Simon McRae

Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis

BACKGROUND Individual risk of recurrent venous thromboembolism affects patient management and might differ between men and women. We did a meta-analysis to assess from available evidence whether men and women have the same risk of recurrent venous thromboembolism after stopping anticoagulant treatment. METHODS Eligible articles were identified by searches of MEDLINE (source PubMed, 1966 to February 2005), EMBase (1980 to February 2005), and the Cochrane database 2005, issue 1. Prospective cohort studies and randomised trials were eligible if they included patients with objectively diagnosed venous thromboembolism treated for a minimum of 1 month and followed up for recurrence after anticoagulant treatment was stopped. Data were extracted for study design, study quality, and the number, sex, and age of enrolled patients, risk factors for venous thromboembolism, treatment given, duration of follow-up, and the number of episodes of recurrent venous thrombosis. FINDINGS 15 studies (nine randomised controlled trials and six prospective observational studies) enrolling a total of 5416 individuals (2729 men), of whom 816 (523 men) had recurrent venous thromboembolism after stopping treatment, were eligible for inclusion. The pooled estimate of the relative risk (RR) of recurrent venous thromboembolism for men compared with for women was 1.6 (95% CI 1.2-2.0). Significant heterogeneity was shown among individual study findings; however, the higher risk of recurrent venous thromboembolism in men than in women was consistent across predefined subgroups. The relative risk for recurrence in men from randomised trials (RR 1.3; 95% CI 1.0-1.8) was lower than that from observational studies (2.1; 1.5-2.9). The lower risk of recurrent venous thromboembolism in women did not seem to be accounted for by a reduced rate of recurrence after venous thromboembolism associated with oestrogen treatment or pregnancy. INTERPRETATION Men seem to have a 50% higher risk than women of recurrent venous thromboembolism after stopping anticoagulant treatment. If confirmed by further prospective studies, this difference in risk of recurrence should be considered when duration of anticoagulant treatment is determined in individual patients.

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management

New oral anticoagulants (NOAC) are becoming available as alternatives to warfarin to prevent systemic embolism in patients with non‐valvular atrial fibrillation and for the treatment and prevention of venous thromboembolism. An in‐depth understanding of their pharmacology is invaluable for appropriate prescription and optimal management of patients receiving these drugs should unexpected complications (such as bleeding) occur, or the patient requires urgent surgery. The Australasian Society of Thrombosis and Haemostasis has set out to inform physicians on the use of the different NOAC based on current available evidence focusing on: (i) selection of the most suitable patient groups to receive NOAC, (ii) laboratory measurements of NOAC in appropriate circumstances and (iii) management of patients taking NOAC in the perioperative period, and strategies to manage bleeding complications or ‘reverse’ the anticoagulant effects for urgent invasive procedures.

Initial Treatment of Venous Thromboembolism

Adequate initial anticoagulant therapy of deep venous thrombosis (DVT) is required to prevent thrombus growth and pulmonary embolism (PE). Intravenous unfractionated heparin (UFH) is being replaced by low-molecular-weight heparin (LMWH) as the anticoagulant of choice for initial treatment of venous thromboembolism (VTE). Both agents are relatively safe and effective when used to treat VTE, with LMWH suitable for outpatient therapy because of improved bioavailability and more predictable anticoagulant response. Serious potential complications of heparin therapy, such as heparin-induced thrombocytopenia (HIT) and osteoporosis, seem less common with LMWH. The potential for fetal harm and changes in maternal physiology complicate the treatment of VTE during pregnancy. Although systemic thrombolysis is used in patients with massive PE and in some patients with proximal DVT, controversy persists with respect to appropriate patient selection for this intervention.

Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study

Summary.  Background: It remains unclear whether a single complete ultrasound examination, which detects calf vein thrombosis, is as safe as a baseline rapid ultrasound examination, repeated after 1 week when negative, which examines the veins in the groin and the knee. Therefore, we compared the safety and feasibility of two diagnostic ultrasound strategies, involving rapid and complete compression ultrasound (CUS) examination. Methods: Consecutive patients with suspected deep vein thrombosis (DVT) underwent clinical probability assessment. In patients with an unlikely clinical probability and a normal D‐dimer finding, DVT was considered to be excluded. All others were randomized to undergo a rapid or a single complete CUS examination. Patients in whom DVT was excluded were followed for 3 months to assess the incidence of venous thromboembolism (VTE). Results: A total of 1002 patients were included. A clinical decision rule indicating DVT to be unlikely and a normal D‐dimer finding occurred in 481 patients (48%), with a VTE incidence of 0.4% [95% confidence interval (CI) 0.05–1.5%] during follow‐up. DVT was confirmed in 59 of the 257 patients (23%) who underwent rapid CUS examination, and in 99 of the 264 patients (38%) who underwent complete CUS examination. VTE during follow‐up occurred in four patients (2.0%; 95% CI 0.6–5.1%) in the rapid CUS arm, and in two patients (1.2%; 95% CI 0.2–4.3%) in the complete CUS arm. Conclusions: A diagnostic strategy with a clinical decision rule, a D‐dimer test and a CUS examination is safe and efficient. Both the rapid and the complete CUS test are comparable and efficient strategies, with differing advantages and disadvantages.

Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period

Venous thromboembolism (VTE) in pregnancy and the postpartum is an important cause of maternal morbidity and mortality; yet, there are few robust data from clinical trials to inform an approach to diagnosis and management. Failure to investigate symptoms suggestive of pulmonary embolism (PE) is a consistent finding in maternal death enquiries, and clinical symptoms should not be relied on to exclude or diagnose VTE. In this consensus statement, we present our recommendations for the diagnosis and management of acute deep venous thrombosis (DVT) and PE. All women with suspected DVT in pregnancy should be investigated with whole leg compression ultrasonography. If the scan is negative and significant clinical suspicion remains, then further imaging for iliofemoral DVT maybe required. Imaging should be undertaken in all women with suspected PE, as the fetal radiation exposure with both ventilation/perfusion scans and CT pulmonary angiography is within safe limits. Low‐molecular‐weight heparin (LMWH) is the preferred therapy for acute VTE that occur during pregnancy. In observational cohort studies, using once‐daily regimens appears adequate, in particular with the LMWH tinzaparin; however, pharmacokinetic data support twice‐daily therapy with other LMWH and is recommended, at least initially, for PE or iliofemoral DVT in pregnancy. Treatment should continue for a minimum duration of six months, and until at least six weeks postpartum. Induction of labour or planned caesarean section maybe required to allow an appropriate transition to unfractionated heparin to avoid delivery in women in therapeutic doses of anticoagulation.

Recommendations for the prevention of pregnancy-associated venous thromboembolism.

Pregnancy is a risk factor for venous thromboembolism (VTE), an important cause of maternal morbidity and mortality. Although there is a 4–5‐fold increased risk compared to that of nonpregnant women of the same age, the absolute risk is low at no more than two episodes of VTE per 1000 pregnancies. There is uncertainty about which women require thromboprophylaxis during pregnancy or postpartum because of a lack of data from appropriate clinical trials. For this reason, recommendations for prophylaxis should be made only after explaining the available evidence to the patient and taking into account her perception of the balance of risk and benefit in thromboprophylaxis. The aim of these recommendations is to provide clinicians with practical advice to assist in decisions regarding thromboprophylaxis in women considered to be at risk of VTE during pregnancy and the postpartum. The authors are clinicians from across New Zealand and Australia representing the fields of haematology, obstetric medicine, anaesthesiology, maternal–fetal medicine and obstetrics. Authors were invited to review the relevant literature and then worked collaboratively to devise recommendations and resolve areas of controversy. The recommendations contained herein were reached by consensus and represent the opinion of the panel. The absence of randomised clinical trials in this area limits the strength of evidence that can be used, and it is acknowledged that they represent level C evidence. The panel advocates for appropriate clinical studies to be carried out in this patient population to address the inadequacy of present evidence.

New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis.

New oral anticoagulants (NOAC) are becoming available as alternatives to warfarin to prevent systemic embolism in patients with non‐valvular atrial fibrillation and for the treatment and prevention of venous thromboembolism. An in‐depth understanding of their pharmacology is invaluable for appropriate prescription and optimal management of patients receiving these drugs should unexpected complications (such as bleeding) occur, or the patient requires urgent surgery. The Australasian Society of Thrombosis and Haemostasis has set out to inform physicians on the use of the different NOAC based on current available evidence focusing on: (i) selection of the most suitable patient groups to receive NOAC, (ii) laboratory measurements of NOAC in appropriate circumstances and (iii) management of patients taking NOAC in the perioperative period, and strategies to manage bleeding complications or ‘reverse’ the anticoagulant effects for urgent invasive procedures.

Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT: results of a large Australian study

Heparin-induced thrombocytopenia (HIT) remains a challenge, with diagnosis confirmed only by functional assays. The gold standard 14C-serotonin release assay (SRA) is highly sensitive but technically challenging and unsuitable for routine use. We conducted a large study to validate whole blood impedance aggregometry (WBIA) as a suitable diagnostic tool for HIT. WBIA and SRA were used to test 181 samples positive for H-PF4 antibodies by PaGIA or ELISA. Using the same high responder donor, 77 samples were positive by WBIA (aggregation with low-dose but not high-dose heparin). Using the strict definition for SRA positivity, 72 samples were true HIT. In nine samples, serotonin release with high-dose heparin dropped by > 50% but was still >20%; these were retested after a one-half dilution and 8/9 became positive. Ten other samples were discrepant between the two assays: one strongly positive (89% release) and six weakly positive samples by SRA (average release 56%) were WBIA negative. When these samples were retested using a random donor, only two remained SRA positive. Three samples were strongly WBIA positive but SRA negative; two were retested by SRA with 0.5IU/ml heparin and one became positive. Under controlled conditions, using the same selected high-responder donor, WBIA and SRA performed similarly with slightly increased sensitivity of the WBIA when using the strict definition of SRA positivity. WBIA is easy to perform with rapid turn-around time and warrants a multi-laboratory trial to complete its validation as a confirmatory assay for platelet-activating HIT antibodies.

Practical management of patients on apixaban: a consensus guide

BackgroundAtrial fibrillation (AF) is a common tachyarrhythmia in Australia, with a prevalence over 10% in older patients. AF is the leading preventable cause of ischaemic stroke, and strokes due to AF have a higher mortality and morbidity. Stroke prevention is therefore a key management strategy for AF patients, in addition to rate and rhythm control. Anticoagulation with warfarin has been an enduring gold standard for stroke prevention in NVAF patients. In Australia, three novel oral anticoagulants (NOACs), apixaban, dabigatran and rivaroxaban are now approved and reimbursed for stroke prevention in patients with non-valvular AF (NVAF). International European Cardiology guidelines now recommend either a NOAC or warfarin for NVAF patients with a CHA2DS2-VASc score ≥2, unless contraindicated. Apixaban is a direct factor Xa inhibitor with a 12-hour half-life and 25% renal excretion that was found in a large trial of NVAF patients to be superior to warfarin in preventing stroke or systemic embolism. In this trial population, apixaban also resulted in less bleeding and a lower mortality rate than warfarin.MethodsClinical experience with apixaban outside of clinical trials has been limited, and there is currently little evidence to guide the management of bleeding or invasive procedures in patients taking apixaban. The relevant currently available animal and ex vivo human data were collected, analyzed and summarized.ResultsThis multi-disciplinary consensus statement has been written to serve as a guide for healthcare practitioners prescribing apixaban in Australia, with a focus on acute and emergency management.ConclusionsThe predictable pharmacokinetics and minimal drug interactions of apixaban should allow for safe anticoagulation in the majority of patients, including temporary interruption for elective procedures. In the absence of published data, patients actively bleeding on apixaban should receive standard supportive treatment. Quantitative assays of apixaban level such as chromogenic anti-Xa assays are becoming available but their utility is unproven in this setting. Specific antidotes for novel anticoagulants, including apixaban, are in clinical development.