Prophylaxis of venous thromboembolism in general surgery in Spain. Analysis of a national survey. / Profilaxis del tromboembolismo venoso en cirugía general en España. Análisis de una encuesta nacional.

INTRODUCTION: Venous thromboembolism (VTE) represents a serious postoperative complication that can be prevented by adequate thromboprophylaxis. Surveys provide relevant information about clinician's attitudes and preferences regarding VTE prophylaxis. METHODS: Transversal, descriptive study based on a survey sent to general surgeons members of the Spanish Association of Surgeons (AEC), that included 31 questions regarding postoperative VTE and its prevention, as well as three clinical scenarios. RESULTS: 530 surgeons, 21.8% of the 2,429 invited by electronic mail to participate, completed the survey. Most of the answering clinicians work on in big teaching hospitals, and 28.5% are residents. VTE represents a serious problem for 28% of participants. Although 81% consider that their knowledge on the prevention of postoperative VTE is adequate, a similar percentage recognizes the need for further education. The vast majority (98.7%) use low molecular weight heparins, which are considered the most effective and safe modality, followed by mechanical methods. The Caprini risk assessment score is used by 81% of surgeons, who usually start pharmacological prophylaxis preoperatively. However, there are remarkable differences in the dosing of heparins, timing of initiation, and duration, especially in non-oncologic surgical patients. CONCLUSIONS: Most Spanish surgeons are interested in the prevention of postoperative VTE. Overall, the level of knowledge on thromboprophylaxis is adequate. However, our results indicate that there is a need for better education on relevant practical aspects of prophylaxis that could be achieved by incorporating recommendations from recent guidelines to local hospital-based protocols.

A multicentre controlled pre-post trial of an implementation science intervention to improve venous thromboembolism prophylaxis in critically ill patients.

PURPOSE: To test whether a multicomponent intervention would increase the use of low molecular weight heparin (LMWH) over unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis in critically ill patients and change patient outcomes and healthcare utilization. METHODS: Controlled pre-post trial of 12,342 adults admitted to 11 ICUs (five intervention, six control) May 1, 2015 to April 30, 2017 with no contraindication to pharmacological prophylaxis and an ICU stay longer than 24 h. Models were developed to examine temporal changes in ICU VTE prophylaxis (primary outcome), VTE, major bleeding, heparin-induced thrombocytopenia (HIT), death and hospital costs. RESULTS: The use of LMWH increased from 45.9% to 78.3% of patient days in the intervention group and from 37.9% to 53.3% in the control group, an absolute increase difference of 17.0% (32.4% vs. 15.4%, p = 0.001). Changes in the administration of UFH were inversely related to those of LMWH. There were no significant differences in the adjusted odds of VTE (ratio of odds ratios [rOR] 1.13, 95% CI 0.51-2.46) or major bleeding (rOR 1.22, 95% CI 0.97-1.54) post-implementation of the intervention (compared to pre-implementation) between the intervention group and the control group. HIT was uncommon in both groups (n = 20 patients). There were no significant changes for ICU and hospital mortality, length of stay and costs. Results were similar when stratified according to reason for ICU admission, patient weight and kidney function. CONCLUSIONS: A multicomponent intervention changed practice, but not clinical and economic outcomes. The benefit of implementing LMWH for VTE prophylaxis under real-world conditions is uncertain.

European guidelines on perioperative venous thromboembolism prophylaxis: Day surgery and fast-track surgery.

: In recent years, day surgery and fast-track surgery have experienced a continuous increase in volume. Many procedures are now performed on an outpatient protocol, including general, orthopaedic, oncological, reconstructive or vascular surgery. The management of these patients is safe, but the incidence of venous thromboembolism in this population remains unknown. Several risk factors can be identified and stratified derived from studies of inpatient surgical management (e.g. Caprini score). Recommendations for thromboprophylaxis should be tailored from the assessment of both personal and procedure-related risk factors, although with a lack of evidence for application in outpatient management. For patients undergoing a low-risk procedure without additional risk factors, we recommend only general measures of thromboprophylaxis (early ambulation, optimal hydration) (Grade 1B). For patients undergoing a low-risk procedure with additional risk factors, or a high-risk procedure without additional risk factors, we recommend general measures of thromboprophylaxis (Grade 1B) and we suggest the administration of pharmacological prophylaxis with low molecular weight heparins (Grade 2B). For patients undergoing a high-risk procedure with additional risk factors we recommend general measures of thromboprophylaxis (Grade 1B) and pharmacological prophylaxis with low molecular weight heparins over other drugs (Grade 1B), or suggest specific mechanical measures in case of increased bleeding risk (Grade 2C). Pharmacological prophylaxis should last a minimum of 7 days (Grade 1B), although in selected cases of fast-track surgery, thromboprophylaxis could be limited to hospitalisation only (Grade 2C) and in specific cases of high-risk procedures, thromboprophylaxis could be extended for up to 4 weeks (Grade 2B).

European guidelines on perioperative venous thromboembolism prophylaxis: Surgery in the obese patient.

: A systematic literature search was performed and patients were selected as obese patients undergoing bariatric surgery or obese patients undergoing nonbariatric surgical procedures. In addition, patients were stratified according to low risk of venous thromboembolism and high risk of venous thromboembolism (age >55 years, BMI >55 kg m, history of venous thromboembolism, venous disease, sleep apnoea, hypercoagulability or pulmonary hypertension). Prophylaxis of venous thromboembolism was analysed depending on the type of modality: compression devices of the lower extremities (including intermittent pneumatic compression and graduated compression stockings), pharmacological prophylaxis or inferior vena cava filters. Two prospective studies compared mechanical devices and pharmacological prophylaxis vs. a mechanical device alone without significant differences. A few randomised controlled studies and most of the prospective nonrandomised studies showed that low-dose low molecular weight heparin (3000 to 4000 anti-Xa IU 12 h subcutaneously) was acceptable for obese patients with a lower risk of venous thromboembolism, but a higher dose of low molecular weight heparin (4000 to 6000 anti-Xa IU 12 h subcutaneously) should be proposed for obese patients with a higher risk of venous thromboembolism. Extended prophylaxis for 10 to 15 days was well tolerated for obese patients with a high risk of venous thromboembolism in the postdischarge period. The safety and efficacy of inferior vena cava filters in bariatric surgical patients is highly heterogeneous. There were no randomised trials that analysed prophylaxis of venous thromboembolism in obese patients undergoing nonbariatric surgery. Higher doses of anticoagulants could be proposed for obese patients with a BMI more than 40 kg m. The lack of good quality randomised trials with a low risk of bias did not allow us to propose strong recommendations.

European guidelines on perioperative venous thromboembolism prophylaxis: Chronic treatments with antiplatelet agents.

: Antiplatelet agents (APA) are considered first-line therapy in preventing cardiovascular thrombotic events, but they are of limited value in the prophylaxis of venous thromboembolism (VTE) during the perioperative period. Consequently, many patients should receive both an APA and an anticoagulant. This combination can increase the bleeding risk and it is necessary to make some recommendations to minimise that risk. In patients receiving APA chronically, if the risk of VTE outweighs the risk of bleeding, we suggest pharmacological prophylaxis (grade 2C). In patients treated with dual antiplatelet therapy undergoing a procedure associated with a high risk of VTE, resuming both APA shortly after the procedure must be prioritised over pharmacological VTE prevention (grade 2C). If the risk of bleeding from a combination of an APA and an anticoagulant outweighs the risk of VTE, we suggest mechanical thromboprophylaxis over anticoagulant prophylaxis, without discontinuing the APA (grade 2C). Patients in whom neuraxial anaesthesia is planned, a higher rate of complications could occur if pharmacological thromboprophylaxis is administered concurrently and postoperative thromboprophylaxis initiation should be suggested (grade 2C). After surgery, the first dose of aspirin should be given once haemostasis is guaranteed (grade 2B). In the case of clopidogrel, give the drug without a loading dose between 24 and 48 h after surgery (grade 2C).

European guidelines on perioperative venous thromboembolism prophylaxis: Surgery during pregnancy and the immediate postpartum period.

: Thromboembolic events in the pregnant and postpartum patient remain rare but potentially fatal complications. The aim of this section was to analyse the few prospective studies addressing the issue of thromboprophylaxis following a surgical procedure during and immediately after pregnancy, as well as national guidelines, and to propose European guidelines on this specific condition. Thromboprophylaxis is broadly recommended due to the combined risks of surgery and pregnancy or the postpartum period, regardless of the mode of delivery. We recommend prophylactic thromboprophylaxis following surgery during pregnancy or the postpartum period when they imply, as a consequence, bed rest, until full mobility is recovered (Grade 1C). Similarly, thromboprophylaxis should be used in cases of perioperative infection during pregnancy or the postpartum period. Concerning thromboprophylaxis following a caesarean section, it seems avoidable only in elective procedures in low-risk patients, after a normal pregnancy, and with an early rehabilitation protocol. The duration of thromboprophylaxis following caesarean section should be at least 6 weeks for high-risk patients, and at least 7 days for the other patients requiring anticoagulation (Grade 1C).

European guidelines on perioperative venous thromboembolism prophylaxis: Patients with preexisting coagulation disorders and after severe perioperative bleeding.

: In patients with inherited bleeding disorders undergoing surgery, we recommend assessment of individual risk for venous thromboembolism, taking into account the nature of the surgery and anaesthetic, type and severity of bleeding disorder, age, BMI, history of thrombosis, the presence of malignancy and other high-risk comorbidities. Venous thromboembolism risk should be balanced against the increased bleeding risk associated with anticoagulant use in patients with known bleeding disorders (Grade 1C). In these patients undergoing major surgery, we recommend against routine postoperative use of pharmacological thromboprophylaxis, especially for patients with haemophilia A and B (Grade 1B). Glomerular filtration rate should be assessed before initiation of each direct oral anticoagulant, and also at least once a year or more frequently as needed, such as postoperatively before the resumption of therapeutic direct oral anticoagulant administration, when it is suspected that renal function could decline or deteriorate (Grade 1C). Reduced dosages of low molecular weight heparins may be used relatively safely during transient severe (<50 × 10 l) thrombocytopaenia (Grade 2C). Monitoring of anti-Xa levels may be used to adjust the doses of low molecular weight heparin in patients with moderate or severe thrombocytopaenia (Grade 2C). The delay between major gastrointestinal bleeding and resuming warfarin should be at least 7 days (Grade 2C). For patients at a high risk of thromboembolism and with a high bleeding risk after surgery, we consider that administering a reduced dose of direct oral anticoagulant on the evening after surgery and on the following day (first postoperative day) after surgery is a good practice (Grade 2B).

European guidelines on perioperative venous thromboembolism prophylaxis: Intensive care.

: Venous thromboembolism is a common and potentially life-threatening complication that occurs in 4 to 15% of patients admitted to ICUs despite the routine use of pharmacological prophylaxis. We therefore recommend an institution-wide protocol for the prevention of venous thromboembolism (Grade 1B). The routine use of ultrasonographic screening for deep vein thrombosis is not recommended when thromboprophylactic measures are in place (Grade 1B), as the detection of asymptomatic deep vein thrombosis may prompt therapeutic anticoagulation that may increase bleeding risk but has no proven reduction of clinically significant thrombotic events. In critically ill patients, we recommend pharmacological prophylaxis with low molecular weight heparin over low-dose heparin (Grade 1B). For critically ill patients with severe renal insufficiency, we suggest the use of low-dose heparin (Grade 2C), dalteparin (Grade 2B) or reduced doses of enoxaparin (Grade 2C). Monitoring of anti-Xa activity may be considered when low molecular weight heparin is used in these patients (Grade 2C). No study has prospectively evaluated the efficacy and safety of deep vein thrombosis prophylaxis in critically ill patients with severe liver dysfunction. Thus, the use of pharmacological prophylaxis in these patients should be carefully balanced against the risk of bleeding. For critically ill patients, we recommend against the routine use of inferior vena cava filters for the primary prevention of venous thromboembolism (Grade 1C). When the diagnosis of heparin-induced thrombocytopaenia is suspected or confirmed, all forms of heparin must be discontinued (Grade 1B). In these patients, immediate anticoagulation with a nonheparin anticoagulant rather than discontinuation of heparin alone is recommended (Grade 1C).

Novel method for the determination of average molecular weight of natural polymers based on 2D DOSY NMR and chemometrics: Example of heparin.

Apart from the characterization of impurities, the full characterization of heparin and low molecular weight heparin (LMWH) also requires the determination of average molecular weight, which is closely related to the pharmaceutical properties of anticoagulant drugs. To determine average molecular weight of these animal-derived polymer products, partial least squares regression (PLS) was utilized for modelling of diffused-ordered spectroscopy NMR data (DOSY) of a representative set of heparin (n=32) and LMWH (n=30) samples. The same sets of samples were measured by gel permeation chromatography (GPC) to obtain reference data. The application of PLS to the data led to calibration models with root mean square error of prediction of 498Da and 179Da for heparin and LMWH, respectively. The average coefficients of variation (CVs) did not exceed 2.1% excluding sample preparation (by successive measuring one solution, n=5) and 2.5% including sample preparation (by preparing and analyzing separate samples, n=5). An advantage of the method is that the sample after standard 1D NMR characterization can be used for the molecular weight determination without further manipulation. The accuracy of multivariate models is better than the previous results for other matrices employing internal standards. Therefore, DOSY experiment is recommended to be employed for the calculation of molecular weight of heparin products as a complementary measurement to standard 1D NMR quality control. The method can be easily transferred to other matrices as well.

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Heparins With Enoxaparin.

Heparin and its low-molecular-weight heparin (LMWH) derivatives are widely used clinical anticoagulants. These drugs are critical for the practice of medicine in applications including kidney dialysis, cardiopulmonary bypass, and in the management of venous thromboembolism. Currently, these drugs are derived from livestock, primarily porcine intestine. The worldwide dependence on a single animal species has made the supply chain for this critical drug quite fragile, leading to the search for other sources of these drugs, including bovine tissues such as bovine intestine or lung. A number of laboratories are currently examining the similarities and differences between heparins prepared from porcine and bovine tissues. The current study is designed to compare LMWH prepared from bovine heparins through chemical ß-elimination, a process currently used to prepare the LMWH, enoxaparin, from porcine heparin. Using top-down, bottom-up, compositional analysis and bioassays, LMWHs, derived from bovine lung and intestine, are shown to closely resemble enoxaparin.

[Are 55 cents always better value than 90 cents for venous thromboembolism prophylaxis? Comparison of three low-molecular-weight heparins with regard to economics and guideline compliance]. / Sind bei der venösen Thrombembolieprophylaxe 55 Cent immer günstiger als 90 Cent? - Vergleich von 3 niedermolekularen Heparinen hinsichtlich Wirtschaftlichkeit und Leitlinien-Compliance.

BACKGROUND: Four low-molecular-weight heparins with different dosage regimens are allowed for venous thromboembolism prophylaxis in patients with a high risk of thromboembolism in Germany. If comparison is made purely on the basis of drug costs, multi-dose vials are the favourable solution. We try to answer the question whether the choice of low-molecular-weight heparin influences the compliance with the S2 guideline "Inpatient and outpatient thromboembolism prophylaxis in surgery and perioperative medicine." Beyond that we ask if multi-dose administration is superior to the pre-filled syringe when total costs are calculated on the basis of procedure and technical application. PATIENTS AND METHODS: After training the nursing and medical staff in guideline-compliant implementation of thromboembolism prophylaxis with pre-filled certoparin safety syringes (03/09-05/09) or nadroparin (06/09-08/09) and enoxaparin (02/10-04/10) from multi-dose vials, we calculated the total costs on the basis of procedure and technical application. Furthermore, the satisfaction of the nursing staff was interrogated and the proportion of non-guideline-compliant prescriptions was determinated prospectively on the basis of a total of 388 patient files. RESULTS: When total costs are calculated on the basis of procedure and technical application, the costs for nadroparin are 1.16 €/0.3 mL, 1.30 €/0.4 mL and 1.58 €/0.6 mL, for enoxaparin 1.04 €/20 and 1.42 €/40, and for certoparin 1.25 €/pre-filled safety syringe. The pre-filled certoparin safety syringe made a very good overall impression on the nursing staff (versus sufficient for nadroparin and enoxaparin). Guideline-compliance was achieved in 100 % with body weight- and risk-independent certoparin, in 79.4 % with risk-adapted enoxaparin, and in 66.4 % with body weight- and risk-dependent nadroparin. CONCLUSION: The complexity of the dosage regimen of a low-molecular-weight heparin has a decisive influence on guideline-compliance. By calculating total costs on the basis of procedure and technical application multi-dose vials only offer a price advantage in patients with a low or moderate risk of thromboembolism compared with pre-filled safety syringes in the venous thromboembolism prophylaxis of orthopaedic and trauma surgery patients.

Characterization of currently marketed heparin products: key tests for LMWH quality assurance.

During the 2007-2008 heparin crisis it was found that the United States Pharmacopeia (USP) testing monograph for heparin sodium or low molecular weight heparins did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS). In response to this concern, new tests and specifications were developed by the Food and Drug Administration (FDA) and USP and put in place to detect not only the contaminant OSCS, but also to improve assurance of quality and purity of these drug products. The USP monographs for the low molecular weight heparins (LMWHs) approved for use in the United States (dalteparin, tinzaparin and enoxaparin) are also undergoing revision to include many of the same tests used for heparin sodium, including; one-dimensional (1D) 500 MHz (1)H NMR, SAX-HPLC, percent galactosamine in total hexosamine and anticoagulation time assays with purified Factor IIa or Factor Xa. These tests represent orthogonal approaches for heparin identification, measurement of bioactivity and for detection of process impurities or contaminants in these drug products. Here we describe results from a survey of multiple lots from three types of LMWHs in the US market which were collected after the 2009 heparin sodium monograph revision. In addition, innovator and generic versions of formulated enoxaparin products purchased in 2011 are compared using these tests and found to be highly similar within the discriminating power of the assays applied.

Familiarity and self-reported compliance with American Urological Association best practice recommendations for use of thromboembolic prophylaxis among American Urological Association members.

PURPOSE: Thromboprophylaxis with subcutaneous heparin or low molecular weight heparin is now an integral part of national surgical quality and safety assessment efforts, and has been incorporated into the current AUA Best Practice Statement. We evaluated familiarity and compliance with the AUA Best Practice Statement, assessed practice patterns in terms of perioperative thromboprophylaxis and specifically examined self-reported compliance in high risk patients undergoing radical cystectomy. MATERIALS AND METHODS: An electronic survey was sent to AUA members with valid e-mail addresses (10,966). Associations between AUA Best Practice Statement adherence and factors such as urological specialty, graduation year and guideline familiarity were assessed using chi-square analyses and generalized estimating equations. RESULTS: With 1,210 survey responses the largest group of respondents was urological oncologists and/or laparoscopic/robotic specialists (26.0%). This group was more likely to use thromboprophylaxis than nonurological oncologists and/or laparoscopic/robotic specialists in high risk patients (OR 1.3, CI 1.1-1.5). Respondents aware of the AUA Best Practice Statement guidelines (50.7%) were more likely to use thromboprophylaxis (OR 1.4, CI 1.2-1.6). Although 18.1% of urological oncologists and/or laparoscopic/robotic specialists and 34.2% of nonurological oncologists and/or laparoscopic/robotic specialists avoided routine thromboprophylaxis in patients undergoing radical cystectomy, the former were more likely to use thromboprophylaxis (p <0.0001) than other respondents. Urologists graduating after the year 2000 used thromboprophylaxis in high risk patients undergoing radical cystectomy more often than did earlier graduates (79.2% vs 63.4%, p <0.0001). CONCLUSIONS: Although younger age and self-reported urological oncologist and/or laparoscopic/robotic specialist status correlated strongly with thromboprophylaxis use, self-reported adherence to AUA Best Practice Statement was low, even in high risk cases with clear AUA Best Practice Statement recommendations such as radical cystectomy. These data identify opportunities for quality improvement in patients undergoing major urological surgery.

Standardisation of unfractionated and low-molecular-weight heparin.

Unfractionated and low-molecular-weight heparins are complex biologicals. Standardisation and global harmonisation of units and methods of measurement are essential for safety and efficacy of this important class of anticoagulants. This chapter describes the traceability of the international unit and current status of the relationship between the international and pharmacopoeial standards, together with a review on current pharmacopoeial assay methods.

A review of the two major regulatory pathways for non-proprietary low-molecular-weight heparins.

With the expiry or pending expiry of originator low-molecular-weight heparin (LMWH) patents, pharmaceutical companies have invested in developing non-proprietary versions of LMWHs. LMWHs are manufactured by depolymerising highly purified unfractionated heparin. In contrast to traditional synthetic drugs with well-defined chemical structures, LMWHs contain complex oligosaccharide mixtures and the different manufacturing processes for LMWHs add to the heterogeneity in their physicochemical properties such that the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) consider existing originator LMWHs to be distinct medicinal entities that are not clinically interchangeable. The FDA views LMWHs as drugs and has approved two non-proprietary (generic) LMWHs, using the Abbreviated New Drug Application pathway. In contrast, the World Health Organization and the EMA view LMWHs as biological medicines. Therefore, the EMA and also the Scientific and Standardization Subcommittee on Anticoagulation of the International Society on Thrombosis and Haemostasis and the South Asian Society of Atherosclerosis and Thrombosis have all published specific guidelines for assessing non-proprietary (biosimilar) LMWHs. This manuscript reviews why there are two distinct pathways for approving non-proprietary LMWHs. Available literature on non-proprietary LMWHs approved in some jurisdictions is also reviewed in order to assess whether they satisfy the requirements for LMWHs in the three guidance documents. The review also highlights some of the significant difficulties the two pathways pose for manufacturers and an urgent need to develop a consensus governing the manufacture and regulation of non-proprietary LMWHs to make them more widely available.

US Food and Drug Administration approval of generic versions of complex biologics: implications for the practicing physician using low molecular weight heparins.

Low-molecular-weight heparins (LMWHs) have shown equivalent or superior efficacy and safety to unfractionated heparin as antithrombotic therapy for patients with acute coronary syndromes. Each approved LMWH is a pleotropic biological agent with a unique chemical, biochemical, biophysical and biological profile and displays different pharmacodynamic and pharmacokinetic profiles. As a result, LMWHs are neither equipotent in preclinical assays nor equivalent in terms of their clinical efficacy and safety. Previously, the US Food and Drug Administration (FDA) cautioned against using various LMWHs interchangeably, however recently, the FDA approved generic versions of LMWH that have not been tested in large clinical trials. This paper highlights the bio-chemical and pharmacological differences between the LMWH preparations that may result in different clinical outcomes, and also reviews the implications and challenges physicians face when generic versions of the original/innovator agents are approved for clinical use.

Low molecular weight heparins differ substantially: impact on developing biosimilar drugs.

Generic drugs are an important component for meaningful health-care reform currently being debated in the United States. Aside from defining the period of drug exclusivity, however, there is a critical need to ensure that generics of biologic medicines (biosimilars) are safe and effective. For low molecular weight heparins (LMWHs), the standard of care for management of venous thromboembolism, their complex structure and polypharmacological actions make producing a generic LMWH more challenging than a generic small molecule medicine. Because biosimilar LMWHs will be used interchangeably with their branded product, inherent variability between products could lead to important differences in potency, safety, or effectiveness, including unanticipated immune responses. Awareness of the specific problems associated with biosimilar LMWH development led to new recommendations from several expert bodies. This article discusses the implications of these differences for the production of biosimilar LMWHs and provides recommendations to address the limitations in the pending U.S. Congress legislation, a well-intentioned undertaking but one that must preserve the health and welfare of citizens who require these critical care medications.

Differences of present recommendations and guidelines for generic low-molecular-weight heparins: is there room for harmonization.

Based on the results of large clinical trials, several low-molecular-weight heparins (LMWHs) have been approved for prophylaxis and the treatment of venous and arterial thromboembolism. As a result of expiration or pending expiration of patent protection of the originator LMWHs, the first generic LMWH enoxaparin has been approved by the Food and Drug Administration for clinical use in all medical indications. The European Medicines Agency has set up guidelines for the production of generic LMWHs. The International Society of Thrombosis, the North American Thrombosis Forum and other scientific organizations raised concerns regarding the safety of generic LMWHs due to economic reasons. These organizations have published statements for the production of generic LMWHs to ensure the quality of the products and the safety for patients. Ideally, the differences between the actual recommendations and guidelines for the production of generic version of LMWHs should be harmonized.