Daily Low Molecular Weight Heparin Research Articles

Continuation of low‐molecular‐weight heparin treatment for cancer‐related venous thromboembolism: a prospective cohort study in daily clinical practice

Background Current guidelines recommend low-molecular-weight heparin (LMWH) monotherapy for 3-6 months as the first-line treatment for cancer-associated venous thromboembolism (VTE). However, although daily administration of LMWH injections over a course of several months may be burdensome, the number of patients who stop treatment because of LMWH side-effects is unknown. Objectives To evaluate the continuation rate and complications of daily LMWH injections in patients with cancer-associated VTE. Methods Consecutive patients with active cancer and objectively confirmed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, treated at three Dutch hospitals and one Spanish hospital, were included to evaluate continuation LMWH therapy during LMWH treatment. Patients were excluded when they received other anticoagulants, were lost to follow-up, or experienced a venous catheter-associated thrombosis. Results A total of 372 patients were analyzed during LMWH treatment for a maximum of 180 days. The cumulative incidence of discontinuation was 21% (95% confidence interval [CI] 17-25) after a median period of 90 days (interquartile range 60-120 days). Only female sex was found to be significantly associated with premature LMWH discontinuation (odds ratio 1.6; 95% CI 1.03-2.5). Thirty patients (8.1%) developed recurrent VTE, 30 patients (8.3%) suffered a major bleed, and 106 patients (28%) died. Conclusion Our study reveals that one of five patients with cancer-associated VTE stopped LMWH injections because of side-effects. This finding provides relevant background information for current clinical trials investigating the efficacy and safety of direct oral anticoagulants as compared with LMWH.

Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme.

A daily injection of low-molecular-weight heparin (LMWH) is often prescribed to women with unexplained recurrent pregnancy loss (RPL), although evidence suggesting a benefit is questionable. To determine whether LMWH increases ongoing pregnancy and live-birth rates in women with unexplained RPL. Controlled, multicenter trial with randomization using minimization conducted from 2006 to 2013. (ClinicalTrials.gov: NCT00400387). 14 university hospitals and perinatal care centers in Germany and Austria. 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 multivitamin pills, and the intervention group received vitamins and 5000 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 [CI, -7.3 to 5.9 percentage points]). There were 3 intrauterine 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 intrauterine growth restriction or placental insufficiency (5 women had used LMWH). Placebo injections were not used, and neither trial staff nor patients were blinded. Daily LMWH injections do not increase ongoing pregnancy or live-birth rates in women with unexplained RPL. Given the burden of the injections, they are not recommended for preventing miscarriage. Pfizer Pharma.

Pharmacodynamics of Multi‐Dose Low Molecular Weight Heparin in Healthy Horses

To compare the pharmacodynamics of once daily and twice daily administration of low molecular weight heparin (LMWH) administration in horses. Randomized cross over study. Adult mixed breed healthy mares (n = 6). LMWH (dalteparin) was administered (50 U/kg subcutaneously) either every 12 or 24 hours for 3 consecutive days. Anti-factor Xa activity was measured before and at select time points after LMWH administration. Packed cell volume (PCV), platelet count, partial thromboplastin time (PTT), and anti-thrombin (AT) activity were monitored throughout the study. No changes in PCV, platelet count, or AT activity were detected with either frequency of daily LMWH administration. Values for PTT increased throughout the study but never exceeded the normal reference interval. Anti-factor Xa activity was maintained within or above the suggested thromboprophylactic range (0.1-0.2 U/mL) when LMWH was administered twice daily, but fell below this range ≈ 16 hours after administration when given once daily. For both once and twice daily LMWH administration, the area under the curve was significantly greater after the last dose of LMWH when compared to the first dose. Administration of LMWH once or twice daily for 3 consecutive days appears to be safe in healthy adult horses. Anti-factor Xa activity was maintained within or above the suggested thromboprophylactic range for 24 hours with twice daily LMWH administration but not with once daily administration.

Long-term therapy with low-molecular-weight heparin in cancer patients with venous thromboembolism

Long-term therapy with low-molecular-weight heparin (LMWH) is the treatment of choice for cancer patients with venous thromboembolism (VTE). However, the ideal doses of LMWH have not been thoroughly studied. We used the RIETE Registry data to assess the influence of the daily LMWH dosage on outcome during the first three months after VTE. We used propensity score-matching to compare patients who received <150 vs. those receiving ≥150 UI/kg/day LMWH. Up to July 2010, 3,222 cancer patients with VTE received long-term therapy with fixed doses of LMWH. Of these, 1,472 (46%) received <150 IU/kg/day (mean, 112 ± 28), and 1,750 received ≥150 IU/kg/day (mean, 184 ± 32). Results of the propensity score matching involved 1269 matched pairs. During follow-up, the incidence of pulmonary embolism (PE) recurrences was similar (1.2% vs. 1.9%), but patients receiving <150 IU/kg/day LMWH had a lower incidence of fatal PE than those treated with ≥150 IU/kg/day (0.2% vs. 1.0%; p=0.004). Multivariate analysis confirmed that patients receiving <150 IU/kg/day LMWH had a lower risk for fatal PE (odds ratio [OR]: 0.2; 95% confidence interval [CI]: 0.06-0.8) and for major bleeding (OR: 0.6; 95% CI: 0.3-1.0) than those treated with ≥150 IU/kg/day. In real life, one in every two cancer patients with VTE received lower doses of LMWH than those used in randomised trials, with large variations from patient to patient. Unexpectedly, patients treated with <150 IU/kg/day LMWH had fewer fatal PE cases and fewer major bleeding events than those receiving ≥150 IU/kg/day LMWH. This finding, however, should be validated in prospective clinical trials.

Management of 273 cases of recurrent implantation failure: results of a combined evidence-based protocol

This study evaluated the results of a management protocol combining a number of investigations and interventions, previously proven beneficial in randomized controlled trials in IVF/intracytoplasmic sperm injection (ICSI) patients with apparently unexplained recurrent implantation failure (defined as two or more previous failed cycles, during which at least six good-quality embryos were transferred). It was a prospective cohort study and included 273 couples with previous recurrent implantation failure. Each patient (all under 40) underwent a pre-treatment work-up, consisting of pelvic ultrasound scan for hydrosalpinx, hysteroscopy and screening for acquired and congenital thrombophilia. Detected abnormalities were dealt with accordingly: proximal occlusion for hydrosalpinx, hysteroscopic management for intrauterine pathology and thromboprophylaxis with daily low-molecular weight heparin from the day of embryo transfer for thrombophilia. The patients then underwent IVF/ICSI with laser-assisted hatching. 112 patients (41%; group 1) had abnormalities detected (17 hydrosalpinx, 11 intrauterine pathology, 63 congenital thrombophilia, 21 acquired thrombophilia) and the remaining 161 (59%; group 2) had normal work-up. The pregnancy rates per cycle started for all patients, group 1 and group 2 were 47%, 55% and 41%, respectively. This suggests that using the described management protocol in couples with previous recurrent implantation failure leads to a favourable chance of success.

Efficacy and safety of once daily low molecular weight heparin (tinzaparin sodium) in high risk pregnancy

Low molecular weight heparin (LMWH) is widely regarded as the anticoagulant treatment of choice for the prevention and treatment of venous thromboembolism during pregnancy. However, previous studies have demonstrated that the pharmacokinetic profiles of LMWH vary significantly with increasing gestation. Consequently, it remains unclear whether LMWH regimens recommended for use in nonpregnant individuals can be safely extrapolated to pregnant women. The aims of this study were to assess the safety and the efficacy of tinzaparin sodium (Innohep) administered only once daily during pregnancy. A systematic retrospective review identified a cohort of 37 high-risk pregnancies which had been managed using tinzaparin 175 IU/kg once daily. In 26 cases, the index pregnancy had been complicated by development of an acute venous thromboembolism (17 deep vein thrombosis and nine pulmonary embolism). For each individual, case notes were examined and data extracted using a predetermined questionnaire. No episodes of recurrent venous thromboembolism were identified amongst this cohort of pregnancies managed using once daily LMWH administration. However, two unusual thrombotic complications were observed, including a parietal infarct in one patient, and a postpartum cerebral venous thrombosis in another. Once daily tinzaparin was well tolerated, with no cases of heparin-induced thrombocytopaenia, symptomatic osteoporosis, or foetal malformations. Tinzaparin dose modification based upon peak anti-Xa levels occurred in 45% of the cases examined. The present study is the largest study to have examined the clinical efficacy of once daily LMWH for use in pregnant women at high risk of venous thromboembolism. Our data support the safety and efficacy of antenatal tinzaparin at a dose of 175 IU/kg. In order to determine whether this once daily regimen provides equivalent (or indeed greater) thromboprophylaxis to twice daily LMWH regimens during pregnancy will require highly powered direct comparative studies.

Presence of a T383G Mutation in the Vitamin K Epoxide Reductase Gene (VKORC1) in a Patient Resistant to Four Different Vitamin K Antagonists.

Resistance to vitamin K antagonists is a rare disorder which until recently has not been associated to a genetic factor. The existence of inherited warfarin resistant rat strains has been related to mutations of the genes involved in the vitamin K cycle. Vitamin K dependent carboxylase was cloned in 19911, while human vitamin K epoxide reductase complex 1 (VKORC1), another enzyme implicated in vitamin K cycle, has been cloned more recently2,3. Mutations in this gene are responsible for both human and rat warfarin resistance 3. In 1997, we reported 4 a 63-year old patient with recurrent pulmonary embolism and deep vein thrombosis without known hereditary or acquired thrombophilia who was found resistant to warfarin (up to 45mg/day), fluindione (up to 80mg/day), acenocoumarol (up to 12 mg/day) and phenprocoumon (up to 30 mg/day). With phenprocoumon, long-acting vitamin K antagonist, drug concentration reached 85 mg/L (usual range 1–5 mg/L) but the INR remained around 1. Daily low molecular weight heparin (LMWH) was continued 3 months. Treatment was discontinued on 2 occasions and a recurrent thrombotic episode was observed. The patient is now receiving a single daily dose of low molecular weight heparin (80 mg Enoxaparin, body weight 120 kg, 67 IU/kg once a day) for the past 10 years without thrombotic or bleeding episodes. Osteodensitometry remains normal after 9 years of treatment. Careful biochemichal investigation had demonstrated a deficiency in vitamin K dependent carboxylation and absence of blockade of vitamin K epoxide reductase by phenprocoumon. This year, we sequenced the three exons of VKORC1 in this patient and detected a heterozygous T383G transversion resulting in a leucine to arginine substitution (L128R). This mutation has been recently identified by Rost3 et al. in an individual with warfarin resistance. It was not found in 259 control subjects that we had tested. Interestingly, another gene mutation of the VKORC1 can be responsible for a combined deficiency of vitamin K dependent clotting factors 3. In conclusion, a resistance to all vitamin K antagonists, including warfarin up to 45 mg/day is extremely rare and the mutation T383G of the VKORC gene has been reported in only one patient before the case reported here. Testing for mutation in VKORC1 will help in explaining some cases of anti vitamin K resistance.