BACKGROUND

Patients with acute proximal deep-vein thrombosis are usually treated first in the hospital with intravenous standard (unfractionated) heparin. However, the longer plasma half-life, better bioavailability after subcutaneous administration, and more predictable anticoagulant response of low-molecular-weight heparins make them attractive for possible home use. We compared these two approaches.

METHODS

Patients with acute proximal deep-vein thrombosis were randomly assigned to receive either intravenous standard heparin in the hospital (253 patients) or low-molecular-weight heparin (1 mg of enoxaparin per kilogram of body weight subcutaneously twice daily) administered primarily at home (247 patients). The study design allowed outpatients taking low-molecular-weight heparin to go home immediately and hospitalized patients taking low-molecular-weight heparin to be discharged early. All the patients received warfarin starting on the second day.

RESULTS

Thirteen of the 247 patients receiving low-molecular-weight heparin (5.3 percent) had recurrent thromboembolism, as compared with 17 of the 253 patients receiving standard heparin (6.7 percent; P=0.57; absolute difference, 1.4 percentage points; 95 percent confidence interval, -3.0 to 5.7). Five patients receiving low-molecular-weight heparin had major bleeding, as compared with three patients receiving standard heparin. After randomization, the patients who received low-molecular-weight heparin spent a mean of 1.1 days in the hospital, as compared with 6.5 days for the standard-heparin group; 120 patients in the low-molecular-weight- heparin group did not need to be hospitalized at all.

CONCLUSIONS

Low-molecular-weight heparin can be used safely and effectively to treat patients with proximal deep-vein thrombosis at home.

BACKGROUND

There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.

METHODS

Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.

RESULTS

The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.

CONCLUSIONS

Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.

This article discusses the perioperative management of antithrombotic therapy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). The primary objectives of this article are the following: (1) to address the perioperative management of patients who are receiving vitamin K antagonists (VKAs) or antiplatelet drugs, such as aspirin and clopidogrel, and require an elective surgical or other invasive procedures; and (2) to address the perioperative use of bridging anticoagulation, typically with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). A secondary objective is to address the perioperative management of such patients who require urgent surgery. The recommendations in this article incorporate the grading system that is discussed in this supplement (Guyatt G et al, CHEST 2008; 133:123S-131S). Briefly, Grade 1 recommendations are considered strong and indicate that the benefits do (or do not) outweigh risks, burden, and costs, whereas Grade 2 recommendations are referred to as suggestions and imply that individual patient values may lead to different management choices. The key recommendations in this article include the following: in patients with a mechanical heart valve or atrial fibrillation or venous thromboembolism (VTE) at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose subcutaneous (SC) LMWH or IV UFH over no bridging during temporary interruption of VKA therapy (Grade 1C); in patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV UFH, or low-dose SC LMWH over no bridging during temporary interruption of VKA therapy (Grade 2C); in patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (Grade 2C). In patients with a bare metal coronary stent who require surgery within 6 weeks of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C); in patients with a drug-eluting coronary stent who require surgery within 12 months of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C). In patients who are undergoing minor dental procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure and co-administering an oral prohemostatic agent (Grade 1B); in patients who are undergoing minor dermatologic procedures and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C); in patients who are undergoing cataract removal and are receiving VKAs, we recommend continuing VKAs around the time of the procedure (Grade 1C).

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

BACKGROUND

An intravenous course of standard (unfractionated) heparin with the dose adjusted to prolong the activated partial-thromboplastin time to a desired length is the standard initial in-hospital treatment for patients with deep-vein thrombosis, but fixed-dose subcutaneous low-molecular-weight heparin appears to be as effective and safe. Because the latter treatment can be given on an outpatient basis, we compared the two treatments in symptomatic outpatients with proximal-vein thrombosis but no signs of pulmonary embolism.

METHODS

We randomly assigned patients to adjusted-dose intravenous standard heparin administered in the hospital (198 patients) or fixed-dose subcutaneous low-molecular-weight heparin administered at home, when feasible (202 patients). We compared the treatments with respect to recurrent venous thromboembolism, major bleeding, quality of life, and costs.

RESULTS

Seventeen of the 198 patients who received standard heparin (8.6 percent) and 14 of the 202 patients who received low-molecular-weight heparin (6.9 percent) had recurrent thromboembolism (difference, 1.7 percentage points; 95 percent confidence interval, -3.6 to 6.9). Major bleeding occurred in four patients assigned to standard heparin (2.0 percent) and one patient assigned to low-molecular-weight heparin (0.5 percent; difference, 1.5 percentage points; 95 percent confidence interval, -0.7 to 2.7). Quality of life improved in both groups. Physical activity and social functioning were better in the patients assigned to low-molecular-weight heparin. Among the patients in that group, 35 percent were never admitted to the hospital at all, and 40 percent were discharged early. This treatment was associated with a mean reduction in hospital days of 67 percent, ranging from 29 percent to 86 percent in the various study centers.

CONCLUSIONS

In patients with proximal-vein thrombosis, treatment with low-molecular-weight heparin at home is feasible, effective, and safe.

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR>> 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age >> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

This article about unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a pentasaccharide, catalyzing the inactivation of thrombin and other clotting factors. UFH also binds endothelial cells, platelet factor 4, and platelets, leading to rather unpredictable pharmacokinetic and pharmacodynamic properties. Variability in activated partial thromboplastin time (aPTT) reagents necessitates site-specific validation of the aPTT therapeutic range in order to properly monitor UFH therapy. Lack of validation has been an oversight in many clinical trials comparing UFH to LMWH. In patients with apparent heparin resistance, anti-factor Xa monitoring may be superior to measurement of aPTT. LMWHs lack the nonspecific binding affinities of UFH, and, as a result, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties. LMWHs have replaced UFH for most clinical indications for the following reasons: (1) these properties allow LMWHs to be administered subcutaneously, once daily without laboratory monitoring; and (2) the evidence from clinical trials that LMWH is as least as effective as and is safer than UFH. Several clinical issues regarding the use of LMWHs remain unanswered. These relate to the need for monitoring with an anti-factor Xa assay in patients with severe obesity or renal insufficiency. The therapeutic range for anti-factor Xa activity depends on the dosing interval. Anti-factor Xa monitoring is prudent when administering weight-based doses of LMWH to patients who weigh>> 150 kg. It has been determined that UFH infusion is preferable to LMWH injection in patients with creatinine clearance of < 25 mL/min, until further data on therapeutic dosing of LMWHs in renal failure have been published. However, when administered in low doses prophylactically, LMWH is safe for therapy in patients with renal failure. Protamine may help to reverse bleeding related to LWMH, although anti-factor Xa activity is not fully normalized by protamine. The synthetic pentasaccharide fondaparinux is a promising new antithrombotic agent for the prevention and treatment of venous thromboembolism.

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

Keywords: COVID-19; SARS-CoV-2; coronavirus; heparan sulfate; heparan sulfate-binding proteins; heparin; lung epithelial cells; pseudotyped virus; spike proteins.

Heparin-induced thrombocytopenia (HIT) is an uncommon but potentially devastating complication of anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Our objective was to determine and compare the incidences of HIT in surgical and medical patients receiving thromboprophylaxis with either UFH or LMWH. All relevant studies identified in the MEDLINE database (1984-2004), not limited by language, and from reference lists of key articles were evaluated. Randomized and nonrandomized controlled trials comparing prophylaxis with UFH and LMWH and measuring HIT or thrombocytopenia as outcomes were included. Two reviewers independently extracted data on thromboprophylaxis (type, dose, frequency, and duration), definition of thrombocytopenia, HIT assay, and rates of the following outcomes: HIT, thrombocytopenia, and thromboembolic events. HIT was defined as a decrease in platelets to less than 50% or to less than 100 x 10(9)/L and positive laboratory HIT assay. Fifteen studies (7287 patients) were eligible: 2 randomized controlled trials (RCTs) measuring HIT (1014 patients), 3 prospective studies (1464 patients) with nonrandomized comparison groups in which HIT was appropriately measured in both groups, and 10 RCTs (4809 patients) measuring thrombocytopenia but not HIT. Three analyses were performed using a random effects model and favored the use of LMWH: (1) RCTs measuring HIT showed an odds ratio (OR) of 0.10 (95% confidence interval [CI], 0.01-0.2; P = .03); (2) prospective studies measuring HIT showed an OR of 0.10 (95% CI, 0.03-0.33; P < .001); (3) all 15 studies measured thrombocytopenia. The OR was 0.47 (95% CI, 0.22-1.02; P = .06). The inverse variance-weighted average that determined the absolute risk for HIT with LMWH was 0.2%, and with UFH the risk was 2.6%. Most studies were of patients after orthopedic surgery.

This chapter describes the pharmacology of approved parenteral anticoagulants, including the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin factor Xa and other clotting factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and have a lower risk of nonhemorrhagic side effects. LMWHs can be administered once or twice daily by subcutaneous injection, without anticoagulant monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin; therefore, HIT and osteoporosis are unlikely to occur. Fondaparinux has excellent bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring. Three parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in HIT patients.

This chapter about antithrombotic therapy in neonates and children is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs, and Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading, see Guyatt et al in this supplement, pages 123S-131S). In this chapter, many recommendations are based on extrapolation of adult data, and the reader is referred to the appropriate chapters relating to guidelines for adult populations. Within this chapter, the majority of recommendations are separate for neonates and children, reflecting the significant differences in epidemiology of thrombosis and safety and efficacy of therapy in these two populations. Among the key recommendations in this chapter are the following: In children with first episode of venous thromboembolism (VTE), we recommend anticoagulant therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1B]. Dosing of IV UFH should prolong the activated partial thromboplastin time (aPTT) to a range that corresponds to an anti-factor Xa assay (anti-FXa) level of 0.35 to 0.7 U/mL, whereas LMWH should achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection for twice-daily dosing. In neonates with first VTE, we suggest either anticoagulation or supportive care with radiologic monitoring and subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 2C). We recommend against the use of routine systemic thromboprophylaxis for children with central venous lines (Grade 1B). For children with cerebral sinovenous thrombosis (CSVT) without significant intracranial hemorrhage (ICH), we recommend anticoagulation initially with UFH, or LMWH and subsequently with LMWH or vitamin K antagonists (VKAs) for a minimum of 3 months (Grade 1B). For children with non-sickle-cell disease-related acute arterial ischemic stroke (AIS), we recommend UFH or LMWH or aspirin (1 to 5 mg/kg/d) as initial therapy until dissection and embolic causes have been excluded (Grade 1B). For neonates with a first AIS, in the absence of a documented ongoing cardioembolic source, we recommend against anticoagulation or aspirin therapy (Grade 1B).

BACKGROUND

Enoxaparin has demonstrated advantages over unfractionated heparin in low- to moderate-risk patients with non-ST-segment elevation acute coronary syndromes (ACS) treated with a conservative strategy.

OBJECTIVE

To compare the outcomes of patients treated with enoxaparin vs unfractionated heparin and to define the role of enoxaparin in patients with non-ST-segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach.

METHODS

The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10 027 high-risk patients with non-ST-segment elevation ACS to be treated with an intended early invasive strategy were recruited.

METHODS

Subcutaneous enoxaparin (n = 4993) or intravenous unfractionated heparin (n = 4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician.

METHODS

The primary efficacy outcome was the composite clinical end point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke.

RESULTS

The primary end point occurred in 14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed between enoxaparin and unfractionated heparin groups, respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%] vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P =.008) but nonsignificant excess in GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P =.08) and transfusions (17.0% vs 16.0%, P =.16).

CONCLUSIONS

Enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with non-ST-segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the advantages of convenience should be balanced with the modest excess of major bleeding.

BACKGROUND

The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization.

METHODS

We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis.

RESULTS

Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis.

CONCLUSIONS

Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism.

The antiphospholipid syndrome (APS) is defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid (aPL) antibodies and is generally treated with anticoagulation therapy. Because complement activation is essential and causative in aPL antibody-induced fetal injury, we hypothesized that heparin protects pregnant APS patients from complications through inhibition of complement. Treatment with heparin (unfractionated or low molecular weight) prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies. Neither fondaparinux nor hirudin, other anticoagulants, inhibited the generation of complement split products or prevented pregnancy loss, demonstrating that anticoagulation therapy is insufficient protection against APS-associated miscarriage. Our data indicate that heparins prevent obstetrical complications in women with APS because they block activation of complement induced by aPL antibodies targeted to decidual tissues, rather than by their anticoagulant effects.

OBJECTIVE

Little information is available regarding current practice in continuous renal replacement therapy (CRRT) for the treatment of acute renal failure (ARF) and the possible clinical effect of practice variation.

METHODS

Prospective observational study.

METHODS

A total of 54 intensive care units (ICUs) in 23 countries.

METHODS

A cohort of 1006 ICU patients treated with CRRT for ARF.

METHODS

Collection of demographic, clinical and outcome data.

RESULTS

All patients except one were treated with venovenous circuits, most commonly as venovenous hemofiltration (52.8%). Approximately one-third received CRRT without anticoagulation (33.1%). Among patients who received anticoagulation, unfractionated heparin (UFH) was the most common choice (42.9%), followed by sodium citrate (9.9%), nafamostat mesilate (6.1%), and low-molecular-weight heparin (LMWH; 4.4%). Hypotension related to CRRT occurred in 19% of patients and arrhythmias in 4.3%. Bleeding complications occurred in 3.3% of patients. Treatment with LMWH was associated with a higher incidence of bleeding complications (11.4%) compared to UFH (2.3%, p = 0.0083) and citrate (2.0%, p = 0.029). The median dose of CRRT was 20.4 ml/kg/h. Only 11.7% of patients received a dose of>> 35 ml/kg/h. Most (85.5%) survivors recovered to dialysis independence at hospital discharge. Hospital mortality was 63.8%. Multivariable analysis showed that no CRRT-related variables (mode, filter material, drug for anticoagulation, and prescribed dose) predicted hospital mortality.

CONCLUSIONS

This study supports the notion that, worldwide, CRRT practice is quite variable and not aligned with best evidence.

BACKGROUND

Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy.

OBJECTIVE

To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI.

METHODS

Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12,092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment.

METHODS

Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months).

RESULTS

Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days.

CONCLUSIONS

In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes.

BACKGROUND

ClinicalTrials.gov Identifier NCT00064428.

BACKGROUND

Evidence-based guidelines recommend that acutely ill hospitalized medical patients who are at risk of venous thromboembolism (VTE) should receive prophylaxis. Our aim was to characterize the clinical practices for VTE prophylaxis in acutely ill hospitalized medical patients enrolled in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE).

METHODS

IMPROVE is an ongoing, multinational, observational study. Participating hospitals enroll the first 10 consecutive eligible acutely ill medical patients each month. Patient management is determined by the treating physicians. An analysis of data on VTE prophylaxis practices is presented.

RESULTS

From July 2002 to September 30, 2006, 15,156 patients were enrolled from 52 hospitals in 12 countries, of whom 50% received in-hospital pharmacologic and/or mechanical VTE prophylaxis. In the United States and other participating countries, 52% and 43% of patients, respectively, should have received prophylaxis according to guideline recommendations from the American College of Chest Physicians (ACCP). Only approximately 60% of patients who either met the ACCP criteria for requiring prophylaxis or were eligible for enrollment in randomized clinical trials that have shown the benefits of pharmacologic prophylaxis actually received prophylaxis. Practices varied considerably. Intermittent pneumatic compression was the most common form of medical prophylaxis utilized in the United States, although it was used very rarely in other countries (22% vs 0.2%, respectively). Unfractionated heparin was the most frequent pharmacologic approach used in the United States (21% of patients), with low-molecular-weight heparin used most frequently in other participating countries (40%). There was also variable use of elastic stockings in the United States and other participating countries (3% vs 7%, respectively).

CONCLUSIONS

Our data suggest that physicians' practices for providing VTE prophylaxis to acutely ill hospitalized medical patients are suboptimal and highlight the need for improved implementation of existing evidence-based guidelines in hospitals.

This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) 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 in whom the risk of HIT is considered to be>> 0.1%, we recommend platelet count monitoring (Grade 1C). For patients who are receiving therapeutic-dose unfractionated heparin (UFH), we suggest at least every-other-day platelet count monitoring until day 14, or until UFH is stopped, whichever occurs first (Grade 2C). For patients who are receiving postoperative antithrombotic prophylaxis with UFH (HIT risk>> 1%), we suggest at least every-other-day platelet count monitoring between postoperative days 4 to 14 (or until UFH is stopped, whichever occurs first) [Grade 2C]. For medical/obstetric patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose low molecular weight heparin (LMWH), postoperative patients receiving intravascular catheter UFH "flushes," or medical/obstetrical patients receiving LMWH after first receiving UFH (risk, 0.1 to 1%), we suggest platelet count monitoring every 2 days or 3 days from day 4 to day 14, or until heparin is stopped, whichever occurs first (Grade 2C). For medical/obstetrical patients who are only receiving LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (risk < 0.1%), we suggest clinicians do not use routine platelet count monitoring (Grade 2C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative anticoagulant, such as lepirudin (Grade 1C+), argatroban (Grade 1C), bivalirudin (Grade 2C), or danaparoid (Grade 1B). For patients with strongly suspected (or confirmed) HIT, we recommend routine ultrasonography of the lower-limb veins for investigation of deep venous thrombosis (Grade 1C); against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered; that the VKA antagonist be administered only during overlapping alternative anticoagulation (minimum 5-day overlap); and begun with low, maintenance doses (all Grade 2C). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (Grade 2C) [corrected] For patients with a history of HIT who are HIT antibody negative and require cardiac surgery, we recommend use of UFH (Grade 1C).

OBJECTIVE

The purpose of this study was to determine the predictors of major bleeding and the impact of major bleeding on outcomes, including mortality, in acute coronary syndromes (ACS).

BACKGROUND

Whether major bleeding independently predicts mortality in patients with ACS undergoing an early invasive strategy is undefined.

METHODS

Patients (n = 13,819) with moderate- and high-risk ACS were randomized to heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI, or bivalirudin monotherapy (plus provisional GPI). Logistic regression was used to determine predictors of 30-day major bleeding and mortality.

RESULTS

Major bleeding rates in patients treated with heparin plus GPI were higher versus bivalirudin monotherapy (5.7% vs. 3.0%, p < 0.001) and similar versus bivalirudin plus GPI (5.7% vs. 5.3%, p = 0.38). Independent predictors of major bleeding were advanced age, female gender, diabetes, hypertension, renal insufficiency, anemia, no prior percutaneous coronary intervention, cardiac biomarker elevation, ST-segment deviation>>/=1 mm, and treatment with heparin plus GPI versus bivalirudin monotherapy. Patients with major bleeding had higher 30-day rates of mortality (7.3% vs. 1.2%, p < 0.0001), composite ischemia (23.1% vs. 6.8%, p < 0.0001), and stent thrombosis (3.4% vs. 0.6%, p < 0.0001) versus those without major bleeding. Major bleeding was an independent predictor of 30-day mortality (odds ratio 7.55, 95% confidence interval 4.68 to 12.18, p < 0.0001).

CONCLUSIONS

Major bleeding is a powerful independent predictor of 30-day mortality in patients with ACS managed invasively. Several factors independently predict major bleeding, including treatment with heparin plus GPI compared with bivalirudin monotherapy. Knowledge of these findings might be useful to reduce bleeding risk and improve outcomes in ACS.

BACKGROUND

Evidence-based cardiac therapies are underutilized in elderly patients. We assessed differences in practice patterns, comorbidities, and in-hospital event rates, by age and type of acute coronary syndrome (ACS).

METHODS

We studied 24165 ACS patients in 102 hospitals in 14 countries stratified by age.

RESULTS

Approximately two-thirds of patients were men, but this proportion decreased with age. In elderly patients >> or = 65 years), history of angina, transient ischemic attack/stroke, myocardial infarction(MI), congestive heart failure, coronary artery bypass graft (CABG) surgery, hypertension or atrial fibrillation were more common, and delay in seeking medical attention and non-ST-segment elevation MI were significantly higher. Aspirin, beta-blockers, thrombolytic therapy, statins and glycoprotein IIb/IIIa inhibitors were prescribed less, while calcium antagonists and angiotensin-converting enzyme inhibitors were prescribed more often to elderly patients. Unfractionated heparin was prescribed more often in young patients, while low-molecular-weight heparins were similarly prescribed across all age groups. Coronary angiography and percutaneous intervention rates significantly decreased with age. The rate of CABG surgery was highest among patients aged 65-74 years (8.1%) and 55-64 years (7.7%), but reduced in the youngest (4.7%) and oldest (2.7%) groups. Major bleeding rates were 2-3% among patients aged < 65 years, and>> 6% in those>> or = 85 years. Hospital-mortality rates, adjusted for baseline risk differences, increased with age (odds ratio: 15.7 in patients>> or = 85 years compared with those < 45 years).

CONCLUSIONS

Many elderly ACS patients do not receive evidence-based therapies, highlighting the need for clinical trials targeted specifically at elderly cohorts, and quality-of-care programs that reinforce the use of such therapies among these individuals.

This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C. Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C]. For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C). We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A]. For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C).

BACKGROUND

Low molecular weight heparins (LMWHs) have become routine thromboprophylaxis in general surgery. However, their actual clinical effect, its magnitude relative to that of unfractionated heparin (UFH), and the optimal dose are still debated.

METHODS

A meta-analysis was performed of all available randomized trials in general surgery comparing LMWH with placebo or no treatment, or with UFH.

RESULTS

Comparison versus placebo or no treatment confirmed that the significant reduction in asymptomatic deep vein thrombosis (DVT) obtained with LMWH (n = 513; relative risk (RR) 0.28 (95 per cent confidence interval 0.14-0.54)) was associated with a significant reduction in clinical pulmonary embolism (n = 5456; RR 0.25 (0.08-0.79)) and clinical venous thromboembolism (VTE) (n = 4890; RR 0.29 (0.11-0.73)), and a trend towards a reduction in overall mortality rate. Comparison versus UFH showed a trend in favour of LMWH, with a significant reduction in clinical VTE (P = 0.049), a trend also found for cancer surgery. LMWH at doses below 3400 anti-Xa units seemed to be as effective as, and safer than, UFH, while higher doses yielded slightly superior efficacy but increased haemorrhagic risk, including that of major haemorrhage.

CONCLUSIONS

Asymptomatic DVT may be regarded as a reliable surrogate endpoint for clinical outcome in studies investigating thromboprophylaxis in general surgery. LMWH seems to be as effective and safe as UFH. Determination of the optimal dose regimen of LMWH for this indication requires further investigation.

BACKGROUND

Unfractionated heparin is often used as adjunctive therapy with fibrinolysis in patients with ST-elevation myocardial infarction. We compared a low-molecular-weight heparin, enoxaparin, with unfractionated heparin for this purpose.

METHODS

We randomly assigned 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive enoxaparin throughout the index hospitalization or weight-based unfractionated heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction through 30 days.

RESULTS

The primary end point occurred in 12.0 percent of patients in the unfractionated heparin group and 9.9 percent of those in the enoxaparin group (17 percent reduction in relative risk, P<0.001). Nonfatal reinfarction occurred in 4.5 percent of the patients receiving unfractionated heparin and 3.0 percent of those receiving enoxaparin (33 percent reduction in relative risk, P<0.001); 7.5 percent of patients given unfractionated heparin died, as did 6.9 percent of those given enoxaparin (P=0.11). The composite of death, nonfatal reinfarction, or urgent revascularization occurred in 14.5 percent of patients given unfractionated heparin and 11.7 percent of those given enoxaparin (P<0.001); major bleeding occurred in 1.4 percent and 2.1 percent, respectively (P<0.001). The composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage (a measure of net clinical benefit) occurred in 12.2 percent of patients given unfractionated heparin and 10.1 percent of those given enoxaparin (P<0.001).

CONCLUSIONS

In patients receiving fibrinolysis for ST-elevation myocardial infarction, treatment with enoxaparin throughout the index hospitalization is superior to treatment with unfractionated heparin for 48 hours but is associated with an increase in major bleeding episodes. These findings should be interpreted in the context of net clinical benefit. (ClinicalTrials.gov number, NCT00077792.).

BACKGROUND

In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients.

RESULTS

Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (P<0.001); in the heparin group, mean RV/LV ratios were 1.20±0.14 and 1.17±0.20, respectively (P=0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 (P<0.001), respectively. At 90 days, there was 1 death (in the heparin group), no major bleeding, 4 minor bleeding episodes (3 in the USAT group and 1 in the heparin group; P=0.61), and no recurrent venous thromboembolism.

CONCLUSIONS

In patients with pulmonary embolism at intermediate risk, a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications.

BACKGROUND

http://www.clinicaltrials.gov. Unique identifier: NCT01166997.