Alex C. Spyropoulos

Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUNDnThis guideline addresses the management of patients who are receiving anticoagulant or antiplatelet therapy and require an elective surgery or procedure.nnnMETHODSnThe methods herein follow those discussed in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement.nnnRESULTSnIn patients requiring vitamin K antagonist (VKA) interruption before surgery, we recommend stopping VKAs 5 days before surgery instead of a shorter time before surgery (Grade 1B). In patients with a mechanical heart valve, atrial fibrillation, or VTE at high risk for thromboembolism, we suggest bridging anticoagulation instead of no bridging during VKA interruption (Grade 2C); in patients at low risk, we suggest no bridging instead of bridging (Grade 2C). In patients who require a dental procedure, we suggest continuing VKAs with an oral prohemostatic agent or stopping VKAs 2 to 3 days before the procedure instead of alternative strategies (Grade 2C). In moderate- to high-risk patients who are receiving acetylsalicylic acid (ASA) and require noncardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C). In patients with a coronary stent who require surgery, we recommend deferring surgery > 6 weeks after bare-metal stent placement and > 6 months after drug-eluting stent placement instead of undertaking surgery within these time periods (Grade 1C); in patients requiring surgery within 6 weeks of bare-metal stent placement or within 6 months of drug-eluting stent placement, we suggest continuing antiplatelet therapy perioperatively instead of stopping therapy 7 to 10 days before surgery (Grade 2C).nnnCONCLUSIONSnPerioperative antithrombotic management is based on risk assessment for thromboembolism and bleeding, and recommended approaches aim to simplify patient management and minimize adverse clinical outcomes.

Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists: Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates

Background— Periprocedural bridging with unfractionated heparin or low-molecular-weight heparin aims to reduce the risk of thromboembolic events in patients receiving long-term vitamin K antagonists. Optimal periprocedural anticoagulation has not been established. Methods and Results— MEDLINE, EMBASE, and Cochrane databases (2001–2010) were searched for English-language studies including patients receiving heparin bridging during interruption of vitamin K antagonists for elective procedures. Data were independently collected by 2 investigators (&kgr;=0.90). The final review included 34 studies with 1 randomized trial. Thromboembolic events occurred in 73 of 7118 bridged patients (pooled incidence, 0.9%; 95% confidence interval [CI], 0.0.0–3.4) and 32 of 5160 nonbridged patients (pooled incidence, 0.6%; 95% CI, 0.0–1.2). There was no difference in the risk of thromboembolic events in 8 studies comparing bridged and nonbridged groups (odds ratio, 0.80; 95% CI, 0.42–1.54). Bridging was associated with an increased risk of overall bleeding in 13 studies (odds ratio, 5.40; 95% CI, 3.00–9.74) and major bleeding in 5 studies (odds ratio, 3.60; 95% CI, 1.52–8.50) comparing bridged and nonbridged patients. There was no difference in thromboembolic events (odds ratio, 0.30; 95% CI, 0.04–2.09) but an increased risk of overall bleeding (odds ratio, 2.28; 95% CI, 1.27–4.08) with full versus prophylactic/intermediate-dose low-molecular-weight heparin bridging. Low-thromboembolic-risk and/or non–vitamin K antagonist patient groups were used for comparison. Study quality was poor with heterogeneity for some analyses. Conclusions— Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall and major bleeding and at similar risk of thromboembolic events compared to nonbridged patients. Randomized trials are needed to define the role of periprocedural heparin bridging.Background— Periprocedural bridging with unfractionated heparin or low-molecular-weight heparin aims to reduce the risk of thromboembolic events in patients receiving long-term vitamin K antagonists. Optimal periprocedural anticoagulation has not been established.nnMethods and Results— MEDLINE, EMBASE, and Cochrane databases (2001–2010) were searched for English-language studies including patients receiving heparin bridging during interruption of vitamin K antagonists for elective procedures. Data were independently collected by 2 investigators (κ=0.90). The final review included 34 studies with 1 randomized trial. Thromboembolic events occurred in 73 of 7118 bridged patients (pooled incidence, 0.9%; 95% confidence interval [CI], 0.0.0–3.4) and 32 of 5160 nonbridged patients (pooled incidence, 0.6%; 95% CI, 0.0–1.2). There was no difference in the risk of thromboembolic events in 8 studies comparing bridged and nonbridged groups (odds ratio, 0.80; 95% CI, 0.42–1.54). Bridging was associated with an increased risk of overall bleeding in 13 studies (odds ratio, 5.40; 95% CI, 3.00–9.74) and major bleeding in 5 studies (odds ratio, 3.60; 95% CI, 1.52–8.50) comparing bridged and nonbridged patients. There was no difference in thromboembolic events (odds ratio, 0.30; 95% CI, 0.04–2.09) but an increased risk of overall bleeding (odds ratio, 2.28; 95% CI, 1.27–4.08) with full versus prophylactic/intermediate-dose low-molecular-weight heparin bridging. Low-thromboembolic-risk and/or non–vitamin K antagonist patient groups were used for comparison. Study quality was poor with heterogeneity for some analyses.nnConclusions— Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall and major bleeding and at similar risk of thromboembolic events compared to nonbridged patients. Randomized trials are needed to define the role of periprocedural heparin bridging.nn# Clinical Perspective {#article-title-50}

Factors at Admission Associated With Bleeding Risk in Medical Patients: Findings From the IMPROVE Investigators

BACKGROUNDnAcutely ill, hospitalized medical patients are at risk of VTE. Despite guidelines for VTE prevention, prophylaxis use in these patients is still poor, possibly because of fear of bleeding risk. We used data from the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) to assess in-hospital bleeding incidence and to identify risk factors at admission associated with in-hospital bleeding risk in acutely ill medical patients.nnnMETHODSnIMPROVE is a multinational, observational study that enrolled 15,156 medical patients. The in-hospital bleeding incidence was estimated by Kaplan-Meier analysis. A multiple regression model analysis was performed to identify risk factors at admission associated with bleeding.nnnRESULTSnThe cumulative incidence of major and nonmajor in-hospital bleeding within 14 days of admission was 3.2%. Active gastroduodenal ulcer (OR, 4.15; 95% CI, 2.21-7.77), prior bleeding (OR, 3.64; 95% CI, 2.21-5.99), and low platelet count (OR, 3.37; 95% CI, 1.84-6.18) were the strongest independent risk factors at admission for bleeding. Other bleeding risk factors were increased age, hepatic or renal failure, ICU stay, central venous catheter, rheumatic disease, cancer, and male sex. Using these bleeding risk factors, a risk score was developed to estimate bleeding risk.nnnCONCLUSIONSnWe assessed the incidence of major and clinically relevant bleeding in a large population of hospitalized medical patients and identified risk factors at admission associated with in-hospital bleeding. This information may assist physicians in deciding whether to use mechanical or pharmacologic VTE prophylaxis.

Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry.

Summary.u2002 Background: Patients who receive long‐term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective surgical or an invasive procedure. Heparin bridging therapy has been used in these situations, although the optimal method has not been established. No large prospective studies have compared unfractionated heparin (UFH) with low‐molecular‐weight heparin (LMWH) for the perioperative management of patients at risk of thromboembolism requiring temporary interruption of long‐term OAC therapy. Patients/methods: This multicenter, observational, prospective registry conducted in North America enrolled 901 eligible patients on long‐term OAC who required heparin bridging therapy for an elective surgical or invasive procedure. Practice patterns and clinical outcomes were compared between patients who received either UFH alone (nu2003=u2003180) or LMWH alone (nu2003=u2003721). Results: Overall, the majority of patients (74.5%) requiring heparin bridging therapy had arterial indications for OAC. LMWH, in mostly twice‐daily treatment doses, represented approximately 80% of the study population. LMWH‐bridged patients had significantly fewer arterial indications for OAC, a lower mean Charlson comorbidity score, and were less likely to undergo major or cardiothoracic surgery, receive intraprocedural anticoagulants or thrombolytics, or receive general anesthesia than UFH‐bridged patients (all Pu2003<u20030.05). The LMWH group had significantly more bridging therapy completed in an outpatient setting or with a <u200324‐h hospital stay vs. the UFH group (63.6% vs. 6.1%, Pu2003<u20030.001). In the LMWH and UFH groups, similar rates of overall adverse events (16.2% vs. 17.1%, respectively, Pu2003=u20030.81), major composite adverse events (arterial/venous thromboembolism, major bleed, and death; 4.2% vs. 7.9%, respectively, Pu2003=u20030.07) and major bleeds (3.3% vs. 5.5%, respectively, Pu2003=u20030.25) were observed. The thromboembolic event rates were 2.4% for UFH and 0.9% for LMWH. Logistic regression analysis revealed that for postoperative heparin use a Charlson comorbidity score >u20031 was an independent predictor of a major bleed and that vascular, general, and major surgery were associated with non‐significant trends towards an increased risk of major bleed. Conclusions: Treatment‐dose LMWH, mostly in the outpatient setting, is used substantially more often than UFH as bridging therapy in patients with predominately arterial indications for OAC. Overall adverse events, including thromboembolism and bleeding, are similar for patients treated with LMWH or UFH. Postoperative heparin bridging should be used with caution in patients with multiple comorbidities and those undergoing vascular, general, and major surgery. These findings need to be confirmed using large randomized trials for specific patient groups undergoing specific procedures.

Predictive and Associative Models to Identify Hospitalized Medical Patients at Risk for VTE

BACKGROUNDnAcutely ill hospitalized medical patients are at risk for VTE. We assessed the incidence of VTE in the observational International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) study and derived VTE risk assessment scores at admission and associative VTE scores during hospitalization.nnnMETHODSnData from 15,156 medical patients were analyzed to determine the cumulative incidence of clinically observed VTE over 3 months after admission. Multiple regression analysis identified factors associated with VTE risk.nnnRESULTSnOf the 184 patients who developed symptomatic VTE, 76 had pulmonary embolism, and 67 had lower-extremity DVT. Cumulative VTE incidence was 1.0%; 45% of events occurred after discharge. Factors independently associated with VTE were previous VTE, known thrombophilia, cancer, age > 60 years, lower-limb paralysis, immobilization ≥ 7 days, and admission to an ICU or coronary care unit (first four were available at admission). Points were assigned to each factor identified to give a total risk score for each patient. At admission, 67% of patients had a score ≥ 1. During hospitalization, 31% had a score ≥ 2; for a score of 2 or 3, observed VTE risk was 1.5% vs 5.7% for a score ≥ 4. Observed and predicted rates were similar for both models (C statistic, 0.65 and 0.69, respectively). During hospitalization, a score ≥ 2 was associated with higher overall and VTE-related mortality.nnnCONCLUSIONSnWeighted VTE risk scores derived from four clinical risk factors at hospital admission can predict VTE risk in acutely ill hospitalized medical patients. Scores derived from seven clinical factors during hospitalization may help us to further understand symptomatic VTE risk. These scores require external validation.

Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT).

Summary.u2002 Background:u2002 The peri‐operative management of patients on oral anticoagulants (OACs) is a common clinical problem. Our aim was to determine the incidence of major bleeding during peri‐operative administration of treatment‐dose enoxaparin and the impact of the extensiveness of the procedure on the risk of bleeding.

Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series

See also Greinacher A. Immunogenic but effective: the HIT‐fondaparinux brain puzzler. This issue, pp 2386–8; Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin‐induced thrombocytopenia: a case series. This issue, pp 2501–3.

A Disease Management Protocol for Outpatient Perioperative Bridge Therapy with Enoxaparin in Patients Requiring Temporary Interruption of Long-Term Oral Anticoagulation

Study Objective. Traditional perioperative bridge therapy for patients receiving long‐term oral anticoagulation involves weight‐adjusted intravenous unfractionated heparin (UFH) in the perioperative period during temporary discontinuation of the oral anticoagulant. We sought to determine whether an alternate strategy of outpatient‐based perioperative disease management with low‐molecular‐weight heparin (LMWH) as bridge therapy provides the potential for cost savings.

The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications.

Hospital-associated venous thromboembolism (VTE) is a leading cause of premature death and disability worldwide. Evidence-based guidelines recommend that anticoagulant thromboprophylaxis be given to hospitalised medical patients at risk of VTE, but suggest against routine use of thromboprophylaxis beyond the hospital stay. The MARINER study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of thromboprophylaxis using rivaroxaban, begun at hospital discharge and continued for 45 days, for preventing symptomatic VTE in high-risk medical patients. Eligible patients are identified using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE VTE) risk score, combined with a laboratory test, D-dimer. The rivaroxaban regimen is 10 mg once daily for patients with CrCl ≥u200950 ml/min, or 7.5 mg once daily for patients with CrCl ≥u200930 ml/min and <u200950 ml/min. The primary efficacy outcome is the composite of symptomatic VTE (lower extremity deep-vein thrombosis and non-fatal pulmonary embolism) and VTE-related death. The principal safety outcome is major bleeding. A blinded clinical events committee adjudicates all suspected outcome events. The sample size is event-driven with an estimated total of 8,000 patients to acquire 161 primary outcome events. Study design features that distinguish MARINER from previous and ongoing thromboprophylaxis trials in medically ill patients are: (i) use of a validated risk assessment model (IMPROVE VTE) and D-dimer determination for identifying eligible patients at high risk of VTE, (ii) randomisation at the time of hospital discharge, (iii) a 45-day treatment period and (iv) restriction of the primary efficacy outcome to symptomatic VTE events.

Management of venous thromboembolism in the elderly.

In this review the authors discuss the use of oral and parenteral anticoagulants for the prevention and treatment of venous thromboembolism (VTE) in the elderly. The use of anticoagulant agents in VTE prophylaxis and treatment in the elderly is complicated by an increase with age in the presence of multiple risk factors and co-morbidities that may increase the risk of both VTE and bleeding. Age itself is identified as an independent risk factor for thromboembolism. VTE is underdiagnosed in the elderly population, and routine prophylaxis frequently falls short of the levels required according to level of risk. Although appropriate anticoagulation of at-risk patients offers a means of reducing the significant VTE burden in this population, concerns have been raised over the use of anticoagulants in a patient group in whom multiple risk factors are common. Bleeding in the elderly can be exacerbated by reduced renal clearance and hypersensitivity to oral anticoagulants that may lead to over-anticoagulation. Although bleeding due to anticoagulant therapy is a serious issue in the elderly, it is often overemphasised, given the therapeutic value otherwise observed in treating this patient group. Warfarin is still used in VTE prophylaxis after orthopaedic surgery and for long-term VTE treatment. Unfractionated and low-molecular-weight heparins (LMWHs) have been shown to be safe and effective in the prophylaxis of VTE, and are now being shown to be as effective as warfarin in the initial and long-term treatment of VTE. LMWHs confer the advantage over unfractionated heparin of subcutaneous once-daily administration with no requirement for laboratory monitoring of their anticoagulant effect, which allows for the convenience of outpatient therapy. New anticoagulants that may be of potential benefit in this patient population include fondaparinux sodium, but clinical experience of this drug in the elderly remains limited.