Additional Risk Factors For Thromboembolism Research Articles

Anticoagulation for mechanical aortic valves: An international survey of current practice patterns and perceptions

IntroductionFor patients with mechanical aortic valves, guideline recommended INR targets range from 2.0 to 3.5, depending on thromboembolic risk factors. Supporting data is largely historical and of low quality. We aimed to characterize clinicians’ practices around INR targets for these patients and perceptions of evidence supporting these recommendations. MethodsA 33-question web-based survey was sent to 75 cardiologists, cardiac surgeons, and thrombosis specialists globally. We inquired about anticoagulation practices for patients with mechanical aortic valves, perceptions of guideline recommendations, and interest in participating in a randomized controlled trial comparing lower and higher INR targets in these patients. ResultsOf 55 respondents (73% response rate), 78% worked in academic hospitals. In patients with mechanical aortic valve and no additional thromboembolic risk factors, 80% targeted an INR of 2.5. Among patients with additional thromboembolic risk factors, 48% targeted an INR of 2.5, while 44% targeted an INR of 3.0. Additionally, 57% of respondents believed that evidence for the guidelines was up to date, and 53% believed that it applied to bi-leaflet valves.However, 57% of respondents said that the evidence was not high quality. Lastly, 66% of respondents would accept a higher thromboembolic risk to reduce risk of major bleeding; 86% were willing to randomize patients with mechanical aortic valve to a target INR of 2.0 if they had no thromboembolic risk factors. ConclusionClinicians target different INRs for patients with mechanical aortic valves; their perception of the evidence and guidelines varies. Of respondents, 86% would randomize patients to lower INR targets.

Thromboembolism in the Complications of Long COVID-19.

SARS-CoV-2 is a +ssRNA helical coronavirus responsible for the global pandemic caused by coronavirus disease 19 (COVID-19). Classical clinical symptoms from primary COVID-19 when symptomatic include cough, fever, pneumonia or even ARDS; however, they are limited primarily to the respiratory system. Long-COVID-19 sequalae is responsible for many pathologies in almost every organ system and may be present in up to 30% of patients who have developed COVID-19. Our review focuses on how long-COVID-19 (3 -24 weeks after primary symptoms) may lead to an increased risk for stroke and thromboembolism. Patients who were found to be primarily at risk for thrombotic events included critically ill and immunocompromised patients. Additional risk factors for thromboembolism and stroke included diabetes, hypertension, respiratory and cardiovascular disease, and obesity. The etiology of how long-COVID-19 leads to a hypercoagulable state are yet to be definitively elucidated. However, anti-phospholipid antibodies and elevated D-dimer are present in many patients who develop thromboembolism. In addition, chronic upregulation and exhaustion of the immune system may lead to a pro-inflammatory and hypercoagulable state, increasing the likelihood for induction of thromboembolism or stroke. This article provides an up-to-date review on the proposed etiologies for thromboembolism and stroke in patients with long-COVID-19 and to assist health care providers in examining patients who may be at a higher risk for developing these pathologies.

Transcatheter Patent Foramen Ovale Closure in Stroke Patients with Thrombophilia: Current Status and Future Perspectives.

Transcatheter patent foramen ovale (PFO) closure is a safe and effective treatment for secondary prevention after a PFO-associated stroke as demonstrated in multiple large randomized clinical trials. However, these trials excluded a significant proportion of patients who could have benefited from percutaneous PFO closure due to coexisting potential confounders such as additional thromboembolic risk factors, namely thrombophilia. Since scarce and conflicting data existed on such patients, current clinical management guidelines on patients with PFO mainly recommended against PFO closure in patients with thrombophilia and failed to provide any recommendation on the type and duration of antithrombotic treatment after transcatheter PFO closure. In the past 2 years, there has been new evidence supporting transcatheter PFO closure as a clinically meaningful alternative (vs. medical treatment) in this high-risk group of patients, along with additional data supporting the important role of systematic screening for thrombophilia in PFO-associated cerebrovascular events. This review article provides an updated overview of the incidence, clinical characteristics and outcomes of PFO closure in patients with thrombophilia, also commenting on the most appropriate medical treatment after PFO closure and future perspectives in the field.

Standard Versus Higher Intensity Anticoagulation for Patients With Mechanical Aortic Valve Replacement and Additional Risk Factors for Thromboembolism

Current guidelines recommend targeting an international normalized ratio (INR) of 2.5 to 3.5 for patients with mechanical aortic valve replacement (AVR) and additional risk factors for thromboembolic events. Available literature supporting the higher intensity (INR) goal is lacking. We aimed to evaluate the association of standard and higher intensity anticoagulation on outcomes in this patient population. The Michigan Anticoagulation Quality Improvement Initiative database was used to identify patients with mechanical AVR and at least one additional risk factor. Patients were classified into 2 groups based on INR goal: standard-intensity (INR goal 2.5) or higher-intensity (INR goal 3.0). Cox-proportional hazard model was used to calculate adjusted hazard ratios. One hundred and forty-six patients were identified of whom 110 (75.3%) received standard-intensity anticoagulation and 36 (24.7%) received higher intensity anticoagulation. Standard-intensity patients were older and more likely to be on aspirin. Atrial fibrillation was the most common additional risk factor for inclusion. The primary outcome of thromboembolic events, bleeding, or all-cause death was 13.9 and 19.5/100-person-years in the standard-intensity and higher intensity groups, respectively (adjusted HR 2.58, 95% confidence interval 1.28 to 5.18). Higher-intensity anticoagulation was significantly associated with any bleeding (adjusted HR 2.52, 95% confidence interval 1.27 to 5.00) and there were few thromboembolic events across both groups (5 events total). These results challenge current guideline recommendations for anticoagulation management of mechanical AVR in patients with additional risk factors.

Anticoagulation for mechanical aortic valve replacement: an international survey

Abstract Introduction Mechanical valves are preferred over biologic valves in younger patients because they are more durable but require long-term anticoagulation which increases the risk of bleeding. For patients with a mechanical aortic valve, the ACCP guidelines recommend a target INR of 2.5 (range 2.0–3.0) for all patients, whereas the ACC/AHA and ESC guidelines recommend a higher target for selected patients with additional risk factors for thromboembolism (TE). Data supporting the guideline recommendations are largely historical and of low quality. Purpose We surveyed physicians who manage anticoagulation for patient with mechanical heart valves to determine their usual practice, perceptions regarding guideline recommendations, and interest in participating in a randomized controlled trial (RCT) comparing lower with higher INR targets in patients with a mechanical aortic valve. Methods A 33-question web-based survey was sent to 75 cardiologists, cardiac surgeons and thrombosis specialists at centres in Canada and internationally (western Europe, South America, and the United States) who participated in previous anticoagulation trials led by investigators at McMaster University. Results Of the 55 respondents (73.3% response rate), 77.8% worked in academic teaching hospitals. Respondents had been in practice for a mean of 23.6 years; 40.9% followed AHA/ACC guidelines, 34.1% followed the ACCP guidelines and 22.7% followed the ESC guidelines. In patients with a mechanical aortic valve and no additional TE risk factors, 80% of respondents targeted an INR of 2.5 (range 2.0–3.0); among patients with additional TE risk factors, 48% targeted an INR of 2.5 (range 2.0–3.0) and 44% targeted an INR of 3.0 (range 2.5–3.5). With respect to guidelines: 57.1% of respondents agreed or strongly agreed that that the evidence for the guidelines was contemporary, 53.1% agreed or strongly agreed that the evidence was derived from patients with modern bi-leaflet mechanical valves, and 57.2% of respondents agreed or strongly agreed that the evidence was not of high quality. A majority of respondents (65.9%) reported that they would accept an increase in TE risk to reduce the risk of a major bleeding event; 86.4% are willing to randomize patients with a mechanical aortic valve to a target INR of 2.0 (range 1.5–2.5) if they had no risk factors for TE and 36.4% would randomize patients to a target INR of 2.0 with additional risk factors for TE. Conclusions Clinicians who participated in the survey followed different guidelines and employed different INR targets for patients with a mechanical aortic valve. A majority of respondents would be willing to randomize these patients to lower INR targets. Mechanical Aortic Valves and INR Targets Funding Acknowledgement Type of funding source: None

Risk of Thrombosis in Adult Philadelphia-Positive ALL Treated with an Asparaginase-Free Pediatric-Inspired ALL Regimen with Imatinib

Background: Venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL) receiving asparaginase (ASNase) based therapy. The MD Anderson Cancer Centre reported an overall VTE incidence of 29% (14/49) in patients with Philadelphia positive ALL (Ph+ ALL) treated with Hyper-CVAD and in the absence of ASNase (Vu et al. Cancer Medicine. 2015;4(1):27-35. doi:10.1002/cam4.332). The VTE incidence in adult Ph+ ALL patients treated with tyrosine kinase inhibitor plus the pediatric-inspired regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol remains unclear. We have previously compared the incidence of VTE in adults with Ph+ ALL treated with or without ASNase during the intensification phase of the modified DFCI treatment. This study suggested that patients with Ph+ve ALL experience high incidence of VTE, even in the absence of ASNase, and that this risk is not restricted to the intensification phase. As ASNase was omitted from the protocol due to toxicity since 2008, in this report, we provide further insight into the risk of VTE in adults with Ph+ ALL during the entire ASNase-free DFCI treatment course. Methods: A single-institution retrospective review of sequential Ph+ ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008-2018 with an imatinib-containing DFCI protocol-based regimen that omitted ASNase. VTE events were recorded from the time of diagnosis to the end of modified DFCI treatment, including at the time of allogenic bone marrow transplantation. Co-variants of age, sex, weight, BMI, Padua score, white blood cell count, and platelet count were also collected. Statistical analyses were performed using the 2-tailed t test. Results: Overall, 130 patients were included for analysis; none received prophylactic anticoagulation. Among the 130 Ph+ ALL patients treated with the modified DFCI protocol, 28 (21.5%) patients had at least 1 VTE events from diagnosis to the end of treatment. The mean age of patients with and without VTE were 56.8 and 49.0 years, respectively (p=0.014) (Table 1). The majority of the VTE events occurred during active treatment, with 9 (7.0%), 11 (8.5%), and 4 (3.1%) occurring during induction, intensification, and maintenance, respectively (Figure 1). Only four patients (3.1%) presented with VTE at the time of diagnosis. Of all VTE events, 14 (50%) were DVT and/or PE, 12 (43%) were line-related, and 2 (7%) involved a cardiac thrombus (Table 2). The average Padua score for these patients was 5.4 with a range of 3-10. All VTE events were treated with low weight molecular heparin (LMWH), with 2 patients experiencing a recurrent episode within a year while on LMWH treatment. Bleeding following anticoagulation was rare. One patient experienced a major bleeding into the psoas muscle while on LMWH plus platelet transfusion for a right atrial clot during the induction phase in ICU. No other significant bleeding event was observed. Conclusion: VTE was observed in more than 20% of adults with Ph+ ALL patients treated with imatinib plus a modified DFCI pediatric ALL protocol. The majority of VTE events occurred during active treatment (induction and intensification), and DVT/PE incidence was similar to that of line-related thrombosis. The high observed VTE incidence suggests that prophylactic anticoagulation should be considered for adult patients with Ph+ ALL even in ASNase-free regimens, especially if additional thromboembolic risk factors are present. Disclosures Maze: Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chan:Celgene: Honoraria, Research Funding; Agios: Honoraria; AbbVie Pharmaceuticals: Research Funding. Gupta:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Yee:Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Schimmer:Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy. Schuh:Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees. McNamara:Novartis Pharmaceutical Canada Inc.: Consultancy.

Thromboembolism in children with cancer: a retrospective multicenter study in Korea.

Thromboembolism (TE) is a major cause of morbidity and mortality in adult cancer patients; however, there is a lack of sufficient knowledge on TE in pediatric cancer patients. We aimed to determine the epidemiology of TE in Korean children with cancer. Between January 2000 and July 2015, we retrospectively analyzed pediatric patients newly diagnosed with cancer at six tertiary hospitals in Korea. Of 3611 children with cancer, 33 (0.91%) had TE. A higher number of patients with acute lymphoblastic leukemia (n = 13), brain tumors (n = 6), lymphoma (n = 4), and bone/soft tissue sarcomas (n = 5) tended to develop TE. The male/female ratio was 17/16, and the median age at TE diagnosis was 10years and 2months. TE was detected a median of 2months after cancer diagnosis. Symptoms including pain and swelling were present in 18 of the 33 patients. In terms of location, three intracerebral, 23 upper venous, six lower venous and one combined upper and lower venous system TEs were observed. Additional risk factors for TE included central venous catheter (CVC) use in 12 patients, steroid and/or L-asparaginase use in nine, and CVC and steroid and/or L-asparaginase use in seven. The TE incidence rate was quite low among Korean children with cancer, but higher than in the general pediatric population and among children hospitalized for diseases other than cancer. Further investigation of a larger pool of patients is warranted to determine the most effective strategies to prevent and treat TE in Korean children with cancer.

THE ROLE OF ANTICOAGULATION THERAPY IN PATIENTS WITH PROSTHETIC HEART VALVES

Cardiac surgery is the only radical method of treatment of valvular defects (congenital or acquired): valve preservation procedures or prosthetics operations. 250 000 – 280 000 valve prostheses are implanted every year worldwide, while the number of prosthetic valves operation increases by an average of 5–7 % per year (biological prostheses – 8–11 %, mechanical prostheses – 3–5 %). Selection of biological or mechanical types of prosthesis, its location, the presence of associated risk factors for embolic events, such as atrial fibrillation, previous embolism, left ventricular dysfunction, hypercoagulable states determine patient management tactics. Particularly high risk of prosthetic thrombosis and thromboembolic complications can be seen in case of mechanical prosthesis implantation. Numerous prospective and retrospective clinical studies have proven high effectiveness of anticoagulants for reduction the risk of cardioembolic complications. The degree of anticoagulation (optimal international normalized ratio (INR)) is determined by risk factors for prosthetic thrombosis and thromboembolic complications in a patient, as well as thrombogenicity of the prosthesis by itself; INR may range from 2.5 to 4.0. International recommendations take into account the presence/absence of additional risk factors for thromboembolism, and based on warfarin administration with the achievement of target INR values combined with low-dose aspirin. Administration of novel direct oral anticoagulation remedies in patients with prosthetic heart valves has not been studied sufficiently up to date and is contraindicated. Thus, warfarin currently is a drug of choice for the prevention of thromboembolic complications in patients with prosthetic heart valves.

Incidence of Unprovoked Venous Thromboembolic Events in Patients with Chronic Lymphocytic Leukemia (CLL)

While lymphoma is a known risk factor for venous thromboembolism (VTE), the thrombogenicity of chronic lymphocytic leukemia (CLL) has not been investigated. One study reported a ten-fold increased risk in VTE compared to the general population, but this included both provoked and unprovoked events, making it difficult to discern the independent contribution of CLL to the thrombogenic predisposition (Whittle A et al. Leuk Res 2011; 35:419-21). Since we found no studies examining only unprovoked VTE in CLL, we sought to estimate the risk of spontaneous VTE occurring in patients with CLL in the absence of known thrombogenic risk factors. The study was approved by the institutional human subjects committee. We examined patients diagnosed with CLL between 1997-2014 by the persistent presence of ≥ 5,000 circulating small, mature, monoclonal, CD5+, CD23+ B lymphocytes (per diagnostic criteria in: Halleck M et al. Blood 2008;111:5446-56) and listed in the Minneapolis VA Tumor Registry. Clinical and laboratory data were obtained from the electronic medical record. Each patient's chart was reviewed individually for VTE, either pulmonary embolism (PE) or deep vein thrombosis (DVT), and the report of a confirmatory imaging study was examined to confirm the diagnosis.We followed patients (n = 308, 99% males, mean age 70 years) starting at the date of CLL diagnosis or the date after CLL diagnosis when the patient began follow-up at the VA and ending at last patient contact or death (122/308 [39.6%] patients died during the observation period). Each patient made at least annual contact with the VA between the start and end dates, with a mean VA follow-up time of 4.6 +/- 2.9 years; 90% patients were followed continuously at the VA since after the diagnosis of CLL. Patients were excluded if there was a preceding period of immobility, serious illness requiring hospitalization, diagnosed hypercoagulable state, or recent chemotherapy known to be associated with increased thrombotic risk. The total follow-up time was 1408 patient-years, during which 10 unprovoked VTE occurred, for an estimated incidence rate of unprovoked VTE of 0.71 per 100 patient-years, 95% CI [0.38, 1.32]. Eight VTE were originally diagnosed at our institution. Confirmatory imaging was available for the 2 VTE diagnosed elsewhere. All 10 patients were males between the ages of 55 to 95 years at the time of CLL diagnosis. Six had DVT, three had PE, and one had both DVT and bilateral PE. Nine patients had symptoms that prompted diagnostic imaging, while one PE was diagnosed incidentally on a chest CT scan. Nine patients had bulky lymphadenopathy at the time of VTE, but these did not compress the relevant vein in any patient. Small, stable monoclonal paraproteinemia was identified in 2/5 VTE patients tested (one patient at 0.39 and 0.35 g/dL, one patient at 0.32 and 0.27 g/dL). At time of development of VTE, 4, 1, 1 and 3 patients had Rai stage I, II, III or IV CLL, respectively. Thus, while there were relatively few events, there did not appear to be any clear relationship of VTE with advanced CLL stage. Recurrence of unprovoked VTE occurred in only 1 of 10 (10%) patients.In a study of the general population in our region of the US (Olmsted County, MN), the overall incidence of VTE in 70-74 year old males was 0.65 per 100 patient-years (Silverstein M et al. Arch Internal Med 1998;158:585-93). Since 17-47% of all VTEs were unprovoked in various population series (Cushman M et al. Thromb Haemost 2001;86[suppl 1]:OC2349, Heit JA et al. Arch Intern Med 2002;162:1245-8, Spencer FA et al. J Thromb Thrombolysis 2009;28:401-9, White RH Circulation 2003;107:I-4-8), the incidence rate of unprovoked VTEs observed in CLL patients in the current series (0.71; 95% CI: 0.38, 1.32) approximates the expected incidence of unprovoked VTEs in the general population. Further, the development of unprovoked VTE would have been expected to be skewed towards patients with advanced stage (Rai stages III/IV), and/or have been associated with more frequent recurrences, if CLL was an independently thrombogenic condition.Conclusion: This is the first long-term study of unprovoked VTE in patients with CLL, with >1400 patient-years of follow-up. The low incidence of unprovoked VTEs observed in our study suggests that primary thromboprophylaxis may not be required in patients with CLL who do not have additional risk factors for thromboembolism. DisclosuresNo relevant conflicts of interest to declare.

Primary Immune Thrombocytopenia in Elderly Patients: Clinical Profile, Efficacy and Safety of Treatment Protocols

Introduction:Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by accelerated platelet destruction and inadequate platelet production mediated by autoantibodies. As there are no specific diagnostic tests, the diagnosis of ITP remains one of exclusion.Although the incidence of ITP increases with age, there are no practice guidelines for elderly patients and few studies have been conducted. Compared with younger patients, older patients have a higher incidence of serious bleeding complications and increased related mortality.Therefore we propose to describe our experience in the management of ITP in patients over 65 years old.Methods:We conducted a retrospective study of 44 patients over 65 years old at the moment of the ITP diagnosis, treated in our center from January 1995 to March 2014. Variables analyzed were age, Charlson score, clinical manifestations and platelet count at diagnosis, type of treatment, response to treatment and adverse events.Results:The median current age is 77 years (IQR, 70-84 years), with a median age at diagnosis of 69 years (IQR, 65-75 years). The ratio of males to females was 0.91. Eighteen (40.9%) patients had a Charlson score greater than or equal to 2. The comorbilities were 27.8% diabetes with damage to target organs; 11.4% coronary disease; 9.8% solid metastatic tumor, 9.8% peripheral vascular disease, 9.8% chronic pulmonary disease; 5% congestive heart failure, 5% peptic ulcer, 5% cerebrovascular disease, 5% moderate-severe liver disease, 5% moderate-severe renal disease y 1.6% connective tissue disease, 1.6% dementia, 1.6% hemiplegia and 1.6% leukemia. The mean platelet count at diagnosis was 28x109 / L (IQR, 8-74x109 / L).Initial presentation was thrombocytopenia on a routine blood count in 43% of patients while the rest presented bleeding symptoms. Fourteen patients (31.8%) required admission on diagnosis. 18.8% showed major bleeding: 6 (13.63%) gastrointestinal haemorrhages, 1 (2.2%) hematuria and 47.7% minor bleeding: 8 (18.18%) bruising, 7 (15.9%) mucosal bleeding and 7 (15.89%) purpura and epistaxis.Regarding treatment, observation was used in 11 patients (25%), all of whom subsequently acheived spontaneous remission. Corticosteroid therapy (prednisone 0.5-1mg/kg), was the initial treatment used in 13 patients (29.5%), 15.9% received intravenous inmunoglobulins (1gr/kg x 2 days) and 18.2% combination therapy. A response was obtained in 75.6% of patients (35.6% CR, 40% R). Seven (16%) subjects received second-line treatment (1 splenectomy, 3 romiplostim, 1 eltrombopag, 1 rituximab, 1 Imurel). The patient that underwent splenectomy obtained CR. Of the 3 patients treated with romiplostim, 2 achieved CR directly, and the third required rescue therapy with eltrombopag to reach CR. The patient that received second line treatment with eltrombopag obtained R and the patient treated with Rituximab failed and needed rescue therapy with romiplostim. Finally the patient treated with azathioprine is in CR but still on treatment. At present we have an 84.1% response rate after a median follow up of 66 months (IQR, 27-100 months).During treatment we observed a single vascular event in the form of deep vein thrombosis with associated pulmonary embolism in a subject with additional thromboembolic risk factors. We found no infections, hyperglycemia or hypertensive crisis which required hospital admission or special monitoring. Five patients (11.4%) developed neoplasms (hepatocellular carcinoma, rectal neoplasm, pancreatic adenocarcinoma and Hürthle cell carcinoma), none of which were haematological. Three patients died: 2 due to neoplasm progression and 1 to acute renal failure.Conclusions:Low and intermediate doses of corticosteroids are a good first line treatment option in elderly patients. Close monitoring of the patient is advisable to ensure the early detection and treatment of adverse events and possible underlying diseases that could justify the thrombocytopenia. In our series the incidence of major bleeding in over 65s with ITP is clearly superior to that reported in younger subjects. Therefore, it is essential to optimize the intensity and duration of treatment in these patients. DisclosuresNo relevant conflicts of interest to declare.

Patients with atrial fibrillation and Cha2ds2-Vasc ≤ 1 still develop stroke — /INS;Why so?

Objective: To determine the influence of AF and of additional thromboembolic risk factors on stroke development and evolution with comparison of several schemas' stroke predictive value.

EFFECT OF DABIGATRAN ON SERUM APOLIPOPROTEIN B AND APOLIPOPROTEIN A1 CONCENTRATIONS

Dabigatran is a direct thrombin inhibitor that reduces stroke risk in patients with atrial fibrillation and additional thromboembolic risk factors. Carboxylesterases, which convert dabigatran etexilate to its’ active form, dabigatran, have also been shown to influence lipid metabolism. We

Long-term anticoagulation with fondaparinux in a patient with a mechanical heart valve

could be seen in a gradual decrease in drug concentration measured as anti-Xa level (initially 0.9–1.0 U/ml, reduced to 0.45–0.5 U/ml), despite increasing the dose. This adverse effect was shown with dalteparin, enoxaparin and nadroparin. Anticoagulation was therefore started with fondaparinux. Due to obesity (BMI, 36 kg/m 2 ), we administered 10 mg once daily sc. During the next 30 months, stable drug concentrations measured as anti-Xa of about 1.0 μg/ml were observed. D-dimers, measured as a degree of coagulation activation, were always below 220 ng/ml. Regular controls revealed no clinical signs or symptoms of thromboembolic complications, and in particular, no neurological deficits. Computed tomography of the head as well as echocardiography did not reveal any thromboembolic complications. The patient did not experience any bleeding. Due to additional risk factors for thromboembolism, 100 mg aspirin was added to the therapy.

Identifying Patients at High Risk for Stroke Despite Anticoagulation

The risk of stroke in patients with atrial fibrillation (AF) is not homogeneous, and various clinical risk factors have informed the development of stroke risk stratification schemes (RSS). Among anticoagulated cohorts, the emphasis should be on the identification of patients who remain at high risk for stroke despite anticoagulation. We investigated predictors of thromboembolism (TE) risk in an anticoagulated AF clinical trial cohort (n = 7329 subjects) and tested the predictive value of contemporary RSS in this cohort: CHADS₂, Framingham, NICE 2006, American College of Cardiology/American Heart Association/European Society of Cardiology 2006, the 8th American College of Chest Physicians guidelines and the CHA₂DS₂-VASc schemes. On multivariate analysis, significant predictors of TE were stroke/TIA (hazard ratio [HR], 2.24; P < 0.001), age 75 years or older (HR, 1.77; P = 0.0002), coronary artery disease (HR, 1.52; P = 0.0047), and smoking (HR, 2.10; P = 0.0005), whereas reported alcohol use (HR, 0.70; P = 0.02) was protective. Comparison of contemporary RSS demonstrated variable classification of AF patients into risk strata, although c-statistics for TE were broadly similar among the RSS tested and varied between 0.575 (NICE 2006) and 0.647 (CHA₂DS₂-VASc). CHA₂DS₂-VASc classified 94.2% as being at high risk, whereas most other RSS categorized two-thirds as being at high risk. Of the 184 TE events, 181 (98.4%) occurred in patients identified as being at high risk by the CHA₂DS₂-VASc schema. There was a stepwise increase in TE with increasing CHA₂DS₂-VASc score (P (trend) < 0.0001), which had the highest HR (3.75) among the tested schemes. The negative predictive value (ie, the percent categorized as "not high risk" actually being free from TE) for CHA₂DS₂-VASc was 99.5%. Coronary artery disease and smoking are additional risk factors for TE in anticoagulated AF patients, whereas alcohol use appears protective. Of the contemporary stroke RSS, the CHA₂DS₂-VASc scheme correctly identified the greatest proportion of AF patients at high risk, despite the similar predictive ability of most RSS evidenced by the c-statistic.

Meta-Analysis of Low Molecular Weight Heparin versus Placebo in Patients Undergoing Total Hip Replacement and Post-Operative Morbidity and Mortality since their Introduction

1) To establish the clinical validity for in-patient low molecular weight heparin (LMWH) following total hip replacement (THR) through a meta-analysis of peer reviewed and published randomised placebo controlled trials (RCTs). 2) To establish whether modern peri-operative practices were associated with changes in rates of clinical venous thromboembolic (VTE) and all-cause mortality after THR by review of series of patients receiving in-patient LMWH published between 1985 and 2000. DATASOURCES: Medline and Embase (from 1980 to 2005), Datastar and Proquest databases were searched and references from bibliographies traced. Studies of adult patients receiving in-patient LMWH following elective primary or revision THR were sought and data abstracted. The first part of our analysis included only randomised placebo controlled trials. For the second part, randomised control trials were included and divided by their year of completion into three groups. We found no difference between LMWH and placebo in the risk of fatal pulmonary embolism (PE), other deaths, all cause mortality or major bleeding. LMWH reduced non-fatal PE (OR=0.14, 95%CI 0.03 to 0.74, p=0.029) at the expense of haematoma formation (7/147 vs 0/149, p=0.015). 35 studies were included in the second part of our analysis. Point estimates of rates of fatal and non-fatal pulmonary embolism and other deaths suggest a decline over time but fell short of statistical significance. Clinically relevant VTEs are a rare complication following THR. The lower risk of VTE narrows the risk benefit of potent pharmacological thromboprophylaxis. We do not support their use in patients undergoing THR without additional thromboembolic risk factors.

Valvular and Structural Heart Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

This chapter about antithrombotic therapy for valvular heart disease is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values might lead to different choices (for a full understanding of the grading see Guyatt et al, <i>CHEST</i> 2008; 133[suppl]:123S–131S). Among the key recommendations in this chapter are the following: for patients with rheumatic mitral valve disease complicated singly or in combination by the presence of atrial fibrillation (AF), previous systemic embolism, or left atrial thrombus, we recommend vitamin K antagonist (VKA) therapy (Grade 1A). For patients with rheumatic mitral valve disease and normal sinus rhythm, without left atrial enlargement, we do not suggest antithrombotic therapy unless a separate indication exists (Grade 2C). For patients with mitral valve prolapse (MVP), not complicated by AF, who have not had systemic embolism, unexplained transient ischemic attacks, or ischemic stroke, we recommend against antithrombotic therapy (Grade 1C). In patients with mitral annular calcification complicated by systemic embolism or ischemic stroke, we recommend antiplatelet agent (APA) therapy (Grade 1B). For patients with isolated calcific aortic valve disease, we suggest against antithrombotic therapy (Grade 2C). But, for those with aortic valve disease who have experienced ischemic stroke, we suggest APA therapy (Grade 2C). For patients with stroke associated with aortic atherosclerotic lesions, we recommend low-dose aspirin (ASA) therapy (Grade 1C). For patients with cryptogenic ischemic stroke and a patent foramen ovale (PFO), we recommend APA therapy (Grade 1A). For patients with mechanical heart valves, we recommend VKA therapy (Grade 1A). For patients with mechanical heart valves and history of vascular disease or who have additional risk factors for thromboembolism, we recommend the addition of low-dose aspirin ASA to VKA therapy (Grade 1B). We suggest ASA not be added to long-term VKA therapy in patients with mechanical heart valves who are at particularly high risk of bleeding (Grade 2C). For patients with bioprosthetic heart valves, we recommend ASA (Grade 1B). For patients with bioprosthetic heart valves and additional risk factors for thromboembolism, we recommend VKA therapy (Grade 1C). For patients with infective endocarditis, we recommend against antithrombotic therapy, unless a separate indication exists (Grade 1B).

Venous Thromboembolism, Thrombophilia, Antithrombotic Therapy, and Pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C.Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C].For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C).We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A].For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C).

Venous Thromboembolism in Patients with Primary Bone or Soft-Tissue Sarcomas

Background: Venous thromboembolism has been independently associated with both malignant disease and orthopaedic surgery. Patients with bone or soft-tissue tumors who undergo orthopaedic surgery may therefore be at high risk for thromboembolic events. The purpose of the present retrospective study was to determine the rate of clinically detected deep venous thrombosis and pulmonary embolism in patients with trunk or extremity bone or soft-tissue sarcomas. Methods: The medical records of patients with a confirmed diagnosis of primary bone or soft-tissue sarcoma who had presented to our unit between 1998 and 2003 were reviewed with use of a standardized chart abstraction tool. The data that were retrieved included patient-related data (demographic characteristics, diagnoses, and surgical interventions), the use of adjuvant chemotherapy or radiation therapy, additional risk factors for thromboembolism, the use of thromboembolic prophylaxis, and confirmed thromboembolic events. Results: Of the 252 patients who were identified, ninety-four had a diagnosis of primary bone sarcoma and 158 had a diagnosis of primary soft-tissue sarcoma. Approximately 70% of the cohort received thromboprophylaxis, with 57% receiving low-molecular-weight heparin. Thirty-seven patients were clinically suspected of having a deep venous thrombosis. Nine patients had a deep venous thrombosis that was confirmed radiographically, and in one case the diagnosis was made at another center, resulting in a rate of clinically evident deep venous thrombosis of 4%. Nine patients had a clinically suspected pulmonary embolism. One patient had confirmation of the pulmonary embolism with use of a ventilation-perfusion scan, one patient died of pulmonary embolism, and one patient had diagnosis of the pulmonary embolism at another center, resulting in an overall rate of pulmonary embolism of 1.2% and a rate of fatal pulmonary embolism of 0.4%. All patients with thromboembolic events had a tumor involving the hip or thigh, with the majority of the events occurring prior to definitive surgery. Conclusions: The risk of a clinically apparent thromboembolic event in patients with bone or soft-tissue sarcomas is comparable with that in other orthopaedic patients. However, tumors in the hip or thigh may be associated with a particularly high risk of thromboembolism. A prospective study is needed to investigate factors that are predictive of thromboembolism and the role of chemical thromboprophylaxis. Level of Evidence: Prognostic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Venous Thromboembolism in Patients with Primary Bone or Soft-Tissue Sarcomas

Venous thromboembolism has been independently associated with both malignant disease and orthopaedic surgery. Patients with bone or soft-tissue tumors who undergo orthopaedic surgery may therefore be at high risk for thromboembolic events. The purpose of the present retrospective study was to determine the rate of clinically detected deep venous thrombosis and pulmonary embolism in patients with trunk or extremity bone or soft-tissue sarcomas. The medical records of patients with a confirmed diagnosis of primary bone or soft-tissue sarcoma who had presented to our unit between 1998 and 2003 were reviewed with use of a standardized chart abstraction tool. The data that were retrieved included patient-related data (demographic characteristics, diagnoses, and surgical interventions), the use of adjuvant chemotherapy or radiation therapy, additional risk factors for thromboembolism, the use of thromboembolic prophylaxis, and confirmed thromboembolic events. Of the 252 patients who were identified, ninety-four had a diagnosis of primary bone sarcoma and 158 had a diagnosis of primary soft-tissue sarcoma. Approximately 70% of the cohort received thromboprophylaxis, with 57% receiving low-molecular-weight heparin. Thirty-seven patients were clinically suspected of having a deep venous thrombosis. Nine patients had a deep venous thrombosis that was confirmed radiographically, and in one case the diagnosis was made at another center, resulting in a rate of clinically evident deep venous thrombosis of 4%. Nine patients had a clinically suspected pulmonary embolism. One patient had confirmation of the pulmonary embolism with use of a ventilation-perfusion scan, one patient died of pulmonary embolism, and one patient had diagnosis of the pulmonary embolism at another center, resulting in an overall rate of pulmonary embolism of 1.2% and a rate of fatal pulmonary embolism of 0.4%. All patients with thromboembolic events had a tumor involving the hip or thigh, with the majority of the events occurring prior to definitive surgery. The risk of a clinically apparent thromboembolic event in patients with bone or soft-tissue sarcomas is comparable with that in other orthopaedic patients. However, tumors in the hip or thigh may be associated with a particularly high risk of thromboembolism. A prospective study is needed to investigate factors that are predictive of thromboembolism and the role of chemical thromboprophylaxis.

Frequency and effect of optimal anticoagulation before onset of ischaemic stroke in patients with known atrial fibrillation

The aims of the study were (i) to examine which antithrombotic therapy patients with known atrial fibrillation use at the point of time when they suffer an ischaemic stroke, (ii) to evaluate the effects of optimal antithrombotic treatment on outcome and severity of the stroke. Patients with known atrial fibrillation before onset of acute ischaemic stroke, and age >60 years were included. Antithrombotic therapy on admission was classified into four groups: no antithrombotic therapy, aspirin, sub-optimal anticoagulation (warfarin and international normalized ratio, INR<2.0) and optimal anticoagulation (warfarin and INR>or=2.0). modified Rankin Scale (mRS) 5 or 6 at day 7 poststroke. (i) death or discharge to a nursing home, (ii) death, (iii) stroke severity on admission assessed by Scandinavian Stroke Scale. A total of 394 patients were included. On admission 109 (28%) patients used no antithrombotic therapy, 169 (43%) aspirin, 52 (13%) warfarin and had an INR<2.0, and 64 (16%) used warfarin and had an INR>or=2.0. The proportion of patients with an mRS 5 or 6 and the corresponding odds ratios were: in the warfarin group with INR<2.0, 16 (31%), OR 3.1 (CI: 1.2-8.0), (P=0.019), in the group with no antithrombotic therapy 29 (27%), 2.5 (1.1-5.9), (P=0.034), and in the aspirin group 41(24%), 2.2 (1.0-5.1) (P=0.054), compared with the warfarin group with INR>or=2.0, where eight (13%) patients had a poor outcome. A significantly higher proportion of patients died or were discharged to a nursing home in the warfarin group with an INR<2.0 (P=0.014), in the aspirin group (P=0.018) and in the no-treatment group (P=0.035), compared with the warfarin group with an INR>or=2.0. No significant differences were found regarding death alone and stroke severity on admission. Few patients with known atrial fibrillation who suffer an ischaemic stroke receive optimal antithrombotic therapy prior to the onset of stroke. Optimal anticoagulation does not only reduce the risk of ischaemic stroke, but also appears to reduce death and severe dependency as well as the need for nursing home care, if an ischaemic stroke occurs.