C50.929 Malignant neoplasm of breast

Other CPT codes related to the CPB:

27130 Arthroplasty, acetabular and proximal femoral prosthetic replacement (total hip arthroplasty), with or without autograft or allograft
27132 Conversion of previous hip surgery to total hip arthroplasty, with or without autograft or allograft

Argatroban:

Other CPT codes related to the CPB:

33946 - 33986 Extracorporeal membrane oxygenation (ECMO)/extracorporeal life support (ECLS) provided by physician [extracorporeal lung support]
96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366     each additional hour (List separately in addition to code for primary procedure)
96374 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug

HCPCS codes covered if selection criteria are met:

J0883 Injection, argatroban, 1 mg (for non-esrd use)
J0884 Injection, argatroban, 1 mg (for esrd on dialysis)

ICD-10 codes covered if selection criteria are met:

D75.82 Heparin induced thrombocytopenia (HIT)

ICD-10 codes not covered for indications listed in CPB (not all-inclusive):

C00.0 - C96.9 Malignant neoplasms
G46.0 - G46.8 Vascular syndromes of brain in cerebrovascular diseases
I24.9 Acute ischemic heart disease, unspecified [acute coronary syndrome]
I65.01 - I66.9 Occlusion and stenosis of precerebral arteries and occlusion of cerebral arteries [stroke]
J80 Acute respiratory distress syndrome [management of persons with acute respiratory distress syndrome undergoing extracorporeal lung support]
K55.011 - K55.069 Acute vascular disorders of intestine [Acute superior mesenteric venous thrombosis]
T82.817+, T82.827+, T82.837+, T82.847+, T82.857+, T82.867+, T82.897+, T82.9xx+ Other specified complications of cardiac device, implant, and graft [for prevention of in-stent re-stenosis after extra-cranial artery stenting]
Z95.811 Presence of heart assist device.[ventricular assist device]

The above policy is based on the following references:

  1. Adi Y, Bayliss S, Rouse A, et al. Air travel as a risk factor for venous thromboembolism (VTE) and the effectiveness of preventive measures. DPHE Report No. 39. Birmingham, UK: West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, University of Birmingham (WMHTAC); 2002. 
  2. Ageno W, Crotti S, Turpie AG. The safety of antithrombotic therapy during pregnancy. Expert Opin Drug Saf. 2004;3(2):113-118.
  3. Akl EA, Barba M, Rohilla S, et al. Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2008;(2):CD006550.
  4. Akl EA, Labedi N, Terrenato I, et al. Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer. Cochrane Database Syst Rev. 2011;11:CD009447.
  5. Akl EA, van Doormaal FF, Barba M, et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst Rev. 2007;(3):CD006652.
  6. Akl EA, Vasireddi SR, Gunukula S, et al. Anticoagulation for the intial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2011;(6):CD006649.
  7. Akl EA, Vasireddi SR, Gunukula S, et al. Anticoagulation for thrombosis prophylaxis in cancer patients with central venous catheters. Cochrane Database Syst Rev. 2011;(4):CD006468.
  8. Alikhan R, Cohen AT, Heparin for the prevention of venous thromboembolism in general medical patients (excluding stroke and myocardial infarction). Cochrane Database Syst Rev. 2010;(2):CD003747.
  9. Almeda FQ, Snell RJ, Parrillo JE. The contemporary management of acute myocardial infarction. Crit Care Clin. 2001;17(2):411-434. 
  10. American College of Obstetricians and Gynecologists (ACOG). Anticoagulation with low-molecular-weight heparin during pregnancy. ACOG Committee Opinion No. 211. Washington, DC: ACOG; November 1998 
  11. Anderson DR, O'Brien B, Nagpal S, et al. Economic evaluation comparing low molecular weight heparin with other modalities for the prevention of deep vein thrombosis and pulmonary embolism following total hip or knee arthroplasty. Technology Report Issue 1. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1998. 
  12. Areia AL, Fonseca E, Areia M, Moura P. Low-molecular-weight heparin plus aspirin versus aspirin alone in pregnant women with hereditary thrombophilia to improve live birth rate: Meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2016;293(1):81-86.
  13. Baglin TP. Low-molecular-weight heparins and new strategies for the treatment of patients with established venous thrombosis. Hemostasis. 1996;26(Suppl 2):10-15. 
  14. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):627S-644S.
  15. Bhutia S, Wong PF. Once versus twice daily low molecular weight heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2013;7:CD003074.
  16. Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate mesylate) capsules, for oral use. Prescribing Information. Ridgefield, CT: Boehringer Ingelheim; revised November 2019.
  17. Bounameaux H, Goldhaber SZ. Uses of low-molecular-weight heparin. Blood Rev. 1995;9(4):213-219. 
  18. Caldeira D, David C, Santos AT, et al. Efficacy and safety of low molecular weight heparin in patients with mechanical heart valves: Systematic review and meta-analysis. J Thromb Haemost. 2014;12(5):650-659.
  19. Camporese G, Bernardi E, Prandoni P, et al; KANT (Knee Arthroscopy Nadroparin Thromboprophylaxis) Study Group. Low-molecular-weight heparin versus compression stockings for thromboprophylaxis after knee arthroscopy: A randomized trial. Ann Intern Med. 2008;149(2):73-82.
  20. Cassinelli G, Dal Bo L, Favini E, et al. Supersulfated low-molecular weight heparin synergizes with IGF1R/IR inhibitor to suppress synovial sarcoma growth and metastases. Cancer Lett. 2018;415:187-197.
  21. Chande N, McDonald JW, Macdonald JK, Wang JJ. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2010;(10):CD006774.
  22. Chande N, McDonald JW, MacDonald JK. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2008;(2):CD006674.
  23. Chen H, Tao R, Zhao H, et al. Prevention of venous thromboembolism in patients with cancer with direct oral anticoagulants: A systematic review and meta-analysis. Medicine (Baltimore). 2020;99(5):e19000.
  24. Chen J, Penrod J, McGregor M. Should the MUHC use low-molecular-weight heparin in inpatient treatment of deep vein thrombosis with or without pulmonary embolism? Report No. 5. Montreal, QC: Technology Assessment Unit of the McGill University Health Centre (MUHC); 2003.
  25. Chen YC, Chi CC, Chan FC, Wen YW. Low molecular weight heparin for prevention of microvascular occlusion in digital replantation. Cochrane Database Syst Rev. 2013;7:CD009894.
  26. Choussat R, Montalescot G. Low molecular weight heparin in unstable angina and myocardial infarction without Q wave. Presse Med. 1999;28(21):1128-1134. 
  27. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337:447-452. 
  28. Cohen M, Demers C, Gurfinkel EP, et al. Low-molecular-weight heparins in non-ST-segment elevation ischemia: The ESSENCE trial. Efficacy and Safety of Subcutaneous Enoxaparin versus intravenous unfractionated heparin, in non-Q-wave Coronary Events. Am J Cardiol. 1998;82(5B):19L-24L. 
  29. Colwell CW Jr. Low molecular weight heparin prophylaxis in total knee arthroplasty: The answer. Clin Orthop. 2001;(392):245-248. 
  30. Colwell CW Jr; Annenberg Center for Health Sciences and Quadrant Medical Education. Thromboprophylaxis in orthopedic surgery. Am J Orthop. 2006;Suppl:1-9.
  31. Cosmi B, Conti E, Coccheri S. Anticoagulants (heparin, low molecular weight heparin and oral anticoagulants) for intermittent claudication. Cochrane Database Syst Rev. 2001;(2):CD001999.
  32. Danchin N, Benedetti ED, Urban P. Acute myocardial infarction. In: Clinical Evidence, Issue 12. London, UK: BMJ Publishing Group; December 2004.
  33. Denton CP, Howell K, Stratton RJ, Black CM. Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: A pilot study. Clin Exp Rheumatol. 2000;18(4):499-502.
  34. Di Nisio M, Wichers IM, Middeldorp S. Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev. 2007;(2):CD004982.
  35. Dong Y, Wang Y, Ma RL, et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: A systematic review and meta-analysis. J Thromb Thrombolysis. 2019;48(3):400-412.
  36. Dorffler-Melly J, Koopman MMW, Prins MH, Büller HR. Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment. Cochrane Database Syst Rev. 2005;(1):CD002071.
  37. Drugs.com. Desirudin. Updated August 13, 2019. Available at: https://www.drugs.com/ppa/desirudin.html. Accessed April 21, 2020. 
  38. Drugs.com. Orgaran (subcutaneous). Updated August 15, 2019. Available at: https://www.drugs.com/cons/orgaran.html. Accessed April 21, 2020.
  39. Dulitzki M, Pauzner R, Langevitz P, et al. Low-molecular-weight heparin during pregnancy and delivery: Preliminary experience with 41 pregnancies. Obstet Gynecol. 1996;87:380-383. 
  40. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2005;(2):CD002859.
  41. Fauno P, Suomalainen O, Rehnberg V, et al. Prophylaxis for the prevention of venous thromboembolism after total knee arthroplasty. A comparison between unfractionated and low-molecular-weight heparin. J Bone Joint Surg Am. 1994;76(12):1814-1818. 
  42. Felder S, Rasmussen MS, King R, et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2019;8:CD004318.
  43. Ferrario M, Merlini PA, Lucreziotti S, et al. Antithrombotic therapy of unstable angina and non-Q-wave myocardial infarction. Int J Cardiol. 1999;68 Suppl 1:S63-S71. 
  44. Ferretti G, Bria E, Giannarelli D, et al. Is recurrent venous thromboembolism after therapy reduced by low-molecular-weight heparin compared with oral anticoagulants? Chest. 2006;130(6):1808-1816.
  45. Fox KA, Antman EM. Treatment options in unstable angina: A clinical update. Eur Heart J. 1998;19 Suppl K:K8-K10.
  46. Garces K, Mamdani M. Fondaparinux for post-operative venous thrombosis prophylaxis. Issues in Emerging Health Technologies Issue 37. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2002.
  47. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996;335(10):701-707. 
  48. Goldhaber SZ. Unsolved issues in the treatment of pulmonary embolism. Thromb Res. 2001;103(6):V245-V255.
  49. Graf J, Janssens U. Low-molecular weight heparins in percutaneous coronary interventions: Current concepts, problems, and perspectives.  Curr Pharm Des.  2004;10(4):375-386.
  50. Greer IA. Antithrombotic therapy for recurrent miscarriage? N Engl J Med. 2010;362(17):1630-1631.
  51. Groom KM, McCowan LM, Mackay LK, et al; Enoxaparin for Prevention of Preeclampsia and Intrauterine Growth Restriction Trial Investigator Group. Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: A randomized trial. Am J Obstet Gynecol. 2017;216(3):296.e1-296.e14.
  52. Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2004;(2):CD000024.
  53. Gurfinkel E, Scirica BM. Low molecular weight heparins (enoxaparin) in the management of unstable angina: The TIMI studies. Heart. 1999;82(Suppl 1):I15-I17. 
  54. Hague WM, North RA, Gallus AS, et al. Anticoagulation in pregnancy and the puerperium. Med J Aust. 2001;175(5):258-263. 
  55. Harris S, Nadkarni NA, Naina HV, Vege SS. Splanchnic vein thrombosis in acute pancreatitis: A single-center experience. Pancreas. 2013;42(8):1251-1254.
  56. Hender K. Low molecular weight heparin in comparison to unfractionated heparin for the management of unstable angina (UA). Update. Evidence Centre Evidence Report. Clayton, VIC: Centre for Clinical Effectiveness (CCE); 2000.
  57. Hickey BA, Watson U, Cleves A, et al. Does thromboprophylaxis reduce symptomatic venous thromboembolism in patients with below knee cast treatment for foot and ankle trauma? A systematic review and meta-analysis. Foot Ankle Surg. 2018;24(1):19-27.
  58. Hirsh J, Hoak J. Statement for Healthcare Professionals From the Council on Thrombosis (in Consultation With the Council on Cardiovascular Radiology), American Heart Association. Management of Deep Vein Thrombosis and Pulmonary Embolism. Circulation. 1996;93:2212-2245. 
  59. Hirsh J, MD, Fuster V. AHA Medical/Scientific Statement: Guide to Anticoagulant Therapy Part 1: Heparin. Circulation. 1994;89:1449-1468. 
  60. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 Suppl):64S-94S. 
  61. Horlocker TT, Wedel DJ. Spinal and epidural blockade and perioperative low molecular weight heparin: Smooth sailing on the Titanic. Anesth Analg. 1998;86:1153-1156. 
  62. Hospira Inc. Argatroban - argatroban injection, solution. Prescribing Information. Lake Forest, IL; revised September 2019. 
  63. Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: A systematic review. Ann Intern Med. 2001;135(10):858-869. 
  64. Hull RD, Pineo GF. Therapeutic use of low molecular weight heparins: Knowledge to date and their application to therapy. Semin Thromb Hemost. 1994;20(4):339-344. 
  65. Hull RD. Thromboprophylaxis in knee arthroscopy patients: Revisiting values and preferences. Ann Intern Med. 2008;149(2):137-139.
  66. Hunt BJ, Doughty HA, Majumdar G, et al. Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thromb Haemost. 1997;77:39-43. 
  67. Hyers TM. Management of venous thromboembolism: Past, present, and future.  Arch Intern Med. 2003;163(7):759-768.
  68. Jackson N. Comparative incidence of heparin-induced thrombocytopenia syndrome (HITS) with unfractionated heparin and low molecular weight heparin. Evidence Centre Evidence Report. Clayton, VIC; Centre for Clinical Effectiveness (CCE); 2002.
  69. Jaff MR, McMurtry S, Archer SL, et. al. Management of massive and submassive pulmonary embolism, iliofemoral deep vien thrombosis, and chronic thromboembolic pulmonary hyptertension. AHA Scientific Statement. Circulation. 2011:123:1788-1830.
  70. Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev. 2009;(1):CD004734.
  71. Kaandorp SP, Goddijn M, van der Post JA, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362(17):1586-1596.
  72. Kakkar VV, Boeckl O, Boneu B, et al. Efficacy and safety of a low-molecular-weight heparin and standard unfractionated heparin for prophylaxis of postoperative venous thromboembolism: European multicenter trial. World J Surg. 1997;21(1):2-8. 
  73. Key NS, Khorana AA, Kuderer NM. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. Journal of Clinical Oncology. 2019;35(5): 496-520.
  74. Khorana AA. The NCCN Clinical Practice Guidelines on Venous Thromboembolic Disease: Strategies for improving VTE prophylaxis in hospitalized cancer patients. Oncologist. 2007;12(11):1361-1370.
  75. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88(1):67-71.
  76. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med. 1996;334(11):682-687. 
  77. Lairikyengbam SK, Davies AG, Anderson MH. Present treatment options for unstable angina and non-Q-wave myocardial infarction. QJM. 2001;94(1):5-11. 
  78. Lecarpentier E, Gris JC, Cochery-Nouvellon E, et al. Angiogenic factor profiles in pregnant women with a history of early-onset severe preeclampsia receiving low-molecular-weight heparin prophylaxis. Obstet Gynecol. 2018;131(1):63-69.
  79. Leizorovicz A, Simonneau G, Decousus H, et al. Comparison of efficacy and safety of low-molecular-weight-heparins and unfractionated heparin in initial treatment of deep venous thrombosis: A meta-analysis. BMJ. 1994;309:299-304. 
  80. Leizorovicz A. Comparison of the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis. An updated meta-analysis. Drugs. 1996;52(Suppl 7):30-37. 
  81. Lensing AW, Prins MH, Davidson BL, et al. Treatment of deep vein thrombosis with low molecular weight heparins: A meta-analysis. Arch Intern Med. 1995;155:601-607. 
  82. LEO Pharma Inc. LEO Pharma Inc. voluntarily recalls innohep (tinzaparin sodium injection) multidose vials. February 10, 2011. Available at: http://www.leo-pharma.us/Files/Billeder/LEO_local_images/LEO-Pharma.US/10%20Feb%202011_Firm_Press_Release_LEO_Pharma_Inc.pdf. Accessed April 21, 2020.
  83. Li G, Cook DJ, Levine MA, et al; PROTECT Investigators for the Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group. Competing risk analysis for evaluation of dalteparin versus unfractionated heparin for venous thromboembolism in medical-surgical critically ill patients. Medicine (Baltimore). 2015;94(36):e1479.
  84. Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: A meta-analysis of randomized trials. J Am Soc Nephrol. 2004;15(12):3192-3206.
  85. Lu X, Lin J.  Low molecular weight heparin versus other anti-thrombotic agents for prevention of venous thromboembolic events after total hip or total knee replacement surgery: A systematic review and meta-analysis. BMC Musculoskelet Disord. 2018;19(1):322. 
  86. Lyman GH, Khorana AA, Falanga A, et al; American Society of Clinical Oncology. American Society of Clinical Oncology guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):5490-5505.
  87. Magee KD, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. Cochrane Database Syst Rev. 2008;(2):CD003462.
  88. Magee KD, Sevcik W, Moher D, Rowe BH. Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes. Cochrane Database Syst Rev. 2003;(1):CD002132.
  89. Makatsaria AD, Bitsadze VO, Dolgushina NV. Use of the low-molecular-weight heparin nadroparin during pregnancy. A review. Curr Med Res Opin. 2003;19(1):4-12.
  90. McLaughlin K, Scholten RR, Parker JD, et al. Low molecular weight heparin for the prevention of severe preeclampsia: Where next? Br J Clin Pharmacol. 2018;84(4):673-678.
  91. McNamara RL, Bass EB, Miller MR, et al. Management of new onset atrial fibrillation. Evidence Report/Technology Assessment No. 12. Rockville, MD: Agency for Healthcare Research and Quality; 2001. 
  92. Medscape. Desirudin (discontinued). Available at: https://reference.medscape.com/drug/iprivask-desirudin-999485. Accessed April 21, 2020.
  93. Menon V, Harrington RA, Hochman JS, et al. Thrombolysis and adjunctive therapy in acute myocardial infarction: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):549S-575S.
  94. Mujika N, Bermejo MC, Capellan JF, Dorronsoro S. Low molecular weight heparins versus traditional heparins in thromboembolic diseases [summary]. D-02-08. Vitoria-Gasteiz, Spain: Basque Office for Health Technology Assessment, Health Department Basque Government (OSTEBA); 2003.
  95. Mylan Institutional LLC. Arixtra - fondaparinux sodium injection, solution. Package Insert. Rockford, IL: Mylan; revised December 2019.
  96. National Horizon Scanning Centre (NHSC). Fondaparinux for venous thromboembolism - horizon scanning review. Birmingham, UK: National Horizon Scanning Centre (NHSC); 2001.
  97. National Horizon Scanning Centre (NHSC). Idraparinux sodium for prevention of stroke in patients with atrial fibrillation - horizon scanning review. Birmingham, UK: National Horizon Scanning Centre (NHSC); 2004.
  98. Nelson-Piercy C, Letsky EA, de Swiet M. Low-molecular-weight heparin for obstetric thromboprophylaxis: Experience of sixty-nine pregnancies in sixty-one women at high risk. Am J Obst Gynecol. 1997;176(5):1062-1068. 
  99. Neumann I, Rada G, Claro JC, et al. Oral direct factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: A systematic review and meta-analysis. Ann Intern Med. 2012;156(10):710-719.
  100. Nicholson T, Milne R, Stein K. Dalteparin and enoxaparin for unstable angina and non-Q-wave myocardial infarction: Update. Development and Evaluation Committee (DEC) Report No. 108. Southampton, UK: Wessex Institute for Health Research and Development (WIHRD); 2000.
  101. Nicholson T, Stein K. Low molecular weight heparins (dalteparin and enoxaparin) compared with unfractionated heparin for unstable angina and non-Q-wave myocardial infarction. DEC Report No. 93. Southampton, UK: Wessex Institute for Health Research and Development (WIHRD); 1999.
  102. Nurmohamed MT, ten Cate H, ten Cate JW. Low molecular weight heparin(oid)s. Clinical investigations and practical recommendations. Drugs. 1997;53(5):736-751. 
  103. Oates-Whitehead RM, D'Angelo A, Mol B. Anticoagulant and aspirin prophylaxis for preventing thromboembolism after major gynaecological surgery. Cochrane Database Syst Rev. 2003;(4):CD003679.
  104. O'Carroll CB, Capampangan DJ, Aguilar MI, et al. What is the effect of low-molecular weight heparin for venous thromboembolism prophylaxis compared with mechanical methods, on the occurrence of hemorrhagic and venous thromboembolic complications in patients with intracerebral hemorrhage? A critically appraised topic. Neurologist. 2011;17(4):232-235.
  105. Othieno R, Abu Affan M, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev. 2007;(3):CD003076.
  106. Paciaroni M, Agnelli G, Micheli S, Caso V. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: A meta-analysis of randomized controlled trials. Stroke. 2007;38(2):423-430.
  107. Pagliari D, Cianci R, Brizi MG, et al. Anticoagulant therapy in the treatment of splanchnic vein thrombosis associated to acute pancreatitis: A 3-year single-centre experience. Intern Emerg Med. 2020 Jan 8 [Epub ahead of print].
  108. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-423.
  109. Pfizer Inc. Fragmin - dalteparin sodium injection. Prescribing Information. New York, NY: Pfizer; revised May 2019.
  110. Pichon Riviere A, Augustovski F, Cernadas C, et al. Low molecular weight heparin in vein thrombosis. Report IRR No. 13. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2003.
  111. Pineo GF, Hull RD. Low-molecular-weight heparin: Prophylaxis and treatment of venous thromboembolism. Annu Rev Med. 1997;48:79-91. 
  112. Purcell H, Fox KM. Current roles and future possibilities for low-molecular-weight heparins in unstable angina. Eur Heart J. 1998;19 Suppl K:K18-K23. 
  113. Qari M, Abdel-Razeq H, Alzeer A, et al. Recent advances in the diagnosis and treatment of deep vein thrombosis: A regional consensus. Curr Opin Investig Drugs. 2003;4(3):309-315.
  114. Qiu Q, Li GJ, Tang L, et al. The efficacy of low molecular weight heparin in severe acute pancreatitis: A systematic review and meta-analysis of randomized controlled trials. J Dig Dis. 201920(10):512-522.
  115. Ramos J, Perrotta C, Badariotti G, Berenstein G. Interventions for preventing venous thromboembolism in adults undergoing knee athroscopy. Cochrane Database Syst Rev. 2007;(2):CD005259.
  116. Rasmussen MS, Jørgensen LN, Wille-Jørgensen P. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2009;(1):CD004318.
  117. Riva N, Donadini MP, Dentali F, et al. Clinical approach to splanchnic vein thrombosis: Risk factors and treatment. Thromb Res. 2012;130 Suppl 1:S1-S3.
  118. Rodger MA, Carrier M, Le Gal G, et al; Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications Study Group. Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood. 2014;123(6):822-828.
  119. Sandercock P, Counsell C, Tseng M. Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke. Cochrane Database Syst Rev. 2008;(3):CD000119.
  120. Savofi-Aventis U.S. LLC. Lovenox (enoxaparin sodium injection), for subcutaneous and intraveous use. Prescribing Information. Bridgewater, NJ; revised December 2018.
  121. Schleussner E, Kamin G, Seliger G, et al; ETHIG II group. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: A multicenter trial with a minimization randomization scheme. Ann Intern Med. 2015;162(9):601-609.
  122. Schmidt GA, Mandel J. Evaluation and management of severe sepsis and septic shock in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2016.
  123. Scoble T, Wijetilleka S, Khamashta MA. Management of refractory anti-phospholipid syndrome. Autoimmun Rev. 2011;10(11):669-673.
  124. Segal JB, Eng J, Jenckes MW, et al. Diagnosis and treatment of deep venous thrombosis and pulmonary embolism. Evidence Report/Technology Assessment 68. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2003. 
  125. Shorr AF, Jackson WL, Sherner JH, Moores LK. Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: A metaanalysis. Chest. 2008;133(1):149-155.
  126. Shukla VK, Otten N. Low molecular weight heparins for major orthopedic surgery: A case for clinical outcomes - summary. Technology Overview Issue 2. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1998.
  127. Singh S, Bahekar A, Molnar J, et al. Adjunctive low molecular weight heparin during fibrinolytic therapy in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized control trials. Clin Cardiol. 2009;32(7):358-364.
  128. Siristatidis C, Dafopoulos K, Salamalekis G, et al. Administration of low-molecular-weight heparin in patients with two or more unsuccessful IVF/ICSI cycles: A multicenter cohort study. Gynecol Endocrinol. 2018;34(9):747-751.
  129. Skeith L, Carrier M, Kaaja R, et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood. 2016;127(13):1650-1655.
  130. Sun G, Wu J, Wang Q, et al. Factor Xa inhibitors and direct thrombin inhibitors versus low-molecular-weight heparin for thromboprophylaxis after total hip or total knee arthroplasty: A systematic review and meta-analysis. J Arthroplasty. 2019;34(4):789-800.
  131. Sundaram V, Barsam A, Virgili G. Intravitreal low molecular weight heparin and 5-Fluorouracil for the prevention of proliferative vitreoretinopathy following retinal reattachment surgery. Cochrane Database Syst Rev. 2013;1:CD006421.
  132. Swedish Council on Technology Assessment in Health Care (SBU). Fondaparinux (Arixtra) - prevention of venous thromboembolism after orthopedic surgery (Alert). Stockholm, Sweden; SBU; 2004.
  133. Testroote M, Stigter WA, Janssen L, Janzing HM. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization. Cochrane Database Syst Rev. 2014;(4):CD006681.
  134. The Medicines Company. Angiomax (bivalirudin) for injection, for intravenous use. Prescribing Information. Parsippany, NJ: The Medicines Company; revised March 2016.
  135. Tooher R, Gates S, Dowswell T, Davis L. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2010;(5):CD001689.
  136. Tulandi T, Al-Fozan HM. Management of couples with recurrent pregnancy loss. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2016.
  137. Turpie AG. Management of acute coronary syndromes with low molecular weight heparin: TIMI 11A and 11B. Can J Cardiol. 1998;14 Suppl E:20E-23E. 
  138. U.S. Food and Drug Administration (FDA). Innohep (tinzaparin sodium injection). Celgene. MedWatch Safety Alerts for Human Medicinal Products. Silver Spring, MD: FDA; 2009. Available at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Innohep. Accessed April 2, 2009.
  139. Valentine KA, Hull RD. Therapeutic use of heparin and low molecular weight heparin. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2014.
  140. Valeriani E, Riva N, Di Nisio M, Ageno W. Splanchnic vein thrombosis: Current perspectives. Vasc Health Risk Manag. 2019;15:449-461.
  141. van der Heijden JF, Hutten BA, Büller HR, Prins MH. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev. 2001;(3):CD002001.
  142. van Dongen CJ, MacGillavry MR, Prins MH. Once versus twice daily LMWH for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2005;(3):CD003074.
  143. van Dongen CJJ, van den Belt AGM, Prins MH, Lensing AWA. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2004;(4):CD001100.
  144. van Zuuren EJ, Fedorowicz Z. Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. Cochrane Database Syst Rev. 2013;6:CD010155.
  145. van Zuuren EJ, Fedorowicz Z. Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. Cochrane Database Syst Rev. 2015;12:CD010155.
  146. Vardi M, Zittan E, Bitterman H. Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2009;(4):CD006771.
  147. Vege SS. Management of acute pancreatitis. UpToDate Inc., Waltham, MA. Last reviewed February 2020.
  148. Velmahos GC, Kern J, Chan L, et al. Prevention of venous thromboembolism after injury. Evidence Report/Technology Assessment No. 22. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2000.
  149. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335. 
  150. Wigley FM, Flavahan NA. Raynaud's phenomenon. N Engl J Med. 2016;375(6):556-565.
  151. Wigley FM. Treatment of the Raynaud phenomenon resistant to initial therapy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2017.
  152. Wilbur J, Shian B. Deep venous thrombosis and pulmonary embolism: Current therapy. American Family Physicians. 2017;95(5):295-302.
  153. Xia ZN, Zhou Q, Zhu W, Weng XS. Low molecular weight heparin for the prevention of deep venous thrombosis after total knee arthroplasty: A systematic review and meta-analysis. Int J Surg. 2018;54(Pt A):265-275.
  154. Zarychanski R, Abou-Setta AM, Kanji S, et al; Canadian Critical Care Trials Group. The efficacy and safety of heparin in patients with sepsis: A systematic review and metaanalysis. Crit Care Med. 2015;43(3):511-518.
  155. Zee AA, van Lieshout K, van der Heide M, et al. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-limb immobilization. Cochrane Database Syst Rev. 2017;8:CD006681.
  156. Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: A systematic review and meta-analysis. Obstet Gynecol. 2010;115(6):1256-1262.

Pediatric Indications

  1. David M, Andrew M. Venous thromboembolism complications in children: A critical review of the literature. J Pediatr. 1993;123:337-346. 
  2. Johnson MC, Parkerson N, Ward S, de Alarcon PA. Pediatric sinovenous thrombosis. J Pediatr Hematol Oncol. 2003;25(4):312-315.
  3. Klaassen ILM, Sol JJ, Suijker MH, et al. Are low-molecular-weight heparins safe and effective in children? A systematic review. Blood Rev. 2019;33:33-42.
  4. Merkel N, Gunther G, Schobess R. Long-term treatment of thrombosis with enoxaparin in pediatric and adolescent patients. Acta Haematol. 2006;115(3-4):230-236.
  5. Monagel P, Andrew M, Halton J, et al. Homozygous protein C deficiency: Description of a new mutation and successful treatment with low molecular weight heparin. Thromb Haemost. 1998;79(4):756-761. 
  6. Monagle P, Chan A, Massicotte P, et al. Antithrombotic therapy in children: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):645S-687S.
  7. No authors listed.  Proceedings of the American College of Chest Physicians 5th Consensus on Antithrombotic Therapy. 1998. Chest. 1998;114(5 Suppl):439S-769S. 
  8. Rimensberger PC, Humbert JR, Beghetti M. Management of preterm infants with intracardiac thrombi: Use of thrombolytic agents.  Paediatr Drugs. 2001;3(12):883-898. 
  9. Shah UK, Jubelirer TF, Fish JD, Elden LM. A caution regarding the use of low-molecular weight heparin in pediatric otogenic lateral sinus thrombosis. Int J Pediatr Otorhinolaryngol. 2007;71(2):347-351.
  10. Streif W. Venous thromboembolic events in pediatric patients. Diagnosis and management. Hematol Oncol Clin North Am. 1998;12(6):1283-1312, vii. 
  11. van Boven HH, Lane DA. Antithrombin and its inherited deficiency states. Semin Hematol. 1997;34:188-204. 

Desirudin (Iprivask)

  1. Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin. Results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am. 1997b;79(3):326-333.
  2. Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med. 1997a;337(19):1329-1335.
  3. Lepor NE. Anticoagulation for acute coronary syndromes: From heparin to direct thrombin inhibitors. Rev Cardiovasc Med. 2007;8 Suppl 3:S9-S17.
  4. Maegdefessel L, Linde T, Michel T, et al. Argatroban and bivalirudin compared to unfractionated heparin in preventing thrombus formation on mechanical heart valves. Results of an in-vitro study. Thromb Haemost. 2009;101(6):1163-1169.
  5. Marathon Pharmaceuticals, LLC. Iprivask 15 mg (desirudin for injection), for subcutaneous injection. Prescribing Information. Northbrook, IL: Marathon Pharmaceuticals; revised November 2014.
  6. Massart D, Sohawon S, Noordally O. Medicinal leeches. Rev Med Brux. 2009;30(5):533-536.
  7. Nafziger AN, Bertino JS Jr. Desirudin dosing and monitoring in moderate renal impairment. J Clin Pharmacol. 2010;50(6):614-622.
  8. Rupprecht HJ. Direct thrombin inhibitors in patients with mechanical heart valves: Ready for clinical trials? Thromb Haemost. 2009;101(6):995-996.
  9. Salazar CA, Malaga G, Malasquez G. Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement. Cochrane Database Syst Rev. 2010;4:CD005981.
  10. Sansone JM, del Rio AM, Anderson PA. The prevalence of and specific risk factors for venous thromboembolic disease following elective spine surgery. J Bone Joint Surg Am. 2010;92(2):304-313.
  11. Trujillo TC. Emerging anticoagulants for venous thromboembolism prevention. Am J Health Syst Pharm. 2010;67(10 Suppl 6):S17-S25.

Argatroban (Argatroban Injection)

  1. Asanuma K, Wakabayashi H, Okamoto T, et al. The thrombin inhibitor, argatroban, inhibits breast cancer metastasis to bone. Breast Cancer. 2013;20(3):241-246.
  2. Barreto AD, Ford GA, Shen L, et al; ARTSS-2 Investigators. Randomized, multicenter trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke). Stroke. 2017;48(6):1608-1616.
  3. Blum EC, Martz CR, Selektor Y, et al. Anticoagulation of percutaneous ventricular assist device using argatroban-based purge solution: A case series. J Pharm Pract. 2018;31(5):514-518.
  4. Cruz-Gonzalez I, Lopez-Jimenez R, Perez-Rivera A, Yan BP. Pharmacokinetic evaluation of argatroban for the treatment of acute coronary syndrome. Expert Opin Drug Metab Toxicol. 2012;8(11):1483-1493.
  5. Ishibashi H, Koide M, Obara S, et al. High-dose argatroban therapy for stroke: Novel treatment for delayed treatment and the recanalization mechanism. J Stroke Cerebrovasc Dis. 2013;22(5):656-660.
  6. Li G, Fan RM, Chen JL, et al. Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral hemorrhage. Clin Exp Immunol. 2014;175(2):285-295.
  7. Menk M, Briem P, Weiss B, et al. Efficacy and safety of argatroban in patients with acute respiratory distress syndrome and extracorporeal lung support. Ann Intensive Care. 2017;7(1):82.
  8. Nishi R, Mano T, Kobayashi Y, et al. Argatroban, aspirin, and clopidogrel combination therapy for acute penetrating artery infarction: A pilot study. Brain Nerve. 2016;68(2):181-189.
  9. Sun H, Cao D, Wu H, et al. Development of low molecular weight heparin based nanoparticles for metastatic breast cancer therapy. Int J Biol Macromol. 2018;112:343-355.
  10. Wada T, Yasunaga H, Horiguchi H, et al. Outcomes of argatroban treatment in patients with atherothrombotic stroke: Observational nationwide study in Japan. Stroke. 2016;47(2):471-476.
  11. Zeng Q, Fu QN, Li FH, et al. Early initiation of argatroban therapy in the management of acute superior mesenteric venous thrombosis. Exp Ther Med. 2017;13(4):1526-1534.
  12. Zhou L, Liu D, Li Y, et al. Argatroban for preventing occlusion and restenosis after extracranial artery stenting. Eur Neurol. 2014;71(5-6):319-325.