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Biomedical subjects

Sam Schulman

Publications and source records attributed to Sam Schulman.

At least 19 recordsLinked to original sources
PubMed2007

Anticoagulants and their reversal.

In an exciting era with many alternatives to the old anticoagulants heparin and warfarin emerging on the scene, awareness of the possibility to reverse their effect is mandatory. In this review, the traditional antidotes for warfarin (vitamin K, plasma, and prothrombin complex concentrate) and for heparin (protamine) are described together with the newer alternatives (recombinant activated factor VII, concatameric peptides, and recombinant platelet factor 4). For some of the newer anticoagulants, possible antidotes have been identified, whereas other alternatives have been discarded. There is a very limited experience of deamino-d-arginine vasopressin or a von Willebrand factor VIII concentrate to counteract hirudin. The small direct thrombin inhibitors may be reversed with activated prothrombin complex concentrate but not with recombinant activated factor VII, whereas the latter agent appears to be effective against the pentasaccharides and the recombinant nematode anticoagulant protein C2. Additional options that may become available in the future are also discussed briefly.

Anticoagulants↗
PubMed2006

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.

Aged↗
PubMed2006

Risk of recurrent venous thromboembolism or bleeding in relation to thrombophilic risk factors in patients receiving ximelagatran or placebo for long-term secondary prevention of venous thromboembolism.

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had > or = 2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.

Antibodies, Anticardiolipin↗
PubMed2006

Thromboprophylaxis in medical patients--why not for all?

Venous thromboembolism (VTE) is a major problem in non-surgical patients admitted to the hospital, both during the hospitalization period and after discharge. Risk factors for VTE are well known and scoring systems have been published. Nevertheless, prophylaxis against VTE is in many hospitals used less often than ideal and also inappropriately. Electronic tools to alert the physicians to provide prophylaxis and suggest suitable measures have shown promising results with a reduction of clinically relevant VTE. Large randomized clinical trials have demonstrated efficacy of low molecular-weight heparin (LMWH), pentasaccharide(fondaparinux) and unfractionated heparin. The results were, however, driven by asymptomatic deep vein thrombosis (DVT), including distal DVT in some studies. A reduction of pulmonary embolism is achieved, but without any significant effect on the mortality. The agents are generally safe, with only a small increase of major bleeding, less with LMWH than with unfractionated heparin. The challenge is still to direct the efforts to the most appropriate patients.

Clinical Trials as Topic↗
PubMed2006

New concepts in optimal management of anticoagulant therapy for extended treatment of venous thromboembolism.

Recent trials on secondary prophylaxis after venous thromboembolism (VTE) have provided a wealth of data on the risk factors for recurrence and, to some extent, also for bleeding. Some of the results are consistent across the studies, but there are also conflicting data. Certain risk factors, such as pulmonary embolism versus deep vein thrombosis or presence of cardiolipin antibodies, have a more pronounced influence on the risk early in the course of disease. Others, such as hereditary thrombophilic defects, seem to gain importance over many years of follow-up. Therefore, it can be difficult to make decisions on an individual patient basis. In this article, data from important and illustrative trials have been extracted and compared and controversies highlighted. The conclusions drawn should help clinicians make balanced decisions on the optimal duration of anticoagulation after an episode of VTE.

Adolescent↗
PubMed2006

Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects.

OBJECTIVE: NXY-059 is a novel, free-radical trapping, neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in the unbound steady-state plasma concentration (Cu(ss)) exposure range of 50-300 micromol/L in healthy young and elderly subjects. RESEARCH DESIGN AND METHODS: The primary objective of this two-centre, randomised, double-blind, placebo-controlled, dose-escalating study was to investigate the safety and tolerability, including renal function parameters and vasoirritative effects, of 8-h and 72-h intravenous infusions of NXY-059 in healthy young (20-45 years) and elderly (55-75 years) male and female subjects. The secondary objective of the study was to evaluate the pharmacokinetics of 8-h and 72-h intravenous infusions of NXY-059 in these subjects, using blood and urine samples taken during and after NXY-059 infusion as well as the doses administered. RESULTS: Of the 104 healthy volunteers who participated in the study, 72 were young and 32 were elderly. The type and incidence of adverse events in NXY-059 and placebo subjects were similar, although headache was more common in the NXY-059 group. Renal function was not altered in either group. Thrombophlebitis was reported in two elderly subjects: one receiving NXY-059 and one receiving placebo. A proportional relationship between AUC and dose for the 8-h and 72-h infusions was observed, and clearance did not change with dose. CONCLUSIONS: NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8-h and 72-h infusions of NXY-059 at doses resulting in an average Cu(ss) in the 52-317 micromol/L range.

Adult↗
PubMed2005

Recombinant FVIIa in children with liver disease.

INTRODUCTION: The aim of this study was to investigate the clinical and biochemical effects of recombinant activated factor VII (rFVIIa) in the treatment of bleeding in children with liver disease. PATIENTS AND METHODS: 12 patients (0.3-15.9 years) with chronic liver disease were included. The indication for treatment was life threatening bleeding and failing conventional therapy (group A, 7 patients) or as prophylaxis before invasive procedures (group B, 6 patients). One patient received treatment on both indications. rFVIIa was administered as intravenous bolus doses of 34-163 microg/kg (median 66 mug/kg) alone or in combination with packed red cells and/or octreotide and/or fresh frozen plasma. The follow-up included repeated INR and haemoglobin measurements as well as clinical evaluation. RESULTS: In group A rFVIIa was given on 22 occasions and bleeding decreased, was unchanged, increased or could not be evaluated on 10, 7, 2 and 3 occasions respectively. On 14 occasions rFVIIa and octreotide were administered simultaneously, in 8 of those bleeding decreased. In group B no bleeding complication was seen, interpreted as a positive effect. One thrombotic event was suspected but could not be verified by computerized tomography. CONCLUSIONS: rFVIIa may be beneficial in the short-term management of life threatening bleeding in some children with liver disease. This effect may be further enhanced with the additional use of octreotide. Furthermore, rFVIIa is useful for prophylaxis at invasive procedures, even without additional treatment with fresh frozen plasma. The possible risk of portal vein thrombosis needs to be considered.

Adolescent↗
PubMed2005

Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis.

OBJECTIVE: Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis. METHODS: A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models. RESULTS: The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat. CONCLUSIONS: The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

Administration, Oral↗
PubMed2005

A step change in oral anticoagulation: lack of coagulation monitoring with ximelagatran.

The clinical development of ximelagatran for the treatment and prevention of various arterial and venous thromboembolic disorders has used fixed-dose regimens without coagulation monitoring in all indications. Although monitoring is not required, effects on the various coagulation assays that are available are seen with its active form melagatran, and there are situations where an assessment of anticoagulant effect may help to inform clinical decisions. However, the sensitivity of different coagulation assays varies considerably. The thrombin clotting time (TT) and ecarin clotting time (ECT) are highly sensitive to plasma melagatran concentrations (IC 50 approximately 0.01 micromol/L and approximately 0.15 micromol/L, respectively), with an approximate linear relationship between plasma melagatran concentration and prolongation of clotting time. In comparison, the activated partial thromboplastin time (APTT) (IC 50 approximately 0.3 to 0.8 micromol/L) and prothrombin time (PT) (IC 50 approximately 0.9 to 2.9 micromol/L) are relatively insensitive, and the concentration-response relationship shows a flattening with increasing plasma melagatran concentration. Commercially available APTT and PT reagents varied considerably in their sensitivity to melagatran. Comparing the various coagulation assays, the APTT, ECT, and TT are suitable choices when an indicator of the anticoagulant effect of ximelagatran is required, although the absence of international standards requires calibration of each test in individual laboratories and the ECT is not widely available.

Anticoagulants↗
PubMed2005

Ximelagatran in the clinic: practical management of patients.

Several case studies are briefly introduced, followed by a description of the clinical problem from an epidemiological point of view. The evidence for established management strategies is reviewed and, finally, practical handling of the case is considered.

Aged↗
PubMed2005

The role of ximelagatran in the treatment of venous thromboembolism.

Clinical-based evidence demonstrates that long-term oral anticoagulant therapy with the vitamin K antagonists is highly effective for the secondary prevention of venous thromboembolism (VTE). However, owing to fear of bleeding complications and the inconvenience of coagulation monitoring, many patients do not receive the required duration of treatment. This can lead to a high incidence of recurrent VTE events and has prompted the evaluation of alternative treatment strategies and the development of new anticoagulants for VTE management. For patient groups in which it is particularly difficult to maintain the target intensity of anticoagulation, low-molecular-weight heparin (LMWH) has been found to significantly reduce the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of LMWH, however, is a drawback for long-term use in the outpatient setting. Long-term warfarin use at a lower intensity (international normalized ratio [INR] 1.5-2.0) has also been assessed as a possible strategy to reduce bleeding complications and the need for monitoring, but results were disappointing when compared with conventional-intensity warfarin (INR 2.0-3.0). New therapies in development that may potentially offer a more favourable benefit-risk profile and greater consistency and predictability of response include the synthetic pentasaccharides, fondaparinux and idraparinux. These par enterally administered indirect factor Xa inhibitors have a predictable pharmacokinetic profile, allowing use without coagulation monitoring. Fondaparinux to date has only been evaluated in the initial treatment (5-7 days) of symptomatic deep vein thrombosis. In contrast, idraparinux, with its longer half-life (80 h) allowing once-weekly parenteral dosing, has the potential for long-term treatment and is currently being assessed in phase III trials for the secondary prevention of VTE. Currently, the most promising new therapeutic option is the first of the oral direct thrombin inhibitors, ximelagatran. The THRombin Inhibitor in VEnous thromboembolism (THRIVE) clinical trial programme has demonstrated that this agent is as effective as standard therapy for the acute treatment (THRIVE Treatment) and secondary prevention (THRIVE lll) of VTE events and is well tolerated when used for 6 months or over extended periods up to 1.5 years. Furthermore, with oral administration, fixed dosing and no requirement for anticoagulation monitoring, ximelagatran has the potential to facilitate optimal use and duration of VTE treatment by overcoming the limitations of current agents.

Anticoagulants↗
PubMed2005

Continuous infusion of recombinant factor VIIa for surgery in patients with deficiency of factor VII.

The administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factor VII (FVII) deficiency. The results of 12 consecutive surgical procedures in 7 patients with congenital FVII deficiency are reported here. rFVIIa was always given in continuous infusion,aiming at plasma FVII activity of 0.5 IU/mL. Treatment was given for 2 to 7 days with a mean total dose of 7.8 mg rFVIIa. Blood loss was as expected from the different types of procedures and the only thromboembolic complication was a superficial thrombophlebitis at the infusion site. This mode of substitution was therefore safe, effective and well tolerated.

Adolescent↗
PubMed2005

Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran.

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.

Adult↗
PubMed2005

Ximelagatran for the secondary prevention of venous thromboembolism: a complementary follow-up analysis of the THRIVE III study.

In the randomized, double-blind THRIVE III trial, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) significantly reduced the incidence of recurrent venous thromboembolism (VTE) versus placebo over 18 months or until premature study drug discontinuation. A complementary follow-up analysis (intention-to-treat) was conducted post-study to evaluate the cumulative risks of locally-confirmed recurrent VTE and death (Kaplan-Meier procedure) over the full 18-month study period, regardless of whether patients discontinued study drug prematurely. Hazard ratios (HRs) between treatments were estimated using Cox proportional hazard modeling. Of 612 and 611 patients receiving ximelagatran and placebo, respectively, 149 and 181 discontinued treatment prematurely. Of these discontinuations, further information could not be collected for 14 and 13 patients in the ximelagatran and placebo groups, respectively; among the remaining patients, four VTE events and four deaths occurred in the ximelagatran group, and one VTE event and five deaths occurred in the placebo group. The resulting cumulative risks of VTE (3.2% vs. 12.7%; HR 0.21; 95% confidence interval [CI], 0.12, 0.36; P < 0.0001) and pulmonary embolism (0.8% vs. 5.2%; HR 0.13; 95% CI 0.04, 0.36; P < 0.0001) were significantly lower in the ximelagatran than in the placebo group over 18 months. Death from any cause over 18 months occurred in 10 and 12 patients, respectively (HR 0.83;95% CI 0.36, 1.93; P = 0.7). This complementary follow-up analysis confirms the benefit of oral ximelagatran 24 mg twice daily, administered without coagulation monitoring or dose adjustment, for the long-term secondary prevention of VTE.

Administration, Oral↗
PubMed2004

Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This chapter about hemorrhagic complications of anticoagulant treatment is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Bleeding is the major complication of anticoagulant therapy. The criteria for defining the severity of bleeding varies considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that vitamin K antagonist therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0 to 3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism (VTE) is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low molecular weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute VTE. UFH and LMWH are not associated with an increase in major bleeding in ischemic coronary syndromes, but are associated with an increase in major bleeding in ischemic stroke. Information on bleeding associated with the newer generation of antithrombotic agents has begun to emerge. In terms of treatment decision making for anticoagulant therapy, bleeding risk cannot be considered alone, ie, the potential decrease in thromboembolism must be balanced against the potential increased bleeding risk.

Anticoagulants↗