Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement

A double blind randomized trial comparing subcutaneous enoxaparin (40 mg once daily) with standard unfractionated calcium heparin administered at a dose of 5,000 units every 8 hours in patients undergoing elective hip replacement has been performed. Treatment regimens began 12 hours preoperatively with enoxaparin, 2 hours preoperatively with standard unfractionated calcium heparin, and were continued for 15 days or until discharge. Venography was performed in all patients. Two hundred thirty-seven patients were included in the study: 113 received unfractionated heparin and 124 received enoxaparin. The incidence of proximal deep vein thrombosis was reduced from 18.5% in the unfractionated heparin group to 7.5% in the enoxaparin group (p = 0.014), and the incidence of total deep vein thrombosis was similarly reduced from 25% to 12.5% (p = 0.03). There were two major bleeding episodes and one minor bleed in the enoxaparin group compared to two minor bleeds in the unfractionated heparin group. Patients who received enoxaparin required fewer red blood cell transfusions and had a significantly higher hemoglobin on postoperative days 3 and 4. Thus prophylaxis with enoxaparin, 40 mg once daily, is simple, safe and more effective than standard low dose unfractionated heparin in preventing deep vein thrombosis in patients undergoing elective hip replacement.     

Unsolved issues in the treatment of pulmonary embolism

The three most controversial and unsolved issues in the treatment of pulmonary embolism (PE) are: (1) the role of thrombolysis, (2) the role of low molecular weight heparin and length of hospital stay, and (3) the optimal duration of anticoagulation. The trend is to use thrombolysis more frequently, to administer low molecular weight heparin and shorten the hospitalization duration in low-risk patients, and to give prolonged courses of anticoagulation with warfarin. PE thrombolysis appears most beneficial in patients at high risk of adverse clinical outcomes in whom the potential hazards of bleeding can be justified by the danger of conservative management with anticoagulation alone. With respect to utilizing low molecular weight heparin as a way of shortening the duration of hospitalization, there are no data to warrant this approach. The current FDA mandate for symptomatic PE patients is to administer intravenous unfractionated heparin administered as a bridge to therapeutic warfarin. Finally, the optimal duration of anticoagulation following acute PE remains mired in controversy. Despite the high rate of recurrent venous thrombosis after discontinuation of anticoagulation, there are currently insufficient data to recommend indefinite warfarin therapy.     

An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis

BACKGROUND: Treatment of deep-vein thrombosis (DVT) with a once-daily regimen of enoxaparin, rather than a continuous infusion of unfractionated heparin (UFH) is more convenient and allows for home care in some patients. This study was designed to compare the efficacy and safety of these two regimens for the treatment of patients with proximal lower limb DVT. METHODS: 201 patients with proximal lower limb DVT from 13 centers in Brazil were randomized in an open manner to receive either enoxaparin [1.5 mg/kg subcutaneous (s.c.) OD] or intravenous (i.v.) UFH (adjusted to aPTT 1.5-2.5 times control) for 5-10 days. All patients also received warfarin (INR 2-3) for at least 3 months. The primary efficacy endpoint was recurrent DVT (confirmed by venography or ultrasonography), and safety endpoints included bleeding and serious adverse events. The rate of pulmonary embolism (PE) was also collected. Hospitalization was at the physician's discretion. RESULTS: Baseline patient characteristics were comparable between groups. The duration of hospital stay was significantly shorter with enoxaparin than with UFH (3 versus 7 days). In addition, 36% of patients receiving enoxaparin did not need to be hospitalized, whereas all of the patients receiving UFH were hospitalized. The treatment duration was slightly longer with enoxaparin (8 versus 7 days). There was a nonsignificant trend toward a reduction in the rate of recurrent DVT with enoxaparin versus UFH, and similar safety. CONCLUSIONS: A once-daily regimen of enoxaparin 1.5 mg/kg subcutaneous is at least as effective and safe as conventional treatment with a continuous intravenous infusion of UFH. However, the once daily enoxaparin regimen is easier to administer (subcutaneous versus intravenous), does not require aPTT monitoring, and leads to both a reduced number of hospital admissions and an average 4-day-shorter hospital stay.     

Outpatient treatment of pulmonary embolism with dalteparin

BACKGROUND: Pulmonary embolism is a common complication of deep vein thrombosis. It has been established that low molecular weight heparin may be used to treat deep vein thrombosis or pulmonary embolism and randomized studies have established that outpatient management of deep vein thrombosis with low molecular weight heparin is at least as effective as in-hospital management with unfractionated heparin. METHODS: This was a prospective cohort study of eligible patients with pulmonary embolism managed as outpatients using dalteparin (200 U/kg s/c daily) for a minimum of five days and warfarin for 3 months. Outpatients included those managed exclusively out of hospital and those managed initially for 1-3 days as inpatients who then completed therapy out of hospital. Reasons for admission included hemodynamic instability; hypoxia requiring oxygen therapy; admission for another medical reason; severe pain requiring parenteral analgesia or high risk of major bleeding. Patients were followed for three months for clinically apparent recurrent venous thromboembolism and bleeding. RESULTS: Between three teaching hospitals, a total of 158 patients with pulmonary embolism were identified. Fifty patients were managed as inpatients and 108 as outpatients. Of the outpatients, 27 were managed for an average of 2.5 days as inpatients and then completed dalteparin therapy as outpatients. The remaining 81 patients were managed exclusively as outpatients with dalteparin. For all outpatients the overall symptomatic recurrence rate of venous thromboembolism was 5.6% (6/108) with only 1.9% (2/108) major bleeds. There were a total of four deaths with none due to pulmonary embolism or major bleed. CONCLUSIONS: This prospective study suggests that outpatient management of pulmonary embolism is feasible and safe for the majority of patients.     

Defibrination during warfarin therapy in a man with protein C deficiency

A 57 year old man presented with apparently spontaneous lower extremity deep vein thrombosis and pulmonary embolism. He was treated in conventional fashion with intravenous heparin and oral warfarin. After 4 daily doses of warfarin the prothrombin and proconvertin (P+P) time was within therapeutic range, and heparin was stopped. Over the next six hours complete defibrination occurred, associated with severe bleeding complications. Functional protein C measured after normalization of routine coagulation tests averaged 40% of normal, and was only 3.5% of normal immediately prior to the episode of defibrination. We conclude that the very low functional protein C levels seen immediately prior to defibrination were caused by a combination of pre-existent protein C deficiency and warfarin therapy, and directly predisposed to defibrination once heparin was stopped, despite "therapeutic" warfarin anticoagulation. Exacerbation of intravascular coagulation should be considered a potential prothrombotic effect of warfarin therapy in protein C deficient individuals.     

The use of enoxaparin in children with acute, nonhemorrhagic ischemic stroke

The use of low-molecular-weight heparin offers multiple advantages over unfractionated heparins in pediatric patients with acute ischemic stroke. The safety and efficacy of low-molecular-weight heparin have been demonstrated in adults, but less is known about their use in children. This study reviews retrospectively the use of low-molecular-weight heparin in children with acute, ischemic, nonhemorrhagic strokes. A database search was used to locate all children who experienced an ischemic stroke between July 1991 and January 2001 and who were subsequently treated with low-molecular-weight heparin. Eight children were identified (aged 37 months to 17 years; median age, 133 months) who were treated with the low-molecular-weight heparin enoxaparin. Enoxaparin was used in one case as the sole treatment, in six cases as a bridge to oral anticoagulant therapy with warfarin, and in one case as a replacement treatment after several days of warfarin therapy. The median duration of treatment with enoxaparin was 4 days. During this period, no major bleeding complications were observed, and no new thrombi or extensions of thrombi occurred. One patient did experience mild oozing at an intravenous site, and another experienced an episode of epistaxis. Enoxaparin was discontinued in one patient because of discomfort associated with the subcutaneous injections. Although the number of patients was limited, it appears that enoxaparin is a safe and efficacious alternative to the use of unfractionated heparin in children with acute, nonhemorrhagic ischemic stroke.     

Treatment and management of acute venous thromboembolic disease

Venous thromboembolic (VTE) disease consists of deep vein thrombosis and/or pulmonary embolism. Either low molecular weight heparin given subcutaneously or unfractionated heparin administered intravenously are used for the initial treatment. Simultaneously, warfarin therapy is initiated. Thrombolytic therapy plays a limited role. Following the initial heparin treatment, anticoagulation clinics provide an excellent means of monitoring the oral anticoagulation. Patient education is important and patients should be well versed in the basic features of oral anticoagulation. The duration of oral anticoagulation is dependent on a number of factors including the presence of inherited risk factors, bleeding risk and patient reliability. Residual thrombus in the affected vein may indicate the need for prolonged anticoagulation. The low intensity oral anticoagulation (INR 1.5-2.0) is useful in preventing recurrent thrombosis following the initial treatment period with full intensity oral anticoagulation.     

Peri-procedural anticoagulation in patients undergoing ablation for atrial fibrillation

Radiofrequency catheter ablation is being used with increasing frequency as a strategy to manage atrial fibrillation. Patients undergoing this procedure are at increased short-term risk of thromboembolism for several days and up to 4 weeks or longer after their ablation, and anticoagulation management surrounding the ablation procedure remains controversial. Although no conclusive recommendations can be made, published guidelines and data support therapeutic anticoagulation with warfarin for 3 weeks prior and intravenous heparin during the ablation. Warfarin may either be continued through the ablation or stopped 2-5 days prior. If the latter approach is chosen, a pre-ablation bridging strategy of enoxaparin 1 mg/kg twice daily is reasonable in selected patients unless the patient’s bleeding risk dictates using a lower dose regimen (0.5 mg/kg twice daily) or avoiding bridging altogether. Fewer data are available for post-ablation management strategies, and current practice patterns are based largely on single-center experiences in smaller, non-randomized studies. For lower risk patients (CHADS₂ 0-1), either warfarin or aspirin may be utilized without bridging. In higher thromboembolic risk patients (CHADS₂ ≥ 2), either enoxaparin (1 mg/kg twice daily) or heparin may be started within the first 12-24 h post-procedure. For patients with bleeding risk factors, enoxaparin may be subsequently reduced to 0.5 mg/kg until the INR is therapeutic, although the efficacy of this lower dosing regimen has not been well studied. In accordance with national guidelines, warfarin should be continued post-ablation for a minimum of 2 months and then indefinitely in patients with a CHADS₂ score ≥ 2.     

Pharmacokinetics of UH and LMWH are similar with respect to antithrombin activity

BACKGROUND: The ability to administer low molecular weight heparins (LMWH) subcutaneously without laboratory monitoring contributes to their popularity for the treatment of thrombotic disorders. Subcutaneous unfractionated heparin, although less expensive, is deemed to require routine laboratory monitoring on the basis of more variability in drug effect compared to LMWH. However, the more predictable pharmacokinetic profiles of low molecular weight heparins are largely based on anti-Xa activity, while antithrombin activity may be at least as important to their mechanisms of action. METHODS: We performed a clinical pharmacokinetic trial to compare the variability in peak antithrombin effect between subcutaneous unfractionated heparin and various LMWHs, all given in recommended weight-adjusted treatment doses. Sixty-one patients enrolled in a warfarin clinic were randomized to receive one of four different weight-adjusted subcutaneous heparin doses: unfractionated heparin, 250 units/kg (n=15); tinzaparin, 175 units/kg (n=15); dalteparin, 200 units/kg (n=15); or enoxaparin, 1 mg/kg (n=16). The areas under the curves of antithrombin levels during the first 3 h after administration were determined for each patient, and the coefficients of variation (CV) and 95% confidence intervals of the AUCs were compared among the treatment groups. RESULTS: There was no statistically significant difference in the coefficients of variation of antithrombin effect between unfractionated heparin (52.8, 95% CI: 32.6-72.9) and enoxaparin (56.5, 95% CI: 35.7-77.4) or dalteparin (43.5, 95% CI 25.4-61.6). Tinzaparin had statistically significant decrease in coefficients of variation (21.6, 95% CI: 12.2-30.9) relative to unfractionated heparin, dalteparin and enoxaparin. CONCLUSIONS: LMWHs, as a class of drugs, are no more predictable in antithrombin effect after subcutaneous injection than unfractionated heparin. There were considerable differences among LMWHs in the observed variability of antithrombin effects, with tinzaparin being somewhat more predictable than the other drugs tested.     

Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients

Background

Information regarding dosing of low-molecular-weight heparins (LMWH) for therapeutic anticoagulation in hemodialysis (HD) patients is limited. The aim of this study was to retrospectively compare the safety and efficacy of enoxaparin versus unfractionated heparin (UFH) for therapeutic anticoagulation in HD patients.

Materials and Methods

This retrospective chart review evaluated HD patients treated with subcutaneous enoxaparin that were matched based on the indication for anticoagulation with patients treated with intravenous UFH to achieve therapeutic anticoagulation. Primary outcome measures included 30-day incidence of thromboembolic events and major bleeding. Secondary outcomes included rehospitalization within 30 days, length of stay, and mortality.

Results

One hundred sixty-four patients were evaluated, 82 in each group. The average daily dose of enoxaparin used to target therapeutic levels was 0.7 ± 0.2 mg/kg/day (range = 0.4-1). Comparing enoxaparin to UFH, there was no significant difference in major bleeding (6.1% vs 11%, p = 0.4) or thromboembolism (0% vs 2.4%, p = 0.5). Hospital length of stay was shorter in the enoxaparin group (20 ± 53.8 vs 28.9 ± 44.5 days, p = 0.02); there was no significant difference between groups in mortality or readmission. Adjusting for risk factors for bleeding there was a slight but statistically non-significant difference between enoxaparin versus UFH (OR = 0.77, 95%CI: 0.2-3.5, p = 0.73).

Conclusions

These findings suggest that therapeutic dosing of enoxaparin, in doses that ranged from 0.4-1 mg/kg/day, was as safe as intravenous UFH in providing therapeutic anticoagulation in stable patients requiring chronic hemodialysis.     

Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized,double-blind study

OBJECTIVES: To compare the efficacy, safety, and overall risk-benefit profile of enoxaparin and unfractionated heparin (UFH) prophylaxis of venous thromboembolic complications in patients with acute ischaemic stroke. METHODS: Patients with ischaemic stroke resulting in lower-limb paralysis lasting for at least 24 h and necessitating bedrest, were randomized within 48 h of the onset of stroke, and treated with enoxaparin (40 mg subcutaneously once daily) or UFH (5000 IU subcutaneously thrice daily) for 10 +/- 2 days. Main outcome measures were deep-vein thrombosis, pulmonary embolism (PE), death from any cause, intracranial haemorrhage including haemorrhagic infarction, or any other major bleeding. RESULTS: Outcome events occurred within 3 months of stroke in 40/106 patients treated with enoxaparin (37.7%) and 52/106 patients treated with UFH (49.1%, P=0.127). Fewer patients treated with enoxaparin (14, 13.2%) than with UFH (20, 18.9%) had evidence of haemorrhagic transformation of ischaemic stroke. CONCLUSIONS: Enoxaparin administered subcutaneously once daily was as safe and effective as subcutaneous UFH given thrice daily in the prevention of thromboembolic events in patients with lower limb paralysis caused by acute ischaemic stroke.     

Safety and efficacy of Direct Oral Anticoagulants in cerebral venous thrombosis: A meta-analysis

Cerebral venous thrombosis (CVT) is caused by partial or complete occlusion of the major cerebral venous sinuses or the smaller feeding cortical veins which predispose to the risk of venous infarction and hemorrhage. Current guidelines recommend treating CVT with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) followed by an oral vitamin K antagonist (VKA) for 3–12 months. Direct oral anticoagulants (DOACs) have already established benefit over warfarin as a long-term treatment of symptomatic venous thromboembolic disorder like deep vein thrombosis (DVT), and pulmonary embolism (PE) given its equal efficacy and better safety profile. The benefit of DOACs over warfarin as a long-term anticoagulation for CVT has likewise been extensively studied, yet it has not been approved as first-line therapy in the current practice. We therefore performed a systematic review and meta-analysis of relevant studies to generate robust evidence regarding the safety and efficacy of DOACs in CVT. This meta-analysis demonstrates that the use of DOACs in CVT has similar efficacy and safety compared to VKAs with better recanalization rate.     

The risk of recurrent venous thromboembolism in patients with unprovoked symptomatic deep vein thrombosis and asymptomatic pulmonary embolism

Patients with a first episode of symptomatic pulmonary embolism (PE) have a higher risk of recurrent venous thromboembolism (VTE) than patients with a first episode of proximal lower extremity deep vein thrombosis (DVT). Patients with symptomatic DVT and silent PE may have a different risk of VTE recurrence than patients that have symptomatic DVT without PE. Therefore, it was the aim of this prospective cohort study to compare the risk of recurrent symptomatic VTE in patients with proximal lower extremity DVT and silent PE to the risk in patients that only have proximal lower extremity DVT. Ninety-one consecutive outpatients presenting to the emergency department of a university hospital subsequently hospitalised with a first episode of unprovoked symptomatic proximal lower extremity DVT, and without new pulmonary symptoms were included. Standard initial treatment consisted of intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin for 5-7 days, overlapped with oral vitamin-K antagonist therapy, with long-term oral vitamin-K antagonist therapy (goal INR 2.5 [2.0-3.0]). Study endpoints were: symptomatic recurrent DVT, new PE, and recurrent PE, evaluated by standard objective testing. At enrollment, 28 of 91 (31%) patients with DVT had silent PE. In the patients with DVT and silent PE, there were 3 VTE recurrences during 20 person-years of follow-up, while there were no VTE recurrences during 61 person-years of follow- up in the patients with isolated DVT. The Kaplan-Meier estimated VTE recurrence rate at 1 year after the diagnosis of DVT was 11% (95% CI: 2-28%) for patients with symptomatic DVT and silent PE, compared to 0% in patients with isolated symptomatic DVT (p=0.0045). In patients with a first episode of unprovoked symptomatic acute proximal lower extremity DVT, the risk of recurrent VTE was significantly higher in those with silent PE compared to those without PE.     

Optimal dosing of subcutaneous unfractionated heparin for the treatment of deep vein thrombosis

Twice-daily, inpatient, subcutaneous unfractionated heparin is at least as effective and safe as continuous intravenous unfractionated heparin for the treatment of acute deep vein thrombosis. Subcutaneous unfractionated heparin therefore may be suitable for outpatient treatment of deep vein thrombosis. The purpose of this study was to develop a dosing nomogram for a dose each 12 hours (2 doses per day) 12-hourly subcutaneous unfractionated heparin that is suitable for outpatient treatment of acute deep vein thrombosis. A cohort study was performed in patients with acute deep vein thrombosis in two phases. In both phases, the first subcutaneous loading dose of unfractionated heparin was 317 U/kg, and the second dose was 231 U/kg. The activated partial thromboplastin time was measured daily, 6 hours after the morning injection, and subsequent doses of unfractionated heparin were adjusted according to a nomogram, which was modified for phase II. Warfarin was started with unfractionated heparin. In phase I (14 outpatients), activated partial thromboplastin time results were frequently subtherapeutic (9:14) the day after starting unfractionated heparin (day 1), and were frequently supratherapeutic (27:40) after the first 2 days of unfractionated heparin therapy. In phase II (21 patients), to explain the frequently subtherapeutic activated partial thromboplastin time results that were obtained on day 1, the activated partial thromboplastin time results were measured after the initial loading dose. Mean activated partial thromboplastin time results of 86 and 61 seconds were obtained 6 and 12 hours after this dose, suggesting that 317 U/kg is a suitable subcutaneous loading dose. In contrast to phase I, in phase II, unfractionated heparin dose was not increased on day 1 in response to a low activated partial thromboplastin time result. This reduced the frequency of supratherapeutic activated partial thromboplastin time results during the early days of therapy without increasing the frequency of subtherapeutic results. Warfarin therapy had a substantal effect on the activated partial thromboplastin time that appeared to account for a high frequency of supratherapeutic results during the later days of unfractionated heparin therapy; the activated partial thromboplastin time increased by 20 seconds (95% CI, 14–27 seconds) with each increase in the International Normalized Ratio of 1.0. We had limited success at developing a dosing nomogram for subcutaneous unfractionated heparin that reliably achieved activated partial thromboplastin time results within the therapeutic range. However, as oral anticoagulants directly increased activated partial thromboplastin time results, we suggest that adjusting unfractionated heparin dose to achieve prespecified activated partial thromboplastin time results may not be appropriate in patients who are receiving concomitant warfarin therapy.     

High utilization rate of vena cava filters in deep vein thrombosis

The objective was to investigate newly diagnosed patients with deep vein thrombosis (DVT) who received inferior vena cava filters (IVCFs). A prospective registry enrolled 5451 patients from 183 US study sites. In all patients, examination by venous duplex ultrasound confirmed the diagnosis of DVT. We collected and analyzed data on 781 patients who received an IVCF. The most frequently prescribed treatments were low-molecular-weight heparin and unfractionated heparin, which were used as a bridge to warfarin in 39% (n=2143) and 35% (n=1926) of patients, respectively. Of the total population, 781 (14%) (235 outpatients, 546 inpatients) underwent IVCF placement. The most common reasons for IVCF placement were contraindication to anticoagulation (n = 271), prophylaxis (n = 259), major bleeding related to anticoagulation therapy (n = 92), and anticoagulation failure (n = 73). Multivariate analysis revealed that patients were more likely to undergo IVCF insertion with multiple system organ failure (odds ratio [OR], 3.6; 95% CI, 1.48-8.60), previous stroke (OR,3.2;95% CI,2.11-4.74), or history of pulmonary embolism (OR,2.4; 95% CI, 1.95-2.91). In conclusion, a surprisingly high 14% (781) of patients with confirmed DVT received an IVCF. Many of these patients may have warranted less invasive methods of venous thromboembolism prophylaxis. Improved physician education regarding mechanical and pharmacologic prophylaxis alternatives might reduce the use of IVCFs.     

Anti-thrombotic efficacies of enoxaparin, dalteparin, and unfractionated heparin in venous thrombo-embolism

BACKGROUND: Few data exist by which the anti-thrombotic efficacy of different anticoagulants may be compared. We used a radiolabeled antibody specific for polymerizing fibrin to compare the in vivo anti-thrombotic potencies of different systemic anticoagulants (enoxaparin, dalteparin, and unfractionated heparin). METHODS AND RESULTS: Deep venous thrombi (DVTs) were induced in dogs' femoral veins. The dogs were then treated with one of the following subcutaneous regimens: enoxaparin 100 units/kg (1.0 mg/kg) every 12 hours (n=4), dalteparin 200 units/kg every 24 hours (n=4), or unfractionated heparin 240 units/kg every 8 hours with dose adjustment via aPTT (n=3). 111Indium-labeled anti-fibrin antibodies, specific for propagating thrombi, were given intravenously and nuclear scans of the legs were taken over the following 24 hours. Thrombus propagation was estimated by the ratio of gamma emissions from the legs containing DVTs divided by the emissions from the contralateral "control" legs. DVTs accumulated labeled anti-fibrin antibodies at the same rates in both the enoxaparin group and the dalteparin group (gamma emissions 171+/-6% and 168+/-36% of control by 24 hours, respectively). DVTs in the adjusted dose unfractionated heparin group tended to accumulate antibodies at a slower rate (129+/-19% of control by 24 hours). CONCLUSIONS: Enoxaparin and dalteparin inhibited propagation of pre-formed thrombi to the same degree. Subcutaneous unfractionated heparin, adjusted every 8 hours by aPTT, tended to suppress ongoing thrombosis more than either LMWH.     

Prevention of fatal pulmonary embolism and mortality in surgical patients: a randomized double-blind comparison of LMWH with unfractionated heparin

The incidences of fatal pulmonary embolism and death in surgical patients receiving low-molecular-weight heparin thromboprophylaxis have not been previously determined in large, adequately designed clinical trials and information on the relative efficacy and safety of unfractionated and low-molecular-weight heparin in preventing these clinical endpoints is not available. In a double-blind study, 23078 surgical patients randomly received the low-molecular-weight heparin, certoparin (3000 anti Xa IU) subcutaneously once-daily, or unfractionated heparin (5000 IU) subcutaneously three-times daily, for a minimum of 5 days. The primary outcome measure, autopsy-proven fatal pulmonary embolism recorded up to 14 days after the end of prophylaxis, occurred in 0.152% (95% confidence interval (CI) 0.10, 0.20%; 35 of 23078 patients) of cases, with no significant difference between the certoparin-treated patients (0.147% (95% CI 0.077, 0.217%; 17 of 11542 patients) and patients treated with unfractionated heparin (0.156% (95% CI 0.084, 0.228%; 18 of 11,536 patients, P=0.868). The autopsy rate was 70.2%. Comparing mortality, there was no significant difference between the groups (1 .44% [166 of 11542 certoparin patients] versus 1.27% [146 of 11536 unfractionated heparin patients]; P=0.279). The safety profiles of both treatment groups were similar. Once-daily certoparin and three-times daily unfractionated heparin are equally effective and safe in reducing fatal pulmonary embolism and death to low levels in surgical patients and mirror the findings of comparative efficacy studies using surrogate endpoints.     

Co-administration of low molecular weight heparin enhances the profibrinolytic effect of warfarin through different mechanisms

Background and Objective

Treatment with vitamin K antagonists (VKA) reduces fibrinolytic resistance through the inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor (TAFI). Because low-molecular weight heparin (LMWH) is co-administered with VKA during initiation of anticoagulant treatment, we evaluated the effect of dual anticoagulation on fibrinolytic resistance.

Patients and Methods

Two groups of patients were studied: 1) patients on stable warfarin; 2) patients starting oral anticoagulant therapy, who were evaluated during dual anticoagulation and after enoxaparin withdrawal. Only samples with an INR between 2 and 3 were compared. The resistance of clots to t-PA-induced fibrinolysis was evaluated in blood and plasma by thromboelastography (TEG) and turbidimetry, respectively.

Results

In patients on dual anticoagulation, blood fibrinolysis time (TEG) was significantly shorter than in patients on warfarin alone and significantly correlated with LMWH level. The profibrinolytic effect was partly ascribable to a reduction of thrombin-dependent TAFI activation: 1) thrombin and TAFIa generation were significantly reduced by dual anticoagulation; 2) the addition of enoxaparin to warfarin-blood reduced TAFI-mediated fibrinolysis inhibition. Patients on dual anticoagulation also displayed a reduction in clot strength, a phenomenon known to reduce fibrinolytic resistance. The profibrinolytic effect of LMWH co-administration was not seen in plasma, likely because TAFIa generation was below the threshold required to inhibit fibrinolysis.

Conclusions

Co-administration of LMWH in patients under VKA reduces the fibrinolytic resistance of blood clots via TAFI-dependent and TAFI-independent mechanisms. Further studies are warranted to assess the clinical implications of these findings.     

Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial

This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.     

The influence of fluid intake on stroke recurrence--a prospective study

PurposeA nationwide survey was conducted regarding anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) on warfarin with nonvalvular atrial fibrillation (NVAF).MethodsA questionnaire on standard therapeutic strategy for warfarin-related ICH in patients with NVAF was mailed to 416 institutes.ResultsA total of 329 physicians (79%) responded with a completed questionnaire. On admission, all respondents stopped warfarin medication and 94% normalized the international normalized ratio (INR) mainly by Vitamin K (63%), followed by fresh frozen plasma (20%), and prothrombin complex concentrate (10%). Afterwards, 91% of the respondents restarted anticoagulation and 3% used antiplatelet for prevention of thromboembolism, but the remaining 6% disagreed with restarting antithrombotic therapy. As contraindications for resuming anticoagulation, recurrent ICH (59%) and poor functional condition (59%) were often chosen. Of those who restarted anticoagulation, the timing was within 4 days in 7%, 5 to 7 days in 21%, 8 to 14 days in 25%, 15 to 28 days in 28% and 29 days or later in 18%. The major key finding on follow-up CT to restart anticoagulation was the absorption tendency of hematomas (47%). When restarting anticoagulation, 76% of the respondents used warfarin alone and 20% used either unfractionated heparin plus warfarin or heparin alone.ConclusionA large majority of respondents responsible for ICH management stopped oral warfarin medication and normalized INR on admission, and restarted anticoagulation after acute ICH in patients with NVAF. However, the strategies to normalize INR and to restart anticoagulant therapy varied greatly and depended on each individual physician's decision.