BACKGROUND

There is uncertainty about the role of intravenous unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in patients with ST-elevation myocardial infarction (STEMI) treated with aspirin and thrombolysis.

RESULTS

We performed a meta-analysis of the randomized trials to assess the effect of UFH and LMWH on reinfarction, death, stroke, and bleeding. Fourteen trials involving a total of 25,280 patients were included (1239 comparing intravenous UFH versus placebo or no heparin; 16,943 comparing LMWH versus placebo; and 7098 comparing LMWH versus intravenous UFH). Intravenous UFH during hospitalization did not reduce reinfarction (3.5% versus 3.3%; odds ratio [OR], 1.08; 95% CI, 0.58 to 1.99) or death (4.8% versus 4.6%; OR, 1.04; 95% CI, 0.62 to 1.78) and did not increase major bleeding (4.2% versus 3.4%; OR, 1.21; 95% CI, 0.67 to 2.18) but increased minor bleeding (19.6% versus 12.5%; OR, 1.72; 95% CI, 1.22 to 2.43). During hospitalization/at 7 days, LMWH compared with placebo reduced the risk of reinfarction by approximately one quarter (1.6% versus 2.2%; OR, 0.72; 95% CI, 0.58 to 0.90; number needed to treat [NNT]=167) and death by &10% (7.8% versus 8.7%; OR, 0.90; 95% CI, 0.80 to 0.99; NNT=111) but increased major bleeding (1.1% versus 0.4%; OR, 2.70; 95% CI, 1.83 to 3.99; number needed to harm [NNH]=143) and intracranial bleeding (0.3% versus 0.1%; OR, 2.18; 95% CI, 1.07 to 4.52; NNH=500). The reduction in death with LMWH remained evident at 30 days. LMWH compared with UFH during hospitalization/at 7 days reduced reinfarction by &45% (3.0% versus 5.2%; OR, 0.57; 95% CI, 0.45 to 0.73; NNT=45), did not reduce death (4.8% versus 5.3%; OR, 0.92; 95% CI, 0.74 to 1.13) or increase major bleeding (3.3% versus 2.5%; OR, 1.30; 95% CI, 0.98 to 1.72), but increased minor bleeding (22.8% vs 19.4%; OR, 1.26; 95% CI, 1.12 to 1.43). The reduction in reinfarction remained evident at 30 days.

CONCLUSIONS

In aspirin-treated patients with STEMI who are treated with thrombolysis, intravenous UFH has not been shown to prevent reinfarction or death. LMWH given for 4 to 8 days compared with placebo reduces reinfarction by approximately one quarter and death by &10% and when directly compared with UFH reduces reinfarction by almost one half. These data suggest that LMWH should be the preferred antithrombin in this setting.

BACKGROUND

The Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) trials evaluated fondaparinux, a synthetic factor Xa inhibitor, in patients with non-ST- and ST-segment elevation acute coronary syndromes, respectively. Combined results for these 2 trials on major efficacy and safety outcomes and data on the effects of fondaparinux in relation to interventional management strategy have not been previously reported.

RESULTS

We performed an individual patient-level combined analysis of 26 512 patients from the OASIS 5 and 6 trials who were randomized in a double-blind fashion to fondaparinux 2.5 mg daily or a heparin-based strategy (dose-adjusted unfractionated heparin or enoxaparin). Results were stratified according to whether an early invasive, a delayed invasive, or an initial conservative management strategy was performed. Fondaparinux was superior to heparin in reducing the composite of death, myocardial infarction, or stroke (8.0% versus 7.2%; hazard ratio [HR], 0.91; P=0.03) and death alone (4.3% versus 3.8%; HR, 0.89; P=0.05). Fondaparinux reduced major bleeding by 41% (3.4% versus 2.1%; HR, 0.59; P<0.00001) and had a more favorable net clinical outcome than heparin (11.1% versus 9.3%; HR, 0.83; P<0.0001). In 19 085 patients treated with an invasive strategy, fondaparinux suppressed ischemic events to an extent similar to heparin and reduced major bleeding by more than one-half, resulting in a superior net clinical outcome (10.8% versus 9.4%; HR, 0.87; P=0.008). A similar benefit also was observed in those treated with a conservative strategy (HR, 0.74; 95% confidence interval, 0.64 to 0.85; P<0.001).

CONCLUSIONS

Compared with a heparin-based strategy, fondaparinux reduced mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and was associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer (The Medicines Company) of bivalirudin to submit evidence for its clinical and cost effectiveness within its licensed indication for the treatment of adults with ST-segment elevation myocardial infarction (STEMI) intended for primary percutaneous coronary intervention (PPCI), as part of NICE's single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG), which produced a review of the evidence within the manufacturer's submission to NICE. This article describes the manufacturer's submission, the ERG review and NICE's subsequent decisions. The main evidence was derived from one randomized controlled trial (RCT) of STEMI patients intended for PPCI, comparing bivalirudin with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors (GPIs). Bivalirudin was associated with a significant reduction in cardiac mortality at 30 days (p = 0.03) and at 1-year follow-up (p = 0.005), and a significant reduction in major bleeding at 30 days (p < 0.001) and 1 year (p < 0.0001), compared with heparin plus GPI. Stent thrombosis up to 24 hours following PPCI was significantly (p < 0.001) more common with bivalirudin. However, there was no significant treatment effect for stent thrombosis from 1 to 30 days (p = 0.28), or at 1-year follow-up (p = 0.53). There were no significant treatment group differences at 30 days and at 1 year in stroke (p = 0.68 and p = 0.99, respectively), in myocardial infarction [MI] (p = 0.90 and p = 0.22, respectively), or in the need for the revascularization of the target vessel for ischaemia (p = 0.18 and p = 0.12, respectively). There were two decision-analytic models: the base-case scenario used 1-year follow-up data from the RCT; and a sensitivity analysis used 3-year follow-up data. Resource use was primarily drawn from this RCT. Health-related quality-of-life (HR-QOL) estimates were drawn from a UK cohort study. Both models evaluated the incremental costs and outcomes of bivalirudin compared with heparin plus GPI for patients with STEMI intended for PPCI. The analysis adopted a UK NHS perspective over a lifetime horizon. Unit costs were based on year 2009-2010 prices. The model adopted a decision-tree structure to reflect initial events for the initial period (stroke, repeat MI, minor/major bleeding events, repeat revascularization and death) and a two-state Markov component to simulate longer-term survival. The economic analysis suggested that bivalirudin is expected to dominate the heparin plus GPI strategy. This finding was consistent across the probabilistic sensitivity analysis and the vast majority of deterministic sensitivity analyses undertaken. Three exceptions to this finding were observed for the following sensitivity analyses: (1) the exclusive use of eptifibatide as the GPI (incremental cost-effectiveness ratio [ICER] = £1,764); (2) the combination of 100 % eptifibatide use, 100 % radial arterial access and no differential length between strategies for initial hospital stay (ICER = £4,106); and (3) a longer length of ward stay (increase of 0.33 days) for the initial hospitalization (ICER = £415). The Appraisal Committee (AC) gave a positive recommendation for bivalirudin for the treatment of adults with STEMI undergoing PPCI.

Venous thromboembolic disease remains the commonest cause of maternal death. The management of thromboprophylaxis in high risk women during pregnancy is contentious. Low molecular weight heparins (LMW) have theoretical advantages compared with unfractionated heparin and warfarin but have been poorly studied in pregnancy. We report on the use of LMW heparin (Fragmin) as thromboprophylaxis in thirty four high risk pregnancies. All the women had a previous thrombosis or a thrombosis in their current pregnancy +/- a recognised thrombophilic state (eleven had the antiphospholipid syndrome). Fragmin was given subcutaneously to maintain trough anti-Xa activity of 0.15-0.2 U/ml and 2 h post injection levels of 0.4-0.6 U/ml. The levels were checked monthly during pregnancy. Most women required 5,000U Fragmin once daily during the first trimester unless they were greater than 100 kg at the start of pregnancy. The mean time for dosage increase was 20.5 week (S.D. 8.2). 26/34 pregnancies (76%) required 5,000 twice daily at the end of pregnancy. Epidural anaesthesia was managed by omitting Fragmin dose or inserting the needle 6 hours after the previous Fragmin injection. There were no thromboembolic events thrombocytopenias or excessive haemorrhage. One woman had osteoporotic vertebral collapse post partum, she had no other risk factors for osteoporosis. LWM heparin (Fragmin) appears to be efficacious in preventing recurrent thromboembolic disease in pregnant women at high risk, but it is notable that osteoporotic fractures occurred post partum in one woman. Further trials are required to determine optimal dosage and safety.

BACKGROUND

The manifestations, complications, and outcomes of cardiovascular disease differ between women and men. The safety and efficacy of pharmacological reperfusion therapy in women with ST-elevation myocardial infarction are of particular interest.

RESULTS

We investigated outcomes in the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 study, which randomized ST-elevation myocardial infarction patients with planned fibrinolysis to enoxaparin or unfractionated heparin. Compared with men (n=15,696), women (n=4783) were older and more likely to have hypertension and diabetes (P<0.001). The unadjusted 30-day mortality rate for women was >2-fold higher than for men (13.2% versus 5.4%; odds ratio, 2.66; 95% CI, 2.40 to 2.96). After adjustment for age, fibrinolytic therapy, revascularization, region, and elements of the TIMI Risk Score, women had a 1.25-fold-higher 30-day risk of death (95% CI, 1.08 to 1.46) but similar risk of intracerebral hemorrhage (adjusted odds ratio, 0.81; 95% CI, 0.52 to 1.26). The 30-day rate of death or nonfatal MI in women was reduced by enoxaparin compared with unfractionated heparin in women (15.4% versus 18.3%; P=0.007). Major bleeding was more frequent in women receiving enoxaparin compared with those receiving unfractionated heparin (2.3% versus 1.4%; P=0.022) but similar among women and men receiving enoxaparin (2.3% versus 2.0%; P=0.39). The rates of death, nonfatal myocardial infarction, or nonfatal major bleeding (net clinical benefit) were lower with enoxaparin (absolute risk reduction, 2.6% in women [P=0.02] and 1.6% in men [P=0.001]).

CONCLUSIONS

In ExTRACT-TIMI 25, women presented with a profile of higher baseline risk and increased short-term mortality. In this large, contemporary clinical trial, women had similar relative and greater absolute risk reductions than men when treated with enoxaparin compared with unfractionated heparin as adjunctive therapy with fibrinolysis.

BACKGROUND

Little information exists on the prevalence and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients admitted for acute exacerbations of chronic obstructive pulmonary disease (COPD).

OBJECTIVE

To review available literature, we performed a Medline search on papers published on this topic between 1966 and 2003.

RESULTS

Pulmonary emboli have been frequently found (up to 30% of cases) in autoptic series that included patients who died from acute exacerbation of COPD, while the real incidence of PE during exacerbation has never been prospectively evaluated by large-scale clinical studies. Diagnosis of concomitant PE in these patients is often missed because symptoms of acute exacerbation of COPD may mimic PE, and non-invasive evaluation by pulmonary scintigraphy or CT scan is less specific. Even if not fatal, undetected and untreated PE may lead to long-term morbidity from pulmonary hypertension and predispose to recurrent venous thromboembolism (VTE). DVT of the lower extremities affects about 10% of patients with acute exacerbation of COPD at admission, but the rate is likely to be underestimated. The results of clinical trials conducted on general medical patients, including COPD patients, indicate that unfractionated heparin (UH) and low molecular weight heparin (LMWH) significantly reduce VTE rates. However, subgroup data on COPD patients are generally not available. In a single randomised, controlled trial specifically conducted on COPD patients, nadroparin reduced the rate of DVT from 28% to 15% without affecting mortality.

CONCLUSIONS

Despite a substantial lack of consistent data, VTE appears as a major threat to patients admitted for acute exacerbation of COPD, and pharmacologic prophylaxis should be considered in all high risk situations. However, methodologically rigorous studies in this setting are still needed.

BACKGROUND

Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications.

RESULTS

We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001).

CONCLUSIONS

In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.

This paper describes studies of initiation of transcription by RNA polymerase I in vitro. The protocols take advantage of the observation that active transcription complexes precipitate when incubated with S100 extracts. The pellets contain less than 5% of the protein present in unfractionated extracts and are stable to centrifugal washing. This permits rapid manipulation of the reaction conditions and facilitates kinetic studies of aspects of the initiation reaction. An initiated complex has been defined which forms rapidly at 30 degrees C and is associated with formation of the first phosphodiester bond of nascent rRNA. Once formed, initiated complexes are capable of elongation in the presence of heparin or KCl in concentrations sufficient to preclude subsequent initiation. One can therefore estimate the number of initiated complexes formed in a given reaction by measuring the number of full length transcripts recovered in a KCl or heparin-start reaction. The number of such complexes formed correlates well with the formation of a presumptive initiator trinucleotide ApCpU.

OBJECTIVE

To estimate the effect of combined heparin and aspirin compared with aspirin monotherapy in pregnant women with antiphospholipid syndrome and recurrent pregnancy loss.

METHODS

We searched the PubMed database up to December 2009 for English-language studies using the key words "aspirin AND (heparin OR low molecular weight heparin), (antiphospholipid OR anticardiolipin OR aPL) AND pregnancy."

METHODS

Two hundred ninety- two studies were initially screened. Randomized controlled trials comparing the effect of heparin (unfractionated heparin or low molecular weight heparin) plus aspirin compared with aspirin alone on the live-birth rate in women with a history of at least two miscarriages and antiphospholipid antibodies were eligible.

RESULTS

The pooled effect of unfractionated heparin and low molecular weight heparin was evaluable in three and two randomized controlled studies, respectively, with regard to live births, which was the major outcome. Overall, treatment effects were in favor of heparin against first-trimester losses (odd ratio [OR] 0.39, 95% confidence interval [CI] 0.24-0.65, number needed to treat 6). More specifically, unfractionated heparin displayed a significant effect (OR 0.26, 95% CI 0.14-0.48, number needed to treat 4), while the pooled effect of low molecular weight heparin was insignificant (OR 0.70, 95% CI 0.34-1.45). Combination therapy of either unfractionated heparin or low molecular weight heparin with aspirin failed to display any significant effect in the prevention of late-pregnancy losses. No significant differences were observed between treatment and control groups for any other outcomes.

CONCLUSIONS

The combination of unfractionated heparin and aspirin confers a significant benefit in live births. However, the efficacy of low molecular weight heparin plus aspirin remains unproven, highlighting the urgent need for large controlled trials.

The systemic effect of 2.4-, 8-, 15- and 22-kDa heparin fractions on saline-mediated angiogenesis in rats was compared with the systemic effect of an unfractionated Na-standard heparin (UFH), which had a mean molecular weight of about 15 kDa. Using the mesenteric-window assay in adult rats, the relative vascularized area was quantified morphometrically. The angiogenic response was strictly related to the mean molecular weight of the saccharides (r = 0.97); the 2.4-kDa fraction suppressed angiogenesis by 46% (p < or = 0.001), whereas the 22-kDa fraction stimulated angiogenesis by 123% (p < or = 0.01), as compared with the UFH. The UFH, thus, contained chain-length-related fragments that induced systemic antiangiogenic and angiogenic activity.

Radial artery occlusion (RAO) is an infrequent, asymptomatic, complication of transradial catheterization and probably 1 of the few. Intravenous heparin and patent hemostasis lower its incidence. A possible local effect of intra-arterially administered heparin during transradial procedures has not been evaluated. We studied 500 consecutive patients randomized to an intravenous group (n = 250), receiving 50 U/kg of unfractionated heparin (maximal dose 5,000 U) intravenously, and an intra-arterial group (n = 250) receiving the same dose intra-arterially. All patients received a vasodilator "cocktail" intra-arterially and underwent cardiac catheterization using a 5F introducer sheath and catheters. The activated clotting time was measured at the end of the procedure. All patients received hemostasis with a radial compression device (TR Band), applied after sheath removal, for 2 hours. A plethysmographic evaluation for RAO was performed at 24 hours and 30 days after the procedure. Early RAO occurred in 5.6% (n = 14) of the intravenous group and 6% (n = 15) of the intra-arterial group. The difference was not statistically significant (chi-square = 0.037, p >0.8). Chronic RAO occurred in 3.2%, (n = 8) of the intravenous group compared to 4% (n = 10) of the intra-arterial group. The difference was not statistically significant (chi-square = 0.231, p >0.6). The activated clotting time was 211 +/- 16 seconds in the intravenous group and 213 +/- 17 seconds in the intra-arterial group, a statistically insignificant difference (t = -1.095, p >0.2). In conclusion, intra-arterial and intravenous heparin administration provide comparable efficacy in preventing RAO, favoring a probable systemically mediated mechanism of action, rather than a local effect.

BACKGROUND

Low molecular weight heparins (LMWHs) and danaparoid are an alternative to unfractionated heparin (UH) for anticoagulation during hemodialysis. Few data are available concerning their duration of action and whether drug accumulation occurs with continued use. We performed a prospective randomized study of the pharmacokinetics of dalteparin and enoxaparin plus danaparoid in 21 hemodialysis patients.

METHODS

Patients were randomly assigned to administration of enoxaparin, 40 mg; dalteparin, 2,500 U; or danaparoid, 34 U/kg, for 4 weeks. Antifactor Xa levels were measured at the end of weeks 1 and 4 immediately before the injection and at prescribed intervals up to 48 hours postinjection.

RESULTS

No bleeding or thrombotic episodes occurred during the study. Mean antifactor Xa activities 4 hours postinjection were 0.2 +/- 0.035 (SEM), 0.38 +/- 0.028, and 0.54 +/- 0.051 U/mL week 1 and 0.26 +/- 0.038, 0.40 +/- 0.055, and 0.64 +/- 0.050 U/mL week 4 for dalteparin, enoxaparin, and danaparoid, respectively. Both weeks 1 and 4, antifactor Xa activity 3 hours postdose was significantly greater for danaparoid sodium compared with enoxaparin and dalteparin. There were no significant differences between antifactor Xa activity week 4 versus week 1 for enoxaparin and dalteparin; however, danaparoid sodium levels during dialysis were significantly greater after 4 weeks of treatment (P = 0.0328, 1 hour; P = 0.003, 2 hours; P = 0.0128, 3 and 4 hours).

CONCLUSIONS

Dalteparin and enoxaparin provide adequate anticoagulation for hemodialysis using single bolus injections at relatively low doses. Danaparoid sodium at the current recommended dosage resulted in greater anticoagulation than enoxaparin or dalteparin and may have an

The anti-inflammatory effect of mammalian heparin analogues, named dermatan sulfate and heparin, isolated from the ascidian Styela plicata was accessed in a TNBS-induced colitis model in rats. Subcutaneous administration of the invertebrate compounds during a 7-day period drastically reduced inflammation as observed by the normalization of the macroscopic and histological characteristics of the colon. At the molecular level, a decrease in the production of TNF-alpha, TGF-beta, and VEGF was observed, as well as a reduction of NF-kappaB and MAPK kinase activation. At the cellular level, the heparin analogues attenuated lymphocyte and macrophage recruitment and epithelial cell apoptosis. A drastic reduction in collagen-mediated fibrosis was also observed. No hemorrhagic events were observed after glycan treatment. These results strongly indicate the potential therapeutic use of these compounds for the treatment of colonic inflammation with a lower risk of hemorrhage when compared with mammalian heparin.

This chapter about antithrombotic therapy for acute myocardial infarction (MI) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients with ischemic symptoms characteristic of acute MI of < 12 h in duration, and ST-segment elevation or left bundle-branch block (of unknown duration) on the ECG, we recommend administration of any approved fibrinolytic agent (Grade 1A). We recommend the use of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over placebo (all Grade 1A). For patients with symptom duration < 6 h, we recommend the administration of alteplase over streptokinase (Grade 1A). For patients with known allergy or sensitivity to streptokinase, we recommend alteplase, reteplase, or tenecteplase (Grade 1A). For patients with acute posterior MI of < 12 h duration, we suggest fibrinolytic therapy (Grade 2C). In patients with any history of intracranial hemorrhage, closed head trauma, or ischemic stroke within past 3 months, we recommend against administration of fibrinolytic therapy (Grade 1C+). For patients with acute ST-segment elevation MI whether or not they receive fibrinolytic therapy, we recommend aspirin, 160 to 325 mg p.o., at initial evaluation by health-care personnel followed by indefinite therapy, 75 to 162 mg/d p.o. (both Grade 1A). In patients allergic to aspirin, we suggest use of clopidogrel as an alternative therapy to aspirin (Grade 2C). For patients receiving streptokinase, we suggest administration of either i.v. unfractionated heparin (UFH) [Grade 2C] or subcutaneous UFH (Grade 2A). For all patients at high risk of systemic or venous thromboembolism (anterior MI, pump failure, previous embolus, atrial fibrillation, or left ventricular thrombus), we recommend administration of IV UFH while receiving streptokinase (Grade 1C+).

Unfractionated heparin (UH) decreases the extent of infarction after transient focal brain ischemia in the rat and abridges neuroinflammatory damage in patients with acute stroke. This study was aimed at assessing whether controlled and steady heparinemia in plasma can reduce infarct volume and exert neuroprotective effects after ischemia. Infarct volume was measured at 24 and 7 days following a 1-hr intraluminal middle cerebral artery (MCA) occlusion in rats treated with UH or with vehicle. After testing several UH administration protocols, we choose to give a bolus of 200 U/kg, which was started 3 hr after the occlusion, followed by a 24-hr intraperitoneal perfusion of 70 U/kg/hr, which maintained a 24-hr steady plasma heparinemia (0.3-0.6 U/ml) and caused no CNS or systemic bleeding. In addition, plasma IL-10 concentration was measured by ELISA, endothelial VCAM-1 expression was evaluated by i.v. injection of a (125)I-labeled monoclonal antibody against VCAM-1, and brain hemeoxygenase-1 (HO-1) expression was determined by Western blot. UH-treated rats showed smaller infarctions than rats treated with vehicle, as well as higher IL-10 plasma levels and HO-1 brain expression and lower endothelial VCAM-1 induction. The study shows that a stable plasma concentration of UH given at nonhemorrhagic doses reduces infarct volume after ischemia-reperfusion in the rat. It also shows that UH prevented the induction of cell adhesion molecules in the cerebral vasculature and increased the expression of molecules with antiinflammatory and prosurvival properties. These findings support further testing of the clinical value of parenteral, adjusted, high-dose UH in patients with acute stroke.

Injecting drug use, mainly of heroin, currently represents a major public health issue in the North East of Scotland. The recent tendency of the committed injecting drug user to inject into the groin has created novel problems for the Infection Unit. Data are presented on 20 consecutive patients admitted between 1994 and 1999 with iliofemoral venous thromboses, often complicated by severe soft tissue infections and bacteraemia as a result of heroin injection into the femoral vein. Nine had coexistent groin abscesses, four had severe streptococcal soft tissue infection of the right thigh, groin and lower abdomen, and two had coincidental soft tissue infections of the upper limb. Nine were bacteraemic on admission. All of the patients were chronic injecting drug users with a median injection duration of 6.5 years. The 18 patients tested for hepatitis C virus were all seropositive. None of the 14 patients tested was positive for HIV. Seventeen patients were treated with subcutaneous low molecular weight heparin (tinzaparin), three having received intravenous unfractionated heparin initially. The tinzaparin was self administered and given for a median duration of seven weeks. One patient declined to have any treatment. Three months after presentation eight patients were asymptomatic, seven had a persistently swollen leg, and five were lost to follow up. None developed clinically apparent pulmonary embolism after institution of anticoagulant therapy. The management of iliofemoral venous thrombosis in injection drug users is problematic because of poor venous access, non-compliance with prescribed treatment, ongoing injecting behaviour, and coexistent sepsis. It is unlikely that a randomised trial of standard treatment with heparin and warfarin versus low molecular weight heparin alone would be practical in this patient group. These retrospective data indicate that the use of tinzaparin in injecting drug users is feasible and appears to result in satisfactory clinical responses. The possibility of concomitant infection in injecting drug users with venous thrombosis should always be addressed, as it appears to be a common phenomenon. Early drainage of abscesses and antimicrobial chemotherapy, often administered intramuscularly or orally because of lack of peripheral venous access, is central to the appropriate care of these patients.

There is now considerable evidence that the blood coagulation system plays an important role in the biology of malignant tumors. This evidence has been derived from a combination of clinical, biochemical, histological, and pharmacological observations that point to the possibility of favorably affecting the course of malignant disease with agents that interfere with blood coagulation pathways. For a number of years our laboratory has used experimental models of blood-borne metastasis to study the events that follow the introduction of procoagulant-bearing tumor cells into the circulating blood. This article summarizes our experience with these models, which suggests that intravascular coagulation is a necessary prelude to lung tumor formation and that interruption of coagulation pathways in various ways may be an effective antimetastatic strategy. We have shown that anticoagulation with commonly used agents such as unfractionated heparin and warfarin (Coumadin) prevent tumor formation by limiting the ability of tumor cells to be retained in the pulmonary microvasculature. Binding of fibrin-coated tumor cells to activated platelets is essential for this retention and, therefore, treatment with potent antiplatelet agents such as abciximab is also effective. The predominant tumor procoagulant is tissue factor (TF), and direct targeting of this protein with concanavalin A, monoclonal antibodies, and tissue factor pathway inhibitor (TFPI) has provided compelling evidence that TF is an important determinant of tumor seeding in these experimental models. Collectively, our data provide strong support for the concept that some form of anticoagulant therapy would be a useful adjunct to existing cancer treatments.

OBJECTIVE

Low-molecular-weight heparins and heparinoids (LMWHs) are superior to unfractionated heparin in the prevention and treatment of venous thromboembolism and acute coronary syndromes. We performed a systematic review of randomized controlled trials (RCTs) to examine the safety and efficacy of LMWH in acute ischemic stroke.

METHODS

Randomized, controlled, and nonconfounded trials of LMWH in acute ischemic stroke were identified from the Cochrane Library (version 2, 1999), previous systematic reviews, and a review of publication quality relating to acute stroke trials. The authors each independently extracted data by treatment group and assessed trial quality using Cochrane Collaboration criteria.

RESULTS

Eleven completed RCTs involving 3048 patients were identified; data were available from 10 of these. Four trials explicitly excluded patients with presumed cardioembolic stroke. Treatment with LMWH was associated with significant reductions in prospectively identified deep vein thrombosis (OR 0.27, 95% CI 0.08 to 0.96) and symptomatic pulmonary embolism (OR 0.34, 95% CI 0.17 to 0.69) and with increased major extracranial hemorrhage (OR 2.17, 95% 1.10 to 4.28). Nonsignificant increases in end-of-treatment (OR 1.20, 95% CI 0.86 to 1.69) and end-of-trial (OR 1.05, 95% CI 0.83 to 1.32) case fatality and symptomatic intracranial hemorrhage (OR 1.77, 95% CI 0. 95 to 3.31) were observed. End-of-trial death and disability was nonsignificantly reduced (OR 0.87, 95% CI 0.72 to 1.06).

CONCLUSIONS

++LMWHs reduce venous thromboembolic events in patients with acute ischemic stroke and increase the risk of extracranial bleeding. A nonsignificant reduction in combined death and disability and nonsignificant increases in case fatality and symptomatic intracranial hemorrhage were also observed. On the basis of the current evidence, LMWH should not be used in the routine management of patients with ischemic stroke.

Thromboembolic disorders are a major cause of morbidity and mortality, and the risk of thromboembolism increases with age. Anticoagulants are recommended for indications including the prevention of venous thromboembolism in surgical and medical patients, treatment of venous thromboembolism and stroke prevention in patients with atrial fibrillation. Traditional anticoagulants that have been used include unfractionated heparin, low molecular weight heparin, fondaparinux and vitamin K antagonists. However, these agents are all associated with drawbacks (i.e. parenteral administration or frequent coagulation monitoring/dose titration), and it has been particularly challenging to treat elderly patients with anticoagulants. Some specific characteristics of elderly patients may influence the safety of anticoagulant therapy, such as decreased renal function, co-morbidities and the use of multiple medications. The complexity of anticoagulation therapy and the increased risk of bleeding complications in elderly patients may prevent some physicians from prescribing anticoagulants to these patients, which leaves them at risk of thromboembolic events. Thus, safer and more convenient anticoagulants are needed, particularly for elderly patients. New oral anticoagulants have been developed in recent years and have shown promise in clinical studies that included elderly patients. These agents could simplify the management of thromboembolic disorders and improve the safety of anticoagulation.

OBJECTIVE

To investigate whether heparin and low-dose aspirin increase the pregnancy rate in antiphospholipid antibody or antinuclear antibody-seropositive women with IVF implantation failure.

METHODS

A double-blind, randomized, transfer-by-transfer of fresh or cryopreserved embryos, crossover trial.A hospital infertility clinic and associated IVF service.

METHODS

Women seropositive for at least one antiphospholipid (APA), antinuclear (ANA), or beta(2) glycoprotein I autoantibody and>>or=10 embryos transferred without achieving pregnancy (n = 143).

METHODS

Subcutaneous unfractionated heparin (5000 IU b.i.d.) and aspirin (100 mg daily) (158 transfers of 296 embryos) or placebo (142 transfers of 259 embryos) from the day of embryo transfer.

METHODS

Fetal heart per embryo transferred (implantation rate).

RESULTS

There was no significant difference in pregnancy rates or implantation rates between treated and placebo cycles; for example, fetal hearts per embryo transferred implantation rates were 6.8% (20/296) and 8.5% (22/259), respectively, and the generalized estimating equation covariate adjusted relative pregnancy rate was 0.65 (95% confidence interval, 0.33-1.28). The implantation rate for seropositive trial participants (42/555, 7.6%) compared favorably with that for IVF implantation-failure patients continuing treatment outside the trial (147/3237, 4.5%).

CONCLUSIONS

Heparin and aspirin did not improve pregnancy or implantation rates for APA-positive or ANA-positive patients with IVF implantation failure.

OBJECTIVE

The role of anticoagulants for the prevention of venous thromboembolism in acute hemorrhagic stroke is uncertain. We performed an updated meta-analysis of studies to obtain the best estimates of the efficacy and safety of anticoagulants for the prevention of venous thromboembolism in patients with acute hemorrhagic stroke.

METHODS

Using electronic and manual searches of the literature, we identified randomized and non-randomized studies comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids) with treatments other than anticoagulants (elastic stockings, intermittent pneumatic compression or placebo) in patients with acute hemorrhagic stroke. Study outcomes included symptomatic and asymptomatic deep venous thrombosis (DVT), symptomatic and asymptomatic pulmonary embolism (PE), any hematoma enlargement or death. Risk ratios (RRs) for individual outcomes were calculated for each study and data from all studies were pooled using the Mantel-Haenszel method.

RESULTS

Four studies (two randomized) involving 1000 patients with acute hemorrhagic stroke met the criteria for inclusion in this meta-analysis. Compared with other treatments, anticoagulants were associated with a significant reduction in PE (1.7% vs. 2.9%; RR, 0.37; 95% CI, 0.17-0.80; P = 0.01), a DVT rate of 4.2% compared with 3.3% (RR, 0.77; 95% CI, 0.44-1.34; P = 0.36), an increase in any hematoma enlargement (8.0% vs. 4.0%; RR, 1.42; 95% CI, 0.57-3.53; P = 0.45), and a non-significant reduction in mortality (16.1% vs. 20.9%; RR, 0.76; 95% CI, 0.57-1.03; P = 0.07).

CONCLUSIONS

Our findings indicate that in patients with hemorrhagic stroke, early anticoagulation is associated with a significant reduction in PE and a non-significant reduction in mortality, with the trade-off of a non-significant increase in hematoma enlargement. These results must be taken with caution and should encourage the assessment of the clinical benefit of antithrombotic prophylaxis in patients with cerebral bleeding by properly designed clinical trials.

The main objective of this study was to determine if the systemic absorption of therapeutic amounts of heparin was possible following nasal administration. Sprague-Dawley rats received nosedrops containing a low molecular weight heparin (LMWH) or unfractionated heparin (UFH) formulated with or without tetradecylmaltoside (TDM). TDM is a nonionic surfactant that has been previously shown to be a potent absorption enhancer in studies with peptide drugs. LMWH/UFH absorption was determined by measuring plasma anti-Factor Xa activity. The inclusion of 0.25% TDM in nasal formulations containing LMWH resulted in a significant increase in the C(max) and area under the curve (AUC) of anti-Factor Xa activity when compared to LMWH formulated in saline alone. The addition of TDM to a nasal formulation containing UFH resulted in a much smaller increase in the C(max) and the AUC of anti-Factor Xa activity. The absolute bioavailability of LMWH was increased from 4.0 +/- 0.4% in the absence of TDM to 19 +/- 0.3% in the presence of TDM. The reversibility of the absorption enhancing effect of TDM was studied by applying LMWH nasally 60 or 120 min after the enhancer. The effect of TDM on the nasal epithelia appeared to be rapidly reversible. In conclusion, nasal delivery of LMWH, but not UFH, was successful when an absorption enhancer was included to increase nasal permeability.

OBJECTIVE

Venous thromboembolism (VTE) is a common complication of acute illness, and its prevention is a ubiquitous aspect of inpatient care. A multicenter blinded, randomized trial compared the effectiveness of the most common pharmocoprevention strategies, unfractionated heparin (UFH) and the low-molecular-weight heparin (LMWH) dalteparin, finding no difference in the primary end point of leg deep-vein thrombosis but a reduced rate of pulmonary embolus and heparin-induced thrombocytopenia among critically ill medical-surgical patients who received dalteparin.

OBJECTIVE

To evaluate the comparative cost-effectiveness of LMWH vs UFH for prophylaxis against VTE in critically ill patients.

METHODS

Prospective economic evaluation concurrent with the Prophylaxis for Thromboembolism in Critical Care Randomized Trial (May 2006 to June 2010). The economic evaluation adopted a health care payer perspective and in-hospital time horizon; derived baseline characteristics and probabilities of intensive care unit and in-hospital events; and measured costs among 2344 patients in 23 centers in 5 countries and applied these costs to measured resource use and effects of all enrolled patients.

METHODS

Costs, effects, incremental cost-effectiveness of LMWH vs UFH during the period of hospitalization, and sensitivity analyses across cost ranges.

RESULTS

Hospital costs per patient were $39,508 (interquartile range [IQR], $24,676 to $71,431) for 1862 patients who received LMWH compared with $40,805 (IQR, $24,393 to $76,139) for 1862 patients who received UFH (incremental cost, -$1297 [IQR, -$4398 to $1404]; P = .41). In 78% of simulations, a strategy using LMWH was most effective and least costly. In sensitivity analyses, a strategy using LMWH remained least costly unless the drug acquisition cost of dalteparin increased from $8 to $179 per dose and was consistent among higher- and lower-spending health care systems. There was no threshold at which lowering the acquisition cost of UFH favored prophylaxis with UFH.

CONCLUSIONS

From a health care payer perspective, the use of the LMWH dalteparin for VTE prophylaxis among critically ill medical-surgical patients was more effective and had similar or lower costs than the use of UFH. These findings were driven by lower rates of pulmonary embolus and heparin-induced thrombocytopenia and corresponding lower overall use of resources with LMWH.

Heparins, including unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), are glycosaminoglycans that are largely used as anti-thrombotic drugs. While the mechanisms of their anticoagulant actions in blood have been extensively studied, their effects on the inflammation of the endothelium are still under investigation since the endothelium plays a central role in sepsis. Furthermore, UFH is much cheaper than LMWH. The aim of this study was to determine how UFH regulates lipopolysaccharide (LPS)-induced inflammatory response on endothelial cells in vitro, and define the role of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) in mediating this effect. Human pulmonary microvascular endothelial cells (HPMECs) were pretreated with UFH (0.01 U/ml-10 U/ml), prior to stimulation with LPS (10 μg/ml). Markers of systemic inflammation and endothelial activation were assessed. Interleukin (IL)-1β, IL-6, E-selectin, intercellular adhesion molecule (ICAM)-1 release were subsequently measured at 2h, 6h and 12h. Phosphorylation of p38 MAPK at 2h, 6h and nuclear translocation of the proinflammatory NF-κB at 2h were assessed. In HPMEC, UFH significantly attenuated LPS-induced production of IL-1β, IL-6, E-selectin and ICAM-1, as well as phosphorylation of p38 MAPK and NF-κB translocation, especially in 10 U/ml. In conclusion, UFH at high dose significantly protects against endothelial-cell-mediated immune response. The inhibition of p38 MAPK and NF-κB activation certainly represents one of the mechanisms by which UFH exerts its anti-inflammatory effect.