Cost-effectiveness impact of rivaroxaban versus new and existing prophylaxis for the prevention of venous thromboembolism after total hip or knee replacement surgery in France, Italy and Spain.

Venous thromboembolism (VTE) has a significant impact on healthcare costs but is largely preventable with anticoagulant prophylaxis using low-molecular-weight heparins (LMWHs), such as enoxaparin or dalteparin. Rivaroxaban and dabigatran etexilate are two new oral anticoagulants (NOACs) both compared with enoxaparin in separate trials. A decision analytic model with a healthcare and national payer perspective over a five-year time horizon was used to evaluate the cost-effectiveness of the NOACs for VTE prophylaxis after total hip replacement (THR) or total knee replacement (TKR) in France, Italy and Spain. Efficacy and safety data were obtained from randomised controlled trials of rivaroxaban vs enoxaparin and an indirect statistical comparison for rivaroxaban vs dabigatran. Rivaroxaban demonstrated dominance across all comparisons, indications and countries. In THR, total per-patient costs were reduced by up to €160 in the enoxaparin comparison and €115 in the dabigatran comparison, respectively. In addition, quality-adjusted life-years (QALYs) were increased by up to 0.0011 and 0.0012 in each comparison, respectively. Similarly, total costs were reduced in TKR by up to €137 and €28 in the enoxaparin and dabigatran comparisons, respectively. The total number of QALYs was increased by up to 0.0014 in the enoxaparin comparison and 0.0005 in the dabigatran comparison. The results were driven by costs since the incremental benefits were minimal. Rivaroxaban use could result in substantial healthcare cost savings and improved quality of life. The results are applicable across three European countries with differing healthcare systems so, potentially, could be generalised to a much wider population.

II Italian intersociety consensus statement on antithrombotic prophylaxis in orthopedics and traumatology.

Pharmacological prophylaxis for preventing venous thromboembolism (VTE) is a worldwide established procedure in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures, but few data exist to its regard in other fields of orthopedics and traumatology. Indeed, no guidelines or recommendations are available in the literature, except for a limited number of weak statements about knee arthroscopy and lower limb fractures. The present paper represents the first multidisciplinary effort to provide suggestions on the prophylaxis of VTE in the remaining fields of orthopedic surgery (minor orthopedic surgery and orthopedic trauma). The Italian Society for Studies on Hemostasis and Thrombosis (SISET), the Italian Society of Orthopedics and Traumatology (SIOT) and the association of Orthopedic Traumatology of Italian Hospitals (OTODI) together with the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) and the Italian Society of General Medicine (SIMG) have set down quick and easy suggestions for VTE prophylaxis in a number of surgical conditions for which only scarce evidence is available. This inter-society consensus statement aims at simplifying the approach to VTE prophylaxis in the single patient with the goal of improving its clinical application.

Emergency reversal of anticoagulation with vitamin K antagonists with 3-factor prothrombin complex concentrates in patients with major bleeding.

Major bleeding is a serious and potentially fatal complication of treatment with vitamin K antagonists (VKAs). Prothrombin complex concentrates (PCCs) can substantially shorten the time needed to reverse VKA effects. To determine the efficacy and safety of 3-factor PCCs for the rapid reversal of VKAs in patients with major bleeding. Patients receiving VKAs and suffering from acute major bleeding were eligible for this prospective cohort study if their international normalized ratio (INR) was higher than or equal to 2.0. Stratified 35-50 IU kg(-1) PCC doses were infused based on initial INR. A total of 126 patients (62 males; mean age: 74 years, range 37-96 years) were enrolled. The mean INR at presentation was 3.3 (range 2-11). At 30 min after PCC administration the mean INR was 1.4 (range: 0.9-3.1), declining to less than or equal to 1.5 in 75 % of patients. The benefit of PCC was maintained for a long time, since in 97 % of all post-infusion time points through 96 h the mean INR remained lower than or equal to 1.5 (mean: 1.19; range: 0.9-2.3). During hospitalization neither thrombotic complications nor significant adverse events were observed and 12 patients died (10 %); none of the deaths was judged to be related to PCC administration. 3-factor PCC administration is an effective, rapid ad safe treatment for the urgent reversal of VKAs in patients with acute major bleeding. Broader use of PCC in this clinical setting appears to be appropriate.

II Italian intersociety consensus statement on antithrombotic prophylaxis in orthopaedics and traumatology: arthroscopy, traumatology, leg immobilization, minor orthopaedic procedures and spine surgery.

Pharmacological prophylaxis for preventing venous thromboembolism (VTE) is a worldwide established procedure in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures, but few data exist in other fields of orthopaedics and traumatology. Thus, no guidelines or recommendations are available in the literature except for a limited number of weak statements about knee arthroscopy and lower limb fractures. In any case, none of them are a multidisciplinary effort as the one here presented. The Italian Society for Studies on Haemostasis and Thrombosis (SISET), the Italian Society of Orthopaedics and Traumatology (SIOT), the Association of Orthopaedic Traumatology of Italian Hospitals (OTODI), together with the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) and the Italian Society of General Medicine (SIMG) have set down easy and quick suggestions for VTE prophylaxis in a number of surgical conditions for which only scarce evidence is available. This inter-society consensus statement aims at simplifying the approach to VTE prophylaxis in the single patient with the goal to improve its clinical application.

A randomized double-blind study of low-molecular-weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum).

BACKGROUND: Optimal doses and duration of low-molecular-weight heparin (LMWH) for the treatment of superficial vein thrombosis (SVT) are still uncertain. OBJECTIVES: To compare the efficacy and safety of different doses and durations of LMWH parnaparin for symptomatic lower limb SVT. PATIENTS AND METHODS: Outpatients with at least a 4-cm-long SVT of long or short saphenous veins or their collaterals were randomized to receive parnaparin either 8500 UI once daily ( o.d.) for 10 days followed by placebo for 20 days (group A) or 8500 UI o.d. for 10 days followed by 6400 UI once daily (o.d.) for 20 days (group B) or 4250 UI o.d. for 30 days (group C) in a double-blind fashion in 16 clinics. Primary outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE) and relapse and/or symptomatic or asymptomatic SVT recurrence in the first 33 days with 60 days follow-up. RESULTS: Among 664 patients, primary outcome occurred in 33/212 (15.6%), 4/219 (1.8%) and 16/217 (7.3%) subjects in groups A, B and C, respectively (B vs. A: absolute risk reduction [ARR]: 13.7%, 95% confidence intervals [CI]: 8-18.9 P<0.001; B vs. C: ARR: 5.5%; 95% CI: 1.6-9.4 P= 0.011; C vs. A: ARR: 8.2%, 95% CI: 2-14 P=0.012). During days 0-93, the event rate was higher in group A (22.6%) than either in group B (8.7%; P=0.001) or C (14.3%, P=0.034). No major hemorrhages occurred. CONCLUSIONS: An intermediate dose of parnaparin for 30 days is superior to either a 30-day prophylactic dose or a 10-day intermediate dose for lower limb SVT treatment.

Italian intersociety consensus statement on antithrombotic prophylaxis in hip and knee replacement and in femoral neck fracture surgery.

Anticoagulant prophylaxis for preventing venous thrombembolism (VTE) is a worldwide established procedure in hip (HR) and knee replacement (KR) surgery, as well as in the treatment of femoral neck fractures (FNF). Different guidelines are available in the literature, with quite different recommendations. None of them is a multidisciplinary effort as the one presented. The Italian Society for Studies on Hemostasis and Thrombosis, the Italian Society of Orthopedics and Traumatology, the association of Orthopedic Traumatology of Italian Hospitals, together with the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care have set down easy and quick suggestions for VTE prophylaxis in HR and KR surgery as well as in FNF treatment. This inter-society consensus statement aims at simplifying the grading system reported in the literature, and thus at improving its proper application. Special focus is given to fragile patients, those with high bleeding risk, and on those receiving chronic antiplatelet and vitamin K antagonists treatment. A special chapter is dedicated to regional anesthesia and VTE prophylaxis.

Italian intersociety consensus statement on antithrombotic prophylaxis in hip and knee replacement and in femoral neck fracture surgery.

Anticoagulant prophylaxis for preventing venous thromboembolism (VTE) is a worldwide established procedure in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures (FNF). Different guidelines are available in the literature, with quite different recommendations. None of them is a multidisciplinary effort as the one presented. The Italian Society for Studies on Haemostasis and Thrombosis (SISET), the Italian Society of Orthopaedics and Traumatology (SIOT), the association of Orthopaedists and Traumatologists of Italian Hospitals (OTODI), together with the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care (SIAARTI) have set down easy and quick suggestions for VTE prophylaxis in hip and knee surgery as well as in FNF treatment. This inter-society consensus statement aims at simplifying the grading system reported in the literature, and its goal is to benefit its clinical application. Special focus is given to fragile patients, those with high bleeding risk, and those receiving chronic antiplatelet (APT) and vitamin K antagonists treatment. A special chapter is dedicated to regional anaesthesia and VTE prophylaxis.

Prevalence and clinical history of incidental, asymptomatic pulmonary embolism: a meta-analysis.

CONTEXT: Recently, there has been an increasing number of reports of incidental pulmonary embolism (PE) in patients undergoing chest computer tomography (CT) for reasons other than the research of suspected PE. Natural history of incidental PE remains unclear. OBJECTIVES: To estimate the prevalence of incidental PE, to assess potential factors associated with incidental PE, and to evaluated its clinical history. DATA SOURCES: MEDLINE, EMBASE databases (up to January 2009). STUDY SELECTION: Studies were included if the prevalence of incidental PE was assessed using CT scanning. DATA EXTRACTION: The prevalence of incidental PE in these patients was documented. Separate data for inpatients and outpatients and according to the reason for CT scanning were collected. Weighted mean proportion of the prevalence of incidental PE was calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to test the association with potential predictors of incidental PE. RESULTS: Twelve studies for a total of more than 10 thousand patients were included. The weighted mean prevalence of incidental PE was 2.6% (95% CI 1.9, 3.4). Hospitalization at the time of CT scanning and the presence of cancer were associated with a significantly increased risk of incidental PE (OR 4.27 and OR 1.80 respectively). CONCLUSIONS: The prevalence of incidental PE is clinically relevant. Future studies are necessary to properly evaluate the clinical history of these patients.

Do Italian vascular centers look for isolated calf deep vein thrombosis? Analysis of isolated calf deep vein thromboses included in the ''Master'' Registry.

AIM: Two diagnostic imaging strategies for suspected deep venous thrombosis (DVT) in symptomatic patients are currently used: a serial compression ultrasound examination of proximal veins, or a single complete ultrasound investigation of proximal and distal veins. These strategies lead to different results since only the latter allows diagnosis of isolated calf DVT (ICDVT). METHODS: We analyzed the approach of Italian centers in looking for ICDVT using the observational MASTER registry which prospectively collected information on patients with acute symptomatic venous thromboembolism. RESULTS: ICDVT was diagnosed in 170 of the 1772 patients with leg DVT (9.6%). The rate of diagnosed ICDVT vs total DVT differed between centers from 0% to 24%. Patients with ICDVT were younger (P<0.0001); diagnosis was more frequently delayed (P<0.0001), temporary risk factors were more frequent, cancer was less frequent (P<0.001), and pulmonary embolism (PE) was more frequent at presentation (P<0.05). More ICDVT patients received LMWH only, not followed by oral anticoagulation (P<0.001). CONCLUSIONS: The diagnostic strategy for suspected leg DVT differs greatly among Italian centers. A relatively high rate of PE was recorded in patients with ICDVT for reasons which are open to debate. Prospective, well designed studies on the clinical risks and the need for diagnosing ICDVT, and the advantages/disadvantages of the two diagnostic procedures are urgently needed.

Prothrombin complex concentrates for urgent anticoagulation reversal in patients with intracranial haemorrhage.

BACKGROUND: Intracranial haemorrhage (ICH) is a serious and potentially fatal complication of oral anticoagulant therapy (OAT). Prothrombin complex concentrates (PCCs) produce a rapid and effective reversal of OAT effects, but little evidence exists on their efficacy and safety in the management of ICH in patients on OAT. AIM: To evaluate the efficacy and safety of PCCs for the rapid reversal of OAT in patients with ICH. METHODS: Patients suffering from acute ICH while receiving OAT were eligible for this prospective cohort study if their international normalized ratio (INR) was > or = 2.0. Stratified 35-50 IU kg(-1) PCC doses were infused based on initial INR. RESULTS: A total of 92 patients (50 males; mean age 74 years, range 34-92 years) were included. The median INR at presentation was 3.3 (range 2-9). At 30 min after PCC administration the median INR was 1.4 (range 0.9-3.1), declining to < or = 1.5 in 75% of patients. The benefit of PCC was maintained for a long time, since in 98% of all post-infusion time points through 96 h the median INR remained < or = 1.5 (median 1.19; range 0.9-2.3). During hospitalization neither thrombotic complications nor significant adverse events were observed and 11 patients died (11.9%). None of the deaths was judged to be related to PCC administration. CONCLUSIONS: PCC administration is an effective, rapid and safe treatment for the urgent reversal of OAT in patients with ICH. Broader use of PCC in this clinical setting appears to be appropriate.

Retrievable vena cava filters: key considerations.

Retrievable filters are a new generation of inferior vena cava (IVC) filters and represent an attractive option because they may be either left in place permanently or safely retrieved after a quite long period when they become unnecessary. In this review the currently available literature regarding retrievable IVC filters is summarized and their efficacy and safety is discussed. Moreover, the appropriate indications for their use are reviewed. Retrievable filters are becoming safer and easier to use; in fact the bioengineering research has optimized the technical characteristics of these devices, in order to reduce the incidence of possible complications. However, there are important unresolved issues, including the appropriate maximum implantation time, the possibility to safely and efficaciously remove the filters without being compromised by entrapped clots, and the use of anticoagulation during the implantation and periremoval periods. Large prospective cohort studies or randomized trials are strongly warranted to definitely clarify the beneficial role of these devices.

Management of primary care patients with suspected deep vein thrombosis: use of a therapeutic dose of low-molecular-weight heparin to avoid urgent ultrasonographic evaluation.

BACKGROUND: Out of hospital management of patients with suspected deep vein thrombosis (DVT) can be problematic. The accuracy of clinical prediction rules in the primary care setting may be inadequate, D-dimer testing may not be available, and the cost-effectiveness of urgent ultrasonographic evaluation is uncertain. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of an empiric single therapeutic dose of low-molecular weight heparin (LMWH) in the time interval preceding ultrasound investigation in patients presenting to primary care physicians (PCPs) for suspicion of DVT. METHODS: Consecutive patients with suspected DVT who presented to the office of a PCP outside regular thrombosis center working hours were enrolled. All eligible patients received a single therapeutic dose of LMWH (100 anti-Xa IU kg(-1) weight) and were scheduled to undergo clinical and instrumental evaluation at the thrombosis center the morning after. Clinical events were documented after a 3-month follow-up. RESULTS: A total of 534 consecutive patients with suspected DVT were included in this study; of these 102 patients had subsequent diagnosis of DVT. We detected no episodes of pulmonary embolism, major bleeding, or death during the 18-h window between the administration of LMWH and objective evaluation. Of the 432 patients in whom diagnosis of DVT was subsequently excluded, only three (0.7%; CI: 0.2-2.0%) developed venous thromboembolic events during the 3-month follow-up period. CONCLUSIONS: Empiric treatment with a single therapeutic dose of LMWH is effective and safe for outpatients with suspected DVT initially managed in a primary care setting. This strategy has the potential to reduce the need for urgent diagnostic imaging.

Clinical experience with retrievable vena cava filters: results of a prospective observational multicenter study.

BACKGROUND: Retrievable inferior vena cava (IVC) filters offer the attractive possibility to be definitive or to be removed when they become unnecessary. OBJECTIVE: The purpose of this study was to evaluate the efficacy and the likelihood to remove the retrievable IVC filter ALN. METHODS: A total of 30 patients (13 males and 17 females, mean age 57 +/- 15 years) underwent placement of ALN filters. Indications for implantation were acute venous thromboembolism (VTE) with a contraindication to anticoagulation in 26 cases (86%), primary prophylaxis after major trauma in two cases (7%) or before surgery in two patients with very high thromboembolic risk (7%). RESULTS: The filter was successfully placed in all patients. After a median follow-up of 18.2 months, there were three cases (10%) of trapped emboli within the filter, one case (3%) of asymptomatic migration of the filter toward the heart and two patients (7%) had deep vein thrombosis (DVT) recurrences. ALN retrieval was attempted through transjugular approach in 18 patients (60%) and the maneuver was successful in 14 of them (78%); when the decision of removal was taken more than 3 months after the implantation, the retrieval was possible only in four of eight patients (50%). The median implantation period was 123 days (range: 30-345). CONCLUSIONS: The present study shows the efficacy of ALN filter; it also demonstrates the feasibility and safety of retrieval after a medium-term period of placement. Removal after 3 months after implantation can be unsuccessful and maximum implantation time requires further studies.

[Antithrombin: prospects in clinical practice. Sespsi: anticoagulant or anti-inflammatory agents?]. / Antitrombina: prospettive nella pratica clinica. Sepsi: anticoagulanti o antinfiammatori?

Sepsis and septic shock represent a frequent cause of mortality in Intensive Care Units, despite of the progress in antibiotic therapy and in the hemodynamic and respiratory support. The most frequent cause of death is the Multi Organ Dysfunction Syndrome (MODS), which is the clinical manifestation of the irreversibile damage of the microvascular bed. During sepsis and septic shock both activation of coagulation /fibrinolysis and release of mediators of inflammation contribute to the pathogenesis of disseminated intravascular coagulation (DIC); in particular the formation of fibrin in the microvascular bed is the pathological substrate of the clinical development of MODS. The rationale for employing antithrombin (AT) concentrates in the treatment of DIC associated to sepsis is based on the consideration that AT plasma levels are always decreased in patients with sepsis or septic shock; furthermore, the degree of the decrease is directly proportional to the severity of the disease and the prognosis and low AT plasma activities correlate with high mortality. AT has a double function: anticoagulant and anti-inflammatory. The most important mechanism responsible of the anti-inflammatory properties of AT is the binding to the glycosaminoglycans of the endothelial cells and the consequent release of prostacyclin. During sepsis and septic shock, treatment with AT was able, especially in animal models but also in clinical studies, to decrease plasma levels of mediators of inflammation and in some case to preserve organ failure and to reduce mortality.