Low-Molecular-Weight Heparins and Thrombin Inhibitors

Number: 0346

Policy

1. Aetna considers the use of low-molecular-weight heparins (LMWHs) medically necessary in certain clinical settings in which they have been found to offer an improved efficacy/safety ratio over standard unfractionated heparins (UFHs).  Consistent with the Medical/Scientific Statements of the American Heart Association and the American Society of Clinical Oncology, Aetna considers LMWHs medically necessary for the following indications:
    
   1. For the prevention of venous thromboembolism for any of the following:
       
      • Acute multiple trauma; or
      • Acute spinal cord injury; or
      • Acute thrombotic stroke; or
      • Hip surgery including replacement and hip fracture surgery (for up to 35 days 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
   • Metastatic breast cancer (using LMWH-based nanoparticles); or
   • Metastatic synovial sarcoma, or
   • Prevention of preeclampsia; or
   • Prevention of proliferative vitreo-retinopathy following retinal re-attachment surgery); or
   • Prevention of re-stenosis following coronary angioplasty; or
   • Raynaud's phenomenon; or
   • Recurrent miscarriage; or
   • Remission induction in persons with ulcerative colitis; or
   • Sepsis/septic shock; or
   • 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. Anticoagulation of percutaneous ventricular assist device
   2. Inhibition of breast cancer metastasis to bone
   3. Management of acute penetrating artery infarction
   4. Management of acute superior mesenteric venous thrombosis not meeting medical necessity criteria above
   5. Management of persons in whom long-term warfarin treatment is generally indicated and appropriate and where either LMWH has not been shown to improve health outcomes compared to warfarin, or who do not exhibit intolerance or have contraindications to warfarin and have not developed recurrent VTE while on therapeutic doses of warfarin
   6. Management of persons with acute coronary syndrome
   7. Management of persons with acute respiratory distress syndrome undergoing extracorporeal lung support
   8. Management of persons with stroke
   9. Prevention of in-stent re-stenosis after extra-cranial artery stenting
   10. Prevention of thrombosis related to long-term indwelling central venous lines in individuals with cancer.

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

Background

Low-Molecular-Weight Heparins

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

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

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

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

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

Innohep (tinzaparin sodium) is a low molecular weight heparin which exhibits antithrombotic properties. It inhibits reactions through plasma protease inhibitor, antithrombin, which is responsible for blood clotting including fibrin clots formation. It also acts as a potent co‐inhibitor of coagulation factors such as Factors Xa and IIa (thrombin).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Recurrent Pregnancy Loss:

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

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

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

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

Sepsis/Septic Shock:

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

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

Raynaud's Phenomenon:

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

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

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

Low Molecular Weight Heparin  for Metastatic Synovial Sarcoma:

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

Low Molecular Weight Heparin  for Preeclampsia Prevention:

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

McLaughlin and colleagues (2017) stated that LMWH has been extensively evaluated for the prevention of preeclampsia in high-risk pregnant women; however, the results from these trials have been conflicting.  This review discussed the potential mechanisms of action of LMWH for the prevention of severe preeclampsia, how to optimize the selection of high-risk women for participation in future trials, and the importance of trial standardization.  The authors concluded that in order to conclusively determine any benefit of LMWH, a standardized, well-powered trial investigating LMWH for prevention of early-onset preeclampsia in diligently selected women at the highest risk of this disease is needed.

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

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

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

Desirudin (Iprivask)

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

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

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

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

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

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

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

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

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

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

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

Argatroban (Argatroban Injection)

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

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

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

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

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

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

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

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

Stroke:

Acute Penetrating Artery Infarction:

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

Anticoagulation of Percutaneous Ventricular Assist Device:

Blum and colleagues (2017) noted that Impella devices are percutaneously inserted ventricular assist devices (VADs), which require a continuous purge solution that contains heparin to prevent pump thrombosis and device failure.  These researchers described 2 patients with HIT supported with an Impella device utilizing an argatroban-based purge solution.  Case 1 involved an 83-year old woman with bi-ventricular failure that resulted in right ventricle Impella support.  The purge solution was changed to include argatroban due to concern of device clotting in the setting of HIT.  Case 2 involved a 55-year old man with worsening cardiogenic shock which resulted in left ventricle Impella support.  Due to decreased purge flow rates and concerns for clotting, argatroban was added to the purge solution.  Both patients' total argatroban regimens were monitored and adjusted by pharmacy, resulting in therapeutic anticoagulation without any major bleeding or thrombotic events.  Subsequently, a protocol was designed and implemented.  The authors concluded that these case reports appeared to demonstrate the safe and effective use of argatroban purge solutions for the necessary anticoagulation with an Impella device.  Moreover, they stated that further studies are needed to confirm these findings and determine the optimal dosing regimen.

Management of Acute Superior Mesenteric Venous Thrombosis:

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

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

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

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

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

Appendix

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

• Concurrent administration of high-dose dexamethasone or doxorubicin; or

• Presence of 2 or more of the following VTE risk factors:

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

Source: Palumbo et al, 2008.

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

Table: Lovenox Dosage According to Indication:

Adjust dose for persons with renal impairment.

Obese patients: Treatment or prophylaxis using Lovenox, the ACCP Clinical Practice Guidelines recommend weight‐based dosing. (Grade 2C)

Source: FDA, 2015.

Table: Fragmin Dosing by Indication

25,0000 U/mL is only available by multiple‐dose vial. Multiple‐dose vial: after first penetration of the rubber stopper, vial should be stored at room temperature and could be used up to 2 weeks (Discard unused solution after 2 weeks).

Source: FDA, 2015.

Innohep Dosing:

The recommended dose of Innohep for the treatment of DVT with or without PE is 175 anti-Xa IU/kg of body weight, administered SC once daily for at least 6 days and until the patient is adequately anticoagulated with warfarin (INR at least 2.0 for two consecutive days). To calculate the volume (mL) of an Innohep 175 anti-Xa IU per kg SC dose for treatment of deep vein thrombosis: Patient weight (kg) X 0.00875 mL/kg = volume to be administered (mL) subcutaneously.

Arixtra Dosing:

• Deep Vein Thrombosis Prophylaxis Following Hip Fracture, or Hip or Knee Replacement Surgeries: In patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily. After hemostasis has been established, the initial dose should be given 6 to 8 hours after surgery. Administration before 6 hours after surgery has been associated with an increased risk of major bleeding. The usual duration of administration is 5 to 9 days, and up to 11 days administration has been tolerated. In patients undergoing hip fracture surgery, an extended prophylaxis course of up to 24 additional days is recommended. In patients undergoing hip fracture surgery, a total of 32 days (peri-operative and extended prophylaxis) has been tolerated.

• Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery: In patients undergoing abdominal surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily. After hemostasis has been established, the initial dose should be given 6 to 8 hours after surgery. Administration before 6 hours after surgery has been associated with an increased risk of major bleeding. The usual duration of administration is 5 to 9 days, and up to 10 days of ARIXTRA injection has been administered.

• Deep Vein Thrombosis and Pulmonary Embolism Treatment: In patients with acute symptomatic DVT and in patients with acute symptomatic PE the recommended dose of ARIXTRA is 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg) or 10 mg (body weight >100 kg) by subcutaneous injection once daily (ARIXTRA treatment regimen). ARIXTRA injection treatment should be continued for a least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2.0 to 3.0). Concomitant treatment with warfarin sodium should be initiated as soon as possible, usually within 72 hours. The usual duration of administration of ARIXTRA is 5 to 9 days; up to 26 days of ARIXTRA injection has been administered.

• Obese patients: For patients with VTE and body weight > 100 kg, a treatment dose of 10 mg daily SC is recommended over the 7.5 mg dose (Grade 2C)

The above policy is based on the following references: