BACKGROUND

The frequency of thromboembolism after major orthopaedic surgery continues to be high despite prophylaxis. New agents such as CGP 39393, a recombinant form of hirudin, may be more effective than existing therapies.

METHODS

In this double-blind, multicentre, European study the efficacy of three doses of CGP 39393, in comparison with unfractionated heparin, were examined in 1119 patients undergoing elective hip surgery. Patients were randomly allocated to receive by subcutaneous injection either 10, 15, or 20 mg of CGP 39393 twice daily or 5000 IU of heparin three times daily. All treatments were started just before surgery and continued for 8-11 days, until bilateral venography was performed.

RESULTS

The occurrence of thromboembolism was significantly reduced in patients treated with CGP 39393 compared to heparin. The frequency of deep-vein thrombosis was 34.2% in the heparin group as compared to 23.9% (p=0.0113), 18.4% (p=0.0003), and 17.7% (p=0.0001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. At all dose levels, CGP 39393 was more effective than heparin in preventing proximal deep-vein thrombosis. The frequency of proximal thrombosis was 19.6% in the heparin group as compared to 8.5% (p<0.001), 3.1% (p<0.001), and 2.4% (p<0.001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. All treatments were well tolerated.

CONCLUSIONS

This study indicates that specific inhibition of thrombin by prophylactic CGP 39393 significantly reduces thromboembolic complications in patients undergoing total hip replacement.

Because of the potential side effects of heparin, methods of regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) have been gaining wider acceptance with the development of simplified and safer protocols. Advantages of RCA include the avoidance of systemic anticoagulation and heparin-induced thrombocytopenia. The disadvantage is that citrate can add complexity and labor intensity to CRRT. Frequent monitoring of electrolytes, ionized calcium, and acid-base status is required, due to the potential for hypernatremia, metabolic alkalosis, and systemic ionized hypocalcemia. If properly monitored, complications associated with RCA are uncommon. A variety of methods of delivering RCA are described in the literature. Overall, studies of RCA, as compared to unfractionated heparin, report better filter survival times and less bleeding. In this section, we summarize the characteristics of citrate as an anticoagulant and provide an update of citrate use in CRRT.

BACKGROUND

Recent studies have documented high rates of non-administration of ordered venous thromboembolism (VTE) prophylaxis doses. Intervention strategies that target all patients have been effective, but prohibitively resource-intensive. We aimed to identify efficient intervention strategies based on patterns of non-administration of ordered VTE prophylaxis.

RESULTS

In this retrospective review of electronic medication administration records, we included adult hospitalized patients who were ordered pharmacologic VTE prophylaxis with unfractionated heparin or enoxaparin over a seven-month period. The primary measure was the proportion of ordered doses of VTE prophylaxis not administered, assessed at the patient, floor, and floor type levels. Differences in non-administration rates between groups were assessed using generalized estimating equations. A total of 103,160 ordered VTE prophylaxis doses during 10,516 patient visits on twenty-nine patient floors were analyzed. Overall, 11.9% of ordered doses were not administered. Approximately 19% of patients missed at least one quarter and 8% of patients missed over one half of ordered doses. There was marked heterogeneity in non-administration rate at the floor level (range: 5-27%). Patients on medicine floors missed a significantly larger proportion (18%) of ordered doses compared to patients on other floor types (8%, Odds Ratio: 2.4, p<0.0001). However, more than half of patients received at least 86% of their ordered doses, even on the lowest performing floor. The 20% of patients who missed at least two ordered doses accounted for 80% of all missed doses.

CONCLUSIONS

A substantial proportion of ordered doses of VTE prophylaxis were not administered. The heterogeneity in non-administration rate between patients, floors, and floor types can be used to target interventions. The small proportion of patients that missed multiple ordered doses accounted for a large majority of non-administered doses. This recognition of the Pareto principle provides opportunity to efficiently target a relatively small group of patients for intervention.

As one of the most widely used drugs worldwide, heparin is an essential anticoagulant required for surgery, dialysis, treatment of thrombosis, cancer, and general circulatory management. Stabilin-2 is a scavenger clearance receptor with high expression in the sinusoidal endothelium of liver. It is believed that Stabilin-2 is the primary receptor for the clearance of unfractionated and low molecular weight heparins in the liver. Here, we identify the modifications and length of the heparin polymer that are required for binding and endocytosis by both human Stabilin receptors: Stabilin-2 and its homolog Stabilin-1 (also found in liver endothelium). Using enzymatically synthesized (35)S-labeled heparan sulfate oligomers, we identified that sulfation of the 3-OH position of N-sulfated glucosamine (GlcNS) is the most beneficial modification for binding and endocytosis via both Stabilin receptors. In addition, our data suggest that a decasaccharide is the minimal size for binding to the Stabilin receptors. These findings define the physical parameters of the heparin structure required for efficient clearance from blood circulation. These results will also aid in the design of synthetic heparins with desired clearance rates.

Here we report the first application of a fractal analysis of the viscoelastic properties of incipient blood clots. We sought to ascertain whether the incipient clot's fractal dimension, D(f,) could be used as a functional biomarker of hemostasis. The incipient clot is formed at the gel point (GP) of coagulating blood, the GP demarcating a functional change from viscoelastic liquid to a viscoelastic solid. Incipient clots formed in whole healthy blood show a clearly defined value of D(f) within a narrow range that represents an index of clotting in health, where D(f) = 1.74 (± 0.07). A significant relationship is found between the incipient clot formation time, T(GP), and the activated partial thromboplastin time, whereas the association of D(f) with the microstructural characteristics of the incipient clot is supported by its significant correlation with fibrinogen. Our study reveals that unfractionated heparin not only prolongs the onset of clot formation but has a significant effect on its fractal microstructure. A progressive increase in unfractionated heparin concentration results in a linear decrease in D(f) and a corresponding prolongation in T(GP). The results represent a new, quantitative measure of clot quality derived from measurements on whole blood samples.

Heparin is a familiar anticoagulant drug with properties that may impede tumor growth; it modifies properties of cells that contribute to malignant dissemination such as angiogenesis, growth factor and protease activity, immune function, proliferation, and gene expression. Heparin has antitumor effects in animal models of malignancy, and studies in human malignancy show improved cancer outcome with heparin treatment. Meta-analyses comparing unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) for treatment of deep-vein thrombosis have shown apparent substantial improvement in cancer outcome in the subset of patients with malignancy who were randomly assigned to receive LMWH. This experience, together with the favorable pharmacokinetic properties of LMWH, provides a rationale for prospective clinical trials of LMWH in patients with cancer. Such trials should provide (a) definitive data on possible antitumor effects of this treatment, (b) insight into possible heterogeneous responses to heparin treatment among different histological types and stages of malignancy, and (c) a setting for exploring mechanisms of antineoplastic effect in human malignancy.

BACKGROUND

We postulated that antibodies to platelet factor 4/heparin complex might contribute to recurrent ischemic events in patients with acute coronary syndrome.

RESULTS

We analyzed serum from patients enrolled in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had high likelihood of prior heparin exposure. We selected 109 patients without thrombocytopenia with the 30-day primary end point (death, myocardial infarction [MI], or revascularization) and 109 age-, gender-, and race-matched controls who did not achieve the primary end point. An ELISA for anti-platelet factor 4/heparin antibodies was performed using 48-hour serum samples. The analyses were done by blinded investigators, and the results were correlated with clinical outcomes. Twenty-three of 218 patients (10.6%) had anti-PF4/heparin antibodies. Patients with anti-PF4/heparin antibodies were more likely to have death or MI (30.4% versus 11.3%, P=0.011) or MI (21.7% versus 6.2%, P=0.008) than patients who were negative for the antibody. After multiple logistic regression analysis, anti-PF4/heparin antibodies remained a predictor of 30-day death or MI (odds ratio, 4.0; 95% CI, 1.4 to 11.3; P=0.0093) and MI (odds ratio, 4.6; 95% CI, 1.4 to 15.0; P=0.0108). The antibody was not associated with the composite end point (death, MI, or revascularization) or with death or revascularization alone.

CONCLUSIONS

Antibodies to the platelet factor 4/heparin complex are a novel, independent predictor of myocardial infarction at 30 days in patients presenting with acute coronary ischemic syndromes. This finding may explain the previous association between thrombocytopenia and adverse events in patients with acute coronary syndrome and may have important implications for the choice of anticoagulant regimens.

Rivaroxaban is an oral, direct activated Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Currently available anticoagulants include unfractionated heparin (UFH) and low molecular weight heparins (LMWHs); however, their use can be restricted by heparin-induced thrombocytopenia (HIT). HIT is usually caused by the production of antibodies to a complex of heparin and platelet factor-4 (PF4). This study was performed to evaluate, in vitro, the potential of rivaroxaban as an anticoagulant for the management of patients with HIT. UFH, the LMWH enoxaparin, fondaparinux and the direct thrombin inhibitor argatroban were tested to enable comparative analyses. Rivaroxaban did not cause platelet activation or aggregation in the presence of HIT antibodies, unlike UFH and enoxaparin, suggesting that rivaroxaban does not cross-react with HIT antibodies. Furthermore, rivaroxaban did not cause the release of PF4 from platelets and did not interact with PF4, unlike UFH and enoxaparin. These findings suggest that rivaroxaban may be a suitable anticoagulant for the management of patients with HIT.

The non-specific binding of anticoagulantly-active heparin to plasma proteins may influence its anticoagulant effect. We used low affinity heparin (LAH) essentially devoid of anti-factor Xa activity to investigate the extent and possible mechanism of this non-specific binding. The addition of excess LAH to platelet-poor plasma containing a fixed amount of unfractionated heparin doubled the anti-factor Xa activity presumably because it displaces anticoagulantly-active heparin from plasma proteins. Although dextran sulfates of varying molecular weights also increased the anti-factor Xa activity, less sulfated heparin-like polysaccharides had no effect. These findings suggest that the ability to displace active heparin from plasma protein binding sites is related to charge and may be independent of molecular size. In contrast to its effect in plasma containing unfractionated heparin, there was little augmentation in anti-factor Xa activity when LAH was added to plasma containing low molecular weight heparin (LMWH), indicating that LMWH binds less to plasma proteins than unfractionated heparin. This concept is supported by studies comparing the anticoagulant activity of unfractionated heparin and LMWH in plasma with that in buffer containing antithrombin III. The anti-factor Xa activity of unfractionated heparin was 2-fold less in plasma than in the purified system. In contrast, LMWH had identical anti-factor Xa activity in both plasma and buffer, respectively. These findings may be clinically relevant because the recovered anti-factor Xa activity of unfractionated heparin was 33% lower in plasma from patients with suspected venous thrombosis than in plasma from healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

Heparin activates lipoprotein lipase (LPL) and hepatic lipase (HL), enhances plasma lipolytic activity and elevates plasma levels of free fatty acids (FFA). The metabolic consequences of this effect are controversial. In this study the plasma lipolytic effect of unfractionated heparin (mean molecular weight, MW, 12,000-15,000) was compared with that of a low molecular weight heparin (LMWH) fragment (Kabi 2165, Fragmin, mean MW 4000-6000). The comparisons which were carried out in vivo and in vitro in both man and rat were based on the antifactor Xa activity of the two heparins. After i.v. injection of LMWH the release of LPL activity was only half as great as with heparin and the increase in plasma FFA was significantly lower. The immediate release of HL activity was the same for both heparins, the release of LPL activity was dose-dependent and the elimination followed first-order kinetics. After subcutaneous administration, LMWH was absorbed faster than heparin but still had a negligible effect on plasma lipolysis. With simultaneous i.v. infusions of fat emulsion, glucose and heparin or LMWH to healthy subjects no different effects on fat oxidation were seen in spite of pathological increases in plasma FFA with heparin. Also, heat production from isolated adipocytes was not affected by heparin or LMWH. Enzyme release was greater with LMWH in tissue preparations of fat, skeletal muscle and heart muscle in vitro, however. In isolated fat cells no difference in the release of LPL was seen between the two heparins. In conclusion, the plasma lipolytic effect of LMWH is significantly weaker than that of heparin. The complex-binding between heparin and LPL is dependent on the degree of sulphation or ionic strength of the heparin. In the LPL-release from tissue preparations, the molecular size of the heparin is of greater significance, however. Regardless of the degree of plasma lipolytic activity of the two heparin preparations, the fat oxidation rate is not affected. Considering the toxic effects of high levels of plasma FFA, LMWH, with its weak lipolytic potential would appear to be preferable to heparin as an anticoagulant agent.

BACKGROUND

Treatment with lytics or primary percutaneous coronary interventions (PCI) reduces the mortality rate of patients with ST-elevation myocardial infarction (STEMI) presenting within 12 hours. Patients presenting >12 hours are generally considered to be ineligible for reperfusion therapy, and there are currently no specific treatment recommendations for this subgroup.Methods- All patients with STEMI <24 hours were included in the Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) randomized trial or registry. Those patients who were ineligible for acute reperfusion, had no cardiogenic shock, and were not planned for revascularization within 48 hours were randomized to 1 of 4 antithrombotic regimens involving enoxaparin or unfractionated heparin (UFH), in combination with tirofiban or placebo for 2 to 8 days. A concurrent registry tracked STEMI patients coming in within <12 hours, and who underwent reperfusion. This registry also tracked the remaining STEMI patients who neither received reperfusion nor were enrolled in the TETAMI randomized trial. The demographics and clinical outcomes of all three groups (received reperfusion therapy, too late for reperfusion and enrolled in the randomized trial, neither received reperfusion therapy nor were enrolled in the randomized trial) were prospectively tracked.

CONCLUSIONS

There were 2,737 patients who presented with STEMI or a new left branch bundle block (LBBB), of which 1,654 (60%) presented < or =12 hours. There were 1,196 (72%) of 1,654 patients who received reperfusion therapy. There were 458 (28%) of the 1,654 patients deemed "ineligible" for reperfusion, mostly because of a contraindication to lytics or for being "too old." In contrast, 1,083 (40%) of 2,737 patients presented >12 hours. Apart from 34 of these patients who had a stuttering infarction and were referred for reperfusion, the remaining patients did not receive reperfusion therapy. Registry patients who received reperfusion therapy, compared with TETAMI randomized patients (all of whom received antithrombotic therapy) and registry patients who did not receive reperfusion, were younger (61 years versus 63 years and 67 years), were more likely to be male (78% versus 73% and 63%), and had persistent ST-segment elevation as opposed to LBBB or Q waves. Registry patients who received reperfusion therapy had better clinical outcomes, even after adjusting for admission Killip class, compared with TETAMI randomized patients and registry patients who did not receive reperfusion therapy. TETAMI randomized patients had better outcomes than registry patients who did not receive reperfusion therapy. The major obstacle to expanding the delivery of reperfusion therapy to patients with STEMI is the large fraction of patients who present too late for reperfusion therapy. Examination of prospectively gathered data on STEMI patients who are ineligible for reperfusion may help optimize their treatment.

Interaction of transmembrane receptors of the Robo family and the secreted protein Slit provides important signals in the development of the central nervous system and regulation of axonal midline crossing. Heparan sulfate, a sulfated linear polysaccharide modified in a complex variety of ways, serves as an essential co-receptor in Slit-Robo signaling. Previous studies have shown that closely related heparin octasaccharides bind to Drosophila Robo directly, and surface plasmon resonance analysis revealed that Robo1 binds more tightly to full-length unfractionated heparin. For the first time, we utilized electron transfer dissociation-based high spatial resolution hydroxyl radical protein footprinting to identify two separate binding sites for heparin interaction with Robo1: one binding site at the previously identified site for heparin dp8 and a second binding site at the N terminus of Robo1 that is disordered in the x-ray crystal structure. Mutagenesis of the identified N-terminal binding site exhibited a decrease in binding affinity as measured by surface plasmon resonance and heparin affinity chromatography. Footprinting also indicated that heparin binding induces a minor change in the conformation and/or dynamics of the Ig2 domain, but no major conformational changes were detected. These results indicate a second low affinity binding site in the Robo-Slit complex as well as suggesting the role of the Ig2 domain of Robo1 in heparin-mediated signal transduction. This study also marks the first use of electron transfer dissociation-based high spatial resolution hydroxyl radical protein footprinting, which shows great utility for the characterization of protein-carbohydrate complexes.

Patients with infective endocarditis (IE) are generally referred to the intensive care unit (ICU) for one or more organ dysfunctions caused by complications of IE. Neurologic events are frequent causes of ICU admission in patients with IE. They can arise through various mechanisms consisting of stroke or transient ischemic attack, cerebral hemorrhage, mycotic aneurysm, meningitis, cerebral abscess, or encephalopathy. Most complications occur early during the course of IE and are a hallmark of left-sided abnormalities of native or prosthetic valves. Occlusion of cerebral arteries, with stroke or transient ischemic attack, accounts for 40% to 50% of the central nervous system complications of IE. CT scan is the most easily feasible neuroimaging in critically unstable patients. However, magnetic resonance imaging is more sensitive and when performed should follow a standardized protocol. In patients with ischemic stroke who are already receiving oral anticoagulant therapy, this treatment should be replaced by unfractionated heparin for at least 2 weeks with a close monitoring of coagulation tests. Mounting evidence shows that, for both complicated left-sided native valve endocarditis and Staphylococcus aureus prosthetic valve endocarditis, valve replacement combined with medical therapy is associated with a better outcome than medical treatment alone. In a recent series, approximately 50% of patients underwent valve replacement during the acute phase of IE before completion of antibiotic treatment. After a neurological event, most patients have at least one indication for cardiac surgery. Recent data from literature suggest that after a stroke, surgery indicated for heart failure, uncontrolled infection, abscess, or persisting high emboli risk should not be delayed, provided that the patient is not comatose or has no severe deficit. Neurologic complications of IE contribute to a severe prognosis in ICU patients. However, patients with only silent or transient stroke had a better prognosis than patients with symptomatic events. In addition, more than neurologic event per se, a better predictor of mortality is neurologic dysfunction, which is associated with location and extension of brain damage. Patients with severe neurological impairment and those with brain hemorrhage have the worse outcome.

BACKGROUND

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is an update of a review first published in February 2012.

OBJECTIVE

To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis.

METHODS

For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013).

METHODS

Randomised controlled trials (RCTs) comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants.

METHODS

Data were extracted on methodological quality, patients, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.

RESULTS

We identified 12 additional RCTs (6323 patients) in the updated search so that this update considered 21 trials with a total of 9861 patients, all evaluating pharmacological interventions and performed mainly in patients with advanced cancer. Overall, the risk of bias varied from low to high. One large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%) with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In patients with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was observed in the patients treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against inactive control and found an incidence of major bleeding of 1% in both study groups while not reporting on VTE. When compared with placebo, warfarin was associated with a statistically insignificant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control. The new oral factor Xa inhibitor apixaban was evaluated in a phase-II dose finding study that suggested a promising low rate of major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in comparison with placebo.

CONCLUSIONS

In this update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin significantly reduced the incidence of symptomatic VTE. However, the broad confidence intervals around the estimates for major bleeding suggest caution in the use of anticoagulation and mandate additional studies to determine the risk to benefit ratio of anticoagulants in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed.

BACKGROUND

Colorectal surgery implies higher risk of postoperative thromboembolic complications as deep venous thrombosis (DVT) and pulmonary embolism (PE) than general surgery. The best prophylaxis in general surgery is heparin and graded compression stockings. No systematic review on combination prophylaxis or on thrombosis prophylaxis in colorectal surgery has been published.

OBJECTIVE

To compare the incidence of postoperative thromboembolism after colorectal surgery using prophylactic methods focussing on heparins and mechanical methods alone and in combinations.

METHODS

Electronic searches was performed in PUBMED, EMBASE, LILACS and the Cochrane Library. Abstract books from major congresses were handsearched as were reference lists from previously performed reviews.

METHODS

RCT or CCT comparing prophylactic interventions and/or placebo. Outcomes were ascending venography, 125 I-fibrinogen uptake test, ultrasound methods, pulmonary scintigraphy. Studies, using thermographic methods, other isotopic methods, plethysmographic methods, and purely clinical methods as the only diagnostic measure were excluded. 558 studies were identified - 477 were excluded. Only 3 of the identified studies focused exclusively on colorectal surgery. Studies of general surgery contain considerable numbers of colorectal patients. The authors of 66 studies in general and/or abdominal surgery were contacted for retrieving the results from the colorectal patients. Answers were received from very few. 19 studies entered this review.

METHODS

All studies and all data extraction were performed by at least two of the authors. Outcome was deep venous thrombosis and/or pulmonary embolism. Analysis of bleeding complications were unfeasible. 12 meaningful outcomes were analysed by means of the fixed effects model with Peto Odds Ratios.

RESULTS

Heparins versus no treatment: Any kind of heparincompared to no treatment or placebo (comparison 07.03, 11 studies). Heparin is better in preventing DVT and/or PE with a Peto Odds ratio at 0.32 (95% Confidence Interval 0.20-0.53) Unfractionated heparin versus low molecular weight heparin (comparison 08.03, 4 studies). The two treatments were found equally effective in preventing DVT and/or PE with a Peto Odds ratio 1.01 (95% Confidence Interval 0.67-1.52). Mechanical methods (comparison 10.3, 2 studies). The combination of graded compression stockings and LDH is better than LDH alone in preventing DVT and/or PE with a Peto Odds ratio at 4.17 (95% Confidence Interval 1.37-12.70).

CONCLUSIONS

The optimal prophylaxis in colorectal surgery is the combination of graduated compression stockings and low-dose unfractionated heparin. The unfractionated heparin can be replaced with low molecular weight heparin.

OBJECTIVE

Cardiac involvement in sarcoidosis is one of the leading causes of death associated with abnormalities of the conduction system. (18)F-FDG PET is useful for detecting inflammatory lesions in cardiac sarcoidosis. However, the relationship between ECG abnormalities and focal (18)F-FDG uptake has not been studied. The aim of this study was to evaluate the relationship between electrocardiogram (ECG) abnormalities and the location of elevated myocardial (18)F-FDG uptake in patients with sarcoidosis.

METHODS

Included in the study were 50 patients (56.3 ± 14.9 years old) with histologically proven sarcoidosis with suspected cardiac involvement based on ECG or echocardiography. All patients had fasted for at least 6 h and were given unfractionated heparin (50 IU/kg) intravenously to reduce the physiological (18)F-FDG uptake in the myocardium. The left ventricle (LV) wall was divided into 17 segments by visual analysis. Obvious accumulation in each segment was defined as positive.

RESULTS

Of the 50 patients, 33 showed some ECG abnormalities, including atrioventricular (AV) block in 13. Patients with abnormal ECG findings had a higher number of regions with (18)F-FDG uptake than patients without ECG abnormality (3.48 ± 2.73 vs. 1.41 ± 2.09 regions, p = 0.0051). Among ECG abnormalities, the predictor for interventricular septum wall (18)F-FDG involvement was AV block (p = 0.0025).

CONCLUSIONS

Patients with ECG abnormalities showed a higher number of abnormal (18)F-FDG myocardial uptake regions than patients without ECG abnormalities. In particular, focal (18)F-FDG uptake in the interventricular septum in cardiac sarcoidosis was associated with AV block. Therefore, determination of regional (18)F-FDG distribution might contribute to patient management in cardiac sarcoidosis.

1 Neutrophil-derived elastase is an enzyme implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Heparin inhibits the enzymatic activity of elastase and here we provide evidence for the first time that heparin can inhibit the release of elastase from human neutrophils. 2 Unfractionated and low molecular weight heparins (UH and LMWH, 0.01-1000 U ml(-1)) and corresponding concentrations (0.06-6000 micro g ml(-1)) of nonanticoagulant O-desulphated heparin (ODH), dextran sulphate (DS) and nonsulphated poly-L-glutamic acid (PGA) were compared for their effects on both elastase release from and aggregation of neutrophils. 3 UH, ODH and LMWH inhibited (P<0.05) the homotypic aggregation of neutrophils, in response to both N-formyl-methionyl-leucyl-phenylalanine (fMLP, 10(-6) M) and platelet-activating factor (PAF, 10(-6) M), as well as elastase release in response to these stimuli, in the absence and presence of the priming agent tumour necrosis factor-alpha (TNF-alpha, 100 U ml(-1)). 4 DS inhibited elastase release under all the conditions of cellular activation tested (P<0.05) but had no effect on aggregation. PGA lacked efficacy in either assay, suggesting general sulphation to be important in both effects of heparin on neutrophil function and specific patterns of sulphation to be required for inhibition of aggregation. 5 Further investigation of the structural requirements for inhibition of elastase release confirmed the nonsulphated GAG hyaluronic acid and neutral dextran, respectively, to be without effect, whereas the IP(3) receptor antagonist 2-aminoethoxydiphenylborate (2-APB) mimicked the effects of heparin, itself an established IP(3) receptor antagonist, suggesting this to be a possible mechanism of action.

Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.

Keywords: ARDS; COVID-19; Nebulised heparin; SARS; SARS-CoV-2; Unfractionated heparin.

OBJECTIVE

Atrial fibrillation ablation requires peri-procedural oral anticoagulation (OAC) to prevent thromboembolic events. There are several options for OAC. We evaluate peri-procedural AF ablation complications using a variety of peri-procedural OACs.

RESULTS

We examined peri-procedural OAC and groin, bleeding, and thromboembolic complications for 2334 consecutive AF ablations using open irrigated-tip radiofrequency (RF) catheters. Pre-ablation OAC was warfarin in 1113 (47.7%), dabigatran 426 (18.3%), rivaroxaban 187 (8.0%), aspirin 472 (20.2%), and none 136 (5.8%). Oral anticoagulation was always interrupted and intraprocedural anticoagulation was unfractionated heparin (activated clotting time, ACT = 237 ± 26 s). Pre- and post-OAC drugs were the same for 1591 (68.2%) and were different for 743 (31.8%). Following ablation, 693 (29.7%) were treated with dabigatran and 291 (12.5%) were treated with rivaroxaban. There were no problems changing from one OAC pre-ablation to another post-ablation. Complications included 12 (0.51%) pericardial tamponades [no differences for dabigatran (P = 0.457) or rivaroxaban (P = 0.163) compared with warfarin], 12 (0.51%) groin complications [no differences for rivaroxaban (P = 0.709) and fewer for dabigatran (P = 0.041) compared with warfarin]. Only 5 of 2334 (0.21%) required blood transfusions. There were two strokes (0.086%) and no transient ischaemic attacks (TIAs) in the first 48 h post-ablation. Three additional strokes (0.13%), and two TIAs (0.086%) occurred from 48 h to 30 days. Only one stroke had a residual deficit. Compared with warfarin, the neurologic event rate was not different for dabigatran (P = 0.684) or rivaroxaban (P = 0.612).

CONCLUSIONS

Using interrupted OAC, low target intraprocedural ACT, and irrigated-tip RF, the rate of peri-procedural groin, haemorrhagic, and thromboembolic complications was extremely low. There were only minimal differences between OACs. Low-risk patients may remain on aspirin/no OAC pre-ablation. There are no problems changing from one OAC pre-ablation to another post-ablation.

A meta-analysis (MA) based on original patient data has been performed comparing low molecular weight heparins (LMWH) with unfractionated heparin (UFH) in thrombosis prophylaxis after major surgical interventions. The analyses have been done for the following prespecified groups of studies: all studies, studies in orthopaedic surgery (OS) and studies in general surgery (GS, with further separation into low-dose studies [GS-LD] and high-dose studies [GS-HD]). Deep vein thrombosis (DVT, all locations) and wound haematoma were used as primary endpoints for efficacy and safety, respectively. The analysis confirms the results of previous publication-based meta-analyses. In GS there is no relevant difference between LMWH and UFH regarding efficacy; the safety results strongly depend on the dosage: under low-dose LMWH the risk of wound haematoma is significantly lower, under high-dose LMWH it is significantly higher than under UFH. However, most of the studies in the last group used regimens of LMWH that are not considered appropriate any more. In OS there is a trend towards a better efficacy and safety of LMWH. In addition, LMWHs are superior to UFH, in OS, with respect to the secondary endpoints proximal DVT and pulmonary embolism. The rates of proximal DVT and pulmonary embolism, respectively, are consistently lower under LMWH than under UFH, whereas slightly smaller rates of distal DVT are observed under UFH.

BACKGROUND

Oral anticoagulant therapies targeted at thrombin are being developed to overcome limitations associated with current standard therapies.

OBJECTIVE

This study was undertaken to assess and compare the antithrombotic and anticoagulant effects of the novel, selective and reversible, direct thrombin inhibitor (DTI), dabigatran, and its oral prodrug dabigatran etexilate, to that of unfractionated heparin (UFH), hirudin and melagatran using a rabbit model of venous thrombosis.

METHODS

A rabbit model of venous thrombosis consisting of endothelial damage with blood flow reduction was used with minor modifications.

RESULTS

All compounds demonstrated a dose-dependent reduction in thrombus formation following i.v. administration with complete or almost complete inhibition at the highest doses. Dabigatran (in the dose range 0.03-0.5 mg kg(-1)) had a 50% effective dose of 0.066 mg kg(-1). By comparison, UFH (5-50 U kg(-1)), hirudin (0.01-0.05 mg kg(-1)) and melagatran (0.01-0.3 mg kg(-1)) had a 50% effective dose of 9.8 U kg(-1), 0.016 mg kg(-1) and 0.058 mg kg(-1), respectively. Similarly, oral dabigatran etexilate (1-20 mg kg(-1)) inhibited thrombus formation in a dose-dependent manner. Maximum inhibition was achieved within 1 h of administration, suggesting a rapid onset of action. For both routes of administration, inhibition of thrombus formation directly correlated with prolongation of the activated partial thromboplastin time.

CONCLUSIONS

These findings demonstrate the potent anticoagulant and antithrombotic activity of dabigatran as a selective thrombin inhibitor in a rabbit model of venous thrombosis. Notably, dose-dependent and long-lasting antithrombotic efficacy was observed after application of its oral form dabigatran etexilate, which is currently undergoing phase III clinical development.

We hypothesized that direct thrombin inhibition could attenuate platelet activation and release of soluble CD40 ligand (sCD40L), a marker of inflammation, during percutaneous coronary intervention (PCI). To assess platelet function under flow conditions with bivalirudin versus unfractionated heparin (UFH), we employed the cone and plate(let) analyzer (CPA) assay in drug-spiked blood samples from volunteers (n = 3) in vitro, and then in PCI patients who received bivalirudin alone (n = 20), UFH alone (n = 15), and clopidogrel pretreatment plus bivalirudin (n = 15). Scanning electron microscopy was employed to image bivalirudin or UFH-treated platelets to determine whether platelet function observations had a morphologic explanation. Enzyme immunoassay was used to measure sCD40L levels in PCI patients. In vitro, bivalirudin decreased platelet surface coverage; UFH increased platelet surface coverage. In PCI patients, bivalirudin alone decreased platelet surface coverage, UFH alone increased platelet surface coverage, and clopidogrel pretreatment plus bivalirudin additively reduced platelet surface coverage. Unlike UFH, bivalirudin did not activate platelets in SEM studies. Bivalirudin alone or coupled with clopidogrel significantly reduced plasma sCD40L in PCI patients. In conclusion, our findings suggest that under flow conditions, bivalirudin alone or coupled with clopidogrel may have an antiplatelet effect versus UFH alone during PCI. These data suggest that bivalirudin and UFH may confer an anti-inflammatory effect by reducing sCD40L during PCI.

Acute myocardial infarction and its consequences (death, chronic ischemic coronary artery disease, heart failure) are still the number 1 causes of death and of cardiovascular diseases in Germany. In this context, patients with STEMI are at the highest risk. The first-line management of STEMI patients often determines if the outcome is life or death. This overview presents the current optimal evidence-based management of STEMI patients as a practice-oriented extract according to the latest ESC guidelines, fully published some weeks ago (http://www.escardio.org).All efforts must be made to keep the respective time intervals between the onset of symptoms and the beginning of reperfusion therapy as short as possible, i.e. best within a dedicated STEMI network. Two of the time intervals are particularly essential: the time delay between the onset of symptoms and the first medical contact (FMC) and the time delay between FMC and the beginning of reperfusion. The time delay between the onset of symptoms and FMC depends on the patient as well as on the organization of the emergency medical service (EMS). Unfortunately, too many patients/bystanders still hesitate to immediately call the EMS. More intense measures must therefore be taken to educate the public. The optimal FMC by medical doctors or paramedics reacts quickly and ideally arrives with ECG equipment for immediate diagnosis of STEMI (persistent ST-segment elevation or presumably new left bundle branch block) before hospital admission. Unfortunately in many cases, the FMC is the emergency room of a hospital. Further decisions can be made without laboratory findings. In Germany, the average time delay between onset of symptoms and FMC is 100 min and therefore longer than in some other European countries.The next critical time interval is that between FMC and the beginning of reperfusion: this interval depends solely on the EMS organization and the distance to the next catheter laboratory with 24 h PCI (percutaneous coronary intervention) availability. The key question for further decisions is whether a primary PCI can be performed within 120 min after FMC. If so, the primary PCI should definitively be preferred. In patients <75 years presenting with a large anterior infarction within 2 h after onset of symptoms, this time interval should not exceed 90 min. For primary PCI an often used measure of quality is the "door-to-balloon" time, which should of course be as short as possible. Therefore, patients with STEMI should be admitted directly to the catheterization laboratory bypassing the emergency room or intensive care unit. In Germany, the average time interval between FMC and start of primary PCI is approximately 120 min just at the upper limit of the guideline recommendations. Some other European countries report a significantly shorter corresponding time delay.If primary PCI is not possible within 120 min (or 90 min) after FMC, thrombolysis must be initiated within 30 min after FMC, either in the EMS ambulance or in a nearby non-PCI hospital. A thrombolytic therapy, however, even if "successful", is not the final therapy: within 24 h (but not before 3 h) cardiac catheterization has to be performed with PCI, if applicable. Analyzing the overall revascularization rates in Germany, 81% receive primary PCI, 7% thrombolysis and 12% no reperfusion therapy. Regarding any reperfusion in STEMI, Germany holds the third place after the Czech Republic and Belgium.Patients presenting at 12-24 h after onset of symptoms or later may possibly benefit from a PCI, even if already asymptomatic, if signs of ischemia/viability in the infarct artery-related area are demonstrable. If this cannot be shown, PCI in these patients is not indicated.The first-line medication aims at dual antiplatelet therapy (DAPT) and anticoagulation. For DAPT, the combination of ASA with a thienopyridine is mandatory. If primary PCI is feasible, DAPT with prasugrel (loading dose of 60 mg, independent of age and weight) is preferred due to its faster onset of action and superior effectiveness over clopidogrel (loading dose of 600 mg). In patients with STEMI, prasugrel when compared to clopidogrel significantly reduced nonfatal myocardial infarction after 15 months from 9.0% to 6.8% and stent thrombosis significantly from 2.8% to 1.6% (ARC definite/probable). If, however, there are contraindications against prasugrel (s/p stroke or TIA) or if thrombolysis had to be performed, clopidogrel is the choice for DAPT.The i.v. administration of glycoprotein IIb/IIIa inhibitors (GPI) has been limited to only those patients with a high intracoronary thrombus burden. The upstream application of GPI is not recommended. Recommendations for the mechanical treatment of thrombus burden include manual thrombus aspiration (which was upgraded) and a mesh-based protection stent device (MGuard™). For anticoagulation, unfractionated heparin (UFH) is recommended as always but bivalirudin is an upcoming alternative, either in the catheterization laboratory on top after an EMS-delivered UFH bolus or as a possible first-line monotherapy. Bivalirudin may be preferred in STEMI patients with a high risk of bleeding. To prevent possible thrombotic events after PCI, bivalirudin should be continued for several hours after primary PCI.Regardless of whether PCI or thrombolysis was the first-line therapy and regardless of whether a stent (BMS or DES) was implanted, DAPT should be continued for 12 months with prasugrel 10 mg/day (or 5 mg/day, if ≥75 years old and/or <60 kg body weight) or clopidogrel (75 mg/day). There is no evidence that higher maintenance doses of clopidogrel may circumvent possible clopidogrel resistance. The usefulness of so far non-standardized in-vitro platelet aggregation measurements or the practice-oriented interpretation of genetic tests for CYP2C19 polymorphism is unknown. With the 12 months DAPT the patient is treated not the stent.

Introduction: A hypercoagulable condition was described in patients with COVID-19 and proposed as a possible pathogenic mechanism contributing to disease progression and lethality.

Aim: We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients.

Methods: In a retrospective observational study, 2,574 unselected patients hospitalised in 30 clinical centres in Italy from February 19, 2020 to May 23, 2020 with laboratory-confirmed SARS-CoV-2 infection, were analysed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores.

Results: Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (HR=0.60; 95%CI: 0.49 to 0.74; E-value=2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation.

Conclusions: In-hospital heparin treatment was associated with lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomised clinical trials are eagerly awaited to provide clear-cut recommendations.