Low Molecular Weight Heparins (Lmwhs)

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Low Molecular Weight Heparins (LMWHs)

Summary

Compared to unfractionated heparin, low molecular weight heparins (LMWHs) produce a more predictable anticoagulant response, reflecting their better bioavailability, longer half-life, and dose- independent clearance.

LMWHs can be administered by subcutaneous (SC) injection and usually do not require laboratory monitoring, making them more convenient for outpatient treatment compared to unfractionated heparin.

LMWHs have different approved indications. Enoxaparin is the only LMWH that is approved for both venous thromboembolism (VTE) prophylaxis and treatment.

Enoxaparin and dalteparin are the only LMWHs approved for the prevention of ischemic complications in patients with untable agnina and non-q-wave myocardial infarction; however enoxaparin is the only LMWH approved for acute ST-segment elevation myocardial infarction (STEMI).

LMWHs should be prescribed according to recommended dose regimens for each clinical indication to ensure optimal safety and efficacy.

Pharmacology LMWHs exert their antithrombotic activity by binding to and accelerating the activity of antithrombin III. By activating antithrombin III, coagulation factor Xa and factor IIa (thrombin) are inhibited. The resultant thrombin inhibition prevents the formation of fibrin clots.

At recommended doses, LMWHs have a weaker effect on platelet activation and are associated with a lower incidence of heparin-induced thrombocytopenia compared to unfractionated heparin. [50252]

Enoxaparin and dalteparin have no effect on prothrombin time or activated partial thromboplastin time (aPTT). Therapeutic doses of tinzaparin for the treatment of deep vein thrombosis prolong aPTT and may slightly prolong prothrombin team. Neither aPTT nor prothrombin time can be used for therapeutic monitoring of any of the LMWHs. Anti-Xa activity is used as a biomarker for treatment; however, routine monitoring is generally not recommended.

Clearance of LMWH is primarily renal.[50254][50255] For this reason, the biologic half-life of LMWHs may be prolonged in patients with renal failure resulting in drug accumulation. Therapeutic Use Therapeutic Use Table

Indications Dalteparin Sodium Enoxaparin Sodium Tinzaparin Sodium

Renal Impairment Dosing Adjustment Yes Yes Yes

Hepatic Impairment Dosing Adjustment acute myocardial infarction Yes † Yes cerebral thromboembolism Yes † Yes † Yes coronary artery thrombosis prophylaxis Yes Yes deep venous thrombosis (DVT) Yes Yes Yes deep venous thrombosis (DVT) prophylaxis Yes Yes percutaneous coronary intervention (PCI) Yes † periprocedural anticoagulation Yes † Yes † pulmonary embolism Yes Yes Yes pulmonary embolism prophylaxis Yes Yes thrombosis prophylaxis Yes Yes unstable angina Yes Yes

Yes – Labeled Yes † – Off-label, Recommended NR – Off-label, Not Recommended

LMWHs can be administered once or twice daily by SC injection, without routine coagulation monitoring. However, in certain clinical situations (e.g., morbid obesity, renal failure), monitoring of anti-factor Xa concentrations may be helpful

LMWHs have different FDA-approved indications for VTE. Enoxaparin is approved for the broadest range of indications. Dalteparin is approved for VTE prevention but not for VTE treatment other than long-term treatment in cancer patients. Tinzaparin is approved for the treatment of VTE but not VTE prophylaxis.[50256]

Laboratory monitoring for LMWH is generally not needed. In select clinical situations, however, monitoring of anti-factor Xa may be helpful to determine whether the dose used is achieving the desired target concentrations. Anti-factor Xa monitoring may be needed to establish the correct dose in patients with renal impairment, pregnancy, obesity, low body weight, those at high risk of bleeding, those receiving long-term LMWH therapy, those with recurrent thrombosis despite LMWH therapy, neonates, and children. FDA-Approved Indications and Dosages of LMWHs for the Treatment and Prevention of VTE Indication LMWH

Enoxaparin Dalteparin Tinzaparin

VTE prophylaxis 30 mg SC every 12 5000 International Units daily SC postoperatively; various preoperative Not after hip hours or 40 mg SC doses indicated Indicated replacement once daily surgery

VTE prophylaxis 30 mg SC every 12 Not Indicated Not after knee hours Indicated replacement surgery

VTE prophylaxis 40 mg SC once daily 2500 International Units SC daily Not after abdominal Indicated surgery Patients at high risk of thromboembolic complications (e.g., malignancy): 5000 International Units SC once daily or 2500 International Units SC 1—2 hours before surgery followed by 2500 International Units SC 12 hours later then 5000 International Units SC once daily postoperatively

VTE prophylaxis 40 mg SC once daily 5000 International Units once daily Not in acutely ill Indicated medical patients

VTE Treatment Inpatient DVT with or Not Indicated 175 without PE: 1 mg/kg International SC every 12 hours or Units/kg SC 1.5 mg/kg SC once once daily daily

Outpatient DVT without PE: 1 mg/kg SC every 12 hours

Secondary VTE Not Indicated 200 International Units/kg SC daily for 1st month, then 150 International Not prophylaxis Units/kg SC daily for months 2—6* Indicated or/extended treatment in cancer patients

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism

*max daily dose of 18,000 International Units/day

Comparative Efficacy

Enoxaparin, as the first approved LWMH, has been included in more comparative studies than the other LMWHs. Key findings from these studies/reviews are:

All LMWHs were generally found to be comparable in safety and efficacy for the treatment of and/or prevention of VTE.

Compared to tinzaparin, enoxaparin was found to more effective in patients with unstable angina pectoris or non-ST-segment elevation myocardial infarction (NSTEMI). LMWH Comparative Efficacy Trials

Citation Design/Regimen Results Conclusion

Planes A, et al. Thromb Randomized controlled trial of Occurrence of DVT: Tinzaparin is as effective and Haemost 1999;81:22-25 440 patients undergoing total hip safe as enoxaparin in the [26321] replacement; compared 20.1% for enoxaparin vs.21.7% for prophylaxis of DVT after total enoxaparin 40 mg or tinzaparin tinzaparin. hip replacement 4500 anti-factor Xa International Proximal DVTs 10.5% for enoxaparin Units once daily vs.9.5% for tinzaparin.

Safety

No overt major bleeding was observed. One patient in the enoxaparin group developed severe thrombocytopenia and died.

Wells PS, et al. Arch Randomized controlled trial of DVT recurrence: Tinzaparin and dalteparin are Intern Med 505 outpatients comparing safe and effective for the 2005;165:733-738 tinzaparin 175 international 3.9% for tinzaparin vs. 3.6% for outpatient treatment of DVT and [39593] units/kg daily vs. dalteparin 200 dalteparin PE international units/kg daily for Major bleeding: treatment of acute DVT and PE 2% for tinzaparin vs. 0.8% for dalteparin

Michalis LK, et al. Am Randomized controlled trial of Angina, MI, or death at 7 days: Compared to tinzaparin, Heart J. 2003;146:304- 438 patients with non-ST enoxaparin significantly Enoxaparin 12.3% vs. tinzaparin 310 [50258] segment elevation ACS; reduced the rate of recurrent compared enoxaparin to 21.2% (p=0.015) angina, MI, or death at 7 days, tinzaparin for up to 7 days 30 days, and 6 months Angina, MI, or death at 30 days:

enoxaparin 17.7% vs tinzaparin 28% (p = 0.012)

Long-term efficacy

Of note, at 6 months, superiority of enoxaparin for the same endpoint was maintained (25.5% vs 44%; p<0.001). [50259]

Adverse Reactions / Side Effects Top 20 Adverse Reactions / Side Effects Table

Adverse Reaction / Side Effect Dalteparin Sodium Enoxaparin Sodium Tinzaparin Sodium

bleeding <13.6% <13% 0.8 - 16%

elevated hepatic enzymes 4.2 - 9.5% 5.9 - 6.1% 8.8 - 13%

fever Reported 5 - 8% 1.5%

hematoma <7.1% <9% 16%

hematuria Reported <2% 1%

thrombocytopenia <13.6% 0.1 - 2.8% 0.1 - 1% Adverse Reaction / Side Effect Dalteparin Sodium Enoxaparin Sodium Tinzaparin Sodium anemia <16% >1% confusion 2.2% >1% diarrhea 2.2% 0.6% dyspnea 3.3% 1.2% ecchymosis <3% Reported edema 2% Reported headache Reported 1.7% nausea 2.5 - 3% 1.7% back pain 1.5% chest pain (unspecified) 2.3% cystitis 3.7% epistaxis 1.9% peripheral edema 3 - 6% pulmonary embolism 2.3%

Bleeding Bleeding is the most serious adverse reaction associated with the use of LMWHs; this can range from minor bleeding, such as bleeding from the gums, to major bleeding episodes (< 1%—4%) defined as those requiring a transfusion, a decrease in hemoglobin > 2 mg/dL, bleeding leading to interruption of treatment or death, intracranial bleeding, ocular hemorrhage, or retroperitoneal bleeding. Bleeding events may include epistaxis, hematoma, or gastrointestinal bleeding (melena, hematochezia, and/or hematemesis). Of pregnant women who received tinzaparin, approximately 10% experienced significant vaginal bleeding. Several cases of spinal hematoma have been reported with epidural anesthesia or spinal puncture leading to long-term injury or permanent paralysis.

Injection site reactions Injection site reactions, including irritation, pain, hematoma, ecchymosis, and erythema, can occur following SC administration of LWMHs. Other adverse skin reactions (nodules, inflammation, oozing, necrosis vesiculobullous rash, purpura, pruritus, urticaria, and vesiculobullous rash), some allergic in nature, have also been reported.

Thrombocytopenia

Cases of thrombocytopenia (platelet count < 100,000/mm3) have been reported in patients treated with LMWHs. Cases of thrombocytopenia with disseminated thrombosis have been observed in clinical practice with both heparins and LMWHs. Some of these cases were complicated by organ infarction or limb ischemia. Although it occurs at a lower rate with LMWHs compared to heparin, heparin-induced thrombocytopenia may also occur.

Hepatotoxicity Asymptomatic elevated hepatic enzymes > 3 times the upper limit of normal have been reported in patients treated with LMWHs. These elevations are reversible.

Osteoporosis Although less common than heparin, osteoporosis may occur in patients receiving long-term treatment with LMWHs. Most cases relate to long-term use in pregnant patients

Drug Interactions

Drugs that increase the risk of bleeding Bleeding is the biggest risk with the LMWHs. The risk of bleeding is increased when used with other drugs that affect the coagulation system, although in some clinical situations, the additive effects are desirable. LMWHs should be used with caution in combination with other anticoagulants (eg, heparin and warfarin), thrombolytics, and antiplatelets. Fish oil (omega-3 fatty acids), Gingko biloba, nonsteroidal anti-inflammatory drugs, aspirin, dipyridamole, sulfinpyrazone, dehydroepiandrosterone, and garlic may increase the risk of bleeding due to their antiplatelet effects. Large doses of salicylates and certain cephalosporin antibiotics may cause hypoprothrombinemia and also increase the risk of bleeding.

Safety Issues Safety Issues Table

Safety Issue Dalteparin Sodium Enoxaparin Sodium Tinzaparin Sodium

REMS

MedGuide benzyl alcohol hypersensitivity X X bleeding X X X epidural anesthesia BBW BBW BBW heparin hypersensitivity X X X heparin-induced thrombocytopenia (HIT) X X X lumbar puncture BBW BBW BBW porcine protein hypersensitivity X X X renal impairment X spinal anesthesia BBW BBW BBW sulfite hypersensitivity X

X – Contraindicated

X-BBW – Contraindicated and Black Box Warning BBW – Black Box Warning, Not Contraindicated Yes – REMS or MedGuide is available

Bleeding Bleeding is the major risk associated with use of LMWHs. LMWHs should not be used in patients with severe bleeding disorders, and coagulopathy should be ruled out prior to initiating therapy. The use of LMWH is contraindicated in patients with active major bleeding, and caution is advised when used in patients with any disease state with an increased risk of hemorrhage.

Spinal hematoma Spinal or epidural hematomas, which may result in permanent or long-term paralysis, may be greater with use of epidural or spinal anesthesia or after lumbar puncture. Additionally, the concomitant use of other drugs affecting hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants may also increase the risk. The LMWHs carry a black box warning cautioning users of this risk. Patients should be monitored frequently for symptoms of neurological impairment if epidural anesthesia, lumbar puncture, or spinal anesthesia are employed.

Heparin-induced thrombocytopenia (HIT) Platelet counts should be monitored in patients receiving LMWHs. If thrombocytopenia occurs, LMWH treatment should be discontinued. LMWHs are contraindicated in patients with HIT or a history of HIT, due to the risk of HIT-associated thrombosis.[50262][49182]

Renal impairment LMWHs are excreted via the kidney; therefore, delayed elimination and subsequent accumulation may occur in patients with renal impairment. Patients with renal impairment should be observed for signs and symptoms of bleeding during LMWH therapy. Anti-factor Xa monitoring may be considered in patients with severe renal impairment to avoid toxicity and ensure therapeutic concentrations. In patients with a CrCl < 30ml/min, tinzaparin and dalteparin use is not recommended; however, enoxaparin has been studied in this population and dose adjustment recommendations are available. In a study comparing enoxaparin and tinzaparin for 8 days in 55 elderly patients with CrCl between 20 and 50 ml/min, enoxaparin was found to accumulate, but tinzaparin did not.[50260]

Geriatric patients Use LMWHs cautiously in geriatric patients, especially those with renal impairment. Tinzaparin should not be used in patients >= 70 years of age with renal impairment and is contraindicated in patients >= 90 years of age with CrCl <= 60 ml/min.