1. Aetna considers the use of low-molecular-weight heparins (LMWHs) medically necessary in certain clinical settings in which they have been found to offer an improved efficacy/safety ratio over standard unfractionated heparins (UFHs).  Consistent with the Medical/Scientific Statements of the American Heart Association and the American Society of Clinical Oncology, Aetna considers LMWHs medically necessary for the following indications:
   
   
   1. For the prevention of venous thromboembolism for any of the following:
      
      
      • Acute multiple trauma; or
      • Acute spinal cord injury; or
      • Acute thrombotic stroke; or
      • Hip surgery including replacement and hip fracture surgery (for up to 1 month post-operatively); or
      • Knee arthroscopy subjects undergoing meniscectomy; or
      • Knee replacement surgery (for up to 2 weeks post-operatively); or
      • Members over the age of 65 who are at high-risk for venous thrombo-embolism (VTE) due to clinical risk factors such as a history of deep venous thrombosis or pulmonary embolism, congestive heart failure, or chest infections; or

      • Members undergoing major abdominal or thoracic surgery who are at high-risk for VTE due to presence of a malignancy or a history of deep venous thrombosis or pulmonary embolism (for up to 2 weeks post-operatively).

   2. For the treatment of venous thrombosis and prophylaxis of the extension of venous thrombosis and/or the prevention of thromboembolism when inpatient care can be diverted to the home setting by using LMWHs since they require less monitoring and less complicated delivery systems;

   3. In accordance with American College of Obstetricians and Gynecologists' Committee Opinion, for thromboprophylaxis in pregnant women with thrombophilic disorders, and for treatment in pregnant women with VTE (i.e., venous thrombosis, pulmonary embolism);

   4. Anti-coagulation of pregnant women with a prosthetic heart valve (consistent with 7th ACCP Consensus Conference on Antithrombotic Therapy (2004);

   5. For unstable angina/non-Q-wave myocardial infarction;

   6. 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;

   7. 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).

   8. 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).

   9. For thromboprophylaxis in persons with multiple myeloma receiving thalidomide or lenalidomide who are at high-risk of VTE (see Appendix).

2. Aetna considers LMWHs experimental and investigational for all other indications, including in any of the following clinical settings, because the current medical literature does not provide enough scientific evidence that their use is associated with better health outcomes as compared to UFHs:

   • Arterial thrombosis; or
   • Femoral-popliteal graft patency; or
   • Members requiring anti-coagulation for hemodialysis; or
   • Members undergoing cerebral, ocular, or spinal surgery (intermittent pneumatic compression of the legs is indicated); or
   • Members with relatively low-risk for VTE undergoing general surgical procedures; or
   • Prevention of re-stenosis following coronary angioplasty; or
   • Recurrent miscarriage; or
   • Remission induction in persons with ulcerative colitis; or
   • Symptomatic pulmonary embolism; or
   • Treatment of acute heparin-induced thrombocytopenia.

Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep), fondaparinux (Arixtra), and danaparoid (Orgaran) are the low-molecular-weight heparins (LMWHs)/low-molecular weight heparinoid currently in use.  While LMWHs should replace unfractionated heparin (UFH) for preventing thromboembolism in certain clinical settings, some unresolved issues remain to be addressed in specific trials before LMWHs can generally replace UFH for all indications.  Clinical trials have enabled the evaluation of the principal roles that standard UFHs or LMWHs play in clinical practice.  Although the anti-thrombotic efficacy and safety of LMWHs are at least equal to that of UFHs, the medical literature supports their use over UFHs only in certain clinical settings.

In December 2008, Celgene issued a Dear Healthcare Professional letter describing a controlled clinical study suggesting that Innohep may increase the risk for death, compared to UFH when used to treat elderly patients with renal insufficiency.  It recommended consideration of alternatives to Innohep when treating these patients for deep vein thrombosis (DVT) with or without pulmonary embolism (PE).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In a Cochrane review, Chande et al (2010) reviewed randomized trials examining the efficacy of UFH or LMWH for remission induction in patients with ulcerative colitis (UC).  The MEDLINE (PUBMED), and EMBASE databases, the Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on UC, and references from identified papers were searched up to June 2010 in an effort to identify all randomized trials studying UFH or LMWH use in patients with UC.  Abstracts from major gastro-enterological meetings were searched to identify research published in abstract form only.  Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above.  The Cochrane Risk of Bias tool was used to assess study quality.  Studies published in abstract form only were included if the authors could be contacted for further information.  A data extraction form was developed and used to extract data from included studies.  At least 2 authors independently extracted data.  Any disagreements were resolved by consensus.  Data were analyzed on an intention-to-treat basis.  The primary outcome was induction of remission, as defined by the studies.  Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy).  Low-molecular-weight heparin administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement.  High-dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (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.

Appendix

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

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

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

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

Source: Palumbo et al, 2008.