OBJECTIVE

The need to study methods of thromboembolism prophylaxis in high-risk trauma patients is well established. The purpose of this study was to evaluate the feasibility of a proposed study design, including current methods of prophylaxis, performance of a risk assessment profile scale, and the use of serial color-flow duplex studies in detecting deep venous thrombosis (DVT).

METHODS

Patients were enrolled into the study, stratified as to their ability to receive anticoagulation and randomized to low-dose unfractionated heparin, low molecular weight heparin, pneumatic compression devices, or foot pumps with or without vena caval filters. Serial ultrasound scans were performed at designated intervals for 4 weeks. Pulmonary angiograms were obtained for clinical signs or symptoms of pulmonary embolism.

RESULTS

Fifty-three patients, 32 male and 21 female patients with a mean age of 44 years, completed the study. The incidence of DVT was 43% (23 of 53 patients) and significantly higher in older patients. There were no pulmonary embolisms. Color-flow duplex proved to be a sensitive method for detecting both proximal and distal thrombi. The risk assessment profile for thromboembolism (RAPT) scale identified a group of patients with a high incidence of DVT. However, the occurrence of DVT was not correlated with the magnitude of the RAPT score.

CONCLUSIONS

The ability to identify a population with a high incidence of thromboembolism by using the RAPT score to detect asymptomatic DVT, and the suggested advantage of low molecular weight heparin, all support the need for an appropriately powered randomized clinical trial.

Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective invasive procedure. Current guidelines allow bridging therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Apart from the risk of embolism, bleeding is an important complication in this setting and the optimal perioperative management of such patients is still under discussion. The aims of this prospective, observational, multicentre registry of patients treated by cardiologists were: 1) to evaluate current practice of perioperative management of OAC in a large outpatient cohort, 2) to document embolic and haemorrhagic events, and 3) to identify risk factors predicting adverse events. In the years 2009 and 2010, 1,000 invasive procedures (cardiac catheterisation n=533, pacemaker implantation n = 128, surgery n = 194, other n = 145) were performed in patients with OAC. Sixty- one (6.1%) of those patients did not receive bridging therapy during interruption of OAC, 937 (93.7%) patients were treated with LMWH, two patients (0.2%) received UFH. In 22 patients (2.2%) LMWHs were given in prophylactic dose, 727 patients (72.7%) were treated with halved therapeutic (i.e. weight-adapted) LMWH doses and 188 (18.8%) received full therapeutic LMWH doses. Four thromboembolic complications were observed during 30 days of follow-up (two retinal embolisms, one stroke, one myocardial infarction; 0.4%). One major bleeding (0.1%) and 35 clinically relevant bleedings (3.5%) occurred. Rehospitalisation after bleedings was necessary in 20 patients. Independent predictors for bleedings were history of mechanical heart valve replacement (MVR) (p=0.0002) and the HAS-BLED score (<0.0001), with a cut off value ≥ 3 being the most predictive variable for haemorrhage (hazard ratio 11.8, 95% confidence interval 5.6-24.9, p<0.0001). A total of 527 patients with atrial fibrillation and a CHADS₂ score ≤ 2 received halved therapeutic or full therapeutic dosages of LMWH despite a low embolic risk, whereas 49 of the patients with heart valve replacement (51%) did not receive dosages of bridging therapy as recommended in guidelines. In conclusion, in this registry of patients treated by cardiologists, 94% of patients who required interruption of OAC before invasive procedures received LMWH as a bridging therapy, of whom 73% were treated with halved therapeutic LMWH-dosages. Guideline recommendations were followed in only 31% of cases. Importantly, 69% of patients with AF were over-treated while 51% of patients with heart valve replacement were under-treated with LMWHs. A HASB-BLED score ≥ 3 was highly predictive of bleeding events.

Heparin possesses anti-inflammatory properties, which appeared to be dependent on the dose, timing, and the route of administration in animal studies. In asthma, a single dose of inhaled heparin only slightly reduced the early asthmatic response (EAR) but failed to protect against the late asthmatic response (LAR) to inhaled allergen. We studied the effect of multiple doses of inhaled heparin on the EAR and LAR to inhaled house-dust mite extract in eight stable asthmatics in a two-period, randomized, double-blind, crossover study. During both study periods, a standardized allergen challenge was performed and PC20 histamine was measured 24 h before and 24 h postallergen. Five doses of unfractionated heparin sodium (1,000 U/kg/dose) or placebo were inhaled 90 and 30 min preallergen, and 2, 4, and 6 h postallergen. Airway response was measured by FEV1, and the EAR (0-3 h) and LAR (3-10 h) were expressed as corresponding areas under the time-response curves (AUC). The acute effects of heparin and placebo on baseline FEV1 were not different (p>> 0.07). Although not reaching significance, heparin attenuated the EAR by an average of 40% (mean AUC(0-3) +/- SEM: 29.5 +/- 6.0 [placebo] and 17.8 +/- 5.5% fall x h [heparin]; p = 0.08), while it significantly reduced the LAR by an average of 36% (AUC(3-10) +/- SEM: 169.3 +/- 20.0 [placebo] and 109.1 +/- 23.6% fall x h [heparin]; p = 0.005). We conclude that inhaled heparin reduces the LAR to allergen in asthmatic subjects, which may be due to its anti-inflammatory activity. Our finding suggests that heparin may have potential as anti-asthma therapy.

Two studies have been done to establish recommendations for dosage and dose adjustment in the treatment of deep vein thrombosis (DVT) with low molecular weight heparin (LMWH). In the first, 56 patients were randomized in a double blind study to be treated either with unfractionated heparin (UFH) or LMWH s.c. every 12 h. Initial doses were given according to age and sex, disregarding bodyweight, and the dose was then adjusted when the peak plasma heparin concentration fell outside the desired range of 0.5-0.8 anti-FXa U/ml. There were fewer dose adjustments in the LMWH group. The correlation between injected dose (U/kg bodyweight) and the heparin concentration was higher in the LMWH group (r = 0.59) than in the UFH group (r = 0.38). The results suggest that, in order to obtain the desired heparin concentration, the initial dose of LMWH should be about 100 U/kg bodyweight every 12 h. In the second, open study, this dosage plan was followed in 15 patients. The peak heparin concentration on Day 2 ranged from 0.40 to 0.75 anti-FXa U/ml and adjustment was only required in 3 patients. Day to day variation in peak heparin activity in the individual patient varied little (CV 11-22%), and there was no accumulation. The results indicate that plasma heparin concentration is more predictable using LMWH than UFH, and they point to definite advantages in the use of LMWH in a bodyweight adjusted dosage.

Background: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population.

Methods: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed.

Findings: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group.

Interpretation: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

Funding: Coalition COVID-19 Brazil, Bayer SA.

To evaluate the thromboprophylactic use of low molecular weight heparins (LMWHs), publications from 27 orthopaedic trials and 35 studies of patients undergoing general or gynaecological surgery were scrutinized and subjected to a partial meta-analysis. In orthopaedic surgery, LMWHs were superior to placebo or dextran and at least as efficient as unfractionated heparin in the prevention of deep vein thrombosis (DVT). Compared with unfractionated heparin, one of the LMWH preparations significantly reduced the total incidence of DVT. The rate of non-fatal pulmonary embolism was 0.49 per cent in patients receiving LMWH and 1.22 per cent in controls. Seven orthopaedic patients (0.15 per cent) died from pulmonary embolism, none of whom received LMWH. In general surgery, the LMWHs were at least as efficient as unfractionated heparin, with a trend towards a lower risk of pulmonary embolism with the former. Compared with unfractionated heparin, LMWHs did not reduce the postoperative mortality rate, nor did they cause haemorrhage. LMWHs provide safe and efficient prophylaxis by administration once daily.

BACKGROUND

Clinical studies suggest a survival advantage in cancer patients receiving low molecular weight heparin (LMWH). A suggested mechanism for this beneficial effect may reside in the antiangiogenic activity of heparins.

OBJECTIVE

In this study we investigated whether two different LMWHs, i.e. enoxaparin and dalteparin, and unfractionated heparin (UFH), affect the angiogenic potential of human microvascular endothelial cells (HMEC-1) promoted by tumor cells.

METHODS

HMEC-1 cells were incubated with tumor cell conditioned media (TCM) derived from human breast cancer and leukemic cells (i.e. MCF-7, MDA.MB.231, and NB4 cell lines) or recombinant cytokines (i.e. VEGF, FGF-2, TNF-alpha) +/-heparins. Capillary-like tube formation in Matrigel and cell proliferation were evaluated.

RESULTS

All three TCM induced a significant (p<0.05) increase in total length of tubes formed by HMEC-1 in Matrigel. These increases were significantly counteracted (62 to 100% mean inhibition) by enoxaparin and dalteparin, but were significantly less affected by UFH. Similarly, the tube formation induced by standard VEGF, FGF-2, or TNF-alpha was 100% inhibited by enoxaparin, and 70-90% by dalteparin, whereas minor or no inhibition was observed with UFH. VEGF was the most active cytokine in TCM of both breast cancer and leukemic cells. EC proliferation was significantly increased by standard angiogenic factors, and slightly affected by breast cancer TCM (p=ns). The addition of heparins significantly counteracted the proliferative stimuli.

CONCLUSIONS

These results support a major role for LMWH compared to UFH in inhibiting the proangiogenic effect exerted by tumor cells or purified angiogenic factors on microvascular endothelium.

BACKGROUND

The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007.

RESULTS

This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal.

CONCLUSIONS

This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation.

BACKGROUND

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715455.

Venous thromboembolism (VTE) is a central concern in the intensive care unit (ICU). However, little is known about both current practices for VTE prevention in the ICU and the risk for VTE in persons with severe sepsis and septic shock. XPRESS was a randomized, double-blind, placebo-controlled trial of prophylactic heparin in patients with severe sepsis and higher disease severity who were treated with drotrecogin alfa (activated) (DAA). Subjects were randomized to unfractionated heparin, low-molecular-weight heparin, or placebo during the DAA infusion period. All patients underwent ultrasonography between days 4-6 to screen for VTE. We assessed baseline utilization of VTE prophylaxis along with application of these methods after completion of the DAA infusion. The study included 1,935 subjects and, prior to enrollment approximately half were given no form of prophylaxis. By day 6, 5% of subjects developed a VTE, and the rate of VTE did not vary based on type of heparin administered. The vast majority of VTE detected by day 6 were clinically silent. Of factors analyzed, history of VTE was the only variable independently associated with development of a VTE (odds ratio, 3.66, 95% confidence interval 1.77-7.56, p = 0.005). Strikingly, patients who were initially receiving heparin prophylaxis prior to enrollment but who then had this discontinued because of randomization to placebo suffered more VTE that persons continuing on some form of heparin. Despite multiple guidelines, physicians do not uniformly prescribe VTE prophylaxis. Nonetheless, early VTE occurs even in persons given DAA. Most VTE in critically ill patients are clinically silent.

OBJECTIVE

The aim of this study was to determine the economic impact of several anticoagulation strategies for moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients managed invasively.

BACKGROUND

The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial demonstrated that bivalirudin monotherapy yields similar rates of ischemic complications and less bleeding than regimens incorporating glycoprotein IIb/IIIa receptor inhibitors (GPI) for moderate- and high-risk NSTE-ACS.

METHODS

In ACUITY, 7,851 U.S. patients were randomized to: 1) heparin (unfractionated or enoxaparin) + GPI; 2) bivalirudin + GPI; or 3) bivalirudin monotherapy. Patients assigned to GPI were also randomized to upstream GPI before catheterization or selective GPI only with percutaneous coronary intervention. Resource use data were collected prospectively through 30-day follow-up. Costs were estimated with standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule.

RESULTS

At 30 days, ischemic events were similar for all groups. Major bleeding was reduced with bivalirudin monotherapy compared with heparin + GPI or bivalirudin + GPI (p < 0.001). Length of stay was lowest with bivalirudin monotherapy or bivalirudin + catheterization laboratory GPI (p = 0.02). Despite higher drug costs, aggregate hospital stay costs were lowest with bivalirudin monotherapy (mean difference range: $184 to $1,081, p < 0.001 for overall comparison) and at 30 days (mean difference range: $123 to $938, p = 0.005). Regression modeling demonstrated that hospital savings were primarily due to less major and minor bleeding with bivalirudin ($8,658/event and $2,282/event, respectively).

CONCLUSIONS

Among U.S. patients in the ACUITY trial, bivalirudin monotherapy compared with heparin + GPI resulted in similar protection from ischemic events, reduced bleeding, and shorter length of stay. Despite higher drug costs, aggregate hospital and 30-day costs were lowest with bivalirudin monotherapy. Thus bivalirudin monotherapy seems to be an economically attractive alternative to heparin + GPI for patients with moderate- and high-risk NSTE-ACS. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

OBJECTIVE

To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint.

RESULTS

We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97).

CONCLUSIONS

When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.

OBJECTIVE

Venous thromboembolic events (VTE) are serious complications in children and for which the standard of care, unfractionated heparin followed by oral anticoagulation (UFH/OA), is problematic. The objective of REVIVE was to compare the efficacy and safety of a low molecular weight heparin (reviparin-sodium) to UFH/OA for the treatment of VTE in children.

METHODS

This multicenter, open-label study, with blinded central outcome adjudication, randomized patients with objectively confirmed VTE to receive either reviparin-sodium or UFH/OA. Dose adjustments were made using nomograms. The efficacy outcome was based on recurrent VTE and death due to VTE during the 3-month treatment period. The safety outcomes were major bleeding, minor bleeding and death. Due to slow patient accrual, REVIVE was closed prematurely.

RESULTS

At 3 months, with reviparin-sodium, 2/36 patients (5.6%) had recurrent VTE or death compared to 4/40 patients (10.0%) receiving UFH/OA (odds ratio=0.53; 95% CI=(0.05, 4.00); Fisher's exact test: 2P=0.677). There were 7 major bleeds, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in UFH/OA group (odds ratio=0.41; 95% confidence interval 0.04, 2.76); Fisher's exact test: P=0.435). There were 5 deaths during the study period, 1 (2.8%) in the reviparin-sodium group and 4 (10.0%) in the UFH/OA group. All five deaths were unrelated to VTE but one was due to an intracranial hemorrhage in the UFH/OA group.

CONCLUSIONS

Although limited by small sample size, REVIVE provides valuable information on the incidence of recurrent VTE, major bleeding and problematic issues associated with therapy of VTE in children.

The standard treatment of deep vein thrombosis is given by continuous intravenous infusion of unfractionated heparin. This entails hospitalisation, nursing care, immobility and repeated laboratory tests (e.g. activated partial thromboplastin time [APTT], platelet count). In addition approximately 10% of patients suffer major haemorrhages. The potential advantages of a low molecular weight heparin (CY 216) given subcutaneously were explored in a randomised trial with blind quantitative evaluation of venograms. The study included 166 patients and both "therapeutic efficacy" and "intention to-treat" analyses showed that subcutaneous CY 216 in fixed doses based only on body weight was more effective on the Arnesen and Marder phlebographic scores than continuous i.v. standard heparin with daily dose adjustment according to results of coagulation tests. There was no increase in the risks of pulmonary embolism, haemorrhage or clot extension.

OBJECTIVE

Unfractionated heparin has been found to reduce symptoms and improve healing as adjuvant therapy in patients with ulcerative colitis. The current study evaluated the efficacy and safety of unfractionated heparin in the treatment of ulcerative colitis in comparison with methylprednisolone.

METHODS

A multicenter randomized trial with blinded endpoint evaluation was conducted in patients hospitalized for moderate or severe ulcerative colitis. Patients were randomized to receive heparin as a continuous infusion or methylprednisolone (0.75-1 mg x kg(-1) x day(-1)).

RESULTS

Twenty-five patients entered the study: 13 received methylprednisolone and 12 received heparin. By day 10, 69% of patients in the methylprednisolone group, but none in the heparin group, achieved significant improvement or remission. C-reactive protein levels significantly decreased in the methylprednisolone group but not in the heparin group. Three patients in the heparin group were withdrawn before day 10 because of an adverse event: rectal bleeding needing transfusion (2 cases) or surgery (1 case). The proportion of patients with persistent rectal bleeding at day 10 was 31% in the methylprednisolone group and 90% in the heparin group (P<0.05).

CONCLUSIONS

Unfractionated heparin as monotherapy is not effective in the treatment of moderate or severe ulcerative colitis and is associated with significant bleeding complications.

OBJECTIVE

Our aim was to determine whether a 600-mg loading dose of clopidogrel compared with 300 mg results in improved clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).

BACKGROUND

A 600-mg loading dose of clopidogrel compared with 300 mg provides more rapid and potent inhibition of platelet activation.

METHODS

In the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, 3,602 patients with STEMI undergoing primary PCI were randomized to bivalirudin (n = 1,800) or unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (n = 1,802). Randomization was stratified by thienopyridine loading dose, which was determined before random assignment.

RESULTS

Patients in the 600-mg (n = 2,158) compared with the 300-mg (n = 1,153) clopidogrel loading dose group had significantly lower 30-day unadjusted rates of mortality (1.9% vs. 3.1%, p = 0.03), reinfarction (1.3% vs. 2.3%, p = 0.02), and definite or probable stent thrombosis (1.7% vs. 2.8%, p = 0.04), without higher bleeding rates. Compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin monotherapy resulted in similar reductions in net adverse cardiac event rates within the 300-mg (15.2% vs. 12.3%) and 600-mg (10.4% vs. 7.3%) clopidogrel loading dose subgroups (p(interaction) = 0.41). By multivariable analysis, a 600-mg clopidogrel loading dose was an independent predictor of lower rates of 30-day major adverse cardiac events (hazard ratio: 0.72 [95% confidence interval: 0.53 to 0.98], p = 0.04).

CONCLUSIONS

In patients with STEMI undergoing primary PCI with contemporary anticoagulation regimens, a 600-mg loading dose of clopidogrel may safely reduce 30-day ischemic adverse event rates compared with a 300-mg loading dose. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966).

BACKGROUND

Adjunctive unfractionated heparin (UFH) during thrombolytic therapy for acute myocardial infarction (AMI) promotes the speed and magnitude of coronary artery recanalization and reduces reocclusion. Low-molecular-weight heparins offer practical and potential pharmacological advantages over UFH in multiple applications but have not been systematically studied as adjuncts to fibrinolysis in AMI.

RESULTS

Four hundred patients undergoing reperfusion therapy with an accelerated recombinant tissue plasminogen activator regimen and aspirin for AMI were randomly assigned to receive adjunctive therapy for at least 3 days with either enoxaparin or UFH. The study was designed to show noninferiority of enoxaparin versus UFH with regard to infarct-related artery patency. Ninety minutes after starting therapy, patency rates (thrombolysis in myocardial infarction [TIMI] flow grade 2 or 3) were 80.1% and 75.1% in the enoxaparin and UFH groups, respectively. Reocclusion at 5 to 7 days from TIMI grade 2 or 3 to TIMI 0 or 1 flow and TIMI grade 3 to TIMI 0 or 1 flow, respectively, occurred in 5.9% and 3.1% of the enoxaparin group versus 9.8% and 9.1% in the UFH group. Adverse events occurred with similar frequency in both treatment groups.

CONCLUSIONS

Enoxaparin was at least as effective as UFH as an adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.

OBJECTIVE

To evaluate the effect of heparin on thrombus formation and infection associated with use of central venous and pulmonary artery catheters.

METHODS

We used MEDLINE, EMBASE, citation review of relevant primary and review articles, personal files, and contact with expert informants.

METHODS

Fourteen randomized controlled trials evaluating prophylactic doses of heparin or heparin bonding were included.

METHODS

In duplicate, independently, we abstracted data on the population, intervention, outcome, and methodologic quality.

RESULTS

Prophylactic heparin decreases catheter-related venous thrombosis (relative risk [RR], 0.43; 95% confidence interval [CI], 0.23, 0.78) and bacterial colonization (RR, 0.18; 95% CI, 0.06, 0.60) of central venous catheters and may decrease catheter-related bacteremia (RR, 0.26; 95% CI, 0.07, 1.03). Heparin bonding decreases the risk of pulmonary artery catheter clot formation within 24 h (RR, 0.08; 95% CI, 0.02, 0.37).

CONCLUSIONS

Heparin administration effectively reduces thrombus formation and may reduce catheter-related infections in patients who have central venous and pulmonary artery catheters in place. Cost-effectiveness comparisons of unfractionated heparin, low molecular weight heparin, and warfarin are needed.

Randomized controlled trials of patients with non-ST segment elevation acute coronary syndromes have established the superiority of enoxaparin (versus unfractionated heparin) for reducing adverse ischemic outcomes. Furthermore, adjunctive abciximab therapy during percutaneous coronary intervention (PCI) is associated with improved clinical outcomes. Since algorithms for integrating these pharmacotherapies have not been determined, patients undergoing elective PCI were enrolled into 2 distinct and separate studies conducted by the National Investigators Collaborating on Enoxaparin (NICE) study groups (NICE 1 and NICE 4 studies). Patients in NICE 1 were administered enoxaparin 1.0 mg/kg intravenously (without abciximab) and those enrolled in NICE 4 were administered a reduced dose (0.75 mg/kg) of enoxaparin in combination with standard-dose abciximab intravenously during PCI. Bleeding events and ischemic outcomes assessed in-hospital and at 30-days post-PCI were infrequent with either pharmacologic regimen. In the dose regimens studied, enoxaparin with or without abciximab appears to provide safe and effective anticoagulation during PCI. The combination of reduced-dose enoxaparin and abciximab was associated with a low incidence of adverse outcomes (bleeding or ischemic events). Additional studies may be required to establish the relative safety and efficacy of this new adjunctive pharmacologic strategy when compared with the combination of low-dose, weight-adjusted unfractionated heparin and abciximab.

BACKGROUND

Sepsis and septic shock represent a systemic inflammatory state with substantial pro-coagulant elements. Unfractionated heparin is a known anticoagulant, which also possesses anti-inflammatory properties. Unfractionated heparin has been shown to increase survival in experimental models of septic shock.

OBJECTIVE

To evaluate the impact of intravenous therapeutic dose unfractionated heparin in a cohort of patients diagnosed with septic shock.

METHODS

Retrospective, propensity matched, multicenter, cohort study.

METHODS

Regional intensive care units in Winnipeg, Canada between 1989 and 2005.

METHODS

Two thousand three hundred fifty-six patients diagnosed with septic shock, of which 722 received intravenous therapeutic dose heparin.

RESULTS

The primary outcome of study was 28-day mortality, and mortality stratified by severity of illness (Acute Physiologic and Chronic Health Evaluation II quartile). Safety was assessed by comparing rates of gastrointestinal hemorrhage, intracranial hemorrhage, and the need for transfusion. By using a Cox proportional hazards model, systemic heparin therapy was associated with decreased 28-day mortality (307 of 695 [44.2%] vs. 279 of 695 [40.1%]; hazard ratio 0.85 [confidence interval (CI) 95% 0.73-1.00]; p = 0.05). In the highest quartile of severity of illness (Acute Physiologic and Chronic Health Evaluation II score 29-53), heparin administration was associated with a clinically and statistically significant reduction in 28-day mortality [127 of 184 (69.0%) vs. 94 of 168 (56.0%); hazard ratio 0.70 (CI 95% 0.54-0.92); p = 0.01]. The use of intravenous unfractionated heparin was associated with successful liberation from mechanical ventilation [odds ratio of 1.42 (CI 95% 1.13-1.80); p = 0.003], and successful discontinuation of vasopressor/inotropic support [odds ratio of 1.34 (CI 95% 1.06-1.71); p = 0.01]. No significant differences in the rates of major hemorrhage or need for transfusion were identified.

CONCLUSIONS

Early administration of intravenous therapeutic dose unfractionated heparin may be associated with decreased mortality when administered to patients diagnosed with septic shock, especially in patients with higher severity of illness. Prospective randomized trials are needed to further define the role of this agent in sepsis and septic shock.

BACKGROUND

The risk of venous thromboembolism is high after spinal cord injury (SCI). This prospective, multicenter study compared unfractionated heparin (UFH) plus intermittent pneumatic compression (IPC) to enoxaparin alone as thromboprophylaxis after SCI.

METHODS

Patients with acute SCI were randomly assigned to receive either UFH, 5,000 U every 8 hours, in combination with IPC or enoxaparin, 30 mg every 12 hours. Outcome measures were deep vein thrombosis, pulmonary embolism, and major bleeding after 2 weeks of prophylaxis.

RESULTS

Among 107 assessable patients, the incidence of venous thromboembolism was 63.3% with UFH-IPC versus 65.5% with enoxaparin (p = 0.81). The incidence of PE was 18.4% with UFH-IPC versus 5.2% with enoxaparin (p = 0.03). Among all randomized patients, the incidence of major bleeding was 5.3% with UFH-IPC versus 2.6% with enoxaparin (p = 0.14).

CONCLUSIONS

In the acute treatment phase after SCI, safety and thromboprophylactic efficacy were generally similar with UFH-IPC and enoxaparin.

OBJECTIVE

Catheter-related bloodstream infection is the greatest threat to the safety of patients on hemodialysis. Catheter lock solutions containing heparin have been linked to an increased risk of hemorrhage and thrombocytopenia.

OBJECTIVE

To ascertain the safety and efficacy for prevention of catheter-related bloodstream infection and catheter loss from patency failure of a novel catheter lock solution with antimicrobial and antithrombotic activity containing 0.24 M (7.0%) sodium citrate, 0.15% methylene blue, 0.15% methylparaben, and 0.015% propylparaben (C-MB-P), compared with heparin.

METHODS

Multicenter, prospective, randomized, open-label trial with patients studied for up to 6 months. An independent clinical evaluation committee assessing trial outcomes was blinded to patients' treatment assignments.

METHODS

Twenty-five outpatient hemodialysis units.

METHODS

Patients with end-stage renal disease receiving maintenance hemodialysis through a percutaneous cuffed and tunneled internal jugular hemodialysis catheters.

METHODS

Participants' catheters were locked between hemodialysis sessions with the C-MB-P lock solution or sterile saline containing 5000 units of unfractionated heparin (control).

RESULTS

We recorded and evaluated catheter-related bloodstream infections, catheter loss attributable to luminal thrombosis, and adverse events. A total of 407 patients participated in the trial (49,565 catheter days), 201 in the C-MB-P group and 206 in the heparin group. Patients in the two lock solution groups were comparable for risk factors predisposing to catheter-related bloodstream infection. Catheters locked with C-MB-P were significantly less likely to cause catheter-related bloodstream infection (0.24 vs. 0.82 per 1000 catheter days; relative risk, 0.29; 95% confidence interval, 0.12-0.70; p = .005) and were less likely to be lost because of patency failure (0 vs. 4; log rank, p = .04).

CONCLUSIONS

The novel C-MB-P lock solution is well tolerated, significantly reduces the risk of catheter-related bloodstream infection, and provides protection comparable to heparin against patency failure.

BACKGROUND

The clinical introduction of new oral anticoagulants (NOACs) has stimulated the development of tests to quantify the effects of these drugs and manage complications associated with their use. Until recently, the only treatment choices for the prevention of venous thromboembolism in orthopedic surgical patients, as well as for stroke and systemic embolism in patients with atrial fibrillation, were vitamin K antagonists, antiplatelet drugs, and unfractionated and low-molecular-weight heparins. With the approval of NOACs, treatment options and consequent diagnostic challenges have expanded.

OBJECTIVE

To study the utility of thromboelastography (TEG) in monitoring and differentiating between 2 currently approved classes of NOACs, direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban).

METHODS

Blood samples from healthy volunteers were spiked with each NOAC in both the presence and absence of ecarin, and the effects on TEG were evaluated.

RESULTS

Both the kaolin test reaction time (R time) and the time to maximum rate of thrombus generation were prolonged versus control samples and demonstrated a dose response for apixaban (R time within the normal range) and dabigatran. The RapidTEG activated clotting time test allowed the creation of a dose-response curve for all 3 NOACs. In the presence of anti-Xa inhibitors, the ecarin test promoted significant shortening of kaolin R times to the hypercoagulable range, while in the presence of the direct thrombin inhibitor only small and dose-proportional R time shortening was observed.

CONCLUSIONS

The RapidTEG activated clotting time test and the kaolin test appear to be capable of detecting and monitoring NOACs. The ecarin test may be used to differentiate between Xa inhibitors and direct thrombin inhibitors. Therefore, TEG may be a valuable tool to investigate hemostasis and the effectiveness of reversal strategies for patients receiving NOACs.

Unfractionated heparin given during cardiopulmonary bypass is remarkably immunogenic, as 25% to 50% of postcardiac surgery patients develop heparin-dependent antibodies during the next 5 to 10 days. Sometimes, these antibodies strongly activate platelets and coagulation, thereby causing the prothrombotic disorder, heparin-induced thrombocytopenia. The risk of heparin-induced thrombocytopenia is 1% to 3% if unfractionated heparin is continued beyond the first postoperative week. When cardiac surgery is urgently needed for a patient with acute or subacute heparin-induced thrombocytopenia, options include an alternative anticoagulant (bivalirudin, lepirudin, or danaparoid) or combining unfractionated heparin with a platelet antagonist (epoprostenol or tirofiban). As heparin-induced thrombocytopenia antibodies are transient, unfractionated heparin alone is appropriate in a patient with previous heparin-induced thrombocytopenia whose antibodies have disappeared.