Increased anticoagulant response to low‐molecular‐weight heparin in plasma from patients with advanced cirrhosis

Summary. Introduction: Cirrhotic patients may present thrombotic complications that warrant anticoagulant therapy. However, the efficacy of low‐molecular‐weight heparin (LMWH) in this clinical setting is still unclear. Aims/methods: To evaluate the in vitro effect of LMWH on thrombin generation (TG) in cirrhotic patients at different stages of liver disease. Thirty cirrhotics (10 Child Pugh A, 10 Child Pugh B and 10 Child Pugh C), 10 subjects with inherited type 1 antithrombin (AT) defect and 10 healthy controls were studied. TG was determined at baseline and with anti‐Xa levels after the addition of enoxaparin at 0.35 and 0.7 U anti‐Xa mL. The endogenous thrombin potential (ETP) ratio at 0.35 and 0.7 U anti‐Xa mL was obtained by dividing ETP with LMWH by ETP at baseline. Results: Mean AT levels in all cirrhotic subgroups and in patients with AT deficiency were significantly lower than in controls. The 0.35 ETP ratio was significantly lower in cirrhotic patients than in controls (0.26 ± 0.1 vs. 0.48 ± 0.1, P < 0.001) and the reduction paralleled the severity of liver disease, in spite of the concomitant decrease in AT and anti‐Xa activity. AT‐deficient subjects showed a significantly increased 0.35 ETP ratio compared with both cirrhotic patients and controls (0.69 ± 1 vs. 0.26 ± 0.1, P < 0.001, and vs. 0.48 ± 0.1, P = 0.04 respectively). LMWH at 0.7 U anti‐Xa mL completely inhibited TG in 9/30 cirrhosis patients with more advanced liver disease (Child Pugh B and C), whereas complete TG abolition was seen in only 1/10 controls. Conclusions: Cirrhotic patients show an increased response to LMWH, which correlates with the severity of liver disease, in spite of reduced AT and anti‐Xa activity levels. Thrombin generation may be a useful tool to monitor the response to LMWH in cirrhotic patients.     

Major bleeding risks of different low‐molecular‐weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis

Essentials

• Low‐molecular‐weight‐heparins (LMWH) kinetics differ which may result in different bleeding risks.
• A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding.
• The absolute major bleeding risk was low among patients registered at the anticoagulation clinic.
• Once‐daily dosing was associated with a lower bleeding risk as compared with twice‐daily.

Summary

Background

Low‐molecular‐weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events.

Objectives

To determine major bleeding risks for different LMWH agents and dosing schedules.

Methods

A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center.

Results

The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7–3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2–17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0‐fold increased major bleeding risk (95% CI, 0.8‐5.1) as compared with a nadroparin o.d. dosing schedule.

Conclusions

Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice‐daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once‐daily dosing, as also suggested in a meta‐analysis of controlled clinical trials.     

A randomized double‐blind study of low‐molecular‐weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum)

Summary. Background: Optimal doses and duration of low‐molecular‐weight heparin (LMWH) for the treatment of superficial vein thrombosis (SVT) are still uncertain. Objectives: To compare the efficacy and safety of different doses and durations of LMWH parnaparin for symptomatic lower limb SVT. Patients and methods: Outpatients with at least a 4‐cm‐long SVT of long or short saphenous veins or their collaterals were randomized to receive parnaparin either 8500 UI once daily ( o.d.) for 10 days followed by placebo for 20 days (group A) or 8500 UI o.d. for 10 days followed by 6400 UI once daily (o.d.) for 20 days (group B) or 4250 UI o.d. for 30 days (group C) in a double‐blind fashion in 16 clinics. Primary outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE) and relapse and/or symptomatic or asymptomatic SVT recurrence in the first 33 days with 60 days follow‐up. Results: Among 664 patients, primary outcome occurred in 33/212 (15.6%), 4/219 (1.8%) and 16/217 (7.3%) subjects in groups A, B and C, respectively (B vs. A: absolute risk reduction [ARR]: 13.7%, 95% confidence intervals [CI]: 8–18.9 P < 0.001; B vs. C: ARR: 5.5%; 95% CI: 1.6–9.4 P = 0.011; C vs. A: ARR: 8.2%, 95% CI: 2–14 P = 0.012). During days 0–93, the event rate was higher in group A (22.6%) than either in group B (8.7%; P = 0.001) or C (14.3%, P = 0.034). No major hemorrhages occurred. Conclusions: An intermediate dose of parnaparin for 30 days is superior to either a 30‐day prophylactic dose or a 10‐day intermediate dose for lower limb SVT treatment.     

Neuroprotective effects of ultra‐low‐molecular‐weight heparin in vitro and vivo models of ischemic injury

This study was conducted to demonstrate ultra‐low‐molecular‐weight heparin’s neuroprotective effects on ischemic injury both in vivo and in vitro studies. In vitro, the effect of ultra‐low‐molecular‐weight heparin was tested in cultured PC12 cells exposed to Earle’s solution containing sodium dithionite, to identify its neuroprotection to PC12 cells damaged by oxygen‐glucose deprivation (OGD). The cell injury was detected by the tetrazolium salt 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5 diphenyl‐2H tetrazolium bromide (MTT) assay. In vivo, male Wistar rats with middle cerebral artery occlusion were evaluated for infarct volume followed by the treatment with ultra‐low‐molecular‐weight heparin. The results in vitro showed that ultra‐low‐molecular‐weight heparin significantly inhibited PC12 cells damage induced by OGD. Results in vivo showed that vein injection of Ultra‐Low‐molecular‐weight heparin at doses of 0.5 and 1.0 mg/kg exerted significant neuroprotective effects on rats with focal cerebral ischemic injury by significantly reducing the infarct volume compared with the injury group. All the findings suggest that ultra‐low‐molecular‐weight heparin might act as a neuroprotective agent useful in the treatment of cerebral ischemia.     

The design and synthesis of new synthetic low‐molecular‐weight heparins

Low‐molecular‐weight heparin (LMWH) has remained the most favorable form of heparin in clinics since the 1990s owing to its predictable pharmacokinetic properties. However, LMWH is mainly eliminated through the kidney, which limits its use in renal‐impaired patients. In addition, the anticoagulant activity of LMWH is only partially neutralized by protamine. LMWH is obtained from a full‐length, highly sulfated polysaccharide harvested from porcine mucosal tissue. The depolymerization involved in LMWH production generates a broad distribution of LMWH fragments (6–22 sugar residues). This, combined with the various methods used to produce commercial LMWHs, results in variable pharmacological and pharmacokinetic properties. An alternative chemoenzymatic approach offers a method for the synthesis of LMWH that has the potential to overcome the limitations of current LMWHs. This review summarizes the application of a chemoenzymatic approach to generate LMWH and the rationale for development of a synthetic LMWH.     

PRODIGE: a randomized placebo‐controlled trial of dalteparin low‐molecular‐weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma

Summary. Background and objectives: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We tested the efficacy of long‐term dalteparin low‐molecular‐weight heparin (LMWH) for prevention of VTE in these patients. Patients/methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti‐Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. Results: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety‐nine patients were randomized to LMWH and 87 to placebo. Twenty‐two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19–1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48–36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12‐month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73–2.0, P = 0.48). Conclusions: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long‐term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.     

Low‐molecular‐weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST‐elevation myocardial infarction: a meta‐analysis

Summary. Background: The aim of the current study was to perform two separate meta‐analyses of available studies comparing low‐molecular‐weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST‐elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. Methods: All‐cause mortality was the pre‐specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. Results: Ten studies comprising 16 286 patients were included. The median follow‐up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41–0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49–0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta‐regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). Conclusions: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta‐analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT

Summary. Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org ) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.     

Fixed-dose low-molecular-weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study.

INTRODUCTION: Secondary prevention of venous thromboembolism (VTE) with vitamin K antagonists is often problematic in patients with cancer. We prospectively evaluated the effectiveness and safety of long-term subcutaneous dalteparin in a series of consecutive patients with symptomatic VTE and metastatic cancer. PATIENTS AND METHODS : The study included 203 patients, aged 36-96 years. The initial treatment consisted of a 7-day course of subcutaneous dalteparin according to body weight. Then, patients received a fixed dose of 10 000 IU dalteparin once daily for at least 3 months. In patients developing transient thrombocytopenia the dose was reduced to 5000 IU daily while the platelet count remained <50,000; and to 2500 IU daily while it remained <10 000. Patients undergoing any surgical intervention during the study were put on 5000 IU daily during the first 4 days, switching thereafter to 10,000 IU. Patients undergoing any other invasive procedure (i.e. biopsies, punctures) received a 5000 IU dose the same day, instead of 10 000 IU. RESULTS: Eleven patients (5.4%) developed major bleeding complications (6 fatal) during the 3-month study period, and 18 patients (8.9%) developed VTE recurrences (2 patients died). There were no higher complication rates in patients with either liver or brain metastases, nor during thrombocytopenia, surgery or invasive procedures. CONCLUSIONS: Fixed dose 10,000 IU subcutaneous dalteparin once daily for 3 months was not associated with more complications in patients with liver or brain metastases. The dose adjustment for patients with thrombocytopenia, surgery or invasive procedures was safe too.     

Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review

Summary. Background: The management of recurrent pregnancy loss is uncertain. Some cohort studies have identified an association between inherited thrombophilias and recurrent or late non‐recurrent pregnancy loss, which has prompted investigators to evaluate the benefit of low molecular weight heparin (LWMH) to achieve live birth. A similar benefit for LMWH has also been proposed independent of thrombophilia status. Objective and methods: We conducted a systematic review of randomized controlled trials to assess the benefit of LMWH in achieving live birth for women with a history of recurrent or late non‐recurrent pregnancy loss in the absence of antiphospholipid antibodies. Results: For the five studies that satisfied the eligibility criteria, the risk ratio of live birth for women with a history of pregnancy loss treated with LWMH compared with control ranged from 0.95 to 3.00. There was considerable heterogeneity among studies in terms of treatment effect (Q‐value was 41.7, P = 0.000, and I² = 90.4%) independent of thrombophilia status. There was also a wide variation among all studies in terms of definition of early or late pregnancy loss, thrombophilic risk factors, and number of prior pregnancy losses. Conclusion: There is a trend for increased live births when using LWMH for the prevention of recurrent pregnancy loss. Currently, there is insufficient evidence to support the routine use of LWMH to improve pregnancy outcomes in women with a history of pregnancy loss. Not only are additional studies necessary but standardized criteria for trials evaluating the benefit of an intervention in recurrent pregnancy loss should be established.     

The safety of dosing dalteparin based on actual body weight for the treatment of acute venous thromboembolism in obese patients.

Data evaluating the safety of using weight-based low-molecular-weight heparin in the treatment of obese patients with acute venous thromboembolism are limited. The product monograph of dalteparin suggests the maximum dose should be limited to 18,000 U subcutaneously once daily. There are no specific data regarding the risk of recurrence or bleeding in patients given dalteparin in a weight-based dose of 200 IU kg(-1). We report a retrospective chart review of 193 obese patients who weighed more than 90 kg and who received dalteparin at or near to 200 IU kg(-1) actual body weight for 5-7 days for acute venous thromboembolism with 90 day follow-up information. Of the patients, 77% had idiopathic venous thromboembolism, 16% had an underlying malignancy, and 7% had a transient risk factor. Warfarin was initiated within 2 days with a target International Normalized Ratio range of 2.0-3.0. All patients were followed for 12 weeks post diagnosis. Only two patients had a major hemorrhage, 4 and 8 weeks from diagnosis. This study supports the safety of dosing dalteparin based on actual body weight in obese patients.     

Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients

Summary.  Background:  Cancer patients with venous thromboembolism (VTE) are at high risk of recurrent VTE despite standard anticoagulation. To date, very little published literature is available to guide the treatment of cancer patients with recurrent VTE. Objectives:  To evaluate the benefit and risk of low molecular weight heparin (LMWH) dose escalation in cancer patients with recurrent VTE. Patients and methods:  This was a retrospective cohort study of consecutive cancer outpatients referred for management of a symptomatic, recurrent VTE while receiving an anticoagulant. Confirmed episodes of recurrent VTE were treated with either dose escalation of LMWH in patients already anticoagulated with LMWH, or initiation of therapeutic dose LMWH in patients who were taking a vitamin K antagonist (VKA). All patients were followed for a minimum of 3 months after the index recurrent VTE unless they died during this period. Results:  Seventy cancer patients with a recurrent VTE despite ongoing anticoagulation were included. At the time of the recurrence, 67% of patients were receiving LMWH, and 33% were receiving a VKA. A total of six patients [8.6%; 95% confidence interval (CI) 4.0–17.5%] had a second recurrent VTE during the 3-month follow-up period, at an event rate of 9.9 per 100 patient-years (95% CI  2.0–17.8%). Three patients (4.3%; 95% CI  1.5–11.9%), or 4.8 per 100 patient-years (95% CI  0.0–10.3%) of follow-up, had bleeding complications. The median time between the index recurrent VTE to death was 11.4 months (range, 0–83.9 months). Conclusions:  Cancer patients with recurrent VTE have a short median survival. Escalating the dose of LMWH can be effective for treating cases that are resistant to standard, weight-adjusted doses of LMWH or a VKA.