Low-Molecular-Weight Heparins and Thrombin Inhibitors

Number: 0346

  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:
      • Acute multiple trauma; or
      • Acute spinal cord injury; or
      • Acute thrombotic stroke; or
      • Hip surgery including replacement and hip fracture surgery (for up to 1 month post-operatively); or
      • Knee arthroscopy subjects undergoing meniscectomy; or
      • Knee replacement surgery (for up to 2 weeks post-operatively); or
      • Members over the age of 65 who are at high-risk for venous thrombo-embolism (VTE) due to clinical risk factors such as a history of deep venous thrombosis or pulmonary embolism, congestive heart failure, or chest infections; or
      • Members undergoing major abdominal or 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)
    2. For the 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;
    3. 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);
    4. Anti-coagulation of pregnant women with a prosthetic heart valve (consistent with 7th ACCP Consensus Conference on Antithrombotic Therapy (2004);
    5. Persons with mechanical heart valves until stable on vitamin K antagonists;
    6. For unstable angina/non-Q-wave myocardial infarction;
    7. Consistent with the 6th ACCP Consensus Conference on Antithrombotic Therapy (2000), Aetna considers LMWHs medically necessary for pediatric members 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;
    8. 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).
    9. 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).
    10. 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
    • Prevention of proliferative vitreo-retinopathy following retinal re-attachment surgery); or
    • Prevention of re-stenosis following coronary angioplasty; or
    • Recurrent miscarriage; or
    • Remission induction in persons with ulcerative colitis; or
    • Symptomatic pulmonary embolism; or
    • Treatment of acute heparin-induced thrombocytopenia; or
    • Treatment of vaso-occlusive crises in members with sickle cell disease.
  3. Aetna considers desirudin (Iprivask) in the outpatient setting medically necessary for prevention of deep vein thrombosis in individuals undergoing elective hip replacement surgery. 

    Aetna considers desirudin experimental and investigational for the following indications (not an all-inclusive list)

    1. 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
    2. Management of persons undergoing elective spine surgery
    3. Management of persons with acute coronary syndrome
    4. Management of persons with mechanical heart valves
    5. Management of persons with severe renal failure
    6. Management of women with 2 or more miscarriages but without antiphospolipid antibodies (APLA) or thrombophilia
    7. Prophylaxis and treatment of thrombosis in persons who have or are at risk for heparin-induced thrombocytopenia (HIT)
    8. Switching from unfractionated heparin (UFH) to treat persons with HIT
    9. To prevent thrombosis related to long-term indwelling central venous lines in individuals with cancer
  4. 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.

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

    1. Inhibition of breast cancer metastasis to bone
    2. 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
    3. Management of persons with acute coronary syndrome
    4. Management of persons with stroke
    5. Prevention of in-stent re-stenosis after extra-cranial artery stenting
    6. 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:


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 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.

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).

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 a recent 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, 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 include (i) all hospitalized cancer patients should be considered for VTE prophylaxis with anti-coagulants in the absence of bleeding or other contraindications; (ii) routine prophylaxis of ambulatory cancer patients with anti-coagulation is not recommended, with the exception of patients receiving thalidomide or lenalidomide; (iii) patients undergoing major surgery for malignant disease should be considered for pharmacologic thromboprophylaxis; (iv) LMWH represents the preferred agent for both the initial and continuing treatment of cancer patients with established VTE; and (v) the impact of anti-coagulants on cancer patient survival requires additional study and can not be recommended at present.

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 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) (, ( 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.

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 activated partial thromboplastin time (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 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.

Argatroban (Argatroban Injection):

Argatroban is indicated as an anti-coagulant for (i) prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia, and (ii) 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.

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.


Table : 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.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015 :
Other CPT codes related to the CPB:
27130 Arthroplasty, acetabular and proximal femoral prosthetic replacement (total hip arthroplasty), with or without autograft or 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
33010 - 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
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
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
I87.8 - I87.9
I99.8 - I99.9
Other and unspecified disorders of circulatory system
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+
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:
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
I74.01 - I74.9 Arterial embolism and thrombosis
K51.00 - K51.919 Ulcerative Colitis
O26.20 - O26.23 Pregnancy care of habitual aborter
Z98.61 Coronary angioplasty status
Desirudin (Iprivask):
No specific code
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
Other CPT codes related to the CPB:
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:
C9121 Injection, argatroban, per 5 mg
ICD-10 codes covered if selection criteria are met:
D75.82 Heparin induced thrombocytopenia (HIT)
I63.30 - I63.39 Cerebral thrombosis
ICD-10 codes not covered for indications listed in CPB (not all-inclusive):
C00.0 - C96.9 Malignant neoplasms
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]
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]

The above policy is based on the following references:
    1. 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. 
    2. Hirsh J, MD; Fuster V. AHA Medical/Scientific Statement: Guide to Anticoagulant Therapy Part 1: Heparin. Circulation. 1994;89:1449-1468. 
    3. 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. 
    4. Pineo GF, Hull RD. Low-molecular-weight heparin: Prophylaxis and treatment of venous thromboembolism. Annu Rev Med. 1997;48:79-91. 
    5. 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. 
    6. 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. 
    7. 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. 
    8. 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. 
    9. 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. 
    10. Bounameaux H, Goldhaber SZ. Uses of low-molecular-weight heparin. Blood Rev. 1995;9(4):213-219. 
    11. 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. 
    12. 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. 
    13. 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. 
    14. 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. 
    15. 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. 
    16. 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. 
    17. ACOG Committee Opinion. Anticoagulation with low-molecular-weight heparin during pregnancy. Number 211, November 1998 
    18. 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. 
    19. 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. 
    20. 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. 
    21. 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. 
    22. 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. 
    23. Choussat R, Montalescot G. Low molecular weight heparin in unstable angina and myocardial infarction without Q wave. Presse Med. 1999;28(21):1128-1134. 
    24. 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. 
    25. 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. 
    26. 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. 
    27. 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. 
    28. Fox KA, Antman EM. Treatment options in unstable angina: A clinical update. Eur Heart J. 1998;19 Suppl K:K8-K10.
    29. 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.
    30. 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. 
    31. 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.
    32. 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.
    33. 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.
    34. National Horizon Scanning Centre (NHSC). Fondaparinux for venous thromboembolism - horizon scanning review. Birmingham, UK: National Horizon Scanning Centre (NHSC); 2001.
    35. 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.
    36. Colwell CW Jr. Low molecular weight heparin prophylaxis in total knee arthroplasty: The answer. Clin Orthop. 2001;(392):245-248. 
    37. 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. 
    38. Hague WM, North RA, Gallus AS, et al. Anticoagulation in pregnancy and the puerperium. Med J Aust. 2001;175(5):258-263. 
    39. Almeda FQ, Snell RJ, Parrillo JE. The contemporary management of acute myocardial infarction. Crit Care Clin. 2001;17(2):411-434. 
    40. Lairikyengbam SK, Davies AG, Anderson MH. Present treatment options for unstable angina and non-Q-wave myocardial infarction. QJM. 2001;94(1):5-11. 
    41. 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. 
    42. Goldhaber SZ. Unsolved issues in the treatment of pulmonary embolism. Thromb Res. 2001;103(6):V245-V255.
    43. 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.
    44. 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.
    45. 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. 
    46. 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.
    47. 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. 
    48. 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.
    49. 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.
    50. Hyers TM. Management of venous thromboembolism: Past, present, and future.  Arch Intern Med. 2003;163(7):759-768.
    51. 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.
    52. 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.
    53. 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.
    54. 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.
    55. 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.
    56. 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.
    57. Ageno W, Crotti S, Turpie AG. The safety of antithrombotic therapy during pregnancy. Expert Opin Drug Saf. 2004;3(2):113-118.
    58. 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.
    59. 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.
    60. 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.
    61. Danchin N, Benedetti ED, Urban P. Acute myocardial infarction. In: Clinical Evidence, Issue 12. London, UK: BMJ Publishing Group; December 2004.
    62. Swedish Council on Technology Assessment in Health Care (SBU). Fondaparinux (Arixtra) - prevention of venous thromboembolism after orthopedic surgery (Alert). Stockholm, Sweden; SBU; 2004.
    63. 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.
    64. Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2004;(2):CD000024.
    65. Dörffler-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.
    66. 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.
    67. 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.
    68. 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.
    69. 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.
    70. Colwell CW Jr; Annenberg Center for Health Sciences and Quadrant Medical Education. Thromboprophylaxis in orthopedic surgery. Am J Orthop. 2006;Suppl:1-9.
    71. 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.
    72. 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.
    73. 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.
    74. 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. 
    75. 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.
    76. 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.
    77. Di Nisio M, Wichers IM, Middeldorp S. Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev. 2007;(2):CD004982.
    78. 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.
    79. Othieno R, Abu Affan M, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev. 2007;(3):CD003076.
    80. 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.
    81. Magee KD, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. Cochrane Database Syst Rev. 2008;(2):CD003462.
    82. 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.
    83. 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.
    84. 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.
    85. 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.
    86. 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.
    87. 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.
    88. Celgene. Innohep (tinzaparin sodium injection). Available at: Accessed April 2, 2009.
    89. 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.
    90. Hull RD. Thromboprophylaxis in knee arthroscopy patients: Revisiting values and preferences. Ann Intern Med. 2008;149(2):137-139.
    91. 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.
    92. 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.
    93. 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.
    94. Vardi M, Zittan E, Bitterman H. Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2009;(4):CD006771.
    95. 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.
    96. 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.
    97. Greer IA. Antithrombotic therapy for recurrent miscarriage? N Engl J Med. 2010;362(17):1630-1631.
    98. 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.
    99. 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.
    100. 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.
    101. 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.
    102. Scoble T, Wijetilleka S, Khamashta MA. Management of refractory anti-phospholipid syndrome. Autoimmun Rev. 2011;10(11):669-673.
    103. 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.
    104. 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.
    105. 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.
    106. 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.
    107. 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.
    108. 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.
    109. 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.
    110. Valentine KA, Hull RD. Therapeutic use of heparin and low molecular weight heparin. Last reviewed January 2014. UpToDate Inc., Waltham, MA.
    111. 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.
    112. 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.

    Pediatric Indications

    1. No authors listed.  Proceedings of the American College of Chest Physicians 5th Consensus on Antithrombotic Therapy. 1998. Chest. 1998;114(5 Suppl):439S-769S. 
    2. Streif W. Venous thromboembolic events in pediatric patients. Diagnosis and management. Hematol Oncol Clin North Am. 1998;12(6):1283-1312, vii. 
    3. David M, Andrew M. Venous thromboembolism complications in children: A critical review of the literature. J Pediatr. 1993;123:337-346. 
    4. 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. 
    5. van Boven HH, Lane DA. Antithrombin and its inherited deficiency states. Semin Hematol. 1997;34:188-204. 
    6. Monagle 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;79:756-761. 
    7. Rimensberger PC, Humbert JR, Beghetti M. Management of preterm infants with intracardiac thrombi: Use of thrombolytic agents.  Paediatr Drugs. 2001;3(12):883-898. 
    8. Johnson MC, Parkerson N, Ward S, de Alarcon PA. Pediatric sinovenous thrombosis. J Pediatr Hematol Oncol. 2003;25(4):312-315.
    9. 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.
    10. 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.
    11. 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.

    Desirudin (Iprivask):

    1. 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.
    2. 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.
    3. Lepor NE. Anticoagulation for acute coronary syndromes: From heparin to direct thrombin inhibitors. Rev Cardiovasc Med. 2007;8 Suppl 3:S9-S17.
    4. Massart D, Sohawon S, Noordally O. Medicinal leeches. Rev Med Brux. 2009;30(5):533-536.
    5. 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.
    6. Rupprecht HJ. Direct thrombin inhibitors in patients with mechanical heart valves: Ready for clinical trials? Thromb Haemost. 2009;101(6):995-996.
    7. Trujillo TC. Emerging anticoagulants for venous thromboembolism prevention. Am J Health Syst Pharm. 2010;67(10 Suppl 6):S17-S25.
    8. Nafziger AN, Bertino JS Jr. Desirudin dosing and monitoring in moderate renal impairment. J Clin Pharmacol. 2010;50(6):614-622.
    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. Food and Drug Administration. Drug Approval Package: Iprivask (Desirudin) Injection. FDA: Silver Spring: MD. Available at: Accessed March 18, 2013.
    11. No authors listed. Product Insert. Iprivask® 15 mg [Desirudin for Injection]. Canyon Pharmaceuticals: Hunt Valley, MD. January 2010. Available at: Accessed March 18, 2013.
    12. 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.

    Argatroban (Argatroban Injection):

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.

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