Lovenox Mechanism of Action

Pharmacotherapeutic Group: Antithrombotic agent. ATC Code: B01AB05.
Pharmacology: Pharmacodynamics: Enoxaparin is a low molecular weight heparin in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. It is characterized by a higher ratio of anti-Xa activity to anti-IIa (or antithrombin) activity.
The ratio between these two activities is 3.6.
As with standard heparin, the anti-Xa and anti-IIa activity of enoxaparin results from its effect on antithrombin.
When used as prophylactic treatment, it does not significantly affect the activated partial thromboplastin time (aPTT).
When used as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.
This prolongation reflects the residual antithrombin activity.
4000 Anti-Xa IU: Prophylactic treatment of venous thromboembolism in patients who are bedridden due to an acute medical disorder: A randomized, double-blind, placebo-contorlled study (Medenox) was carried out to compare the safety and efficacy of enoxaparin 2000 anti-Xa IU/0.2 ml (20 mg/0.2 ml) and 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) in preventing venous thromboembolism. The study medication or placebo were administered once daily for 6 to 14 days to 1102 patients who were bedridden due to an acute medical disorder occurring within the previous three days and who were at moderate risk of venous thromboembolism. The patients were over 40 years of age and had heart failure (NYHA class III or IV), acute respiratory failure revealing or complicating chronic respiratory insufficiency, an acute infectious or rheumatic disease associated with at least one thromboembolic risk factor (age >75 years, cancer, history of venous thromboembolism, obesity, varicose, hormone therapy, chronic heart or respiratory failure).
Medical patients at high risk of venous thromboembolism complications (acute phase of myocardial infarction, heart disease such as arrhythmia or valvular disease requiring anticoagulant therapy, intubated patients or patients who had experienced a stroke within the last three months) were not included in the study.
The primary efficacy criterion was the incidence of venous thromboembolic events on treatment day 10 (±4) defined as: deep vein thrombosis (DVT) documented systematically by venography (83.4% of evaluable patients) or by Doppler ultrasound (16.6% of evaluable patients) in patients with symptomatic DVT. Non-fatal symptomatic pulmonary embolism confirmed by pulmonary angiography or spiral CT; or fatal pulmonary embolism.
A significant decrease in the incidence of venous thromboembolic events was observed in the 866 evaluable patients on day 10 (±4), 16/291 (5.5%) in the Lovenox 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) group versus 43/288 (14.9%) in the placebo group (p=0.0002). This was mainly due to the significant decrease in the incidence of total DVT (proximal and distal), i.e., 16/291 (5.5%) in the Lovenox 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) group versus 41/288 (14.2%) in the placebo group (p=0.0004). Most DVTs were asymptomatic (only 6 were symptomatic). The observed benefit was maintained after 3 months.
Fifty-nine percent (59%) of patients in the Lovenox 4000 anti-Xa IU/0.4 ml (40 mg/0.4 ml) group regained autonomous mobility (>10 meters) during the treatment period.
Regarding safety, the incidence of hematomas or ecchymoses larger than 5 cm at the injection site was significantly higher in the Lovenox 4000 anti-Xa IU/0.4 ml/day (40 mg/day) group than in the placebo group.
This study showed no significant difference in efficacy between Lovenox 2000 anti-Xa IU/0.2 ml (20 mg/0.2 ml) and the placebo.
6000 Anti-Xa IU: Treatment of acute ST-segment elevation myocardial infarction in combination with a thrombolytic agent in patient who are eligible or not for subsequent coronary angioplasty: In a large multicenter study, 20479 patients with acute ST-segment elevation myocardial infarction having received fibrinolytic, treatment were randomized to receive either: enoxaparin as an IV bolus injection of 3 000 anti-Xa IU immediately followed by a dose of 100 anti-Xa IU/kg SC, then by an SC injection of 100 anti-Xa IU/kg every 12 hours, or unfractionated heparin by the IV route as a bolus injection of 60 IU/kg (maximum 4 000 IU) followed by a continuous infusion at a dose adjusted to the activated partial thromboplastin time. The SC injections of enoxaparin were administered until discharge from hospital or for a maximum period of 8 days (in 75% of cases for at least 6 days). Half the patients receiving heparin were administered the drug for less than 48 hours (in 89.5% of cases ≥36 hours). All the patients were also treated with aspirin for at least 30 days. The enoxaparin dosage was adjusted for patients aged 75 years or more: 75 IU/kg as an SC injection every 12 hours, without an initial IV bolus injection.
During the study, 4716 (23%) patients underwent coronary angioplasty under antithrombotic treatment using blinded study drugs.
Patients did not receive an additional dose if the last SC injection of enoxaparin had been given less than 8 hours balloon inflation, or, received an IV bolus injection of 30 anti-Xa IU/kg if the last SC injection of enoxaparin had been given more than 8 hours before balloon inflation.
Enoxaparin significantly reduced the incidence of primary end point events (composite end point consisting of myocardial infarction relapse and all-cause mortality within 30 days after inclusion : 9.9% in the enoxaparin group versus 12.0% in the unfractionated heparin group (relative risk reduction of 17% (p<0.01)). The incidence of myocardial infarction relapse was significantly lower in the enoxaparin group (3.4% versus 5%, p<0.001, relative risk reduction 31%). The incidence of deaths was lower in the enoxaparin group, with no statistically significant difference between the groups (6.9% versus 7.5%, p=0.11).
The benefit of enoxaparin in terms of the primary endpoint was consistent, irrespective of sub-group: age, sex, location of myocardial infarction, history of diabetes of myocardial infarction, type of thrombolytic administered and interval between the first clinical signs and treatment initiation.
Enoxaparin demonstrated a significant benefit versus unfractionated heparin in terms of the primary efficacy criterion, both in patients who had undergone coronary angioplasty within 30 days after inclusion (10.8% versus 13.9%, 23% reduction in relative risk) and in patients who did not have coronary angioplasty (9.7% versus 11.4%, 15% reduction in relative risk).
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the enoxaparin group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial bleeding was similar in both groups (0.8% with enoxaparin versus 0.7% with heparin).
The analysis of the composite criteria measuring overall clinical benefit showed statistically significant superiority (p<0.0001) for enoxaparin versus unfractionated heparin: a relative risk reduction of 14% in favor of enoxaparin (11.0% versus 12.85) for the composite criteria consisting of death, myocardial infarction relapse, or major bleeding (TIMI criteria) at 30 days, and of 17% (10.1% versus 12.2%) for the composite criteria consisting of death, myocardial infarction relapse or intracranial bleeding at 30 days.
Pharmacokinetics: The pharmacokinetic parameters of enoxaparin have been evaluated based on the time course of plasma anti-Xa and anti-IIa activity at the recommended doses (validated amidolytic methods) following single and repeated SC administration, and following single IV injection.
Bioavailability: Subcutaneously administered enoxaparin is rapidly and almost completely absorbed (nearly 100%). Peak plasma activity is observed between 3 and 4 hours after administration.
This peak activity (expressed as Anti-Xa IU) is 0.18±0.04 (after administration of 2000 Anti-Xa IU), 0.43±0.11 (after administration of 4000 Anti-Xa IU) in prophylactic treatment, and 1.01±0.14 (after administration of 10,000 Anti-Xa IU) in curative treatment.
Enoxaparin pharmacokinetics appears to be linear over the recommended dose ranges. Intra- and inter-patient variability is low. After repeated SC administration of Anti-Xa 4000 IU once daily in healthy volunteers, the steady state is reached on day 2 with mean enoxaparin activity of approximately 15% higher than that obtained after a single dose. Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics.
After repeated SC administration of 100 Anti-Xa IU/kg twice daily, the steady state is reached between day 3 and 4 with mean exposure about 65% higher than after a single dose, and with maximum and minimum anti-Xa activity of about 1.2 and 0.52 Anti-Xa IU/ml, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and is within the therapeutic range.
Plasma anti-IIa activity after SC administration is about 10-fold lower than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3-4 hours following SC injection and reaches 0.13 anti-IIa IU/ml following repeated administration of a 100 Anti-Xa IU/kg-dose twice daily.
6000 Anti-Xa IU: An IV bolus injection of 3000 Anti-Xa IU followed by 100 anti-Xa IU/kg by the SC route every 12 hours leads to a first peak in anti-Factor Xa levels of 1.16 IU/ml (n=16) and a mean exposure corresponding to 88% of the steady state level. Steady state is reached as of the second day of treatment.
No pharmacokinetic interaction has been observed between enoxaparin and the thrombolytic agent when co-administered.
Distribution: The volume of distribution of enoxaparin anti-Xa activity is about 5 liters and is close to the blood volume.
Metabolism: Enoxaparin is primarily metabolized in the liver (desulfation, depolymerization).
Elimination: Following SC injection, the apparent anti-Xa activity elimination half-life is higher for LMWHs than for unfractionated heparins.
Enoxaparin exhibits a monophasic elimination pattern with a half-life of about 4 hours after a single SC dose to about 7 hours after repeated dosing by SC route.
With LMWH, plasma decay occurs more quickly for anti-IIa activity than for anti-Xa activity.
Enoxaparin and its metabolites are eliminated via the renal route (nonsaturable mechanism) and by the biliary route. Renal clearance of fragments with anti-Xa activity accounts for about 10% of the administered dose, and the total renal excretion of active and non-active compounds for 40% of the dose.
Special Populations: Elderly Subjects: As kidney function is physiologically impaired in this population, elimination is slower. This does not affect doses or the administration schedule in prophylactic treatment as long as the renal function of these patients remains within acceptable limits i.e., only slightly impaired.
It is essential to systematically assess renal function in elderly patients aged over 75 years using the Cockcroft formula before initiating treatment with LMWH.
2000/4000 Anti-Xa IU: Hemodialysis: LMWH is injected in the arterial line of the dialysis circuit at sufficient doses to avoid coagulation in the circuit.
The pharmacokinetic parameters remain, in principle, unchanged except in cases of overdose or where the drug passes into the general circulation, causing high anti-Xa activity related to end-stage renal failure.
Pregnancy: Low molecular weight heparins are unlikely to cross the placental barrier, but data on the subject remain insufficient.
6000 Anti-Xa IU: Patients with mild to moderate renal failure (i.e. creatinine clearance >30 ml/min): In certain cases, it may be useful to monitor the circulating anti-factor Xa activity to prevent overdose when enoxaparin is used as curative treatment.