Extended enoxaparin monotherapy for acute symptomatic pulmonary embolism

We investigated the efficacy and safety of extended enoxaparin monotherapy in symptomatic patients with acute pulmonary embolism (PE). We randomized 40 patients in a 1:1 allocation to enoxaparin monotherapy (1 mg/kg twice daily for 10-18 days, and then 1.5mg/kg once daily until day 90) (n = 20) or to enoxaparin 1.0 mg/kg twice daily as a bridge to warfarin with a target international normalized ratio of 2.0-3.0 for 90 days (at least 10 doses of enoxaparin overlapping with warfarin for at least 4 days) (n = 20). All patients underwent echocardiography, cardiac troponin I (TnI), and brain natriuretic peptide testing to identify patients with an increased likelihood of adverse clinical outcomes. The end-points were newly diagnosed deep venous thrombosis (DVT) or PE and bleeding events through day 90. In 15 patients on extended enoxaparin therapy, we used repeated measure analysis of variance (ANOVA) to investigate differences in anti-Xa levels obtained at 2, 4, 8 and 12 weeks. The patients' mean age was 52 +/- 17 years; the most common comorbidities were obesity (58%), hypertension (30%), concomitant DVT (30%) and cancer (15%). Twelve (30%) patients had elevated cardiac Tnl >0.1 mg/l and 11 (28%) had moderate or severe right ventricular dysfunction on echocardiography. Ten (25%) patients received thrombolysis with a continuous infusion of 100 mg alteplase prior to randomization. During a 90-day follow-up, one patient from the enoxaparin monotherapy group suffered symptomatic distal DVT; one from the warfarin group had recurrent symptomatic PE (p = 1.0). None of the study patients had major hemorrhage; two warfarin group patients had minor bleeding compared with none in the enoxaparin monotherapy group (p = 0.49). Repeated measure ANOVA did not reveal significant differences in anti-Xa levels over time (p = 0.217). In patients with acute symptomatic PE, extended enoxaparin monotherapy is feasible and warrants further investigation in a large clinical trial.     

Utilization and outcomes of enoxaparin treatment for deep-vein thrombosis in a tertiary-care hospital

The availability of a low-molecular-weight heparin, enoxaparin, to treat deep-vein thrombosis (DVT) offers the option for outpatient therapy for certain DVT patients. We monitored the utilization and outcomes of enoxaparin treatment for DVT in our tertiary-care hospital. A retrospective chart survey was performed for all DVT patients treated at our facility between October 1998 and September 1999. We tracked treatment received (unfractionated heparin or enoxaparin), clinical outcomes (recurrent thromboembolism or bleeding), and whether the patient would have met practice guideline criteria for outpatient enoxaparin therapy. A total of 266 patients were either admitted to the hospital for DVT or experienced DVT during their hospitalization. Of 266 DVT patients, 73 (27%) received enoxaparin. Sixty-four (88%) patients receiving enoxaparin met practice guideline criteria. Nine patients (12%) who did not meet criteria also received the drug. Major bleeding occurred in 3 patients (4%) receiving enoxaparin; one patient had a life-threatening hemorrhage. Two of the three patients with major bleeding had contraindications to enoxaparin use. Only 45% of our DVT patients were appropriate candidates for outpatient enoxaparin therapy. We conclude that in tertiary-care hospitals with acutely ill patients, most DVT patients will not be candidates for outpatient therapy with enoxaparin. Limitations to enoxaparin use are not widely appreciated.     

Periprocedural bridging therapy with low-molecular-weight heparin in chronically anticoagulated patients with prosthetic mechanical heart valves: experience in 116 patients from the prospective BRAVE registry

BACKGROUND AND AIM of the study: The study aim was to determine the safety and feasibility of a standardized bridging regimen in patients with mechanical heart valves at high thromboembolic risk, using low-molecular-weight heparin (LMWH). METHODS: Since the year 2000, all patients at the authors' institution, with mechanical heart valves and a need for periprocedural interruption of oral anticoagulation (OAC), were prospectively enrolled in this registry. Patients were treated with enoxaparin following a pre-specified, standardized bridging regimen. The main outcome measures were the incidence of hemorrhagic or thromboembolic events. The follow up period was 30 days after hospital discharge. RESULTS: A total of 116 patients was included (31 with mitral valve replacement, 76 aortic valve replacement, nine double valve replacement). Patients underwent either major surgery (n = 25), minor surgery (n = 36), pacemaker implantation (n = 21), or coronary catheterization (n = 34). Bridging therapy with enoxaparin was administered for a mean of 7.0 +/- 4.6 days. Eighteen patients (15.5%) were treated as outpatients. In 35 patients (34%) with renal impairment (creatinine clearance <50 ml/min), LMWH dosage was halved. No thromboembolic (95% CI 0-3.1%) and only one major bleeding complication occurred (0.86%; 95% CI 0.02-4.7%); minor bleeding occurred in 10 patients (8.6%; 95% CI 4.2-15.3%). The hemorrhages arose after a mean of 5.4 +/- 1.4 days LMWH therapy. CONCLUSION: Bridging therapy following a standardized LMWH-based regimen with enoxaparin was effective and relatively safe in a large cohort of patients with mechanical heart valves. Extended duration of LMWH therapy seems to promote the incidence of hemorrhage. Neither dose reduction in patients with renal impairment nor outpatient treatment affected the safety and efficacy of this bridging regimen. These findings warrant that more extensive studies be conducted to investigate the safety of this approach.     

Prehospital administration of enoxaparin before primary angioplasty for ST-elevation acute myocardial infarction.

We hypothesized that primary percutaneous coronary intervention (PCI) could be performed with prehospital injections of enoxaparin for ST segment elevation myocardial infarction (STEMI). Enoxaparin has been studied in combination with fibrinolysis in STEMI, but has not been evaluated as anticoagulant regimen for primary PCI. In a prospective registry, 143 consecutive patients with STEMI received prehospital 0.5 mg/kg intravenous (i.v.) bolus followed by 1 mg/kg subcutaneous enoxaparin before immediate transport for PCI. We focused on anti-Xa activities before and after PCI, bleedings, infarct-related artery patency, and major adverse cardiac events at day 30. Anti-Xa activity was at the target level (>0.5 IU/ml) in 99% of patients during PCI, and in 100% 4 hr after injections; over-anticoagulation (>1.5 IU/ml) was noted in 9 and 2%, respectively at start and 4 hr after injections. Bleeding complications with enoxaparin were rare: major in 1.4% (no intracranial hemorrhages), minor in 2.1%. A patent infarct-related artery (TIMI 2 + 3) was observed in 40.6% of the patients before PCI. TIMI 3 flow was obtained in 88.1% of the cases after PCI. Major adverse cardiac events at 30 days occurred in 5.6% of cases: death 2.8%, reinfarction 3.5%, and target lesion revascularisation 3.5%. Prehospital i.v. and subcutaneous enoxaparin provides simple and rapid anticoagulation for PCI in STEMI patients. Enoxaparin dose needs to be reduced regarding the 9% of over-anticoagulation. This study suggests the potential of enoxaparin as an alternative anticoagulant regimen for primary PCI.     

Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation

OBJECTIVE: To determine optimal intensity of international normalized ratio (INR) of warfarin therapy for the prevention of ischemic events in patients with non-valvular atrial fibrillation (NVAF), we evaluated the risk of severe recurrent stroke, systemic embolism and major hemorrhagic complications according to INR and age. METHODS: We carried out the National Cardiovascular Center (NCVC) NVAF Secondary Prevention Study and analyzed data with those of Japanese Nonvaluvular Atrial Fibrillation-embolism Secondary Prevention Cooperative Study to elucidate relationships of major stroke and hemorrhage with INR and age. In both studies, all patients with cardioembolic stroke were given warfarin, monitored with INR every month, and followed up for primary endpoints of stroke and embolism to other parts of the body, and for secondary endpoints of major hemorrhagic complications requiring blood transfusion or hospitalization. We regarded ischemic stroke with NIH stroke scale (NIHSS) score > or = 10 or systemic embolism as a major ischemic event and ischemic stroke with NIHSS score <10 as a minor ischemic event. There were 203 patients enrolled in total (152 men and 51 women). We investigated the relationship of occurrence of the events with INR and age, and calculated the incidence rates of major and minor ischemic events and major hemorrhagic events. RESULTS: During the mean follow-up of 653 days, major ischemic stroke and systemic embolism occurred in only 4 patients with INR <1.6, minor ischemic stroke in 10 patients with INR 1.50-2.66, and major hemorrhage in 9 patients with INR 2.30-3.56. Patients with major ischemic or hemorrhagic events were significantly older than those without any events (75+/-4 years vs. 67+/-7 years, p<0.001 unpaired t test). Incidence rates of any events at INR < or = 1.59, 1.60-1.99, 2.00-2.59 and > or = 2.60 were 8.6%, 3.8%, 4.9%, and 25.7%/year, respectively. CONCLUSIONS: Major ischemic or hemorrhagic events occur often in the elderly NVAF patients, in whom an INR value of between 1.6 and 2.6 seems optimal to prevent such events.     

Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease

BACKGROUND: Low-molecular-weight heparins administered subcutaneously once or twice daily have been reported to be as safe and efficacious as intravenous unfractionated heparin in the treatment of acute venous thromboembolic disease. OBJECTIVE: To determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute symptomatic venous thromboembolic disease. DESIGN: Randomized, controlled, partially blinded equivalence trial. SETTING: 74 hospitals in 16 countries. PATIENTS: 900 patients with symptomatic lower-extremity deep venous thrombosis, including 287 (32%) with confirmed pulmonary embolism. INTERVENTIONS: Initial therapy with dose-adjusted intravenous unfractionated heparin compared with subcutaneous enoxaparin at fixed dosages of 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Long-term oral anticoagulation was started in all patients within 72 hours of randomization. MEASUREMENTS: Clinical end points assessed during a 3-month follow-up period. RESULTS: Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Symptomatic venous thromboembolism recurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once-daily enoxaparin (4.4%), and 9 of 312 patients receiving twice-daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, -3.04% to 3.49%) for once-daily enoxaparin and -1.2% (CI, -4.2% to 1.7%) for twice-daily enoxaparin. Incidence of major hemorrhage did not differ among the three treatment groups. Major hemorrhage occurred in 6 of 290 patients (2.1%) in the unfractionated heparin group, 5 of 298 patients (1.7%) in the once-daily enoxaparin group, and 4 of 312 patients (1.3%) in the twice-daily enoxaparin group. CONCLUSIONS: Subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin in the prevention of recurrent symptomatic venous thromboembolic disease.     

Extended venous thromboembolism prophylaxis after total hip replacement: a comparison of low-molecular-weight heparin with oral anticoagulant

BACKGROUND: Oral anticoagulants and low-molecular-weight heparin are both recommended for venous thromboembolism prophylaxis after total hip replacement. To date, these regimens have not been compared by means of clinical end points in the extended prophylaxis setting. METHODS: We randomly assigned 1279 patients 3 days after total hip replacement surgery to fixed-dose subcutaneous low-molecular-weight heparin (reviparin sodium, 4200 anti-Xa IU) or adjusted-dose oral anticoagulant (international normalized ratio, 2-3; acenocoumarol) for a 6-week period. The primary end point was the failure rate, defined as the combined clinical events of a confirmed symptomatic thromboembolic event, a major hemorrhage, or death. All patients were followed up throughout the study interval. The primary objective was to compare the observed cumulative failure rate in the low-molecular-weight heparin vs oral anticoagulant group. RESULTS: In the intent-to-treat population, objectively documented symptomatic thromboembolic events occurred in 15 (2.3%) of 643 patients vs 21 (3.3%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.30; 95% confidence interval for the difference, -0.8% to 2.8%). Major bleeding occurred in 9 (1.4%) of 643 patients vs 35 (5.5%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.001). The failure rate was 24 (3.7%) of 643 patients compared with 53 (8.3%) of 636 patients who received low-molecular-weight heparin or oral anticoagulants (P =.001). CONCLUSIONS: A significantly higher benefit-risk ratio was observed for patients undergoing elective hip replacement who received extended out-of-hospital prophylaxis with low-molecular-weight heparin vs acenocoumarol. Low-molecular-weight heparin prophylaxis was at least as effective as oral anticoagulants, but with a marked improvement in safety.     

Closure devices and vascular complications among percutaneous coronary intervention patients receiving enoxaparin, glycoprotein IIb/IIIa inhibitors, and clopidogrel.

The objectives of this study were to explore the rate of vascular complications using closure devices (CDs) vs. manual compression (MC) among percutaneous coronary intervention (PCI) patients receiving enoxaparin, clopidogrel, aspirin, and GP IIb/IIIa inhibitors. The Evaluating Enoxaparin Clotting Times (ELECT) study enrolled patients receiving enoxaparin, clopidogrel, and GP IIb/IIIa inhibitors when necessary. Any approved CD or MC was allowed post-PCI, and clinical outcome data were prospectively collected. Four hundred forty-five patients had anti-Xa levels measured by a core laboratory and by a novel point-of-care device that reports ENOX times. All received enoxaparin, aspirin, and clopidogrel, and 75% received a concomitant GP IIb/IIIa inhibitor. Major and minor bleeding were defined according to TIMI criteria. "Any bleeding" included the occurrence of access site complications including hematoma, significant rebleeding, or bleeding delaying hospital discharge. TIMI major plus minor bleeding occurred in 1.5% of the patients who received CD vs. 1.8% of patients with MC (P = 0.83). Any bleeding occurred in 12.2% of CD vs. 5.7% MC (P = 0.02), and in 9.5% of patients receiving GP IIb/IIIa inhibitor vs. 2.8% (P = 0.01) among those who did not. For patients receiving both a GP IIb/IIIa inhibitor and CD, any bleeding was observed in 13.7% vs. 3.4% (P = 0.006) among patients who received neither. While minor and major TIMI bleeding remained very low in both groups, CD was associated with a twofold increase in risk of any-bleeding event when compared to MC, especially when using GP IIb/IIIa inhibitors.     

Effects of various anticoagulant treatments on von Willebrand factor release in unstable angina

OBJECTIVES: We tested the hypothesis that different anticoagulant treatments may produce different platelet effects and von Willebrand factor (vWf) release in unstable angina. BACKGROUND: The early increase of vWf has been reported to be a risk factor for adverse outcome in unstable angina. Anticoagulant drugs play a key role in stabilization of unstable angina, but they may not have the same efficacy and the same effects on acute vWf release. METHODS: We studied 154 patients enrolled in several clinical trials testing four different anticoagulant treatments in unstable angina or non-Q-wave myocardial infarction. Patients were treated during at least 48 h by either intravenous unfractionated heparin, one of two different low molecular weight heparins (enoxaparin or dalteparin) or the direct thrombin inhibitor PEG-hirudin. All patients received aspirin but no Ib/IIIa inhibitors. RESULTS: The release of vWf over the first 48 h (delta vWf) did not relate to the baseline clinical characteristics. At 30 days of follow-up, delta vWf was sevenfold higher in patients with an end point (death, myocardial infarction, revascularization) than in patients free of events (+53 +/-7% vs. +7 +/-14%, p = 0.004). The same trend was present for each component of the composite end point with the highest levels for one-month mortality (+87 +/- 32% vs. +26 +/- 8%, p = 0.09). The vWf values did not increase over 48 h in patients receiving either enoxaparin or PEG-hirudin (+10 +/- 9% and -5 +/- 20%, respectively). A serious rise ofvWf was measured in unfractionated heparin-treated patients (+87 +/- 11%), which differed significantly from the enoxaparin group (p = 0.0006) and PEG-hirudin group (p < 0.0001). In dalteparin-treated patients, delta vWf was elevated (+48 +/- 8%) and did not differ from the unfractionated heparin group (NS). CONCLUSIONS: We confirm that, in unstable angina patients, a rise of vWf over the first 48 h is associated with an impaired outcome at 30 days. Moreover, the four different anticoagulant treatments tested here do not provide the same protection with regards to vWf release, which may have important prognostic implications and explain different results observed in recent clinical trials.     

Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non-ST-segment elevation acute myocardial infarction.

Patients with unstable angina pectoris (UAP) or non-ST-segment elevation acute myocardial infarction (AMI) are at risk of death or recurrent ischemic events, despite receiving aspirin and unfractionated heparin (UFH). This study investigates the effect of the low molecular weight heparin, enoxaparin, on the incidence of hemorrhage and thrombocytopenia in relation to baseline characteristics and subsequent invasive procedures. Rates of hemorrhage and thrombocytopenia were analyzed for UAP or non-ST-segment elevation AMI in patients included in the prospective, randomized, double-blind Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) study. Patients received either enoxaparin or UFH, plus aspirin, for 2 to 8 days. The overall rate of major hemorrhage (at 30 days) was comparable between the 2 groups (6.5% for enoxaparin vs. 7.0% for UFH, p = 0.6). The rate of major hemorrhage while on treatment was slightly higher in the enoxaparin group, but this was not significant (1.1% vs 0.7% for UFH, p = 0.204), as was the rate of major hemorrhage within 48 hours of coronary artery bypass grafting performed within 12 hours of treatment. However, the rate of minor hemorrhage was significantly higher in the enoxaparin group, with the majority being injection-site ecchymoses or hematomas (11.9% vs. 7.2% with UFH, p <0.001). Thrombocytopenia (platelet count <100,000 per mm(3)) occurred mainly in association with coronary bypass surgery, with a similar rate in both groups. Thus, enoxaparin is a well-tolerated alternative to UFH in the management of UAP or non-ST-segment elevation AMI. Despite the more effective antithrombotic effect, which results in fewer ischemic events, enoxaparin is not associated with an increase in the rate of major hemorrhagic complications, and is not significantly associated with thrombocytopenia, but is associated with an increase in minor injection site ecchymosis.     

Anticoagulation prescribing patterns in patients with cancer

Cancer is a known hypercoagulable state that leads to an increased risk of venous thromboembolism (VTE). Low molecular weight heparin remains the preferred anticoagulant for VTE in patients with cancer over vitamin K antagonist. However, the preferred anticoagulant in prevention of stroke and systemic embolism in atrial fibrillation (AF) in patients with cancer has yet to be determined. The direct oral anticoagulants (DOACs) are increasingly being utilized; however their role in cancer has only recently been investigated. The objective of this retrospective cohort was to describe real-world anticoagulation prescribing patterns in cancer patients at a large academic medical center between January 1, 2013 and October 31, 2016. We sought to assess the safety, tolerability, and efficacy of DOACs in patients with cancer for either VTE and/or AF. Patient demographic, clinical characteristics, as well as bleeding and thrombotic events were collected. There were 214 patients in our analysis, of which 71 patients (33%) received a DOAC [apixaban (n?=?22), dabigatran (n?=?17), and rivaroxaban (n?=?32)]. There were fewer bleeding events and/or discontinuations in the DOAC group compared to enoxaparin (13 vs. 27, p?=?0.022). There was no difference in major or minor bleeds or thromboembolic events in comparing DOAC to enoxaparin or DOAC to warfarin. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs compared to warfarin or enoxaparin in patients with cancer. DOACs may represent an alternative to warfarin or enoxaparin in patients with cancer for VTE and/or stroke reduction in AF.     

Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation

BACKGROUND: Warfarin sodium therapy in patients with atrial fibrillation markedly reduces the incidence of embolic stroke. However, in elderly patients warfarin therapy is often underused owing to the perceived higher risk of hemorrhagic complications. OBJECTIVES: To assess the quality of anticoagulant control and the incidence of hemorrhagic complications and stroke in an elderly population (>75 years old) compared with a younger control group (between 60 and 69 years) and to assess the quality of anticoagulant control and incidence of hemorrhagic complications in those patients who recently commenced receiving warfarin therapy (first year of therapy). PATIENTS AND METHODS: In this retrospective follow-up study, anticoagulant control and the incidence of hemorrhagic complications and stroke were assessed in an elderly population (>75 years old) compared with a younger control group (between 60 and 69 years), all with atrial fibrillation(target international normalized ratio [INR] 2.5) and attending a hospital outpatient anticoagulant clinic. RESULTS: A total of 328 patients were studied over a 21-month period. There were 204 patients in the control group providing 288 patient-years of follow-up and 124 patients in the elderly group providing 170 patient-years of follow-up. The percentage of INR results in the target range was not statistically significantly different between the elderly and control groups (71.5% vs 66.1%) and the occurrences of incidences of INR greater than 7 were 4.2% in the control group and 4.7% in the elderly group (P =.96). The incidences of major hemorrhage were 2.8% per year in the elderly group and 2.9% per year in the control group (P =.96); overall incidence was 2.8% (95% confidence interval, 1.3%-4.4%). One hundred one of the 328 patients studied commenced warfarin therapy during or within 3 months of the start of the study. In this induction group, 62.1% of INRs were within the target range compared with 70.9% of INRs in patients who had been receiving warfarin therapy for more than 3 months at the start of the study (P =.002). The incidences of INR greater than 7 and major hemorrhage were 7.9% per year and 6.9% per year, respectively, in the cohort who recently began warfarin therapy compared with 3.4% per year and 1.7% per year in the group who were receiving warfarin therapy for more than 3 months. CONCLUSION: While it was impossible to consider any selection bias at the level of referral to the clinic, these findings suggest that the elderly population attending our anticoagulant clinic did not have poorer anticoagulant control or an increased incidence of hemorrhage while receiving warfarin therapy.     

Effectiveness and safety of reduced-dose enoxaparin in non-ST-segment elevation acute coronary syndrome followed by antiplatelet therapy alone for percutaneous coronary intervention

Adjunctive pharmacotherapy for stabilizing patients with acute coronary syndrome/non-ST-segment elevation myocardial infarction (ACS/NSTEMI) and for subsequent percutaneous coronary intervention (PCI) includes a combination of anticoagulant and antiplatelet agents. However, all anticoagulants have been shown to paradoxically activate platelets and induce other prothrombotic activities, increase bleeding, and/or cause thrombocytopenia. A single-center experience of 1,400 consecutive patients presenting with ACS/NSTEMI managed using decreased-dose anticoagulation (enoxaparin) and dual-antiplatelet therapy (aspirin and clopidogrel) followed by triple-antiplatelet therapy (aspirin, clopidogrel, and eptifibatide) alone, without additional anticoagulation, during subsequent PCI was retrospectively analyzed. Patients received a median of 3 doses of enoxaparin at a mean dose of 0.51 mg/kg. The final dose was administered 10.8 hours (mean) before PCI. Medical management "failed" in 8 patients (0.6%), and each required emergency PCI. The overall technical success rate was 99.8%. One major adverse clinical event (0.1%) occurred within 24 hours after PCI. Non-Q-wave myocardial infarction occurred in 1.8% of patients, major and minor bleeding complications, in 0.1% and 2.1%, respectively, and thrombocytopenia in 1.3%. Five additional major adverse clinical events (0.4%) occurred within 30 days after PCI, none involving target vessel thrombosis. In conclusion, for patients with ACS/NSTEMI, reduced-dose enoxaparin combined with dual-antiplatelet therapy followed by triple-antiplatelet therapy alone (without additional anticoagulation) during subsequent PCI appears safe and may prove efficacious.     

Enoxaparin versus unfractionated heparin in patients treated with tirofiban, aspirin and an early conservative initial management strategy: results from the A phase of the A-to-Z trial.

AIMS: In high risk patients with non-ST elevation acute coronary syndromes (ACS), enoxaparin is generally preferred to unfractionated heparin (UFH). However, less is known about the relative merits of these two forms of heparin in patients receiving concomitant glycoprotein IIb/IIIa inhibitors. METHODS AND RESULTS: The A phase of the A-to-Z trial was an open label non-inferiority trial in which 3987 patients with non-ST elevation ACS were randomised to receive either enoxaparin or UFH in combination with aspirin and tirofiban. Inclusion required either ST depression or cardiac biomarker elevation. While the selection of an early management strategy (invasive or conservative) was at the discretion of the local investigator, investigators were asked to designate their plans for an invasive or conservative strategy on the case record form. An early conservative strategy was specified for 1778 patients (45%); this subgroup forms the population for the present analyses. Among patients with a planned conservative strategy, baseline characteristics were similar between those randomised to UFH (n = 872) and those randomised to enoxaparin (n = 906). The primary endpoint of death, new MI, or documented refractory ischaemia within 7 days of randomisation occurred in 10.6% of patients randomised to UFH and 7.7% of patients randomised to enoxaparin (HR 0.72; 95% CI 0.53-0.99; p = 0.04). The combined rate of TIMI major, minor, or loss no-site bleeding was 1.3% in patients treated with UFH and 1.8% in those treated with enoxaparin (p = ns). CONCLUSIONS: When a conservative approach to catheterisation and PCI was planned for ACS patients receiving tirofiban and aspirin, enoxaparin was associated with superior efficacy and similar bleeding vs UFH.     

Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin

OBJECTIVES: To compare the rates of bleeding complications in patients with renal insufficiency who receive anticoagulation therapy with the full therapeutic dose, unfractionated heparin (UFH), or with twice-daily enoxaparin. SETTING: A 325-bed community teaching hospital. STUDY TYPE: Retrospective cohort study. METHODS: The medical records of all patients with renal insufficiency who received anticoagulation therapy with UFH or enoxaparin during a 13-month period were reviewed for the occurrence of major and minor bleeding. Incidence rates were computed per 1,000-person days of anticoagulation therapy. Comparisons were made across categories of renal insufficiency and other potential confounders. RESULTS: A total of 620 patients with estimated glomerular filtration rates of < 60 mL/min were studied. Of these, 331 received anticoagulation therapy with UFH, 250 with enoxaparin, and 39 with both (not simultaneously). The major bleeding rates were 26.3 per 1,000 person-days for UFH and 20.7 per 1,000 person-days for enoxaparin. Major bleeding complications were similarly increased for both UFH and enoxaparin therapy across categories of worsening renal insufficiency. Patients with severe renal insufficiency while receiving enoxaparin had a 154% excess incidence of minor bleeding compared to those receiving UFH (incidence ratio, 2.54; 95% confidence interval, 1.01 to 6.36). Worsening renal insufficiency, female gender, and prolonged duration of anticoagulation therapy emerged as the main determinants for bleeding complications. CONCLUSION: Both the twice-daily enoxaparin and UFH regimens are associated with comparable increases in major bleeding complications in patients with renal dysfunction receiving full-dose anticoagulation therapy. Both agents should be used with caution in anticoagulation therapy for patients with renal insufficiency.     

Risk of thromboembolism with short-term interruption of warfarin therapy

BACKGROUND: Significant uncertainty surrounds the treatment of patients who must discontinue warfarin sodium therapy before an invasive procedure. In part, the uncertainty results from the lack of published information about the risk of thromboembolism associated with short-term warfarin therapy interruption. We aimed to assess the frequency of thromboembolism and bleeding within a large cohort of patients whose warfarin therapy was temporarily withheld for an outpatient invasive procedure. METHODS: This prospective, observational cohort study was performed at 101 sites (primarily community-based physician office practices) in the United States. Enrollment was conducted from April 4, 2000, to March 6, 2002. The main outcome measures were thromboembolism or clinically significant hemorrhage within 30 days of warfarin therapy interruption. RESULTS: A total of 1293 episodes of warfarin therapy interruption in 1024 individuals were included. The mean (SD) patient age was 71.9 (10.6) years; 438 (42.8%) were female. The most common indications for anticoagulant therapy were atrial fibrillation (n=550), venous thromboembolism (n=144), and mechanical heart valve (n=132). The most common procedures were colonoscopy and oral and ophthalmic surgery. Perioperative heparin or low-molecular-weight heparin was used in only 8.3% of cases overall. Seven patients (0.7%; 95% confidence interval [CI], 0.3%-1.4%) experienced postprocedure thromboembolism within 30 days. None of the 7 patients who experienced thromboembolism received periprocedural bridging therapy. Six patients (0.6%; 95% CI, 0.2%-1.3%) experienced major bleeding, whereas an additional 17 patients (1.7%; 95% CI, 1.0%-2.6%) experienced a clinically significant, nonmajor bleeding episode. Of these 23 patients who had bleeding episodes, 14 received periprocedural heparin or low-molecular-weight heparin. The duration of warfarin therapy interruption was variable; however, more than 80% of patients had warfarin therapy withheld for 5 days or fewer. CONCLUSIONS: For many patients receiving long-term anticoagulation who need to undergo a minor outpatient intervention, a brief (< or =5 days) periprocedural interruption of warfarin therapy is associated with a low risk of thromboembolism. The risk of clinically significant bleeding, even among outpatients undergoing minor procedures, should be weighed against the thromboembolic risk of an individual patient before the administration of bridging anticoagulant therapy.     

Comparison of apixaban to rivaroxaban and enoxaparin in acute cancer-associated venous thromboembolism

To provide direct comparison between apixaban and rivaroxaban in patients with acute cancer-associated venous thromboembolism (Ca-VTE), consecutive patients treated with apixaban, rivaroxaban, or enoxaparin at Mayo Thrombophilia Clinic (March 1, 2013 to January 31, 2018)) were followed prospectively. The primary effectiveness outcome was venous thromboembolism (VTE) recurrence, and the secondary was mortality. The primary safety outcome was major bleeding, the secondary clinically relevant safety outcome was non-major bleeding (CRNMB), and the third a composite of major and CRNMB. There were 750 patients treated for acute Ca-VTE with apixaban (n = 224), rivaroxaban (n = 163), and enoxaparin (n = 363) within 14 days of diagnosis and for at least 3 months, or until study event. Recurrent VTE was diagnosed in 11 receiving apixaban, 7 receiving rivaroxaban (apixaban vs rivaroxaban hazard ratio (HR) 1.31, 95% confidence interval (95% CI) 0.51-3.36) and 17 in the enoxaparin receiving group (apixaban vs enoxaparin HR 1.14, 95% CI: 0.54, 2.42 and rivaroxaban vs enoxaparin HR 0.85, 95% Cl: 0.36, 2.06). There were 82 deaths in apixaban, 74 rivaroxaban (apixaban vs rivaroxaban HR 1.67, 95% Cl: 1.20, 2.33) and 171 in enoxaparin group (rivaroxaban vs enoxaparin HR 0.73, 95% Cl: 0.56, 0.96). Major bleeding occurred in 11 apixaban, 12 rivaroxaban (apixaban vs rivaroxaban HR 0.73, 95% Cl: 0.32, 1.66) and 21 enoxaparin group (apixaban vs enoxaparin HR 0.89, 95% Cl: 0.43, 1.84 and rivaroxaban vs enoxaparin HR 1.23, 95% Cl: 0.61, 2.50). The CRNMB rate was higher in rivaroxaban compared to apixaban (P = .03) and LMWH (P = .01) groups. Recurrence of VTE and major bleeding were similar in apixaban, rivaroxaban, and enoxaparin groups. Rivaroxaban was associated with higher CRNMB but lower mortality compared to apixaban and enoxaparin.     

Short-term triple therapy with aspirin, warfarin, and a thienopyridine among patients undergoing percutaneous coronary intervention.

OBJECTIVES: To assess bleeding complications among patients undergoing percutaneous coronary intervention (PCI) and receiving triple therapy of warfarin, aspirin, and a thienopyridine. BACKGROUND: Triple therapy of warfarin, aspirin, and a thienopyridine is strongly discouraged, given the potential risk of bleeding complications. METHODS AND RESULTS: Post-PCI patients receiving triple therapy thereafter underwent assessment for bleeding complications. Continuous variables are presented as median (25th-75th percentiles). The study group included 180 patients (80% males; age 65 (52, 75.5)). PCI was on an urgent/emergent basis in 86.6%. The main indications for warfarin use were left ventricular mural thrombus and atrial fibrillation (46.9 and 36.9% respectively). Glycoprotein IIb/IIIa receptor antagonists were used in 47.7%. Post-PCI triple therapy duration was 30 days (30, 30). During the post-triple therapy, 104 patients (57.8%) continued treatment with warfarin and aspirin for 376 days (150, 775). During the triple therapy period, 20 patients developed bleeding complications, (mean INR 2.1 +/- 0.7 at 7 (6, 8.5) days post-PCI): 2 major groin hematoma (initial phase of warfarin treatment during overlap with heparin) and 18 minor. During post-triple therapy, primarily under warfarin and aspirin, 19 patients developed bleeding complications: 1 major and 18 minor. CONCLUSION: Short-term triple therapy after PCI was not associated with prohibitively high bleeding complication rates, and thus should be favorably considered in patients with a clear indication for warfarin use.     

Impact of anticoagulation regimens on sheath management and bleeding in patients undergoing elective percutaneous coronary intervention in the STEEPLE trial

Objective: To evaluate the impact of sheath management on bleeding rates. Background: The procedural characteristics and anticoagulant regimen determine the frequency of postoperative bleeding complications following percutaneous coronary intervention (PCI). Methods: This subanalysis of the SafeTy and Efficacy of Enoxaparin in PCI patients, an internationaL randomized Evaluation (STEEPLE) trial evaluated the relative impact of enoxaparin or unfractionated heparin (UFH) on the rate of non‐coronary artery bypass graft‐related major and minor bleeding, according to sheath management procedures in 3,528 patients undergoing elective PCI with a femoral approach. Results: Sheaths were removed at a median time of 54 min with enoxaparin 0.5 mg/kg, compared with 3 hr 14 min with enoxaparin 0.75 mg/kg and 2 hr 24 min with UFH. Early sheath removal (within 30 min from the end of PCI) was associated with reduced bleeding in patients receiving 0.5 or 0.75 mg/kg enoxaparin compared with UFH (enoxaparin 0.5 mg/kg: 4.9% vs. 10.8%; P < 0.001; enoxaparin 0.75 mg/kg: 5.0% vs. 10.8%; P < 0.001). Compared with UFH, major and minor bleeding was halved when enoxaparin (0.5 mg/kg and 0.75 mg/kg) was used in combination with a closure device (4.4% and 5.3% vs. 10.5% with UFH) or smaller (<7 Fr) sheath sizes (4.9% and 6.0% vs. 9.3%). Conclusion: This analysis shows that early sheath removal can be performed safely following elective PCI in patients receiving enoxaparin. Enoxaparin use was associated with less major and minor bleeding compared with UFH, when either a closure device or a smaller sheath size was used. © 2009 Wiley‐Liss, Inc.     

Randomized comparison of enoxaparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction.

AIMS: To compare the efficacy and safety of low molecular weight heparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction. METHODS AND RESULTS: Three-hundred patients receiving fibrinolytic therapy following acute myocardial infarction were randomly assigned to low molecular weight heparin as enoxaparin (40 mg intravenous bolus, then 40 mg subcutaneously every 8 h, n=149) or unfractionated heparin (5000 U intravenous bolus, then 30 000 U. 24 h(-1), adjusted to an activated partial thromboplastin time 2-2.5x normal, n=151) for 4 days in conjunction with routine therapy. Clinical and therapeutic variables were analysed, in addition to use of enoxaparin or unfractionated heparin, to determine independent predictors of the 90-day composite triple end-point (death, non-fatal reinfarction, or readmission with unstable angina). The triple end-point occurred more frequently in patients receiving unfractionated heparin rather than enoxaparin (36% vs. 26%; P=0.04). Logistic regression modelling of baseline and clinical variables identified the only independent risk factors for recurrent events as left ventricular failure, hypertension, and use of unfractionated heparin rather than enoxaparin. There was no difference in major haemorrhage between those receiving enoxaparin (3%) and unfractionated heparin (4%). CONCLUSION: Use of enoxaparin compared with unfractionated heparin in patients receiving fibrinolytic therapy for acute myocardial infarction was associated with fewer recurrent cardiac events at 90 days. This benefit was independent of other important clinical and therapeutic factors.