Low-Molecular-Weight Heparins

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Low-Molecular Weight Heparin for Improvement of Pregnancy Outcomes Among Pregnant Women with Inherited Thrombophilia

In a systematic review and meta-analysis, Chen et al (2022) examined if the use of LMWH would improve the pregnancy outcomes in women with inherited thrombophilia. These investigators carried out a systematic literature search of several databases through September 19, 2020 to identify relevant studies. The outcomes of interest included live-birth and adverse pregnancy outcomes (APOs). The overall risk estimates were pooled using random-effects meta-analysis. A total of 10 RCTs and 12 cohort studies were included. In the meta-analyses of RCTs, the effectiveness of LMWH-treatment was found to be statistically significant in decreasing the risk of APOs (RR = 0.76; 95 % CI: 0.61 to 0.95; p = 0.020), rather than in increasing the rate of live-birth (RR = 1.12; 95 % CI: 0.93 to 1.34; p = 0.230). In the meta-analyses of cohort studies, results showed that the use of LMWH was associated with a significantly higher proportion of live-birth (RR = 1.86; 95 % CI: 1.09 to 3.19; p = 0.020) as well as a significantly lower ratio of APOs (RR = 0.46; 95 % CI: 0.31 to 0.69; p < 0.001) in women with inherited thrombophilia. The authors concluded that the use of LMWH may have a potentially beneficial effect on reducing the risk of APOs and even increasing the live-birth rate in women with inherited thrombophilia. Moreover, these researchers stated that further well-designed clinical trials with large samples are needed to address the role of LMWH in improving pregnancy outcomes among pregnant women with inherited thrombophilia.

Low-Molecular Weight Heparin for Lower-Leg Immobilization

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

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

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

Low-Molecular Weight Heparin for Metastatic Synovial Sarcoma

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

Low-Molecular Weight Heparin for Preeclampsia Prevention

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

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

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

Cruz-Lemini and colleagues (2021) stated that evidence on the impact of LMWH, alone or in combination with low-dose aspirin (LDA), for the prevention for pre-eclampsia (PE) in high-risk patients is conflicting. In a systematic review and meta-analysis, these researchers examined the effectiveness of LMWH for the prevention of PE and other placenta-related complications in high-risk women. They carried out a systematic search to identify relevant studies, using the databases PubMed and Cochrane Central Register of Controlled Trials, without publication time restrictions. RCTs comparing treatment with LMWH or UFH (with or without LDA), in high-risk women, defined as either history of PE, intra-uterine growth restriction (IUGR), fetal demise, or miscarriage or being at high risk after 1st-trimester screening of pre-eclampsia were selected for analysis. The systematic review was carried out according to the Cochrane Handbook guidelines. The primary outcome was the development of PE. They conducted pre-specified subgroup analyses according to combination with LDA, LMWH type, gestational age (GA) when treatment was started, and study population (patients with thrombophilia, at high risk of pre-eclampsia or miscarriage). Secondary outcomes included SGA, peri-natal death, miscarriage, and placental abruption. Pooled ORs with 95 % CIs were calculated using a random-effects model. Quality of evidence was assessed using the GRADE methodology. A total of 15 studies (2,795 participants) were included. In high-risk women, treatment with LMWH was associated with a reduction in the development of PE (OR, 0.62; 95 % CI: 0.43 to 0.90; p = 0.010); SGA (OR, 0.61; 95 % CI: 0.44 to 0.85; p = 0.003), and peri-natal death (OR, 0.49; 95 % CI: 0.25 to 0.94; p = 0.030). This reduction was stronger if LMWH was started before 16 weeks' gestation (13 studies, 2,474 participants) for PE (OR, 0.55; 95 % CI: 0.39 to 0.76; p = 0.0004). When only studies including LDA as an intervention were analyzed (6 RCTs, 920 participants), a significant reduction was observed in those with combined treatment (LMWH plus LDA) compared with LDA alone (OR, 0.62; 95 % CI: 0.41 to 0.95; p = 0.030). Overall, AEs were neither serious nor significantly different. Quality of evidence ranged from very low to moderate, mostly because of the lack of blinding, imprecision, and inconsistency. The authors concluded that LMWH reduced the incidence of PE and placenta-mediated complications in high-risk women with previous adverse obstetrical history, especially in those included for previous placental complications and when treatment was started before 16 weeks’ gestation. Combined treatment with LDA was associated with a substantial reduction in the risk of PE compared with LDA alone. However, this meta-analysis gave rise to concerns regarding the low quality of evidence available; thus, although pooled effect estimates were associated with marked PE reduction, heterogeneity (clinical and statistical) questioned the validity of this conclusion. These researchers stated that future trials examining the prevention of placental complications by LMWH in addition to LDA are needed before any clinical application is adopted.

The authors stated that the main drawback of this meta-analysis was that methodological quality of the studies ranged from moderate to very low owing to concerns regarding the risk of bias. The prediction interval of 0.24 to 1.63 indicated that although the intervention appeared to be effective, it may not be always so, in a given individual setting; thus, further research would be needed to identify the reasons for the differences in specific subgroups of patients. Furthermore, compliance of prescribed treatments was uncertain, with a number of women withdrawing their consent for participation. Sub-analyses considering the concomitant use of LDA were methodologically difficult because in some studies, LDA administration was recorded as standard of care or depended on physician prescription, with different doses used even in the same trials. Therefore, these researchers had only considered for this sub-analysis those studies where it was administered as part of the intervention or to the whole study population systematically (n = 6 RCTs) and separated those where it was not controlled as part of the study. However, these investigators recognized that an individual patient meta-analysis would be necessary to better answer if LMWH combined with LDA was better than LDA alone in reducing PE in high-risk pregnancies. These researchers were aware that some of the subgroups included patients with rare outcomes, and these analyses were restricted by the small samples. There was also a lack of detail regarding important methodological issues in some studies, substantial heterogeneity detected in the analyses, and wide CIs indicating imprecision in the results, which could question their validity. Moreover, the fact that the positive effect of heparin in preventing PE was statistically significant solely in single-center trials could indicate possible publication bias because negative results from single-center studies tend to go unpublished. Another drawback that could be argued was that heparin doses were not adjusted by anti-factor Xa levels in any of the studies; however, it has been reported that enoxaparin dose adjusted according to anti-factor Xa levels compared with a fixed dose did not change the risk of recurrence of placental complications in women with thrombophilia.

In a systematic review and meta-analysis, Zheng et al (2022) examined the safety and effectiveness of adding LMWH or unfractionated heparin to low-dose aspirin (LDA) started 16 weeks or less gestation in the prevention of PE in high-risk women. PubMed, Cochrane Library, Embase, and ClinicalTrials.gov databases were searched from their inception to April 2022 for RCTs that examined if the combined treatment of LMWH and LDA was better than single anti-coagulant drug in preventing PE and improving live-birth rate of fetus in high-risk women with pregnancy of 16 weeks or less. These investigators also searched Embase, OVID Medline and OVID Medline in-process using the OVID platform. A total of 14 RCTs entailing 1,966 women were found. The LMWH (or UFH) and LDA groups included 1,165 women, and the LDA group included 960 women. The meta-analysis showed that the addition of LMWH to LDA reduced the risk of PE (RR: 0.59, 95 % CI: 0.44 to 0.79, p < 0.05), SGA (RR: 0.71, 95 % CI: 0.52 to 0.97, p = 0.03), fetal and neonatal death (RR: 0.45, 95 % CI: 0.23 to 0.88, p = 0.02) and gestational hypertension (RR: 0.47, 95 % CI: 0.25 to 0.90, p = 0.02). It is worth emphasizing that LMWH (or UFH) combined with LDA did not increase the risk of bleeding. The authors concluded that LMWH combined with LDA could effectively improve the pregnancy outcome of women with high-risk factors for PE and its complications. Moreover, these researchers stated that although this study showed that combined medication also did not increase the risk of bleeding, such results lacked the support of large sample size studies. These investigators stated that further clinical safety analysis of LMWH combined with LDA in patients with PE should be performed.

The authors stated that this study had several drawbacks. First, the quality grades of the included studies were inconsistent. Among them, 5 studies did not adopt blind design, and the random allocation method of 2 studies was unclear. Second, because many women chose to withdraw from the trial, there was uncertainty regarding the treatment compliance of the subjects. Third, 4 of all included RCTs in recurrent miscarriage did not report whether LMWH combined with LDA could reduce the incidence of PE. Furthermore, only 3of the 14 included studies reported on intra-partum or post-partum hemorrhage, resulting in publication bias in the results. Fourth, the study did not examine the impact of long-term maternal and infant outcomes. These researchers stated that more large-sample, multi-center and long-term follow-up studies are needed to confirm the long-term impact of combined drugs on maternal and infant outcomes. Fifth, the Begg's and Egger's test results of PE showed potential publication bias, indicating that the statistical analysis results may be unstable, and it was recommended researchers should conduct studies with higher quality and more rigorous experimental design.

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

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

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

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

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

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

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

He et al (2023) noted that AP is a common disease with substantial morbidity and mortality, and its incidence has grown in recent years. Mild AP has a self-limited course and only needs supportive treatment while non-mild AP referring to moderately severe and severe AP (MSAP and SAP) is associated with local and systemic complications, notably pancreatic necrosis and organ failure, claiming the poor prognosis. MSAP is defined as AP having local complications with or without transient organ failure (less than 48 hours) while SAP is characterized by persistent organ failure (greater than 48 hours). Non-mild AP could be complicated with vascular thrombosis (e.g., splanchnic vein thrombosis, thrombosis of portal vein and superior mesenteric vein), which showed poor effect on the ultimate prognosis. Conventional therapy includes early fluid resuscitation, analgesics, enteral nutrition, and symptomatic treatment. Currently, there is a lack of effective pharmacotherapies for AP; however, in the past 10 years, there were several RCTs regarding the effects of LMWH therapy in non-mild AP, of which the results were inconsistent.

Low-Molecular Weight Heparin for Thromboprophylaxis in Hospitalized COVID-19 Patients

The American Thoracic Society (Moores, et al., 2020) recommends that all hospitalized patients with COVID-19 receive thromboprophylaxis therapy unless otherwise contraindicated. Low-molecular-weight heparin or fondaparinux should be used for thromboprophylaxis over unfractionated heparin and direct oral anticoagulants. The guidelines state that thromboprophylaxis for COVID-19 patients is not indicated in the outpatient setting.

National Institutes of Health (NIH, 2023) COVID-19 treatment guidelines state: "Guidelines for the use of antithrombotic therapy in patients with COVID-19 have been released by multiple organizations, including the American College of Chest Physicians, the American Society of Hematology, the Anticoagulation Forum, the International Society on Thrombosis and Haemostasis, the Italian Society on Thrombosis and Haemostasis, the National Institute for Health and Care Excellence (NICE), and the Royal College of Physicians. The guidelines referenced above agree that hospitalized, nonpregnant patients with COVID-19 should receive, at a minimum, a prophylactic dose of anticoagulation to prevent VTE." The NIH COVID-19 guidelines state: "• In hospitalized patients, low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) is preferred over oral anticoagulants (AIII). Because these types of heparin have shorter half-lives, their effects can be reversed quickly. They can also be administered intravenously or subcutaneously, and they have fewer drug-drug interactions than oral anticoagulants."

In a meta-analysis, Alsagaff et al (2022) compared the outcomes of the administration of LMWH and UFH in hospitalized COVID-19 patients. These investigators systematically searched several databases and included observational studies or clinical trials that compared the outcomes of the administration of LMWH and UFH in hospitalized COVID-19 patients. A total of 9 studies comprising 9,637 patients were included. Meta-analysis showed that LMWH administration was associated with a lower in-hospital mortality and 28/30-day mortality compared with UFH administration (RR 0.44; 95 % CI: 0.32 to 0.61; I2: 87.9 % and RR 0.45; 95 % CI: 0.24 to 0.86; I2: 78.4 %), respectively. Patient with LMWH had shorter duration of hospital and ICU LOS compared with UFH (weighted mean difference [WMD] -2.20; 95 % CI -3.01 to -1.40; I2: 0 % and WMD -1.41; 95 % CI: -2.20 to -0.63; I2: 0 %), respectively. The risk of ICU admission or mechanical ventilation was lower in patients who received LMWH than in those who received UFH (RR 0.67; 95 % CI: 0.55 to 0.81; I2: 67.3 %). However, there was no difference in the incidence of bleeding with LMWH compared with UFH (RR 0.27; 95 % CI: 0.07 to 1.01; I2: 64.6 %). The authors concluded that this meta-analysis showed that administration of LMWH was associated with better outcomes compared with UFH in hospitalized COVID-19 patients. Moreover, these researchers stated that prospective cohorts and RCTs are needed to examine the definitive effect of LMWH to provide direct high-certainty evidence.

The authors stated that this meta-analysis had several drawbacks. First, possible publication bias was noted in several outcomes, as well as substantial heterogeneity. Most of the included studies were retrospective, observational, which were not matched or adjusted for confounders; thus, the strength of the association could not be measured accurately. Second, the dose definition of the prophylactic or therapeutic LMWH or UFH, including the route of administration, also varied slightly across studies. Third, the presence of both prophylactic and therapeutic dosing in the studies included outcome, especially in non-critically ill COVID-19 patients. Some studies did not mention the specific type of LMWH, and not all studies provided details regarding the selection criteria for LMWH or UFH (reason for using LMWH or UFH at an individual level could not be identified), such as the use of UFH, which was the preferred choice for patients with renal dysfunction or disseminated intra-vascular coagulation. These problems may translate into uncertain effect estimates from these individual studies. Fourth, most studies also did not mention pre-existing conditions that have been anti-coagulated before admission. The definition of bleeding also varied across studies. Fifth, 1 study by Lopes et al (2021) only included hospitalized adult patients with elevated D-dimer levels.

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

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

Acute Penetrating Artery Infarction

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

Anticoagulation of Percutaneous Ventricular Assist Device

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

Management of Acute Superior Mesenteric Venous Thrombosis

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

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

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

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

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

M'Pembele et al (2022) noted that the number of patients treated with ECMO devices is increasing. Anti-coagulation therapy is crucial to prevent thrombosis during ECMO therapy. Predominantly, heparin has been used as primary anti-coagulant; however, direct thrombin inhibitors (DTI) have been established as alternatives. In a systematic review and meta-analysis, these investigators examined clinical outcomes in patients treated with heparin compared to different DTI during ECMO. They carried out a systematic search; and full scientific studies were sought for inclusion if heparin anti-coagulation was compared to DTI (argatroban/bivalirudin) in ECMO patients. Risk of bias was evaluated by Newcastle Ottawa scale. Primary endpoint was in-hospital mortality. Bleeding events, thrombotic events, hours of ECMO support, days of hospital stay, percentage of time within therapeutic range and time to therapeutic range were extracted from full texts as secondary endpoints. Results were presented as Forrest-plots; and GRADE was used for confidence assessment in outcomes. The systematic search identified 4.385 records; 18 retrospective studies (a total of 1942 patients) complied with the pre-defined eligibility criteria: 15 studies examined bivalirudin and 3 studies examined argatroban versus heparin. Risk of bias was high for most studies. In-hospital mortality, major bleeding events and pump-related thrombosis were less frequent in DTI group as compared to heparin (mortality: OR 0.69, 95 % CI: 0.54 to 0.86; major bleeding: OR 0.48, 95 % CI: 0.29 to 0.81; pump thrombosis: OR 0.55, 95 % CI: 0.40 to 0.76). Furthermore, percentage of time within therapeutic range was higher for DTI (SMD 0.54, 95 % CI: 0.14-0.94); GRADE approach revealed a very low level of certainty for each outcome. The authors concluded that in this meta-analysis, DTI and especially bivalirudin showed beneficial effects on clinical outcomes in ECMO patients as compared to heparin. However, these researchers stated that due to the lack of randomized trials, certainty of evidence was low. These researchers stated that before drawing final conclusions whether DTI are really superior to the standard therapy heparin, well-designed, prospective (randomized) studies are needed. Until these data are available, DTI may at least be regarded as a safe, effective and potentially beneficial strategy for anti-coagulation in this cohort.

The authors stated that despite promising results, this meta-analysis had several drawbacks. First, due to the lack of RCTs, which introduced high risk of bias, certainty in these findings must be regarded as very limited. These investigators tried to address reporting bias by contacting authors and requesting additional data for analysis as not all studies reported for every outcome. However, only 4 authors responded to the request; thus, a majority of data could not be included into this analysis. Of note these researchers were able to include unpublished data of a retrospective, multi-center study which complemented the existing data in this field. Second, the definitions of secondary outcomes (e.g., minor/major bleeding or patient- and pump-related thrombosis) may be different in the included studies. Third, there might be several other important factors clinicians might consider when deciding about the choice of anti-coagulation. Mortality data alone probably will not be sufficient and although several secondary endpoints have been examined, multiple other factors are still lacking. In particular, there were no data on more patient-centered outcomes such as life impact or quality of life (QOL) which became more and more important in the setting of mechanical circulatory support. Fourth, center effects, publication bias or reporting bias have to be considered when interpreting the results. Fifth, although comparing 2 DTI is a strength of this study, this may also be regarded as a drawback as the information gathered was only through comparing them via heparin as an intermediary which limited this comparison.

Raynaud's Phenomenon

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

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

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

Recurrent Pregnancy Loss

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

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

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

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

In a systematic review and meta-analysis, Jiang and colleagues (2021) examined the roles of the LMWH on RPL. The relevant studies of all RCTs were retrieved, and the systematic evaluation was carried out. PubMed, Embase, and Cochrane library databases were searched by using keywords, including low-molecular-weight heparin or LMWH, and recurrent miscarriage or recurrent pregnancy loss in pregnant women from their earliest data to February 2020; 2 investigators independently evaluated eligibility; RRs and their corresponding 95 % CIs were determined. To pool the results, this meta-analysis was performed using random-effect model due to the high heterogeneity among these 8 studies. A total of 8 RCTs entailing 1,854 subjects were included in the meta-analysis involving 963 patients with RPL who were prescribed LMWH (enoxaparin, tinzaparin, or dalteparin) alone, and 891 patients who were treated with no LMWH interventions (placebo, folic acid or non-treatment) were compared. Pooled data from the remaining 8 RCTs showed the differences between intervention groups and control groups. Compared with control groups, LMWH had significantly improved live-births (RR,1.19; 95 % CI: 1.03 to 1.38; p = 0.02), and reduced miscarriage rates (RR, 0.62; 95 % CI: 0.43 to 0.91; p = 0.01). The authors concluded that the findings of this study suggested that LMWH could improve the live-births and reduce the miscarriage rates of RPL; thus, LMWH might be a good treatment choice for women with unexplained PRL. Moreover, these researchers stated that because of the small sample sizes of currently available publications and the limitations in this study, further more high-quality studies including multiple centers and a larger number sample sizes are needed to validate the safety and effectiveness of LMWHs, and to confirm the ideal dosage and duration time of LMWH therapy for women with RPL.

The authors stated that this meta-analysis had several drawbacks. First, this systematic review and meta-analysis was based on only 8 RCTs, with different types of LMWHs, which may have different efficacies and safety profiles. Second, the ideal dosages are still unknown. There is a wide variation in the present publications for the ideal dosages of the different types of LMWHs, including fixed dosages, rising dosages as pregnancy progresses, or dosages according to the weight of women; thus, more RCTs with large sample sizes are needed to ascertain if different dosages affect outcomes and the ideal dosages for women with RPL through subgroups. Third, the characteristics of the subjects enrolled into each study were different, such as age, the beginning and duration time of using LMWHs and the precious patients’ medical histories. So far, the LMWH treatment which should be stopped at 24 to 48 hours before delivery has been regarded as appropriate, although some reports suggested 36th week of pregnancy. These investigators stated that further studies might examine the exact time when LMWH treatment should be started and stopped. Fourth, some studies were evaluated as the unclear risk of the allocation concealment, because these studies did not mention it; however, the allocation concealment might exist in the actual situations in these studies, resulting in false high risk of bias.

Sepsis / Septic Shock

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

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

Stroke

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.

Desirudin (Iprivask)

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

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

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

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

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

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

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

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

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

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

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

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

Improvement of Survival of Individuals with Cancer

Ripsman and colleagues (2020) stated that the therapeutic effects of LMWH may extend past thrombosis prevention, with pre-clinical evidence showing anti-metastatic properties. Clinical evidence on the topic, however, remains controversial. In a systematic review, these researchers examined the anti-metastatic properties of LMWHs in solid tumor animal models. Medline, Embase, Web of Science and PubMed were searched from inception to May 12, 2020. All articles were screened independently and in duplicate. Studies that compared LMWH to a placebo or no treatment arm in solid tumor animal models were included. The primary outcome was the burden of metastasis; secondary outcomes included primary tumor growth and mortality. The risk of bias was evaluated in duplicate using a modified Cochrane Risk of Bias tool. A total of 42 studies were included in the review. Administration of a LMWH was associated with a significant decrease in the burden of metastasis (standard mean difference [SMD] -2.18; 95 % CI: -2.66 to -1.70). Furthermore, the administration of a LMWH was also associated with a significant reduction in primary tumor growth (SMD -1.95; 95 % CI: -2.56 to -1.34) and risk of death (RR 0.39; 95 % CI: 0.16-0.97). All included studies were deemed to be at an unclear risk of bias for at least 1 methodological criterion. The authors concluded that these findings showed that LMWH could effectively reduce metastatic burden and reduce tumor growth in pre-clinical animal models of solid tumor malignancies. These researchers stated that reasons for the contradiction with clinical evidence require further investigations.

Montroy and associates (2020) noted that LMWH are often used as a 1st-line therapy for the prevention of thrombosis in cancer patients. Pre-clinical evidence from animal models suggested that LMWH may have anti-metastatic properties. Clinical evidence of this effect is inconclusive. In a systematic review, these investigators examined the effect of LMWH on overall survival in patients with solid tumor malignancies. Medline, Embase, and the Cochrane Central Register of Controlled trials were searched from inception to November 26, 2018. These researchers included RCTs that compared LMWH to placebo, a no-treatment arm, or a short-term prophylactic course of LMWH in adult patients with solid tumors. The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), the occurrence of VTE, and major bleeding events. The risk of bias was assessed in duplicate using the Cochrane Risk-of-Bias tool. A total of 45 articles were included in the review. Overall, no difference in OS was observed between groups (RR: 1.00; 95 % CI: 0.98 to 1.02; I2 = 36.5 %). In their a priori defined subgroup analyses, the effect was not shown to vary by the type of LMWH, duration of LMWH use, length of study follow-up, comparator used in the study, or the setting in which the LMWH was administered. The majority of studies had an unclear risk of bias for at least 1 methodological criterion. The authors concluded that although LMWH is thought to possess anti-metastatic properties and thus have the potential to improve survival in cancer patients, existing data do not support this hypothesis.

Prevention of Central Venous Catheter-Related Thrombosis in Children

Pelland-Marcotte and colleagues (2020) noted that the prevalence of children diagnosed with thrombotic events has been increasing in the last decades. The most common thrombosis risk factor in neonates, infants and children is the placement of a central venous catheter (CVC). It is unclear if anti-coagulation prophylaxis with LMWH decreases CVC-related thrombosis in children. This is an update of the Cochrane Review published in 2014. These investigators examined the effect of LMWH prophylaxis on the incidence of CVC-related thrombosis and major and minor bleeding complications in children. Additional objectives were to examine the effect of LMWH on occlusion of CVCs, number of days of CVC patency, episodes of catheter-related blood-stream infection (CRBSI), other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopenia and osteoporosis) and mortality during therapy. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialized Register, CENTRAL, Medline, Embase and CINAHL databases and World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to May 7, 2019. These investigators undertook reference checking of identified trials to identify additional studies. They included RCTs and quasi-randomized trials comparing LMWH to no prophylaxis (placebo or no treatment), or low-dose UFH either as continuous infusion or flushes (low-dose UFH aims to ensure the patency of the central line but has no systemic anti-coagulation activity), given to prevent CVC-related thrombotic events in children. These investigators selected studies conducted in children aged 0 to 18 years. Two review authors independently identified eligible studies, which were evaluated for study methodology including bias, and extracted unadjusted data where available. In the data analysis step, all outcomes were analyzed as binary or dichotomous outcomes. The effects of interventions were summarized with RR and their respective 95 % CI. These researchers examined the certainty of evidence for each outcome using the GRADE approach. One additional study was included for this update bringing the total to 2 included studies (with 1,135 subjects). Both studies were open-label RCTs comparing LMWH with low-dose UFH to prevent CVC-related thrombosis in children. These investigators identified no studies comparing LMWH with placebo or no treatment. Meta-analysis found insufficient evidence of an effect of LMWH prophylaxis in reducing the incidence of CVC-related thrombosis in children with CVC, compared to low-dose UFH (RR 0.68, 95 % CI: 0.27 to 1.75; 2 studies; 787 subjects; low-certainty evidence). One study (158 subjects) reported symptomatic and asymptomatic CVC-related thrombosis separately and detected no evidence of a difference between LMWH and low-dose UFH (RR 1.03, 95% CI 0.21 to 4.93; low-certainty evidence; RR 1.17, 95% CI 0.45 to 3.08; low-certainty evidence; for symptomatic and asymptomatic subjects, respectively). There was insufficient evidence to determine if LMWH impacted the risk of major bleeding (RR 0.27, 95 % CI: 0.05 to 1.67; 2 studies; 813 subjects; low-certainty evidence); or minor bleeding. One study reported minor bleeding in 53.3 % of subjects in the LMWH arm and in 44.7 % of subjects in the low-dose UFH arm (RR 1.20, 95 % CI: 0.91 to 1.58; 1 study; 158 subjects; very low-certainty evidence), and the other study reported no minor bleeding in either group (RR: not estimable). Mortality during the study period was reported in 1 study, where 2 deaths occurred during the study period. Both were unrelated to thrombotic events and occurred in the low-dose UFH arm. The 2nd study did not report mortality during therapy per arm but showed similar 5-year OS (low-certainty evidence). No additional adverse effects were reported. Other pre-specified outcomes (including CVC occlusion, patency and CRBSI) were not reported. The authors concluded that pooling data from 2 RCTs did not provide evidence to support the use of prophylactic LWMH for preventing CVC-related thrombosis in children (low-certainty evidence). Evidence was also insufficient to confirm or exclude a difference in the incidence of major and minor bleeding complications in the LMWH prophylaxis group compared to low-dose UFH (low and very low certainty, respectively). No evidence of a clear difference in overall mortality was observed. Studies did not report on the outcomes of catheter occlusion, days of catheter patency, episodes of CRBSI and other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopenia and osteoporosis). The certainty of the evidence was down-graded due to risk of bias of the included studies, imprecision and inconsistency, preventing conclusions with regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombosis in children.

Prevention of Microvascular Occlusion in Digital Replantation

Lin and colleagues (2020) stated that the success of digital replantation is highly dependent on the patency of the repaired vessels after microvascular anastomosis. Anti-thrombotic agents are frequently used for preventing vascular occlusion; LMWH has been reported to be as effective as UFH in peripheral vascular surgery, but with fewer adverse effects. Its benefit in microvascular surgery such as digital replantation is unclear. This is an update of the review first published in 2013 (Chen et al, 2013). These investigators examined if treatment with subcutaneous LMWH improves the salvage rate of the digits in patients with digital replantation after traumatic amputation. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialized Register, CENTRAL, Medline, Embase, AMED and CINAHL databases, and the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers, to March 17, 2020. The authors searched PubMed, China National Knowledge Infrastructure (CNKI) and Chinese Electronic Periodical Services (CEPS) on March 17, 2020 and sought additional trials from reference lists of relevant publications. They included RCTs or quasi-RCTs comparing treatment with LMWH versus any other treatment in subjects who received digital replantation following traumatic digital amputation. Two review authors independently extracted data and evaluated the risk of bias of the included trials using Cochrane's "Risk of bias" toot. Disagreements were resolved by discussion. These researchers evaluated the certainty of evidence using the GRADE approach. They included 2 new randomized trials in this update, bringing the total number of included trials to 4. They included a total of 258 subjects, with at least 273 digits, from hospitals in China; 3 studies compared LMWH versus UFH, and 1 compared LMWH versus no LMWH. The mean age of subjects ranged from 24.5 to 37.6 years. In the studies reporting the sex of subjects, there were a total of 145 men and 59 women. The certainty of the evidence was down-graded to low or very-low because all studies were at high risk of performance or reporting bias (or both) and there was imprecision in the results due to the small numbers of subjects. The 3 studies comparing LMWH versus UFH reported the success rate of replantation using different units of analysis (subject or digit), so these investigators were unable to combine data from all 3 studies (1 reported findings for both subjects and digits). No evidence of a benefit in success of replantation was found in the LMWH group when compared with UFH, regardless of whether the outcomes were reported by number of subjects (RR 0.98, 95 % CI: 0.87 to 1.10; 130 subjects, 2 studies; very-low certainty evidence); or by number of digits (RR 0.97, 95 % CI: 0.90 to 1.04; 200 digits, 2 studies; low certainty evidence). No studies reported the incidence of compromised microcirculation requiring surgical or non-surgical therapy, or any systemic/other causes of microvascular insufficiency. There was no evidence of a clear difference between the LMWH and UFH groups in occurrence of arterial occlusion (RR 1.08, 95 % CI: 0.16 to 7.10; 54 subjects, 1 study; very-low certainty evidence) or venous occlusion (RR 0.81, 95 % CI: 0.20 to 3.27; 54 subjects, 1 study; very-low certainty evidence); 2 studies reported adverse effects. The LMWH and UFH groups showed no evidence of a difference in wound bleeding (RR 0.53, 95 % CI: 0.23 to 1.23; 130 subjects, 2 studies; low certainty evidence), hematuria (RR 0.43, 95 % CI: 0.09 to 2.11; 130 subjects, 2 studies; very-low certainty evidence), ecchymoses (RR 0.82, 95 % CI: 0.21 to 3.19; 130 subjects, 2 studies; very-low certainty evidence), epistaxis (RR 0.27, 95 % CI: 0.03 to 2.32; 130 subjects, 2 studies; very-low certainty evidence), gingival bleeding (RR 0.18, 95 % CI: 0.02 to 1.43; 130 subjects, 2 studies; very-low certainty evidence), and fecal occult blood (RR 0.27, 95 % CI: 0.03 to 2.31; 130 subjects, 2 studies; very-low certainty evidence). These investigators could not pool data on coagulation abnormalities as varying definitions and tests were used in the 3 studies; 1 study compared LMWH versus no LMWH. The success rate of replantation, when analyzed by digits, was reported as 91.2 % success in the LMWH group and 82.1 % in the control group (RR 1.11, 95 % CI: 0.93 to 1.33; 73 digits, 1 study; very-low certainty evidence). Compromised microcirculation requiring surgical re-exploration, analyzed by digits, was 11.8 % in the LMWH group and 17.9 % in the control group (RR 0.86, 95 % CI: 0.21 to 3.58; 73 digits, 1 study; very-low certainty evidence). Compromised microcirculation requiring incision occurred in 5 out of 34 digits (14.7 %) in the LMWH group and 8 out of 39 digits (20.5 %) in the control group (RR 0.72, 95 % CI: 0.26 to 1.98; 73 digits; very-low certainty evidence). Microvascular insufficiency due to arterial occlusion, analyzed by digits, was 11.8 % in the LMWH group and 17.9 % in the control group (RR 0.66, 95 % CI: 0.21 to 2.05; 73 digits, 1 study; very-low certainty evidence), and venous occlusion was 14.7 % in the LMWH group and 20.5 % in the control (RR 0.72, 95 % CI: 0.26 to 1.98; 73 digits, 1 study; very-low certainty evidence). The study did not report complications or adverse effects. The authors concluded that there is currently low-to very-low certainty evidence, based on 4 RCTs, suggesting no evidence of a benefit from LMWH when compared to UFH on the success rates of replantation or affect microvascular insufficiency due to vessel occlusion (analyzed by digit or subject). LMWH had similar success rates of replantation; and the incidence rate of venous and arterial microvascular insufficiency showed no evidence of a difference between groups when LMWH was compared to no LMWH (analyzed by digit). Similar rates of complications and adverse effects were observed between UFH and LMWH. There was insufficient evidence to draw conclusions on any effect on coagulation when comparing LMWH to UFH or no LMWH. The certainty of the evidence was down-graded due to performance and reporting bias, as well as imprecision in the results. These researchers stated that further adequately powered studies are needed to provide high-certainty evidence.

Prevention of Portal Vein System Thrombosis After Splenectomy

In a systematic review and meta-analysis, Yang and Liu (2020) examined the safety and efficacy of LMWH in the prevention of portal vein system thrombosis (PVST) after splenectomy. These researchers carried out a systematic search using PubMed, Embase, Springer and Cochrane Library databases to screen out studies comparing the prognoses between post-splenectomy patients treated with and without LMWH. The incidences of PVST and bleeding complications were used as parameters to examine the effect of LMWH. A total of 6 articles met the selection criteria and were included in this study. A total of 740 patients were involved in these 6 studies, including 336 patients treated with LMWH (LMWH group) and 385 patients not treated with LMWH (control group). The incidence of PVST in the LMWH group was significantly lower than that in the control group (RR 1.782 (1.449 to 2.192); p = 0.285; I2 = 19.7 %), while the incidence of post-operative bleeding in the LMWH group was significantly higher (RR 0.592 (0.195 to 1.799); p = 0.817; I2 = 0.0 %). The authors concluded that LMWH might decrease the incidence of PVST after splenectomy without a potential risk of bleeding. Moreover, these researchers stated that further RCTs are needed to further confirm the safety and effectiveness of LMWH in patients after splenectomy.

The authors stated that this study had several drawbacks. First, the primary outcome proved that LMWH was effective; however, the retrospective non‐randomized trials group and the RCT group in the process of subgroup analysis have come to a different conclusion. Generally, without randomization, it is hard to control for confounding variables, as there may have been surgeon and institution factors influencing outcomes. Second, the doses of LMWH administered to the patients were different in included studies, between 300,0and 10,000 U per day. Finally, 5 of the 6 studies performed in Asian countries were included in this meta‐analysis, which might result in regional bias. Nevertheless, further multi-center trials with large patient samples are needed to overcome the above‐mentioned drawbacks and confirm these findings.

Low-Molecular Weight Heparin for Patients with Coronavirus Disease 2019 (COVID-19)

Giossi and associates (2021) stated that anti-thrombotic treatment, including LMWH or UFH, has been proposed as a potential therapy for coronavirus disease 2019 (COVID-19) to lower diffuse intravascular clotting activation; however, it is unclear whether prophylactic or therapeutic doses have similar efficacy in reducing mortality. In a systematic review and meta-analysis, these investigators examined the effectiveness of heparins (either LMWH, UFH, or fondaparinux) in COVID-19 patients. Heparin treatment was compared to no anti-coagulation. A subgroup analysis on prophylactic or therapeutic doses compared to no anti-coagulation was carried out. Prophylactic dose was also compared to full dose anti-coagulation. Primary endpoint was all-cause mortality; and secondary endpoints were major bleeding and hospital length of stay (LOS). A total of 33 studies (31 observational, 2 RCT) were included for a total overall population of 32,688 patients. Of these, 21,723 (66.5 %) were on heparins; 31 studies reported data on all-cause mortality, showing that both prophylactic and full dose reduced mortality (pooled HR 0.63, 95 % CI: 0.57 to 0.69 and HR 0.56, 95 % CI: 0.47 to 0.66, respectively). However, the full dose was associated with a higher risk of major bleeding (OR 2.01, 95 % CI: 1.14 to 3.53) compared to prophylactic dose. Finally, hospital LOS was evaluated in 3 studies; no difference was observed between patients with and without heparins (0.98, -3.87, 5.83 days). The authors conclude that heparin at both full and prophylactic dose was effective in reducing mortality in hospitalized COVID-19 patients, compared to no treatment; however, full dose was associated with an increased risk of bleeding.

The authors stated that this study had several drawbacks. First, fondaparinux was not well represented among studies, so that these results could not be applied to this drug with certainty. Furthermore, in 2 studies, a small number of patients were treated with apixaban, an oral inhibitor of Xa factor, which has the same target of heparin, possibly representing a potential confounding factor. Moreover, the quality of studies was generally unsatisfactory, with only 11 studies included having a score of greater than or equal to 7 in the Newcastle-Ottawa scale evaluation. The risk of bias, assessed with ROBINS-I tool, showed an overall serious risk of bias, especially due to confounding. In addition, very different regimens of heparin treatments were used. Another aspect related to the effectiveness of heparin according to COVID-19 severity; indeed, the proportion of severe patients was highly variable among studies, and this may have affected the overall results. These researchers stated that further study in severe patients is needed. Also, the rationale for treatment assignment was not univocal across studies and included disease severity, D-dimer levels, and physician choice. D-dimer levels were expressed only in a limited number of studies and with high variability in the unit of measurement used. For this reason, these investigators could not use D-dimer levels for further analyses.

Lopes and colleagues (2021) noted that COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anti-coagulation would improve outcomes in hospitalized COVID-19 patients is unclear. In an, open-label (with blinded adjudication), multi-center RCT, these researchers compared the safety and effectiveness of therapeutic versus prophylactic anti-coagulation in this population. This trial was carried out at 31 sites in Brazil. Patients (aged greater than or equal to18 years) hospitalized with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomization, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anti-coagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice-daily) or intravenous UFH (to achieve a 0.3 to 0.7 IU/ml anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anti-coagulation was standard in-hospital enoxaparin or UFH. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalization, or duration of supplemental oxygen to day 30, analyzed with the win ratio method (a ratio of greater than 1 reflected a better outcome in the therapeutic anti-coagulation group) in the intention-to-treat (ITT) population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. From June 24, 2020, to February 26, 2021, a total of 3,331 patients were screened and 615 were randomly allocated (311 [50 %] to the therapeutic anti-coagulation group and 304 [50 %] to the prophylactic anti-coagulation group); 576 (94 %) were clinically stable and 39 (6 %) clinically unstable; 1 patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28,899 (34.8 %) wins in the therapeutic group and 34,288 (41.3 %) in the prophylactic group (win ratio 0.86 [95 % CI: 0.59 to 1.22], p = 0.40). Consistent results were observed in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8 %) patients assigned therapeutic anti-coagulation and 7 (2 %) assigned prophylactic anti-coagulation (RR 3.64 [95 % CI: 1.61 to 8.27], p = 0.0010). Allergic reaction to the study medication occurred in 2 (1 %) patients in the therapeutic anti-coagulation group and 3 (1 %) in the prophylactic anti-coagulation group. The authors concluded that in patients hospitalized with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anti-coagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anti-coagulation; thus, the use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anti-coagulation. Moreover, these researchers stated that ongoing clinical trials will address the safety and effectiveness of other anti-thrombotic regimens in patients with COVID-19.

Sadeghipour and co-workers (2021) stated that thrombotic events are commonly reported in critically ill patients with COVID-19; however, limited data exist to guide the intensity of anti-thrombotic prophylaxis. In a randomized, multi-center study, these researchers examined the effects of intermediate-dose versus standard-dose prophylactic anti-coagulation among patients with COVID-19 admitted to the intensive care unit (ICU). This trial had a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose versus standard-dose prophylactic anti-coagulation (1st hypothesis) and statin therapy versus matching placebo (2nd hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) versus standard prophylactic anti-coagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extra-corporeal membrane oxygenation (ECMO), or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Pre-specified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for non-inferiority (a non-inferiority margin of 1.8 based on OR), and severe thrombocytopenia (platelet count of less than 20 ×103/µL). All outcomes were blindly adjudicated. Among 600 randomized patients, 562 (93.7 %) were included in the primary analysis (median [inter-quartile range (IQR)] age, 62 [50 to 71] years; 237 [42.2 %] women). The primary efficacy outcome occurred in 126 patients (45.7 %) in the intermediate-dose group and 126 patients (44.1 %) in the standard-dose prophylaxis group (absolute risk difference [RD], 1.5 % [95 % CI: -6.6 % to 9.8 %]; OR, 1.06 [95 % CI: 0.76 to 1.48]; p = 0.70). Major bleeding occurred in 7 patients (2.5 %) in the intermediate-dose group and 4 patients (1.4 %) in the standard-dose prophylaxis group (RD, 1.1 % [1-sided 97.5 % CI: -∞ to 3.4 %]; OR, 1.83 [1-sided 97.5 % CI: 0.00 to 5.93]), not meeting the non-inferiority criteria (p for non-inferiority > 0.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 versus 0 patients; RD, 2.2 % [95 % CI: 0.4 % to 3.8 %]; p = 0.01). The authors concluded that among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anti-coagulation, compared with standard-dose prophylactic anti-coagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days. These findings did not support the routine empirical use of intermediate-dose prophylactic anti-coagulation in unselected patients admitted to the ICU with COVID-19.

Sholzberg et al (20210 presented the protocol of a RCT that examines the effect of therapeutic anti-coagulation, with low LMWH or UFH (high-dose nomogram), compared to standard of care (SOC) in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. This is an open-label, parallel, 1:1, phase-III, 2-arm trial. The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants will be recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the U.S. Intervention is therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high-dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. A total of 462 patients (231 per group) are needed to detect a 15 % risk difference, from 50 % in the control group to 35 % in the experimental group, with power of 90 % at a 2-sided alpha of 0.05. The authors noted that recruitment began on May 11, 2020; and recruitment is expected to be completed March 2022.

Furthermore, an UpToDate review on “COVID-19: Management in hospitalized adults” (Kim and Gandhi, 2022) does not mention LMWHs as a management / therapeutic option.

Post-Operative Low Molecular Weight Heparin Bridging Treatment for Patients at High Risk of Arterial Thromboembolism

In a prospective, double blind, RCT, Kovacs and colleagues (2021) examined the safety and effectiveness of dalteparin post-operative bridging treatment versus placebo for patients with atrial fibrillation (AF) or mechanical heart valves when warfarin is temporarily interrupted for a planned procedure. This trial was carried out in 10 thrombosis research sites in Canada and India between February 2007 and March 2016. A total of 1,471 patients aged 18 years or older with AF or mechanical heart valves who required temporary interruption of warfarin for a procedure were included in this study. Subjects were randomly assigned to dalteparin (n = 821; 1 patient withdrew consent immediately after randomization) or placebo (n = 650) after the procedure. Main outcome measures included major thromboembolism (stroke, transient ischemic attack [TIA], proximal DVT, pulmonary embolism, myocardial infarction [MI], peripheral embolism, or vascular death) and major bleeding according to the International Society on Thrombosis and Hemostasis criteria within 90 days of the procedure. The rate of major thromboembolism within 90 days was 1.2 % (8 events in 650 patients) for placebo and 1.0 % (8 events in 820 patients) for dalteparin (p = 0.64, risk difference -0.3 %, 95 % CI:-1.3 to 0.8). The rate of major bleeding was 2.0% (13 events in 650 patients) for placebo and 1.3 % (11 events in 820 patients) for dalteparin (p = 0.32, risk difference -0.7, 95 % CI: -2.0 to 0.7). The results were consistent for the AF and mechanical heart valves groups. The authors concluded that in patients with AF or mechanical heart valves who had warfarin interrupted for a procedure, no significant benefit was found for post-operative dalteparin bridging for the prevention of major thromboembolism. These researchers stated that further studies are needed to determine the need for bridging before procedures in patients with mechanical heart valves.

The authors stated that this study had several drawbacks. First, these researchers did not achieve the full sample size because of the decreased availability of patients with AF on warfarin because of the introduction of direct oral anticoagulant treatment. Second, the total number of patients with mechanical heart valves was relatively low, although to the authors’ knowledge, this was the largest population and the only randomized trial in this group of patients to-date. Furthermore, the rate of major thromboembolism in this subgroup was very low, with only 1 event, and that patient was in the bridging arm. Further randomized studies in this group would be ideal but are likely to be logistically difficult, which was the authors’ experience. Third, all of the patients had bridging with dalteparin before the procedure. Given the results of the BRIDGE trial, LMWH bridging for AF before the procedure was probably not necessary. Moreover, a recent trial suggested that bridging before and after the procedure is not necessary for patients receiving direct oral anticoagulants for AF. These investigators could not make any conclusions regarding bridging before the procedure for patients with mechanical heart valves and high-risk AF given that all patients in this study received this treatment; this aspect requires further study. Finally, because these researchers excluded patients with mechanical heart valves and a history of stroke or TIA, or those with multiple mechanical valves, the results from this study should not be applied to those patients.

Combined 5-Fluorouracil and Low Molecular Weight Heparin for the Prevention of Post-Operative Proliferative Vitreoretinopathy in Patients with Retinal Detachment

Chen and colleagues (2021) noted that post-operative proliferative vitreoretinopathy (PVR) remains a dilemma for retinal surgeons. In a meta-analysis, these researchers examined if combined 5-fluorouracil (5-FU) and LMWH treatment were effective in improving the primary success of vitrectomy and preventing post-operative PVR occurrence in patients with retinal detachment (RD). Databases including PubMed, Embase, the Cochrane library, and China National Knowledge Infrastructure (CNKI) were searched from inception to May 2021. Comparative studies approaching the effects of combined 5-FU and LMWH on post-operative PVR were included. Quality assessment was carried out using RoB 2 and ROBINS-I tool. Study data were pooled using Review manager 5.4.1. The main outcome measures included the primary success of vitrectomy at 6 months and the post-operative PVR occurrence. Secondary outcomes included number of patients who underwent vitreoretinal re-operations and the number of vitreoretinal re-operations due to post-operative PVR. Subgroup analyses and sensitivity analyses were also carried out. A total of 6 clinical trials with 1,208 subjects were included. These investigators found that combined 5-FU and LMWH infusion did not improve the primary success of vitrectomy at 6 months (RR = 1.00, 95 % CI: 0.95 to 1.07, p = 0.89, I2 = 50 %). Furthermore, the conjunct therapy had no effect on reducing the number of patients who underwent vitreoretinal re-operations (RR = 1.00, 95 % CI: 0.78 to 1.28, p = 1.00, I2 = 42 %). The overall effect of the treatment on preventing post-operative PVR was negative. However, in patients with PVR grade C (PVRC) before intervention, the 5-FU and LMWH treatment significantly reduced PVR occurrence. Visual acuity (VA) was not different between the treatment and control groups. Nevertheless, in 1 RCT, a significant reduction of VA was observed in the treatment group in macular-sparing patients with RD. No complications were attributed to the conjunct therapy. The authors concluded that the combined 5-FU and LMWH treatment neither improved the primary success of vitrectomy at 6 months nor decreased number of patients who underwent vitreoretinal re-operations; therefore, the treatment should not be routinely used in vitrectomy for patients with RD. However, the treatment proved beneficial in reducing post-operative PVR in patients with PVRC before intervention. These researchers stated that more studies in patients at high risk of PVR and patients with PVRC before intervention are needed to confirm these results. They noted that based on current evidence, 5-FU and LMWH therapy should not be routinely used in vitrectomy for rhegmatogenous RD patients, especially in patients with potential good VA.

The authors stated that this meta-analysis had several drawbacks. First, the 3 high-quality RCTs were conducted fully or partially in the same center; thus, this might have resulted in selection bias. Second, the limited number of studies and the difference in subjects contributed to the unstableness of the meta-analyses for 2 outcomes (post-operative PVR occurrence, and a number of vitreoretinal re-operations due to PVR). Third, the positive results (p < 0.05) from a 1-study subgroup or after a particular study was omitted need to be taken with caution.

Appendix

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

Source: Palumbo et al, 2008.

1A: Strong recommendation, high‐quality evidence

1B: Strong recommendation, moderate‐quality evidence

2B: Weak recommendation, moderate‐quality evidence

VKA = vitamin K antagonists (i.e., warfarin);

LMWH = low molecular weight heparin

Scope of Policy

This Clinical Policy Bulletin addresses low-molecular-weight heparins and thrombin inhibitors.

Medical Necessity

Aetna considers low-molecular-weight heparins (LMWHs) and thrombin inhibitors medically necessary for the following indications when criteria are met:

Use of LMWHs 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:

For the prevention of venous thromboembolism (VTE) for a

of the following:

Argatroban (Argatroban Injection) in the outpatient setting for prophylaxis of cerebral thrombosis, and thrombosis in members with heparin-induced thrombocytopenia (HIT), and treatment of cerebral thrombosis, and thrombosis in individuals with HIT.

Experimental and Investigational

LMWHs and thrombin inhibitors are considered experimental and investigational for the following indications (not an all-inclusive list) because the effectiveness for these indications has not been established:

LMWHs for all other indications, including in

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: