OBJECTIVE

To compare the effectiveness and safety of low-dose unfractionated heparin and a low-molecular-weight heparin as prophylaxis against venous thromboembolism after colorectal surgery.

METHODS

In a multicenter, double-blind trial, patients undergoing resection of part or all of the colon or rectum were randomized to receive, by subcutaneous injection, either calcium heparin 5,000 units every 8 hours or enoxaparin 40 mg once daily (plus two additional saline injections). Deep vein thrombosis was assessed by routine bilateral contrast venography performed between postoperative day 5 and 9, or earlier if clinically suspected.

RESULTS

Nine hundred thirty-six randomized patients completed the protocol and had an adequate outcome assessment. The venous thromboembolism rates were the same in both groups. There were no deaths from pulmonary embolism or bleeding complications. Although the proportion of all bleeding events in the enoxaparin group was significantly greater than in the low-dose heparin group, the rates of major bleeding and reoperation for bleeding were not significantly different.

CONCLUSIONS

Both heparin 5,000 units subcutaneously every 8 hours and enoxaparin 40 mg subcutaneously once daily provide highly effective and safe prophylaxis for patients undergoing colorectal surgery. However, given the current differences in cost, prophylaxis with low-dose heparin remains the preferred method at present.

BACKGROUND

Acute pulmonary embolism (PE) may be rapidly fatal if not diagnosed and treated. IV heparin reduces mortality and recurrence of PE, but the relationship between survival and timing of anticoagulation has not been extensively studied.

METHODS

We studied 400 consecutive patients in the ED diagnosed with acute PE by CT scan angiography and treated in the hospital with IV unfractionated heparin from 2002 to 2005. Patients received heparin either in the ED or after admission. Time from ED arrival to therapeutic activated partial thromboplastin time (aPTT) was calculated. Outcomes included in-hospital and 30-day mortality, hospital and ICU lengths of stay, hemorrhagic events on heparin, and recurrent venous thromboembolism within 90 days.

RESULTS

In-hospital and 30-day mortality rates were 3.0% and 7.7%, respectively. Patients who received heparin in the ED had lower in-hospital (1.4% vs 6.7%; P = .009) and 30-day (4.4% vs 15.3%; P < .001) mortality rates as compared with patients given heparin after admission. Patients who achieved a therapeutic aPTT within 24 h had lower in-hospital (1.5% vs 5.6%; P = .093) and 30-day (5.6% vs 14.8%; P = .037) mortality rates as compared with patients who achieved a therapeutic aPTT after 24 h. In multiple logistic regression models, receiving heparin in the ED remained predictive of reduced mortality, and ICU admission remained predictive of increased mortality.

CONCLUSIONS

We report an association between early anticoagulation and reduced mortality for patients with acute PE. We advocate further study with regard to comorbidities to assess the usefulness of modifications to hospital protocols.

Intravenous heparin followed by oral anticoagulant therapy (e. g. with coumarin) is still the most widely used treatment for deep venous thromboembolism. Self-administered subcutaneous injections of heparin have been thought of as a promising alternative to coumarin, but the high doses required for ongoing prophylaxis have raised concerns about the possible development of bone disease. Certainly, long-term heparin therapy has been reported to cause osteoporosis in both laboratory animals and humans. This study aimed to compare the efficacy and safety of unfractionated (UF) heparin with that of a low molecular weight heparin (Fragmin, Kabi Pharmacia) in the prevention of recurrent deep venous thrombosis (DVT) and pulmonary embolism (PE) in a consecutive series of patients with contraindications to coumarin therapy. The patients comprised 40 men and 40 women, aged between 19 and 92 years (mean age, 68 years). They had all previously been diagnosed as having acute DVT and had been treated with conventional doses of heparin while in hospital. All patients had at least one of the following conditions: recent blood loss (either spontaneous or during admission while receiving heparin therapy); active gastroduodenal ulcer disease; psychological or physical inability or unwillingness to understand and accept the need for regular laboratory monitoring during coumarin treatment; chronic alcoholism; dementia; pregnancy; recent neurosurgery, and pericardial effusion; or were over 80 years of age. They were randomly allocated to receive either UF heparin, 10,000 IU s.c. b.d., or Fragmin, 5000 IU anti-Factor Xa s.c. b.d., for a period of 3-6 months.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

When unfractionated heparin is used to treat acute venous thromboembolism, it is usually administered by intravenous infusion with coagulation monitoring, which requires hospitalization. However, subcutaneous administration of fixed-dose, weight-adjusted, unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism.

OBJECTIVE

To determine if fixed-dose, weight-adjusted, subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism.

METHODS

Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zealand conducted from September 1998 through February 2004. Of the randomized patients, 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety.

METHODS

Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (n = 345). Low-molecular-weight heparin (dalteparin or enoxaparin) was administered subcutaneously at a dose of 100 IU/kg every 12 hours (n = 352). Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy.

METHODS

Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of randomization.

RESULTS

Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, -2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, -0.3%; 95% confidence interval, -2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group.

CONCLUSIONS

Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment.

BACKGROUND

clinicaltrials.gov Identifier: NCT00182403.

BACKGROUND

Temporary interruption of oral anticoagulation for procedures is often required, and some propose using bridging anticoagulation. However, the use and outcomes of bridging during oral anticoagulation interruptions in clinical practice are unknown.

RESULTS

The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry is a prospective, observational registry study of US outpatients with atrial fibrillation. We recorded incident temporary interruptions of oral anticoagulation for a procedure, including the use and type of bridging therapy. Outcomes included multivariable-adjusted rates of myocardial infarction, stroke or systemic embolism, major bleeding, cause-specific hospitalization, and death within 30 days. Of 7372 patients treated with oral anticoagulation, 2803 overall interruption events occurred in 2200 patients (30%) at a median follow-up of 2 years. Bridging anticoagulants were used in 24% (n=665), predominantly low-molecular-weight heparin (73%, n=487) and unfractionated heparin (15%, n=97). Bridged patients were more likely to have had prior cerebrovascular events (22% versus 15%; P=0.0003) and mechanical valve replacements (9.6% versus 2.4%; P<0.0001); however, there was no difference in CHA2DS2-VASc scores (scores ≥ 2 in 94% versus 95%; P=0.5). Bleeding events were more common in bridged than nonbridged patients (5.0% versus 1.3%; adjusted odds ratio, 3.84; P<0.0001). The incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days was also significantly higher in patients receiving bridging (13% versus 6.3%; adjusted odds ratio, 1.94; P=0.0001).

CONCLUSIONS

Bridging anticoagulation is used in one quarter of anticoagulation interruptions and is associated with higher risk for bleeding and adverse events. These data do not support the use of routine bridging, and additional data are needed to identify best practices concerning anticoagulation interruptions.

BACKGROUND

http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

BACKGROUND

Patients with acute coronary syndromes (ACS; unstable angina and non-ST-segment elevation myocardial infarction) are at significant risk for death and myocardial infarction. Early angiography followed by revascularization is considered the treatment of choice for moderate- to high-risk patients with ACS. However, despite the integration of newer therapies including stents, glycoprotein IIb/IIIa inhibitors, and thienopyridines, the rate of adverse ischemic events still remains unacceptably high, and the intensive pharmacologic regimens used to stabilize the disrupted atherosclerotic plaque and support angioplasty and surgical revascularization procedures elicit a high rate of bleeding complications. Pilot trials suggest that the thrombin-specific anticoagulant bivalirudin may improve clinical outcomes in ACS.

METHODS

In the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial, 13,800 patients with moderate- to high-risk ACS are being prospectively randomly assigned at up to 600 centers to unfractionated heparin or enoxaparin + IIb/IIIa inhibition, versus bivalirudin + IIb/IIIa inhibition, versus bivalirudin + provisional IIb/IIIa inhibition. All patients undergo cardiac catheterization within 72 hours, followed by percutaneous or surgical revascularization when appropriate. In a second random assignment, patients assigned to receive IIb/IIIa inhibitors are subrandomized to upstream drug initiation, versus IIb/IIIa inhibitor administration during angioplasty only. The primary study end point is the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days. Clinical follow-up will continue for 1 year.

CONCLUSIONS

The ACUITY trial is the largest study yet performed in patients with ACS undergoing an invasive strategy. In addition to evaluating the utility of bivalirudin in ACS, this study will also provide important guidance regarding the necessity for and timing of IIb/IIIa inhibitor administration.

Heparin is one of the oldest biological medicines, and has an established place in the prevention and treatment of venous thrombosis. Low-molecular-weight heparins (LMWH) have been developed by several manufacturers and have advantages in terms of pharmacokinetics and convenience of administration. They have been shown to be at least as effective and safe as unfractionated heparin and have replaced the latter in many indications. In this article the chemistry, mechanisms of action, measurement of anticoagulant activities, and clinical status of heparin and LMWH are reviewed.

Malignant conditions are frequently associated with a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Heparin and, its pharmacokinetically improved versions, low-molecular-weight heparins (LMWH) are effective in the prevention and treatment of thromboembolic events in cancer patients. There are several lines of preclinical evidence suggesting potential benefits of LMWH in hypercoagulation and thrombosis as well as in various processes involved in tumour growth and metastasis. Tinzaparin is a LMWH produced by controlled enzymatic depolymerisation of unfractionated heparin. The efficacy of tinzaparin has been documented in several clinical trials across various conditions and in special patient populations. The main objective of this review is to present the existing knowledge on the preclinical anti-cancer properties of tinzaparin and other LMWH. The evidence for tinzaparin, as well as other LMWH, regarding interference with cancer-induced hypercoagulation, cancer cell proliferation, degradation of extra-cellular matrix, angiogenesis, selectin-mediated binding of platelet and cancer cells, chemokine signalling, tumour progression, and metastasis are reviewed. Certain clinical trials suggest improved survival of cancer patients with deep venous thrombosis treated with LMWH versus unfractionated heparin and when added to the promising preclinical anti-cancer properties of LMWH this warrants further investigations in prospective, randomised, controlled clinical trials in cancer patients. The benefits of LMWH in cancer might at least in part, be independent from its anti-coagulant activities, but may still be partially dependent on its anti-coagulant activities.

Two likely mechanisms for the initiation of arterial platelet thrombus formation under conditions of elevated fluid shear stresses are: (1) excessive adhesion and aggregation of platelets from rapidly flowing blood onto the exposed sub-endothelium of injured, atherosclerotic arteries; or (2) direct, fluid shear stress-induced aggregation of platelets in constricted arteries with intact endothelial cells. Mechanism (1) was simulated using a parallel plate flow chamber, fibrillar collagen type I-coated slides, and mepacrine-labeled (fluorescent) platelets in whole blood anticoagulated with citrate, hirudin, unfractionated porcine heparin, or low molecular weight heparin flowing for 1 to 2 minutes at wall shear rates of 100 to 3,000 seconds-1 (4 to 120 dynes/cm2). The precise sequence of interactions among von Willebrand factor (vWF), glycoprotein (GP)Ib, and GPIIb-IIIa during platelet adhesion and subsequent aggregation were resolved by direct real-time observation using a computerized epifluorescence video microscopy system. Adhesion at high shear rates was the result of the adsorption of large vWF multimers onto collagen and the binding of platelet GPIb to the insolubilized vWF. Aggregation occurred subsequently and required the binding of ligands, including vWF via its RGD binding domain, to GPIIb-IIIa. Mechanism (2) was modeled by producing shear stresses of 90 to 180 dynes/cm2 in a rotational cone and plate viscometer, which aggregates platelets from platelet-rich-plasma (PRP) anti-coagulated with citrate, hirudin, or either type of heparin in reactions that require large vWF multimers, Ca2+, adenosine diphosphate, and both GPIb and GPIIb-IIIa. Both vWF-mediated shear-aggregation in PRP and platelet-collagen adhesion in flowing whole blood (anticoagulated with citrate and hirudin) are inhibited by two potentially useful anti-arterial thrombotic agents: polymeric aurin tricarboxylic acid (ATA; 28.5 to 114 micrograms/mL), which binds to vWF and inhibits its attachment of GPIb, and a recombinant vWF fragment (rvWF445-733; 30 to 200 micrograms/mL) that binds to platelet GPIb (in the absence of any modulator) and blocks attachment of vWF multimers. Unfractionated heparin, but not low molecular weight heparin, apparently binds to rvWF445-733 and counteracts the inhibitory effects of the vWF fragment in vitro on shear-aggregation and platelet-collagen adhesion.

BACKGROUND

Hip fracture patients have a high risk of thrombo-embolic complications following surgical management.

OBJECTIVE

To examine the effects of heparin (unfractionated (U), and low molecular weight (LMW) heparins), and physical methods (compression stockings, calf or foot pumps) for prevention of deep venous thrombosis (DVT) and pulmonary embolism after surgery for hip fracture in the elderly.

METHODS

We searched the Cochrane Musculoskeletal Injuries Group specialised register (up to March 2002), MEDLINE (1966 to March 2002), EMBASE (1980 to March 2002), CINAHL (1982 to February week 4 2002), Current Contents (1993 week 26 to 2002 week 12), reference lists of published articles and contacted trialists and other workers in the field. Date of most recent search: March 2002.

METHODS

Randomised and quasi-randomised trials evaluating the use of heparins and physical agents for prevention of DVT and pulmonary embolism in patients undergoing surgery for hip fracture.

METHODS

Two reviewers independently assessed methodological quality and extracted data. Trials were grouped into five categories (heparin versus control, mechanical versus control, LMW heparin versus U heparin, heparin versus mechanical, and miscellaneous) and results pooled where possible.

RESULTS

The 31 included trials involved at least 2958 predominantly female and elderly patients. Overall, trial quality was disappointing. Ten trials involving 826 patients which compared U heparin with control, and five trials of 373 patients which compared LMW heparin with control, showed a reduction in the incidence of lower limb DVT (124/474 (26%) versus 219/519 (42%); relative risk (RR) 0.60; 95% confidence interval (CI) 0.50 to 0.71). There were insufficient data to confirm the efficacy of either agent in the prevention of pulmonary embolism. There was no statistically significant difference in overall mortality (42/356 (12%) versus 38/374 (10%); RR 1.16; 95%CI 0.77 to 1.74). Data were inadequate for all other outcomes including wound complications. There is insufficient evidence from five trials, involving 644 patients, to establish if LMW heparin was superior to U heparin. Most trials evaluating heparins had methodological defects. Five trials, involving 487 patients, testing mechanical pumping devices were also methodologically flawed, and so pooled results need to be viewed cautiously. Mechanical pumping devices may protect against DVT (16/221 (7%) versus 52/229 (22%); RR 0.31; 95%CI 0.19 to 0.51) and pulmonary embolism. Data were insufficient to establish any effect on the incidence of fatal pulmonary embolism and overall mortality. Problems with skin abrasion and compliance were reported.

CONCLUSIONS

U and LMW heparins protect against lower limb DVT. There is insufficient evidence to confirm either protection against pulmonary embolism or an overall benefit, or to distinguish between various applications of heparin. Foot and calf pumping devices appear to prevent DVT, may protect against pulmonary embolism, and reduce mortality, but compliance remains a problem. Good quality trials of mechanical methods as well as direct comparisons with heparin and low dose aspirin should be considered.

BACKGROUND

Treatment for venous thromboembolism (VTE) is highly effective in preventing morbidity and mortality, yet pulmonary embolism (PE) accounts for up to 25% of early deaths after stroke. This is because the current diagnostic paradigm is reactive rather than proactive: the clinician responds to VTE when it becomes symptomatic, in the expectation that initiation of treatment will prevent progression to more serious manifestations. This approach is flawed, because sudden death from PE is frequently unheralded and nonfatal symptomatic pulmonary emboli are often unrecognized or misdiagnosed.

RESULTS

Morbidity and mortality from PE could be reduced either by more effective thromboprophylaxis or earlier diagnosis and treatment of established VTE. The fact that early use of short-term, low-dose, unfractionated heparin (UFH) is not associated with sustained, clinically meaningful benefit suggests that a fundamental change in the diagnostic approach to VTE is needed, one which requires a greater appreciation that clinically apparent events are merely the tip of the thromboembolism iceberg.

CONCLUSIONS

Research into a strategy of screening for subclinical VTE in these patients is needed, with a view to identifying a subgroup at risk of progression to symptomatic and life-threatening events, in whom outcome might be improved by anticoagulation.

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.

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.

BACKGROUND

Cardiopulmonary bypass (CPB) induces platelet activation with release of platelet factor 4 (PF4), and patients are exposed to high doses of heparin (H). We investigated whether this contributes to the development of antibodies to H-PF4 and heparin-induced thrombocytopenia (HIT).

RESULTS

CPB was performed with unfractionated heparin (UFH) in 328 patients. After surgery, patients received UFH (calcium heparin, 200 IU. kg-1. d-1) (group 1, n=157) or low-molecular-weight heparin (LMWH, Dalteparin, 5000 IU once daily) (group 2, n=171). Eight days after surgery, antibodies to H-PF4 were present in 83 patients (25.3%), 46 in group 1 and 37 in group 2 (P=0.12). Most patients (61%) had IgG1 to H-PF4, but only 8 samples with antibodies induced platelet activation with positive results on serotonin release assay. HIT occurred in 6 patients in group 1, but no thrombocytopenia was observed in subjects receiving LMWH, although 2 had high levels of antibodies with positive serotonin release assay results. When antibodies to H-PF4 were present, mean platelet counts were lower only in patients with FcgammaRIIA R/R131 platelets.

CONCLUSIONS

These results provide evidence that the development of antibodies to H-PF4 after CPB performed with UFH is not influenced by the postoperative heparin treatment. The antibodies associated with high risk of HIT are mainly IgG1, which is present at high titers in the plasma of patients continuously treated with UFH.

Venous thromboembolism (VTE) is a common complication of surgical procedures. The risk for VTE in surgical patients is determined by the combination of individual predisposing factors and the specific type of surgery. Prophylaxis with mechanical and pharmacological methods has been shown to be effective and safe in most types of surgery and should be routinely implemented. For patients undergoing general, gynecologic, vascular, and major urologic surgery, low-dose unfractionated heparin or low-molecular-weight heparin (LMWH) are the options of choice. For low-risk urologic surgery, early postoperative mobilization of patients is the only intervention warranted. For higher-risk patients, including those undergoing elective hip or knee replacement and surgery for hip fracture, vitamin K antagonists, LMWH, or fondaparinux are recommended. For patients undergoing neurosurgery, graduated elastic stockings are effective and safe and may be combined with LMWH to further reduce the risk of VTE. The role of prophylaxis is less defined in patients undergoing elective spine surgery, as well as laparoscopic and arthroscopic surgery. A number of issues related to prophylaxis of VTE after surgery deserve further clarification, including the role of screening for asymptomatic deep vein thrombosis, the best timing for initiation of pharmacological prophylaxis, and the optimal duration of prophylaxis in high-risk patients.

OBJECTIVE

To compare the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis for the reduction of recurrent thromboembolic events, death, extension of thrombus, and haemorrhages.

METHODS

Meta-analysis of results from 16 randomised controlled clinical studies.

METHODS

2045 patients with established deep venous thrombosis.

METHODS

Treatment with low molecular weight heparins or unfractionated heparin.

METHODS

Incidences of thromboembolic events (deep venous thrombosis or pulmonary embolism, or both); major haemorrhages; total mortality; and extension of thrombus.

RESULTS

A significant reduction in the incidence of thrombus extension (common odds ratio 0.51, 95% confidence interval 0.32 to 0.83; P = 0.006) in favour of low molecular weight heparin was observed. Non-significant trends also in favour of the low molecular weight heparins were observed for the recurrence of thromboembolic events (0.66, 0.41 to 1.07; P = 0.09), major haemorrhages (0.65, 0.36 to 1.16; P = 0.15), and total mortality (0.72, 0.46 to 1.4; P = 0.16).

CONCLUSIONS

Low molecular weight heparins seem to have a higher benefit to risk ratio than unfractionated heparin in the treatment of venous thrombosis. These results, however, remain to be confirmed by using clinical outcomes in suitably powered clinical trials.

The incidence of anticoagulant-associated intracerebral hemorrhage (AAICH) quintupled during the 1990 s, probably due to increased warfarin use for the treatment of atrial fibrillation. Anticoagulant-associated intracerebral hemorrhage now accounts for nearly 20% of all intracranial hemorrhage (ICH). Among patients using warfarin for atrial fibrillation, the annual risk of ICH in trials is 0.3 to 1.0%. Predictors of potential anticoagulant-associated hemorrhage are increasing age, prior ischemic stroke, hypertension, leukoaraiosis, the early period of warfarin use, higher intensity anticoagulation, and antiplatelet use in addition to anticoagulation. Compared with other intracranial hemorrhage patients, anticoagulated patients have a greater risk of hematoma expansion, subsequent clinical deterioration and death, necessitating vigorous reversal of their coagulopathy. Recommended methods of warfarin reversal are administration of intravenous vitamin K and either prothrombin complex concentrates or fresh frozen plasma. Reversal of unfractionated heparin is accomplished with intravenous protamine sulfate. Surgical treatment of intracranial hemorrhage may be life saving in select cases, but has not reduced morbidity or mortality in large randomized trials.

BACKGROUND

Venous thromboembolism prophylaxis with low molecular weight heparin or unfractionated heparin is recommended in acute ischaemic stroke, but which regimen provides optimum treatment is uncertain. We aimed to compare the efficacy and safety of enoxaparin with that of unfractionated heparin for patients with stroke.

METHODS

1762 patients with acute ischaemic stroke who were unable to walk unassisted were randomly assigned within 48 h of symptoms to receive either enoxaparin 40 mg subcutaneously once daily or unfractionated heparin 5000 U subcutaneously every 12 h for 10 days (range 6-14). Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe stroke>> or =14, less severe stroke <14). The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep vein thrombosis, symptomatic pulmonary embolism, or fatal pulmonary embolism. Primary safety endpoints were symptomatic intracranial haemorrhage, major extracranial haemorrhage, and all-cause mortality. This study is registered with ClinicalTrials.gov, number NCT00077805.

RESULTS

In the efficacy population (ie, one or more dose received, presence of deep vein thrombosis or pulmonary embolism, or assessment for venous thromboembolism), enoxaparin (n=666) and unfractionated heparin (669) were given for 10.5 days (SD 3.2). Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0.57, 95% CI 0.44-0.76, p=0.0001; difference -7.9%, -11.6 to -4.2); this reduction was consistent for patients with an NIHSS score of 14 or more (26 [16%] vs 52 [30%]; p=0.0036) or less than 14 (42 [8%] vs 69 [14%]; p=0.0044). The occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; p=0.83). The frequency of the composite of symptomatic intracranial and major extracranial haemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs unfractionated heparin 6 [1%]; p=0.23). We noted no difference for symptomatic intracranial haemorrhage between groups (4 [1%] vs 6 [1%], respectively; p=0.55); the rate of major extracranial bleeding was higher with enoxaparin than with unfractionated heparin (7 [1%] vs 0; p=0.015).

CONCLUSIONS

Our results suggest that for patients with acute ischaemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits to risk ratio and convenience of once daily administration.

BACKGROUND

Treatment of cerebral venous sinus thrombosis with anticoagulants has been controversial. Anticoagulants may prevent new venous infarcts, neurologic deterioration and pulmonary embolism but may also promote haemorrhages.

OBJECTIVE

To assess the effectiveness and safety of anticoagulant therapy in patients with confirmed cerebral venous sinus thrombosis.

METHODS

We searched the Cochrane Stroke Group Trials Register (last searched August 2010), MEDLINE (1950 to August 2010), EMBASE (1980 to August 2010) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011 Issue 1). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers and reference lists of relevant articles, and contacted authors.

METHODS

Unconfounded randomised controlled trials in which anticoagulant therapy was compared with placebo or open control in patients with cerebral venous sinus thrombosis (confirmed by intra-arterial contrast, or venography with magnetic resonance, or venography with computed tomography imaging).

METHODS

Two review authors independently extracted outcomes for each of the two treatment groups (anticoagulant treatment and control). The outcome data for each patient were analysed in the treatment group to which the patient was originally allocated (intention-to-treat analysis). We calculated a weighted estimate of the treatment effects across trials (relative risk, absolute risk reduction).

RESULTS

We included two small trials involving 79 patients. One trial (20 patients) examined the efficacy of intravenous, adjusted dose unfractionated heparin. The other trial (59 patients) examined high dose, body weight adjusted, subcutaneous, low-molecular weight heparin (nadroparin). Anticoagulant therapy was associated with a pooled relative risk of death of 0.33 (95% confidence interval (CI) 0.08 to 1.21) and of death or dependency of 0.46 (95% CI 0.16 to 1.31). The absolute reduction in the risk of death or dependency was 13% (95% CI 30% to -3%). No new symptomatic intracerebral haemorrhages were observed. One major gastro-intestinal haemorrhage occurred after anticoagulant treatment. Two control patients (placebo) had a diagnosis of probable pulmonary embolism (one fatal).

CONCLUSIONS

Based upon the limited evidence available, anticoagulant treatment for cerebral venous sinus thrombosis appeared to be safe and was associated with a potentially important reduction in the risk of death or dependency which did not reach statistical significance.

Background. Heparin, used clinically as an anticoagulant, also has anti-inflammatory properties. The purpose of this systematic review was to provide a comprehensive review regarding the efficacy and safety of heparin and its derivatives as anti-inflammatory agents. Methods. We searched the following databases up to March 2012: Pub Med, Scopus, Web of Science, Ovid, Elsevier, and Google Scholar using combination of Mesh terms. Randomized Clinical Trials (RCTs) and trials with quasi-experimental design in clinical setting published in English were included. Quality assessments of RCTs were performed using Jadad score and Consolidated Standards of Reporting Trials (CONSORT) checklist. Results. A total of 280 relevant studies were reviewed and 57 studies met the inclusion criteria. Among them 48 studies were RCTs. About 65% of articles had score of 3 and higher according to Jadad score. Twelve studies had a quality score>> 40% according to CONSORT items. Asthma (n = 7), inflammatory bowel disease (n = 5), cardiopulmonary bypass (n = 8), and cataract surgery (n = 6) were the most studied disease condition. Forty studies use unfractionated heparin (UFH) for intervention; the remaining studies use low molecular weight heparin (LMWH). Conclusion. Despite the conflicting results, heparin seems to be a safe and effective anti-inflammatory agent; although it is shown that heparin can decrease the level of inflammatory biomarkers and improves patient conditions, still more data from larger rigorously designed studies are needed to support use of heparin as an anti-inflammatory agent in clinical setting. However, because of the association between inflammation, atherogenesis, thrombogenesis, and cell proliferation, heparin and related compounds with pleiotropic effects may have greater therapeutic efficacy than compounds acting against a single target.

Recent studies in this laboratory demonstrated that several sulphated polysaccharides can inhibit metastasis of the rat mammary adenocarcinoma 13762 MAT, probably by preventing the passage of tumour cells through the walls of blood vessels. In order to directly test this possibility, 13762 MAT cells were cultured with (35S)O4(=)-labelled subendothelial extracellular matrices (ECM) and ECM degradation was monitored in either the presence or absence of different sulphated polysaccharides. Degradation products were detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis and subsequent autoradiography. The 5 sulphated polysaccharides that had previously been shown to possess anti-metastatic activity were potent inhibitors of the degradation of subendothelial ECM by 13762 MAT cells. In contrast, of the 4 polysaccharides tested that failed to inhibit metastasis, 3 had no effect on ECM breakdown and one (carrageenan-kappa) was substantially less effective at inhibiting ECM degradation than the anti-metastatic preparations. It was also shown that 13762 MAT cells produce a heparan sulphate-specific glycosidase (heparanase) that degrades the heparan sulphate side-chains of the ECM, the action of this enzyme rather than that of other ECM-solubilizing enzymes being inhibited by the antimetastatic sulphated polysaccharides. Additional experiments indicated that the anti-coagulant activity of the polysaccharides probably plays a minor role in their anti-metastatic effects since heparin, almost completely depleted (98-99.5%) of heparin molecules with anti-coagulant activity by passage over an anti-thrombin III column, retained its ability to inhibit 13762 MAT heparanases and was almost as effective as unfractionated heparin at inhibiting tumour-cell metastasis. Collectively, these data suggest that sulphated polysaccharides inhibit the metastasis of 13762 MAT cells by inhibiting tumour-cell-derived heparanases involved in the penetration of the vascular endothelium and its underlying basement membrane by tumour cells.

OBJECTIVE

Venous thromboembolism prevention during critical illness is a widely used quality metric. The objective of this systematic review was to systematically review the efficacy and safety of heparin thromboprophylaxis in medical-surgical patients in the ICU.

METHODS

We searched EMBASE, MEDLINE, the Cochrane Controlled Trials Register, Clinicaltrials.gov, and personal files through May 2012.

METHODS

Randomized trials in adult medical-surgical ICU patients comparing any heparin (unfractionated heparin or low-molecular-weight heparin) with each other or no anticoagulant prophylaxis, evaluating deep vein thrombosis, pulmonary embolism, major bleeding, or mortality.

METHODS

Independently, in duplicate, we abstracted trial characteristics, outcomes, and risk of bias.

RESULTS

Seven trials involved 7,226 patients. Any heparin thromboprophylaxis compared with placebo reduced rates of deep vein thrombosis (pooled risk ratio, 0.51 [95% CI, 0.41, 0.63]; p<0.0001; I=77%) and pulmonary embolism (risk ratio, 0.52 [95% CI, 0.28, 0.97]; p=0.04; I=0%) but not symptomatic deep vein thrombosis (risk ratio, 0.86 [95% CI, 0.59, 1.25]; p=0.43). Major bleeding (risk ratio, 0.82 [95% CI, 0.56, 1.21]; p=0.32; I=50%) and mortality (risk ratio, 0.89 [95% CI, 0.78, 1.02]; p=0.09; I=0%) rates were similar. Compared with unfractionated heparin, low-molecular-weight heparin reduced rates of pulmonary embolism (risk ratio, 0.62 [95% CI, 0.39, 1.00]; p=0.05; I=53%) and symptomatic pulmonary embolism (risk ratio, 0.58 [95% CI, 0.34, 0.97]; p=0.04) but not deep vein thrombosis (risk ratio, 0.90 [95% CI, 0.74, 1.08]; p=0.26; I=0%), symptomatic deep vein thrombosis (risk ratio, 0.87 [95% CI, 0.60, 1.25]; p=0.44; I=0%), major bleeding (risk ratio, 0.97 [95% CI, 0.75, 1.26]; p=0.83; I=0%), or mortality (risk ratio, 0.93 [95% CI, 0.82, 1.04]; p=0.20; I=31%).

CONCLUSIONS

Trial evidence to date suggests that any type of heparin thromboprophylaxis decreases deep vein thrombosis and pulmonary embolism in medical-surgical critically ill patients, and low-molecular-weight heparin compared with bid unfractionated heparin decreases pulmonary embolism and symptomatic pulmonary embolism. Major bleeding and mortality rates do not appear to be significantly influenced by heparin thromboprophylaxis in the ICU setting. Trial methodology, indirectness, and the heterogeneity and imprecision of some results temper inferences from this literature.

The Third Universal Definition of Myocardial Infarction (MI) requires cardiac myocyte necrosis with an increase and/or a decrease in a patient's plasma of cardiac troponin (cTn) with at least one cTn measurement greater than the 99(th) percentile of the upper normal reference limit during: (1) symptoms of myocardial ischemia; (2) new significant electrocardiogram (ECG) ST-segment/T-wave changes or left bundle branch block; (3) the development of pathological ECG Q waves; (4) new loss of viable myocardium or regional wall motion abnormality identified by an imaging procedure; or (5) identification of intracoronary thrombus by angiography or autopsy. Myocardial infarction, when diagnosed, is now classified into five types. Detection of a rise and a fall of troponin are essential to the diagnosis of acute MI. However, high sensitivity troponin assays can increase the sensitivity but decrease the specificity of MI diagnosis. The ECG remains a cornerstone in the diagnosis of MI and should be frequently repeated, especially if the initial ECG is not diagnostic of MI. There have been significant advances in adjunctive pharmacotherapy, procedural techniques and stent technology in the treatment of patients with MIs. The routine use of antiplatelet agents such as clopidogrel, prasugrel or ticagrelor, in addition to aspirin, reduces patient morbidity and mortality. Percutaneous coronary intervention (PCI) in a timely manner is the primary treatment of patients with acute ST segment elevation MI. Drug eluting coronary stents are safe and beneficial with primary coronary intervention. Treatment with direct thrombin inhibitors during PCI is non-inferior to unfractionated heparin and glycoprotein IIb/IIIa receptor antagonists and is associated with a significant reduction in bleeding. The intra-coronary use of a glycoprotein IIb/IIIa antagonist can reduce infarct size. Pre- and post-conditioning techniques can provide additional cardioprotection. However, the incidence and mortality due to MI continues to be high despite all these recent advances. The initial ten year experience with autologous human bone marrow mononuclear cells (BMCs) in patients with MI showed modest but significant increases in left ventricular (LV) ejection fraction, decreases in LV end-systolic volume and reductions in MI size. These studies established that the intramyocardial or intracoronary administration of stem cells is safe. However, many of these studies consisted of small numbers of patients who were not randomized to BMCs or placebo. The recent LateTime, Time, and Swiss Multicenter Trials in patients with MI did not demonstrate significant improvement in patient LV ejection fraction with BMCs in comparison with placebo. Possible explanations include the early use of PCI in these patients, heterogeneous BMC populations which died prematurely from patients with chronic ischemic disease, red blood cell contamination which decreases BMC renewal, and heparin which decreases BMC migration. In contrast, cardiac stem cells from the right atrial appendage and ventricular septum and apex in the SCIPIO and CADUCEUS Trials appear to reduce patient MI size and increase viable myocardium. Additional clinical studies with cardiac stem cells are in progress.

BACKGROUND

Antithrombin therapy has become a guidelines-recommended standard of care in the treatment of acute coronary syndromes (ACS), but recent trials comparing use of enoxaparin and unfractionated heparin in ACS have yielded less robust efficacy and safety results than have earlier trials of these antithrombin therapies.

OBJECTIVE

To systematically evaluate the end points of all-cause death and nonfatal myocardial infarction (MI), transfusion, and major bleeding observed in the 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in treatment of ACS.

METHODS

The primary data sets for ESSENCE, A to Z, and SYNERGY were available at the Duke Clinical Research Institute. Baseline characteristics and event frequencies for TIMI 11B, ACUTE II, and INTERACT were provided by the principal investigator of each study.

METHODS

All 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in non-ST-segment elevation ACS were selected for analysis.

METHODS

Efficacy and safety end points were extracted from the overall trial populations and the subpopulation receiving no antithrombin therapy prior to randomization.

RESULTS

Systematic evaluation of the outcomes for 21 946 patients was performed using a random-effects empirical Bayes model. No significant difference was found in death at 30 days for enoxaparin vs unfractionated heparin (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85-1.17). A statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs unfractionated heparin in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; number needed to treat, 107). A statistically significant reduction in the combined end point of death or MI at 30 days was also observed for enoxaparin in the populations receiving no prerandomization antithrombin therapy (8.0% vs 9.4%; OR, 0.81; 95% CI, 0.70-0.94; number needed to treat, 72). No significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89-1.14) or major bleeding (OR, 1.04; 95% CI, 0.83-1.30) at 7 days after randomization in the overall safety population or in the population of patients receiving no prerandomization antithrombin therapy.

CONCLUSIONS

In a systematic overview of approximately 22 000 patients across the spectrum of ACS, enoxaparin is more effective than unfractionated heparin in preventing the combined end point of death or MI.

BACKGROUND

New treatments are available for treatment of venous thromboembolism.

OBJECTIVE

To review the evidence on the efficacy of interventions for treatment of deep venous thrombosis (DVT) and pulmonary embolism.

METHODS

MEDLINE, MICROMEDEX, the Cochrane Controlled Trials Register, and Cochrane Database of Systematic Reviews from the 1950s through June 2006.

METHODS

Randomized, controlled trials; systematic reviews of trials; and observational studies; all restricted to English-language articles.

METHODS

Paired reviewers assessed study quality and abstracted data. The authors pooled results about optimal duration of anticoagulation.

RESULTS

This review includes 101 articles. Low-molecular-weight heparin (LMWH) is modestly superior to unfractionated heparin at preventing recurrent DVT and is at least as effective as unfractionated heparin for treatment of pulmonary embolism. Outpatient treatment of venous thromboembolism is likely to be effective and safe in carefully chosen patients, with appropriate services available. Inpatient or outpatient use of LMWH is cost-saving or cost-effective compared with unfractionated heparin. In observational studies, catheter-directed thrombolysis safely restored vein patency in select patients. Moderately strong evidence supports early use of compression stockings to reduce postthrombotic syndrome. Limited evidence suggests that vena cava filters are only modestly efficacious for prevention of pulmonary embolism. Conventional-intensity oral anticoagulation beyond 12 months may be optimal for patients with unprovoked venous thromboembolism, although patients with transient risk factors benefit little from more than 3 months of therapy. High-quality trials support use of LMWH in place of oral anticoagulation, particularly in patients with cancer. Little evidence is available to guide treatment of venous thromboembolism during pregnancy.

CONCLUSIONS

The authors could not address all management questions, and excluded non-English-language literature.

CONCLUSIONS

The strength of evidence varies across the study questions but generally is strong.