Indication For Anticoagulant Treatment Research Articles

Low-Molecular-Weight Heparin Versus Standard Pregnancy Care for Women with Recurrent Miscarriage and Inherited Thrombophilia (ALIFE2): An Open-Label, Phase III Randomized Controlled Trial

Background Studies have shown an association between recurrent miscarriage and inherited thrombophilia. It has been hypothesized that anticoagulant therapy might reduce both number of miscarriages and adverse pregnancy outcomes in these women and this is widely practiced despite lack of solid evidence. In the absence of randomized controlled trials that assess the efficacy of low-molecular-weight heparin (LMWH) therapy in women with recurrent miscarriage and inherited thrombophilia, a randomized clinical trial that addresses this topic was highly needed. Methods Design: The ALIFE 2 trial was an investigator-initiated, international open-label randomized controlled trial. The Netherlands coordinated recruitment in 15 hospitals in the Netherlands, USA, Belgium, and Slovenia. The UK coordinated 26 sites including sites in England, Scotland, Wales and Northern Ireland. The study protocol was approved by the institutional review boards of all participating centres, and in the UK, NRES, MHRA and HRA. Written informed consent was obtained from all patients prior to randomization. The trial was registered within the Dutch Trial Register (NTR3361) and EudraCT (UK: 2015-002357-35). Study population: Women (18-42 years) who had two or more pregnancy losses and confirmed inherited thrombophilia (factor V Leiden, prothrombin 20210A mutation, antithrombin, protein C or protein S deficiency) who were actively trying to conceive or less than 7 weeks pregnant were eligible for inclusion. Women were excluded if duration of current pregnancy was 7 weeks or more, if they had an indication for anticoagulant treatment during pregnancy, a contraindication for LMWH, a known allergy for LMWH or previous enrolment in this trial. Randomisation and intervention: Women were randomly assigned (1:1) to use subcutaneous LMWH once daily (enoxaparin 40 mg, dalteparin 5,000 IU, tinzaparin 4,500 IU or nadroparin 3,800 IU) versus standard pregnancy surveillance once they had a positive urine pregnancy test. LMWH was started ≤ 7 weeks of pregnancy and continued until the end of pregnancy. Outcomes: The primary outcome measure was live birth rate. Secondary outcomes included adverse pregnancy outcomes, such as miscarriage, obstetric complications (premature delivery, pre-eclampsia, HELLP syndrome, intrauterine growth restriction), and congenital malformations. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions to the prescribed study medication. Statistical analysis: Analysis includedall available datafrom all women who were randomized and did not withdraw consent to be followed up, as per the intention-to-treat principle. Exploratory subgroup analyses investigated the effect of age, number of previous miscarriages, previous live birth and type of inherited thrombophilia. Results Between August 2012 and January 2021, 10,626 women with recurrent miscarriage were assessed for eligibility, most of whom were not eligible due to absence of inherited thrombophilia. A total of 428 women were registered, of whom 326 women conceived and were randomized. 164 were assigned to the LMWH group and 162 were assigned to the standard surveillance group. The mean age was 33 years, approximately one third being 36 years or older, and the majority was of caucasian ethnicity (83%). The median number of miscarriages prior to randomization was 3, and 70% had a history of 3 or more miscarriages. The most common thrombophilia types were heterozygosity for factor V Leiden (56%), prothrombin 20210A mutation (25%), and protein S deficiency (14%). Aspirin was used as co medication in 11%. Observed live birth rates were 116/162 (71.6%) in the LMWH group and 112/158 (70.9%) in the standard surveillance group (adjusted OR 1.08 (95% CI 0.65 to 1.78)(absolute difference 0.7% (95% CI -9.2% to 10.6%). Adverse events were reported for 39 women (23.8%) in the LMWH group and 37 (22.8%) women in the standard surveillance group. Interpretation Compared with standard surveillance, the use of LMWH did not result in higher live birth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. On the basis of our findings, we do not advise routine use of LMWH in women with recurrent pregnancy loss and confirmed inherited thrombophilia, and we advise against routine testing for inherited thrombophilia in women with recurrent pregnancy loss.

STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage: Protocol for a randomised controlled trial

Background and aimsMany patients with prior intracerebral haemorrhage have indications for antithrombotic treatment with antiplatelet or anticoagulant drugs for prevention of ischaemic events, but it is uncertain whether such treatment is beneficial after intracerebral haemorrhage. STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage will assess (i) the effects of long-term antithrombotic treatment on the risk of recurrent intracerebral haemorrhage and occlusive vascular events after intracerebral haemorrhage and (ii) whether imaging findings, like cerebral microbleeds, modify these effects.MethodsSTudy of Antithrombotic Treatment after IntraCerebral Haemorrhage is a multicentre, randomised controlled, open trial of starting versus avoiding antithrombotic treatment after non-traumatic intracerebral haemorrhage, in patients with an indication for antithrombotic treatment. Participants with vascular disease as an indication for antiplatelet treatment are randomly allocated to antiplatelet treatment or no antithrombotic treatment. Participants with atrial fibrillation as an indication for anticoagulant treatment are randomly allocated to anticoagulant treatment or no anticoagulant treatment. Cerebral CT or MRI is performed before randomisation. Duration of follow-up is at least two years. The primary outcome is recurrent intracerebral haemorrhage. Secondary outcomes include occlusive vascular events and death. Assessment of clinical outcomes is performed blinded to treatment allocation. Target recruitment is 500 participants.Trial status: Recruitment to STudy of Antithrombotic Treatment after IntraCerebral Haemorrhage is on-going. On 30 April 2020, 44 participants had been enrolled in 31 participating hospitals. An individual patient–data meta-analysis is planned with similar randomised trials.

Rhythm and Conduction Disorders in Patients Receiving Ibrutinib

Aim. Early diagnosis and treatment of rhythm and conduction disorders in patients receiving ibrutinib. Materials & Methods. The trial included 206 patients with indications for ibrutinib, 193 of them are at different stages of treatment from 1.5 to 51 months. The trial enrolled the patients with chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia, aged 59 to 72 years (with median age of 66 years): 70 women aged 54 to 71 years (with median age of 64 years), and 123 men aged 60 to 72 years (with median age of 66 years). For early detection of rhythm and conduction disorders all the patients received ECG monitoring and 24-hour Holter ECG monitoring. Results. Atrial fibrillation (AF) was identified in 21 (12 %) patients during ibrutinib therapy period of 1 to 24 months. Most often AF is registered within the first 6 months of ibrutinib therapy. Before its administration 18 (10.5 %) patients had history of prior AF. Thus, a total of 39 ibrutinib recipients with AF are followed-up. According to CHA<sub>2</sub>DS<sub>2</sub>-VASc 27 (69 %) of them have an indication for anticoagulant treatment. Severe atrioventricular block was diagnosed in 2 (1 %) patients that necessitated a pacemaker. In 2 (1 %) female patients severe supraventricular tachycardia with up to 295 BPM was registered which required ablation. In a patient with permanent atrial fibrillation rhythm pauses were identified and a pacemaker was installed. Conclusion. The presence of AF in ibrutinib recipients is not a withdrawal criterion and does not require ibrutinib therapy to be discontinued. Anticoagulants were administered to patients with AF according to existing guidelines in compliance with CHA<sub>2</sub>DS<sub>2</sub>-VASc which had to be approached with caution and required dynamic monitoring of patients. Severe rhythm and conduction disorders in ibrutinib recipients arise in rare cases (2 %). Such patients require cardiac surgery with subsequent ibrutinib treatment without dose reduction. Timely diagnosis and the correction of rhythm and conduction allow to avoid changing of antitumor therapy plan.

437. Controversies in thrombophilia testing & use of newer anticoagulants agents in pregnancy & lactation

Saskia Middeldorp will first delve into the association between thrombophilia and complications during pregnancy including recurrent miscarriage and fetal loss, pre-eclampsia/eclampsia, intrauterine growth restriction, and placental abruption. These complications are clinical characteristics of the acquired thrombophilia antiphospholipid syndrome. There is also a modest association of some of these complications with inherited thrombophilia, which include factor V Leiden, prothrombin 20210A mutation and deficiencies of the anticoagulant proteins antithrombin, protein C or protein S. Despite absence of evidence in most situations, the use of antithrombotics with the aim to improve pregnancy outcome is widespread. She will review the evidence supporting or refuting the effectiveness of antithrombotics including aspirin and low-molecular-weight heparin in various clinical scenarios. The second part of the lecture will discuss direct oral anticoagulants (DOACs), also referred to as novel or non-vitamin K antagonist oral anticoagulants (NOACs). These agents are now the recommended drugs of choice for treatment and secondary prevention of venous thromboembolism and atrial fibrillation. These agents are small molecules and hence, pass the placenta. Saskia Middeldorp will discuss the current available data regarding safety of DOACs in pregnancy and lactation, and discuss the management strategies in women who are using DOACs who intend to become pregnant, or have an indication for anticoagulant treatment or prophylaxis in pregnancy.

Genetic causes of resistance to vitamin K antagonists in Polish patients: a novel p.Ile123Met mutation in VKORC1 gene.

: Mutations in the genes encoding vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) largely contribute to the inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Up to 50% of the dosage variability can be explained by genetic polymorphisms in these genes. We sought to identify the mutations responsible for VKA resistance in a series of Polish patients. Of the 607 patients treated with VKA, 35 (6%) individuals with the VKA resistance defined as a daily dose of acenocoumarol more than 8 mg (n = 15, 43%) or warfarin more than 10 mg (n = 20, 57%) were selected for further mutational analysis using Sanger sequencing (VKORC1) or real-time PCR genotyping (CYP2C9). The indications for anticoagulant treatment were venous thromboembolism (n = 28, 80%), atrial fibrillation (n = 6, 17%), or artificial heart valve (n = 1, 3%). Patients taking medication interfering with VKA were ineligible. Almost all of VKA-resistant patients (n = 34, 97%) possessed at least one VKORC1*3 (n = 29, 83%) or VKORC1*4 (n = 15, 43%) haplotypes. In a 70-year-old man atrial fibrillation patient on the daily acenocoumarol dose of 16 mg, a novel p.Ile123Met (c.369C>G) VKORC1 mutation was found. In-silico analysis showed that the p.Ile123Met can functionally underlie the acenocoumarol resistance, presumably by altering VKA binding. To our knowledge this is the first cohort of Polish patients resistant to VKA evaluated for the causal genetic background. We found one new detrimental mutation underlying VKA resistance. Our study highlights a key role of unidentified environmental factors in VKA resistance in daily clinical practice.

Accidents in patients under anticoagulant therapy in the Department of Cardiology at the Yalgado Ouedraogo Teaching Hospital, Ouagadougou (Burkina Faso)

Etudier le profil des patients hospitalisés pour hémorragie sous traitement anticoagulant. Il s’est agi d’une étude rétrospective à visée descriptive sur une période de 02 ans allant du 1er Janvier 2007 au 31 Décembre 2008, dans le Service de Cardiologie du Centre Hospitalier Universitaire-Yalgado Ouédraogo. Tous les patients hospitalisés présentant une hémorragie sous anticoagulant ont été inclus dans l'étude. L’âge moyen des patients était de 49,31 ± 17,68 ans, le sex-ratio était de 2,17. L’infarctus du myocarde était la première indication du traitement anticoagulant avec une fréquence de 21,05%. L’anti Vitamine K (AVK) a été pourvoyeur d’hémorragies dans 63,16% (n = 12) des cas contre 36,84% (n = 7) pour les Héparines de Bas Poids Moléculaire (HBPM); Il s’agissait de 10 cas d’hémorragie majeure et de neuf cas d’hémorragie mineure. La durée moyenne du traitement AVK était de 16 semaines ± 58 semaines. Le saignement par le tractus digestif était le plus fréquent (31,58%) et dans 89,47% des cas, le traitement était associé à un antiagrégant plaquettaire. L’arrêt définitif de l’anticoagulant constituait la prise en charge de l’accident hémorragique dans 73,68%. Il y avait quatre (21,05%) décès. L’inaccessibilité des antidotes comme le sulfate de protamine et les PPSD (Prothrombine Proconvertine Stuart B) constituent un véritable frein à la prise en charge adéquate des complications; mais une meilleure éducation de patients utilisateur de ces drogues constituerait la plus importante des préventions, car plus de 50% de ces accidents sont évitables.

Anticoagulant Therapy In Ischemic Stroke Or TIA

Stroke is the leading cause of disability and the third leading cause of death . Anticoagulants have been used to treat patients with acute ischemic stroke for many years. Despite their widespread use, the usefulness of emergency anticoagulation is a subject of debate. Disagreements exist about the best agent to administer, the route of administration, the use of a bolus dose to start treatment, the level of anticoagulation required, and the duration of treatment. There are 2 types of anticoagulants: Parenteral and oral. Heparin is an anticoagulant that used parenteral. Oral anticoagulants are including Warfarin and new anticoagulants such as Dabigatrn,Rivaroxaban ,Apixaban and other newer drugs.In patients with noncardioembolic ischemic stroke or TIA antiplatelet agents are treatment of choice and preferred to anticoagulants.In cardioembolic ischemic stroke or TIA with high risk of reembolization anticoagulants are considered as preferred treatment. Warfarin, apixaban10mg/d ,Rivaroxaban20mg/d, and dabigatran 150 mg/d are all indicated for the prevention of recurrent stroke in patients with nonvalvular AF, whether paroxysmal or permanent.Also anticoagulant therapy is recommended for ischemic stroke or TIA patients in the setting of acute MI, atrial or ventricular thrombosis or dilated and restricted cardiomyopathy. Some valvular heart diseases are other indication for anticoagulant therapy in ischemic stroke or TIA patients.Ischemic Stroke or TIA in patients with Cerebral vein thrombosis and known hypercoagulable state specially anti phospholipid antibody syndrome are other indications for anticoagulant treatment.

Outpatient oral anticoagulation in Poland in 2012: a single centre experience

Oral anticoagulants reduce embolic complications in patients with atrial fibrillation (AF) and are used in the treatment and prevention of venous thromboembolism. In Poland, chronic oral anticoagulation is usually managed by primary care physicians, and the most commonly used drugs are vitamin K antagonists (VKA). To evaluate effectiveness of oral anticoagulation in 104 patients receiving chronic VKA treatment in primary care from Jan 01, 2011 to Dec 31, 2011. We performed a retrospective analysis of data of 104 patients receiving chronic VKA treatment in a primary care practice (Niepubliczny Zakład Opieki Zdowotnej ESCULAP Gniewkowo) from Jan 01, 2011 to Dec 31, 2011. These patients comprised 1.1% of the population remaining under care of this primary care practice. We determined minimum, maximum and mean values of the international normalised ratio (INR), the proportion of results within the therapeutic range, the number of INR measurements, and indications for anticoagulant treatment. In patients with AF, we determined the risks of bleeding complications and thrombotic events. Among patients receiving chronic VKA treatment, 56.84% of INR measurements were within the therapeutic range. Only 29.8% of patients had more than 70% of INR measurements within the therapeutic range. We found no association between the number of INR measurements and treatment effectiveness. The effectiveness of anticoagulation in primary care is unsatisfactory. In our study population, an acceptable time in the therapeutic range was achieved in only just below 30% of patients.

Managing Patients With an Indication for Anticoagulant Therapy After Transcatheter Aortic Valve Implantation

Patients who undergo transcatheter aortic valve implantation are generally discharged on dual-antiplatelet therapy. However, many of these patients also have indications for anticoagulant therapy, and it is unclear what the best antithrombotic strategy is in these cases. Data from 360 patients who underwent transcatheter aortic valve implantation were retrospectively analyzed, of whom 60 (16.7%) had indications for anticoagulant treatment, mainly because of atrial fibrillation. The antithrombotic regimen was decided according to clinical evaluation of thrombotic and hemorrhagic risk; most of these patients (n= 43) were discharged with warfarin plus a single antiplatelet drug. Their outcomes were compared to those in a group with no indications for anticoagulation (n= 300) treated with dual-antiplatelet therapy. During the follow-up period (median 11 months), 53 patients (15%) died; mortality was not associated with antithrombotic regimen. The incidence of cerebral events or intracranial hemorrhage (4.6% and 1.1%, respectively) was low in the study population, and no significant differences were detected between groups; the bleeding rate was also unaffected by antithrombotic therapy. In conclusion, when anticoagulation is indicated after transcatheter aortic valve implantation, many variables must be taken into account. The most frequent scenario in this study was patients in atrial fibrillation, most of whom were discharged with warfarin plus a single antiplatelet medication. When bleeding was a concern, especially in the absence of coronary disease, warfarin alone was prescribed. These results suggest that this approach is safe, but data from larger, randomized studies are needed.

Características clínicas y manejo de la fibrilación auricular en las consultas de cardiología y su adecuación a las guías europeas de 2010

Introduction and objectives Atrial fibrillation (AF) is a prevalent condition that leads to a high number of consultations in clinical practice. The aim of our study is to describe the clinical characteristics of patients with AF treated in the cardiology clinic, to evaluate how cardiologists treat these patients and whether prevention of stroke performed in routine clinical practice is according to the antithrombotics criteria recommended by the 2010 European clinical practice guidelines (ECPG) in AF. Methods We analysed all patients evaluated in the cardiology clinic for two consecutive weeks during September 2010. We collected the clinical characteristics of patients, the type of AF, drug treatment, and determined the risk of stroke according to different criteria used by the ECPG. Results Of the 759 patients treated, 160 (21%) had AF, and were included in the registry. Thirty-two patients (20%) were <65 years and 137 suffered non-valvular AF. Sex differences were observed in prevalence of dyslipidaemia (49.4% vs 31.6%, P = .02), smoking (14.8% vs 3.1%, P = .01), valve disease (6.2% vs 22.8%, P = .003), age ( P = .05), peripheral arterial disease (37% vs 8.9%, P = .0001), in the rhythm in the ECG ( P = .01) and the type of AF ( P = .05) and age of these ( P = .002), but there were no differences in the treatment used. Ninety five patients were anticoagulated, but only 64% of patients with CHADS 2 ≥2, and 50% with CHA 2DS 2VASc ≥2. Conclusions One out of every 5 patients with AF evaluated in our clinics are under 65 years. The indication for anticoagulant treatment will probably increase in the next few years. The adherence to the recommendations for anticoagulation of the ECPG is good, but could be improved.

The risk of bleeding with anticoagulant treatments

SummaryAnticoagulant treatments are given to prevent and/or treat thrombotic complications in many clinical conditions, including atrial fibrillation (the most frequent indication for anticoagulant treatment), venous thromboembolism, acute coronary syndromes and after invasive cardiac procedures. Anticoagulation with vitamin K antagonists (VKAs) is currently almost the unique kind of therapy for chronic anticoagulation. It is highly effective in the prevention or treatment of thrombotic events but it is associated with a non negligible risk of bleeding, that is the most important complication of this therapy and a major concern for both physicians and patients. The risk of bleeding and the difficulties for the patients and health care providers associated with the necessary correct management of this treatment are limiting factors for a more widespread prescription of the treatment, leaving without an effective therapy a significant proportion of patients who would have a clear clinical indication for chronic anticoagulation. This review analyses the treatment- and person-associated risk factors for bleeding during VKAs and the tools that have been proposed to assess the individual risk of bleeding. New oral anticoagulant drugs seem to overcome at least some of the limitations of VKAs. Potentially, they can allow a less demanding and more stable anticoagulant treatment, with less side-effects allowing that more patients can receive an appropriate anticoagulant treatment. Based on the so far available phase III clinical studies, it is possible to assume that also these new drugs are associated with a risk of bleeding, that is probably related to the intensity of treatment.

Use of the term “superficial femoral vein” in ultrasound

To determine the frequency of use of the term "superficial femoral vein" (SFV) in the radiologic reports from a sample of sonographic investigations for suspected deep vein thrombosis and to assess the potential for clinical error in their interpretation. Retrospective review of 425 consecutive reports from medical patients attending the Imaging Department over a 6-month period for the presence of the term "superficial femoral vein" and for the presence of thrombus. A questionnaire was sent to a sample of referring clinicians to assess their understanding of the anatomy of the deep venous system of the leg and indications for anticoagulant treatment. Of the 425 sonographic investigations reviewed, 90 (21.2%) used the term "superficial femoral vein," and 12 (13.3%) were positive for SFV thrombus. Among 87 clinicians, 74.7% believed the SFV to be part of the superficial venous system and that its thrombosis did not require anticoagulant treatment, although anticoagulation is now indicated in selected cases of superficial venous thrombosis. Seventy-five percent of clinicians do not recognize the SFV as being part of the deep venous system and that its thrombosis requires anticoagulant treatment. In this study, 13% of SFV examined were positive for thrombus, and four patients (4.4%) had an isolated SFV thrombus that could have been left untreated due to this misunderstanding. Use of the term "superficial femoral vein" is prone to misinterpretation by clinicians and potentially hazardous to patients. It should be replaced by "common femoral vein" and "femoral vein" in reports.

Who receives anticoagulant treatment with warfarin and why? A population-based study in Finland

Objective. To ascertain the age and gender distribution of patients receiving anticoagulant (AC) treatment with warfarin, and to establish the prevalence of AC treatment and its indications among the Finnish population. Design. A cross-sectional study in which the patients were identified from the patient records of health centres. Setting. Primary health care in the Hospital District of South Ostrobothnia in Finland. Patients. Those inhabitants of 15 municipalities in the study area who received AC treatment with warfarin on 1 April 2004. The total number of inhabitants was 132 621 at the end of 2003. Main outcome measures. Patient age and gender distributions, the prevalence of AC treatment in the study area, and indications for AC treatment. Results. Altogether 2389 patients were identified, 51.4% of them men. The mean age of the patients was 72.4 years. The prevalence of AC treatment was 1.8%; when age-adjusted to match the Finnish population it was 1.64%. The proportion of men receiving AC treatment was higher than that of women in all age groups. Atrial fibrillation (AF) was the most common main (60.2%) and second (7.2%) indication for AC treatment. Conclusion. Compared with Finnish figures 12 years earlier the prevalence of AC treatment has more than doubled, and the proportion of AF among indications has increased from 47% to 67%. New current care guidelines on AF and the increasing proportion of the elderly among the population are probable explanations.

Aspirin and Aspirin Combined with Low-Molecular-Weight Heparin in Women with Unexplained Recurrent Miscarriage: a Randomized Controlled Multicenter Trial (ALIFE Study).

Abstract 488▪▪This icon denotes an abstract that is clinically relevant. BackgroundUnexplained recurrent miscarriage (RM) is extremely stressful for women and effective treatment is eagerly awaited. Aspirin and (low-molecular-weight) heparin are being used increasingly, even though evidence to support its use is not availabel. The aim of the ALIFE study was to investigate whether aspirin alone or combined with low-molecular-weight heparin, compared to placebo, improved the live birth rate in women with unexplained RM. MethodsWe conducted a multicenter, randomized, controlled trial in 8 centers in The Netherlands. Women aged between 18 and 42 years were eligible if they were diagnosed with unexplained RM and attempted to conceive or were less than 6 weeks pregnant. RM was defined as at least 2 miscarriages with an upper gestational age of 20 weeks (calculated from the first day of the last menstrual period). Unexplained RM was diagnosed in case of normal parental karyotype, the absence of uterine pathology on pelvic ultrasound, absence of antiphospholipid syndrome (lupus anticoagulant and anticardiolipin IgG and IgM), and a normal fasting level of homocysteine (< 16 μmol/L). Exclusion criteria were previous venous or arterial thromboembolism, indication for anticoagulant treatment during pregnancy or endocrine disorders.After written informed consent was obtained, randomization was performed centrally with stratification for age (< or ≥36 years), number of previous miscarriages (2 or ≥3), and center.Oral medication was started at the day of inclusion. Aspirin was given as calcium carbasalate 100 mg (Ascal®, Vemedia BV, Diemen, The Netherlands), equivalent to 80 mg of acetylsalicylic acid. Aspirin and placebo study medication was packed in sachets of identical appearance. Patients, doctors, and trial nurses were blinded for these treatment allocations. Women allocated to receive open-label nadroparin 2850 IU s.c. received oral aspirin and started nadroparin injections when a viable intrauterine pregnancy was confirmed by ultrasound from 6 weeks of gestational age. Aspirin or placebo was given until 36 weeks of gestational age or stopped at time of miscarriage, ectopic pregnancy or premature delivery. LMWH was given throughout gestation and stopped 12 hours before delivery.The primary outcome measure was live birth rate. Secondary outcomes included miscarriage rate, uterine and umbilical blood flow profile and prevalence of obstetric complications. Differences in live birth rates will be expressed as relative risks and 95% confidence intervals with the placebo group as reference. Data were analyzed according to the intention-to-treat principle. Preliminary resultsBetween February 2004 and January 2008, 364 women were included in the trial. On July 1st 2009, 25 were not pregnant 2 years after inclusion, 16 were not pregnant, 8 were pregnant, 26 women had decided to withdraw from the study, and 3 had been included erroneously. The results presented in this abstract are based on a pre-scheduled interim analysis of 281 women who had reached an endpoint (live birth or miscarriage) on July 1st 2009.AspirinAspirin and nadroparinPlacebon=95n=91n=95Live birth, n (%)64 (67.4)65 (71.4)67 (70.5)Relative risk (95%CI)0.96 (0.79-1.16)1.01 (0.84-1.22)1 (reference)The live birth rate did not differ between women assigned to aspirin, aspirin combined with nadroparin, and placebo. The Data Safety Monitoring Board advised the Steering Committee of the ALIFE study that further continuation of the study was futile. At the time of submission of this abstract, the database is being finalized, with closure scheduled on October 1st 2009. We will present definite data, including those of the a priori defined subgroup of women with hereditary thrombophilia, at the ASH meeting in December 2009. ConclusionsAspirin, and aspirin combined with nadroparin did not improve the live birth rate in women with unexplained RM (Current Controlled Trial number, ISRCTN58496168).Funding: ZonMW, the Dutch Organization for Health Research and Development (945-27-003). Vemedia BV supplied study medication (calcium carbasalate and placebo). GlaxoSmithKline BV offered a grant. Funding sources were not involved in study protocol preparation, trial management or data analysis. Disclosures:Off Label Use: Calcium carbasalate (equivalent to acetyl salicylic acid) and nadroparin to prevent recurrent miscarriage.. Buller:GSK: Consultancy, Honoraria, Research Funding. Middeldorp:GSK: Consultancy, Honoraria, Research Funding.

Primary care anticoagulant management using near patient testing.

Indications for anticoagulant treatment are increasing and new approaches to anticoagulant services require a shift from hospital to primary care. To pragmatically test the validity and effectiveness of primary care anticoagulant management using near patient testing. Twelve CoaguCheck monitors were supplied to 16 rural practices that had previously provided supervision of anticoagulant therapy. Practices were required to record data for eligible patients from September 1998 to April 1999 and to forward one blood sample per week to the regional hospital laboratory for parallel testing. Nine practices returned data on 122 patients. Indications for anticoagulation Included atrial fibrillation (n = 56), valve replacement (n = 12) and deep venous thrombosis or pulmonary embolus (n=12). Regression of the mean of 185 paired readings against their difference confirmed the validity of the CoaguCheck monitor (r2 = 0.00 [95% CI -0.38 to 0.38]). There were 692 International Normalised Ratio (INR) tests performed representing an average of 5.7 tests per patient. The desired therapeutic range was provided for 609 (88%) of these tests; 294 (48.3%) were within the desired therapeutic range. Results differed significantly between practices. This study confirmed the validity of anticoagulant management using the CoaguCheck monitor in primary care.

Oral anticoagulation and risk of death: a medical record linkage study

Abstract Objective: To study how mortality varies with different degrees of anticoagulation reflected by the international normalised ratio (INR). Design: Record linkage analysis with death hazard estimated as a continuous function of INR. Data sources: 46 anticoagulation clinics in Sweden with computerised medical records. Subjects: Records for 42 451 patients, 3533 deaths, and 1.25 million INR measurements. Main outcome measures: Mortality from all causes and from intracranial haemorrhage. Results: Mortality from all causes of death was strongly related to level of INR. Minimum risk of death was attained at 2.2 INR for all patients and 2.3 INR for patients with mechanical heart valve prostheses. A high INR was associated with an excess mortality: with an increase of 1 unit of INR above 2.5, the risks of death from cerebral bleeding (149 deaths) and from any cause were about doubled. Among patients with an INR of 3.0, 1069 deaths occurred within 7 weeks; if the risk coincided with that with an INR of 2.9, the expected number of deaths would have been 569. Thus at least 500 deaths were associated with a high INR value, but not necessarily caused by the treatment. Conclusions: The excess mortality associated with high INR values supports the use of less intensive treatment and a small therapeutic window, with INR close to 2.2-2.3 irrespective of the indication for anticoagulant treatment. More preventive actions should be taken to avoid episodes of high INR. What is already known on this topic The optimal degree of anticoagulation (expressed as the international normalised ratio (INR)) for different indications is still unclear, but the increased risk of death due to bleeding at high INR values is well known What this study adds This large study of medical records from anticoagulation clinics in Sweden confirmed the substantial excess mortality at high INR values and indicated optimal treatment to be in a small therapeutic window with INR close to 2.2-2.3, irrespective of the indication for anticoagulant treatment

Diagnosis of pulmonary embolism.

The patient with suspected pulmonary embolism presents a challenging diagnostic problem. The symptoms and signs are nonspecific, and objective testing is required to establish or exclude the presence of pulmonary embolism. Lung scanning continues to be a first-line test, but in 40% to 70% of all patients, the results do not definitively provide indication for either giving or withholding anticoagulant treatment even when combined with the clinical assessment. Pulmonary angiography is the reference standard, but it is invasive and may not be available in all clinical settings. Pulmonary embolism is strongly associated with proximal deep-vein thrombosis of the legs (popliteal, femoral, or iliac vein thrombosis). Objective testing for proximal deep-vein thrombosis is useful in patients with suspected pulmonary embolism. A positive result from such testing provides an indication for anticoagulant treatment. Serial testing for proximal deep-vein thrombosis is a safe and effective alternative to pulmonary angiography in patients with adequate cardiorespiratory reserve. The assay for plasma D-dimer using either a rapid enzyme-linked immunospecific assay technique or a bedside whole-blood agglutination technique is promising as a test for excluding venous thromboembolism. A positive result by spiral CT imaging is useful for ruling in a diagnosis of pulmonary embolism, but the safety of withholding treatment in patients with negative spiral CT results remains uncertain. Pulmonary angiography continues to have an important role in selected patients in whom it is critical to definitively confirm or exclude the presence of pulmonary embolism.

Thrombotic Events during Oral Anticoagulant Treatment: Results of the Inception-cohort, Prospective, Collaborative ISCOAT Study

The paper reports on rate and type of thrombotic events occurring during the observational, prospective, inception-cohort, multicenter ISCOAT study. 2,745 unselected, daily practice patients, consecutively referring to 34 Italian anticoagulation clinics to monitor the oral anticoagulant treatment, were included in the study from beginning of their first anticoagulant course. During a total follow-up of 2,011 patient-years of treatment 70 thrombotic events (3.5 per 100 patient years) were recorded in 67 patients: 20 fatal (1%), 39 major (1.9%) and 11 minor (0.6%). 34/70 events occurred within the first 90 days of treatment (relative risk - at multivariate analysis - of < or =90 days vs. >90 = 20.6, C.I. 12.7-33.5; p <0.0001). The risk was higher in patients aged > or =70 y (1.62, C.I. 1.0-2.61; p <0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p <0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were < 1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs <2.0 vs. > or =2 = 1.88, C.I. 1.16-3.07; p <0.05). The recorded rate of thrombotic events was lower than that reported in the few available studies. A greater risk should be expected during the first 90 days of treatment, when anticoagulation levels are <2.0 INR, in patients > 70 years and in those with cerebrovascular/peripheral arterial disease.

Anticoagulant treatment in primary health care in Finland.

To establish the prevalence of anticoagulant (AC) treatment, the indications, and the quality of care in primary health care. A cross-sectional study, in which patients on AC treatment were identified from laboratory records. The main and second indications for AC treatment and the last value of the AC-test were taken from medical records. Eight Finnish health centres with a total population of 182091 inhabitants. A total of 1255 patients on AC treatment were identified, 48% of them men. The mean age was 68.9 years. The age-adjusted prevalence of AC treatment was 0.65%. The commonest main indication was atrial fibrillation (38%). It was the main or second indication in 591 patients (age-adjusted prevalence 0.30%). The next commonest main indication was deep vein thrombosis (15%), followed by pulmonary embolism (8%). A total of 274 (22%) patients were anticoagulated for cerebral circulatory disturbances. 86% of the latest prothrombin time values fell within recommended ranges. The prevalence of AC treatment in Finland seems to be high. The proportion of patients with atrial fibrillation is high, differing from the results in other countries. The monitoring of AC-treatment as the general practitioner's responsibility functions well. The quality of care is good, even in older age groups.

The intact porcine bioprosthesis: early world-wide clinical experience and analysis of a single institution's experience

The Intact porcine bioprosthesis is a new-generation valve fixed under stress-free conditions and subjected to a mineralization-inhibiting treatment. The valve is undergoing multi-centre prospective clinical evaluation sponsored by Medtronic, Inc., with 19 centres participating world wide. Since April 1986, 1465 valves have been implanted in the aortic position (AVR, n = 965), mitral position (MVR, n = 438), or both (n = 62), and followed up to 5 years. The data recorded at our participating centre, with 115 valves implanted (AVR n = 93, MVR n = 22) closely match the overall event and death rates in the prospective study. Early mortality in the overall study is 5.6% in AVR and 6.6% in MVR; 3-year actuarial survival rates are 88.5% in AVR and 85.6% in MVR; structural valve-failure-free rates at 3 years are 99.8% in AVR and 98.5% in MVR; 3-year freedom from valve-related reoperation is 97.3% in AVR and 95.8% in MVR. The preferential use of bioprosthetic valves in patients aged 70 years and older with no other indication for anticoagulant treatment entails the not infrequent occurrence of patient/prosthesis mismatch in AVR. Hence, when implanting bioprostheses in old patients, the acceptance of some mismatch has to be weighed against the freedom from anticoagulation treatment and the expected long-term freedom from structural valve failure. Further long-term follow-up will be required to demonstrate the greater durability expected from the stress-free fixation and the anti-mineralization treatment.