Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry1

Summary. Background: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. Objectives: We assessed the incidence, risk factors and prognosis of heparin‐associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Patients/Methods: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25 369 patients with confirmed VTE until February 2009. Among them, 24 401 patients were treated either with UFH or with LMWH, and had available information about the 6‐month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150 000 mm^–3. Results: One hundred and forty‐one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6‐month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79–2.17) than in the LMWH group (0.54%, 95% CI 0.44–0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58–9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64–3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH‐associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. Conclusions: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non‐cancerous patients.     

Individual patient data meta‐analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients

Summary. Background: Unfractionated heparin (UFH) and low‐molecular‐weight heparin (LMWH) are both recommended for venous thromboembolism (VTE) prophylaxis in hospitalized medical patients. Objective: To perform an individual patient data meta‐analysis to evaluate the relative efficacy and safety of the LMWH enoxaparin and UFH in preventing VTE in hospitalized medical patients. Methods: Randomized clinical trials comparing subcutaneous enoxaparin (4000 IU once‐daily) and UFH (5000 IU subcutaneous two‐ or three‐times daily) for VTE prevention were identified by a systematic search. Individual patient data were obtained from each eligible trial. Results: Overall, four trials were eligible, including 3600 patients randomized to receive enoxaparin (n = 1799) or UFH (n = 1801). Median patient age was 71 years, and 49.3% were female. Compared with UFH, enoxaparin was associated with risk reductions of 37% for total VTE [relative risk (RR) 0.63, 95% confidence interval (CI) 0.51–0.77] and 62% for symptomatic VTE (RR 0.38, 95% CI 0.17–0.85) at day 15. RR for total VTE in stroke and non‐stroke patients was 0.59 (95% CI 0.47–0.74) and 0.87 (95% CI 0.51–1.50), respectively. Major bleeding rates were consistently low and similar between treatment groups at day 15 (RR 1.13, 95% CI 0.53–2.44). There was a trend towards reduced risk for mortality in patients receiving enoxaparin (RR 0.83, 95% CI 0.64–1.08), compared with UFH. Conclusions: Enoxaparin significantly reduces VTE in hospitalized medical patients, compared with UFH, without increasing the risk for major bleeding, and was associated with a trend towards reduced all‐cause mortality.     

Fondaparinux for thromboembolic treatment and prophylaxis of heparin-induced thrombocytopenia

OBJECTIVE: To review literature evaluating the use of fondaparinux for thromboembolic treatment and prophylaxis in patients with heparin-induced thrombocytopenia (HIT). DATA SOURCES: A MEDLINE search (1966-February 2006) was conducted using the search terms fondaparinux, heparin, low-molecular-weight heparin, and thrombocytopenia to identify English-language articles. Additional sources were identified from bibliographies of select articles and the manufacturer. DATA SYNTHESIS: Fondaparinux, a pentasaccharide that selectively inhibits factor Xa, has been reported to have negligible or no cross-reactivity in vitro with HIT antibodies. Thromboembolic treatment and prophylaxis with fondaparinux in patients with HIT has been described. Three cases reported patients who were successfully treated for thromboembolic events with fondaparinux after developing HIT during therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Another report showed positive outcomes using fondaparinux for prophylaxis in a patient who had previously developed HIT after receiving UFH. Moreover, 2 case series, one using fondaparinux for prophylaxis in patients with a previous diagnosis of HIT and the other using fondaparinux for treatment in patients who developed HIT while receiving UFH or LMWH, reported normal platelet counts during fondaparinux treatment. Finally, results of a retrospective review demonstrated that fondaparinux prevented thromboembolic events or recurrent thrombocytopenia in patients with a prior HIT diagnosis. CONCLUSIONS: Limited data support the use of fondaparinux for thromboembolic treatment or prophylaxis in patients with antibody assay-confirmed HIT who do not have a contraindication for fondaparinux use. Randomized controlled trials have not been published; therefore, questions remain regarding efficacy, safety, optimal doses, treatment duration, and incidence of thromboembolic events when fondaparinux is used in this setting. Prospective trials evaluating the efficacy and safety of fondaparinux in this patient population need to be conducted to answer these questions.     

International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer

Summary. Background: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. Objectives: To establish a common international consensus addressing practical, clinically relevant questions in this setting. Methods: An international consensus working group of experts was set up to develop guidelines according to an evidence‐based medicine approach, using the GRADE system. Results: For the initial treatment of established VTE: low‐molecular‐weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case‐by‐case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long‐term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3–6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit‐risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12–2 h preoperatively and continued for at least 7–10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l ‐asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low‐dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl < 30 mL min^?1), thrombocytopenia and pregnancy. Guidances are provided in these contexts. Conclusions: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.     

Prevention of venous thromboembolism after acute ischemic stroke

Venous thromboembolism (VTE) is a common complication after acute ischemic stroke. When screened by 125I fibrinogen scanning or venography, the incidence of deep-vein thrombosis (DVT) in stroke patients is comparable with that seen in patients undergoing hip or knee replacement. Most stroke patients have multiple risk factors for VTE, like advanced age, low Barthel Index severity score or hemiplegia. As pulmonary embolism is a major cause of death after acute stroke, the prevention of this complication is of crucial importance. Prospective trials have shown that both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effective in reducing DVT and pulmonary embolism in stroke patients. Current guidelines recommend the use of these agents in stroke patients with risk factors for VTE. Some clinicians are concerned that the rate of intracranial bleeding associated with thromboprophylaxis may outweigh the benefit of prevention of VTE. Low-dose LMWH and UFH seem, however, safe in stroke patients. Higher doses clearly increase the risk of cerebral bleeding and should be avoided for prophylactic use. Both aspirin and mechanical prophylaxis are suboptimal to prevent VTE. Graduated compression stockings should be reserved to patients with a clear contraindication to antithrombotic agents.     

Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation

Background

Clinical trials have shown low-molecular weight heparin (LMWH) to be at least as safe and efficacious as unfractionated heparin (UFH) for preventing venous thromboembolism (VTE) in acutely-ill medical inpatients.

Objective

To compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice.

Methods

Using a large, multi-hospital, US database, we identified persons aged ≥40 years hospitalized for ≥6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs. RESULTS: 479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups.

Conclusion

We observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.     

Thrombosis, cancer and renal insufficiency: low molecular weight heparin at the crossroads

Background

Venous thromboembolism (VTE) and renal insufficiency are common in cancer patients. Prompt treatment is necessary to reduce the high rates of VTE-related mortality and morbidity. VTE prophylaxis is underused in cancer patients. We review current recommendations for the treatment and prevention of VTE in cancer patients and discuss low molecular weight heparin (LMWH) use in cases of renal failure.

Design

This study is a retrospective literature review.

Results

There are few published recommendations for LMWH use in cancer patients with renal insufficiency. Treatment guidelines largely follow recommendations for other patients with renal failure. Enoxaparin therapy is complicated by the need for regular monitoring of renal function and anti-Xa levels and for dosage adjustment to prevent bleeding. Few data are available to support the systematic use of dalteparin. Tinzaparin is least likely to bioaccumulate in patients with renal failure.

Conclusion

VTE is the second most common cause of death in cancer patients. Renal insufficiency is present in 50–60?% of cancer patients. Data from renal patients suggest that tinzaparin may be safe and effective for VTE treatment and prevention in cancer patients with renal failure.     

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.     

低分子肝素钠对血液透析患者钙磷代谢影响的临床观察

目的探讨低分子肝素钠对维持性血液透析（MHD）患者钙磷代谢的影响。方法选择在上海市闸北区中心医院肾内科血液净化中心无明显出血倾向透析龄超过3个月的MHD患者78例,随机分成低分子肝素钠（LMWH）组38例和普通肝素（UFH）组40例。分别观察二组患者在治疗前、治疗后3、6、12个月的血钙、血磷、血清甲状旁腺激素（iPTH）、血清碱性磷酸酶（AKP）的水平。同时观察患者出血、体外循环的凝血情况及不良反应等。结果①二组患者治疗前血钙、血磷、PTH、AKP水平无统计学意义（P〉0.05）;②LMWH组随着透析时间延长,血磷及PTH水平逐渐降低,有统计学意义（均P〈0.05）;UFH组随着透析时间延长,血磷、PTH水平治疗前后无明显变化（P〉0.05）;二组治疗前后血钙和AKP水平均无统计学意义（均P〉0.05）;③LMWH组透析5708例次,各部位出血共发生58例次,发生率为1.02%;UFH组透析6012例次,各部位出血共发生1310例次,发生率为21.8%,6例患者退出UFH组。LMWH组的出血发生率较UFH组明显降低（P〈0.01）,二组体外循环凝血发生率无统计学意义（P〉0.05）。结论长期使用低分子肝素抗凝,可使血液透析患者所存在的钙磷代谢异常得到部分缓解,提示低分子肝素可能有改善钙磷代谢异常的作用。     

The use of long-term low-molecular weight heparin for the treatment of venous thromboembolism in palliative care patients with advanced cancer: a case series of sixty two patients

The advantages of low-molecular weight heparin (LMWH) over warfarin, in the treatment of cancer associated venous thromboembolism (VTE) are well reported. However the studies supporting LMWH include few patients representative of the palliative care population. Although LMWH has advantages over warfarin it is still unclear, within the palliative care environment, how long anticoagulation should be continued, what dose of LMWH should be used and whether palliative care patients experience different complication rates such as bleeding, heparin-induced thrombocytopenia and osteoporosis.We report a case series of 62 patients with advanced malignancy and VTE treated with long-term LMWH according to either the CLOT (full dose) or Montreal (reduced dose) regime. Seventy-four percent of patients self-administered LMWH, whereas 24% had it given by a carer and 2% by the district nurse. LMWH was given for median duration of 97 days; the most common reason for discontinuation of therapy being admission to die or commencement of the care pathway (n = 50, 81%). A further 11% (n = 7) stopped after 6 months of treatment. Of these 3 (43%) developed clinical symptomatic recurrence of VTE. The overall minor bleeding rate was 8.1% (95% confidence interval 3.5-17.5%), and this was not associated with NSAID or steroid use. No major bleeding events were observed. No patients developed evidence of heparin-induced thrombocytopenia or osteoporosis.Long-term LMWH appears effective in treatment of VTE in the palliative care population with advanced cancer. A randomised control trial is required to identify the best dose required to ensure optimum efficacy and safety.     

Meta-analysis of venous thromboembolism prophylaxis in medically Ill patients

BACKGROUND: Venous thromboembolism (VTE) prophylaxis in medically ill patients has received a level 1A recommendation in previously published clinical guidelines. Pharmacologic prophylaxis for VTE includes unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Few direct comparisons between anticoagulants exist in medically ill patients. OBJECTIVE: This meta-analysis was conducted to assess UFH and LMWH (including the selective factor Xa inhibitor fondaparinux) in the reduction of in-hospital VTE in unselected medically ill patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry databases from January 1981 through September 2007 (English language) for randomized controlled trials using the following terms: dalteparin, enoxaparin, fondaparinux, nadroparin, and heparin. References of included articles and key review papers for additional studies were also searched. Data from studies were included in the analysis if the studies included medically ill patients with risk factors for VTE who had been followed up for 7 to 21 days. RESULTS: A total of 12,391 patients (of whom 8357 were in placebo-controlled trials) from 9 studies were included. Mean age for the entire cohort was 72.8 years; mean (SD) body mass index, 25.6 kg/m2; and mean (SD) actual body weight, 68.2 kg. Deep vein thrombosis (DVT) was significantly reduced with the addition of an LMWH compared with placebo (odds ratio [OR], 0.60; 95% CI, 0.47-0.75; P < or = 0.001), but rates of DVT were similar when comparing LMWH with UFH (OR, 0.92; 95% CI, 0.56-1.52). No significant differences in pulmonary embolism (PE) or death were found among the UFH, LMWH, and placebo groups. LMWH was associated with a significant increased risk for minor bleeding compared with placebo (OR, 1.64; 95% CI, 1.18-2.29; P = 0.003). However, no significant difference was found between LMWH and UFH (OR, 0.68; 95% CI, 0.27-1.70). Major bleeding events were similar among all groups: LMWH/fondaparinux versus placebo, OR, 1.65 (95% CI, 0.8-3.4); LMWH/fondaparinux versus UFH, OR, 0.69 (95% CI, 0.29-1.68); LMWH/fondaparinux versus UFH or placebo, OR, 1.16 (95% CI, 0.66-2.04). CONCLUSIONS: This analysis suggests that VTE prophylaxis with an LMWH (including fondaparinux) or UFH is effective in reducing the rate of DVT, but this benefit did not extend to enhanced protection against PE. Additionally, LMWH and UFH had similar bleeding outcomes.     

Management of venous thromboembolism during pregnancy

Summary.  The incidence of venous thromboembolism (VTE) probably increases 2–4-fold in pregnancy and is higher after a caesarean section than after vaginal delivery. Management of VTE in pregnancy is challenging. Many diagnostic tests are less accurate in pregnant than in non-pregnant patients and some radiologic procedures expose the fetus to ionizing radiation, although this can be reduced by taking appropriate precautions. Compression ultrasonography (CUS) is the test of choice for deep vein thrombosis (DVT), whereas for PE, V/Q lung scan is the first-line test, followed by CUS if the results are non-diagnostic.
Anticoagulants that have been evaluated for the prevention and treatment of VTE in pregnancy include heparin and heparin compounds, and coumarin derivatives. When determining the optimal treatment regimens, it is important to consider: (i) the safety of the drug for the fetus and mother; (ii) the efficacy of the regimen; and (iii) the dose regimens for acute and secondary treatment, and during delivery and postpartum. Heparins are safer than coumarins for the fetus, as they do not cross the placental barrier. Heparins, particularly unfractionated heparin (UFH) and low molecular weight heparin (LMWH) tend also to be safer for the mother than other compounds. Of the two, LMWHs, although more expensive, are associated with lower rates of bleeding complications, and heparin-induced thrombocytopenia and osteoporosis, than UFH, and should therefore be the treatment of choice in VTE during pregnancy.
Patients with prior VTE or a hypercoagulable state have an increased risk of VTE during pregnancy. Depending on the presence of one or both of these factors, clinical surveillance, with anticoagulant treatment where necessary, is recommended.     

Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants

Summary. Background: The management of venous thromboembolism (VTE) requires an initial treatment with unfractionated heparin (UFH) or low‐molecular‐weight heparin (LMWH), followed by oral anticoagulants (OA) for at least 3 months. OA treatment however, requires laboratory monitoring of anticoagulation, carries a definite risk of bleeding, and may be contraindicated in some patients. As an alternative to vitamin K antagonists, subcutaneous LMWH has been proposed and evaluated in randomized clinical trials, but they are all small studies that lack the power to establish if these two treatment modalities are equivalent in efficacy or safety. Objectives: The objective of this review was to evaluate the efficacy (VTE recurrence) and safety (bleeds and deaths) of long‐term treatment of VTE with LMWH compared with OA. A secondary endpoint was to evaluate the effect of LMWH on cancer mortality. Methods: Computerized searches of MedLine and EmBase were performed. In addition, randomized clinical trials were located through personal communication with colleagues, and through the manual scanning of meeting proceedings and reference lists of relevant studies. When necessary, the authors of the selected papers were called to obtain additional information. Two reviewers (AI and FG) reviewed and extracted data independently using a standard form. The primary analysis was performed for efficacy and safety endpoints on an intention‐to‐treat basis for the study period of randomized treatment. A meta‐regression analysis was used to investigate the relationship between daily dose and clinical outcome. Results: Seven studies that fulfillled our predefined criteria were identified, for a total of 1379 patients. When all studies were combined, a statistically non‐significant reduction in the risk of VTE (OR 0.66; 95% confidence interval [CI] 0.41, 1.07) and in the risk of major bleeding (OR 0.45; 95% CI 0.18, 1.11) in favor of LMWH treatment was found. No difference in total mortality (OR 1.19; 95% CI 0.78, 1.83) or in cancer‐related mortality was observed between the LMWH and the OA treatment. Conclusions: The results of this meta‐analysis indicate that a 3‐month course of LMWH is as effective and safe as a corresponding period of OA treatment, and may thus be considered as a valuable alternative option for patients in whom OA treatment appears contraindicated or problematic.     

Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry.

BACKGROUND: Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective surgical or an invasive procedure. Heparin bridging therapy has been used in these situations, although the optimal method has not been established. No large prospective studies have compared unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for the perioperative management of patients at risk of thromboembolism requiring temporary interruption of long-term OAC therapy. PATIENTS/METHODS: This multicenter, observational, prospective registry conducted in North America enrolled 901 eligible patients on long-term OAC who required heparin bridging therapy for an elective surgical or invasive procedure. Practice patterns and clinical outcomes were compared between patients who received either UFH alone (n = 180) or LMWH alone (n = 721). RESULTS: Overall, the majority of patients (74.5%) requiring heparin bridging therapy had arterial indications for OAC. LMWH, in mostly twice-daily treatment doses, represented approximately 80% of the study population. LMWH-bridged patients had significantly fewer arterial indications for OAC, a lower mean Charlson comorbidity score, and were less likely to undergo major or cardiothoracic surgery, receive intraprocedural anticoagulants or thrombolytics, or receive general anesthesia than UFH-bridged patients (all P < 0.05). The LMWH group had significantly more bridging therapy completed in an outpatient setting or with a < 24-h hospital stay vs. the UFH group (63.6% vs. 6.1%, P < 0.001). In the LMWH and UFH groups, similar rates of overall adverse events (16.2% vs. 17.1%, respectively, P = 0.81), major composite adverse events (arterial/venous thromboembolism, major bleed, and death; 4.2% vs. 7.9%, respectively, P = 0.07) and major bleeds (3.3% vs. 5.5%, respectively, P = 0.25) were observed. The thromboembolic event rates were 2.4% for UFH and 0.9% for LMWH. Logistic regression analysis revealed that for postoperative heparin use a Charlson comorbidity score > 1 was an independent predictor of a major bleed and that vascular, general, and major surgery were associated with non-significant trends towards an increased risk of major bleed. CONCLUSIONS: Treatment-dose LMWH, mostly in the outpatient setting, is used substantially more often than UFH as bridging therapy in patients with predominately arterial indications for OAC. Overall adverse events, including thromboembolism and bleeding, are similar for patients treated with LMWH or UFH. Postoperative heparin bridging should be used with caution in patients with multiple comorbidities and those undergoing vascular, general, and major surgery. These findings need to be confirmed using large randomized trials for specific patient groups undergoing specific procedures.     

Hospital-based costs associated with venous thromboembolism treatment regimens

Summary.  Introduction:  Venous thromboembolism (VTE) poses a significant health and economic burden in US hospitals. Clinical guidelines for acute VTE treatment recommend antithrombotic therapy (at least 5 days) with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). With upcoming US national performance measures requiring successful implementation of evidence-based therapy, cost considerations for anticoagulant choice are of increasing importance to hospitals. Methods:  This retrospective cohort analysis utilizes discharge records from a large real-world US population (January 2002 to December 2006) to provide total, direct, inpatient medical costs associated with LMWH and UFH for acute VTE treatment. Furthermore, for both LMWH and UFH discharges, we compare VTE-related readmission rates at 30 and 90 days after discharge. Results:  In total, 57 131 discharges were identified (57.7% LMWH; 42.3% UFH). After adjustment for covariates, including age, severity of illness, and length of stay, total direct medical costs per hospital discharge for UFH were $3476.22 vs. $3056.42 for LMWH ( P  < 0.0001; difference $420). Costs were significantly higher in the UFH group for most cost categories. Notably, drug acquisition cost was higher for LMWH. LMWH treatment was 12% [odds ratio (OR) 0.876; P  < 0.001] and 10% (OR 0.895; P  = 0.0006) less likely to result in VTE readmission within 30 and 90 days, respectively. Conclusions:  This study provides the first large, real-world analysis of the total direct medical costs of treating VTE in-hospital. It confirms that, despite higher drug acquisition costs, LMWH is cost-saving compared with UFH in the inpatient setting, and is associated with a lower VTE readmission rate at 30 and 90 days than is UFH.     

低分子量肝素在血液透析应用中的评价

目的：比较低分子量肝素与普通肝素在常规血液透析抗凝中的有效性和安全性。方法：40例血液透析患分别用低分子量肝素和普通肝素抗凝进行自身对照，并作低分子肝素组与普通肝素组的组间对照。观察透析器及透析管道的凝血状态，内瘘穿刺点的压迫止血时间，抗因子Xa活性(AFXa)、凝血酶时间(TT)和活化部分凝血活酶时间(APTT)。结果：两组患均能顺利完成5小时透析，透析器及透析管道凝血程度及穿刺点压迫止血时间两组均无显差异(P＞0．05)。两组患使用低分子肝素抗凝透析结束时AFXa较血液透析前有显性差异(P＜0．001)，且透析开始后30分钟及透析结束时均明显高于普通肝素组，而APTT、TT在LMWH抗凝过程中无显延长，而普通肝素组则明显延长。结论：低分子量肝素在血液透析抗凝过程中较之普通肝素更有效，安全，方便，可替代普通肝素。     

Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly

Heparin‐induced thrombocytopenia (HIT) is the most common drug‐induced, antibody‐mediated cause of thrombocytopenia and thrombosis. HIT is caused by IgG antibodies that bind to epitopes on platelet factor 4 (PF4) released from activated platelets that develop when it forms complexes with heparin. Anti‐PF4/antibodies develop in over 50% of patients undergoing surgery involving cardiopulmonary bypass (CPB), an incidence 20‐fold higher than HIT. Why might this occur? Binding of HIT IgG occurs only over a narrow molar ratio of reactants, being optimal at 1 mol PF4 tetramer to 1 mol unfractionated heparin (UFH). At these ratios, PF4 and UFH form ultralarge (>670 kD) complexes that bind multiple IgG molecules/complex, are highly antigenic, and promote platelet activation. Low molecular weight heparin (LMWH), which is less antigenic, forms ultralarge complexes less efficiently and largely at supratherapeutic concentrations. In transgenic mice that vary in expression of human PF4 on their platelets, antigenic complexes form between PF4 and endogenous chondroitin sulfate. Binding of HIT IgG to platelets and induction of thrombocytopenia in vivo is proportional to PF4 expression. Heparin prolongs the duration and exacerbates the severity of the thrombocytopenia. High doses of heparin, as used in CPB, or protamine, which competes with PF4 for heparin, disrupts antigen formation and prevents thrombocytopenia induced by HIT antibody. These studies may help explain the disparity between the incidence of antibody formation and clinical disease and may help identify patients at risk for HIT (high platelet PF4). They also demonstrate that this autoimmune disease can be modulated at the level of autoantigen formation and point to rational means to intervene proximal to thrombin generation. J. Clin. Apheresis. 22:, 2007 © 2007 Wiley‐Liss, Inc.     

Cost-minimization analysis of low-molecular-weight heparin (dalteparin) compared to unfractionated heparin for inpatient treatment of cancer patients with deep venous thrombosis

Goals Low-molecular-weight heparin (LMWH) has shown to be as effective as unfractionated heparin (UFH) in the treatment of deep venous thrombosis (DVT). Although the acquisition cost of LMWH is significantly greater than that of UFH, we hypothesized that once-daily dalteparin, a LMWH, could reduce treatment costs of cancer patients with DVT by eliminating anticoagulation monitoring and shortening hospitalization.Patients and methods We developed a cost-minimization model by using outcomes and resource utilization data from two retrospective matched cohorts of cancer patients who, between 1994 and 1999, were hospitalized at our comprehensive cancer center for treatment of DVT with either LMWH (n=21) or UFH (n=168). We assumed all LMWHs and UFH to be equally effective. The total costs for the dalteparin strategy and the UFH strategy were calculated in year 2003 U.S. dollars, from the providers perspective, by multiplying the number of resources used for inpatient treatment of DVT by their unit costs.Results The mean total cost for inpatient care was $3,383 (95% CI= $2,683– $4,083) for dalteparin and $4,952 (95% CI=$4,718–$5,185) for UFH. Substantial savings resulted from shorter hospitalization among the dalteparin-treated patients (mean 3.19 versus 5.22 days). Sensitivity analysis did not change the conclusion that dalteparin is less expensive than UFH.Conclusions Savings realized from less anticoagulant monitoring and shorter hospitalization offset the higher acquisition cost of dalteparin. The dalteparin strategy is less expensive than the UFH strategy for the inpatient treatment of DVT among cancer patients.Presented in part at the 3rd Annual Houston Area Health Services & Outcomes Research Conference, Houston, TX, USA, November 25, 2002     

Primary and secondary prophylaxis of venous thromboembolism with low-molecular-weight heparins: prolonged thromboprophylaxis, an alternative to vitamin K antagonists

Low-molecular-weight heparins (LMWHs) are used widely in the treatment and prevention of venous thromboembolism (VTE). The LMWHs dalteparin and enoxaparin reduce the rate of VTE by at least 50% if administered for 4-5 weeks following major orthopedic surgery, compared with in-hospital prophylaxis for 7-15 days. Meta-analyses have confirmed that the size of the reduction is similar for both clinical and asymptomatic VTE. Vitamin K antagonists (VKAs) have been shown to be associated with significantly higher bleeding rates compared with LMWH when used as prolonged prophylaxis against VTE following major orthopedic surgery. Patients with cancer are a recognized group at high risk of VTE, and those undergoing major surgery for their malignancy are at particular risk. Evidence from clinical trials is amassing to show that prolonged prophylaxis with LMWH (dalteparin, enoxaparin) in these patients can significantly reduce the rate of postoperative VTE. In cancer patients with acute VTE, the traditional approach is to initiate acute treatment with unfractionated heparin or LMWH followed by long-term treatment with VKA to prevent recurrence. However, clinical trial data have confirmed that the LMWH dalteparin, when administered for 6 months, is significantly more effective than VKA in preventing recurrence, cutting the rate of VTE by 52% without increasing the risk of bleeding. A new and intriguing area of interest is whether LMWH can enhance survival in patients with cancer. Preliminary data suggest that a biological effect of LMWH may act to prolong survival in patients with cancer.     

Heparins

Unfractionated heparin (UH) and low-molecular-weight heparins (LMWH) are antithrombotic drugs covering virtually all indications requiring immediately effective anticoagulation. For prevention and treatment of venous thromboembolism (VTE) UH have mainly been replaced by LMWH due to their practical usefulness (one or two subcutaneous daily doses without laboratory test for dose adjustment) and their more favourable risk-benefit profile. With respect to arterial occlusions this statement is also valid for unstable angina pectoris. The risk to develop heparin-induced thrombocytopenia (HIT) appears to be ten times lower with LMWH. In hospitals the use of UH is reserved for complex cases with high bleeding risk and the necessity to interrupt heparin effects rapidly. Therapeutic doses of UH are monitored by the classical coagulation assays, activated partial thromboplastin time (aPTT) and thrombin time (TT), but also by automated chromogenic tests of anti-factor Xa activity. There are no prospective studies directly comparing the efficiency of these three approaches. Disagreements between tests are not rare in individual cases. However, dosing recommendations for UH treatment of VTE (intravenous bolus of 80 IU/kg, followed by 18 IU/kg/h infusion) and average doses used are concordant. 0.30-0.70 anti-Xa IU/ml are considered as therapeutic range for UF infusion. Higher UH activities required during extracorporeal circulation in heart surgery or during coronary angioplasty are usually guided by bedside ACT (activated clotting time). For LMWH tests of anti-Xa activities may only be necessary during weight adjusted treatment of pregnant women, children, or cases with reduced kidney function (glomerular filtration rate < 30 ml/min.) or increased bleeding risk. Expected anti-Xa activities are 0.5-1.1 IU/ml and 1.0-2.0 IU/ml 4 hours after subcutaneous LMWH for dosing intervals of 12 hours and 24 hours respectively.