Seminars in Vascular Medicine (Semin Vasc Med)

Publications in this journal

• Article: Fibrin D-dimer testing for venous and arterial thrombotic disease.

  Jan Jacques Michiels, Gualtiero Palareti, Philippe de Moerloose
  Seminars in Vascular Medicine 12/2005; 5(4):311-4.
• Article: D-dimer testing in ischemic stroke and cerebral sinus and venous thrombosis.

  Alessandro Squizzato, Walter Ageno
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  ABSTRACT: D-dimer measurement is commonly included in the diagnostic workup of patients with suspected acute symptomatic deep venous thrombosis and pulmonary embolism. As a haemostatic marker, it could be theoretically useful in other thromboembolic disorders, such as acute cerebrovascular events. In this review we summarize published literature on D-dimer testing in acute ischemic stroke and cerebral sinus and venous thrombosis (CSVT), discussing possible clinical diagnostic and therapeutical applications. In ischemic stroke, mounting evidence suggests a possible role of D-dimer in the acute diagnosis of ischemic stroke subtypes, especially in identifying tromboembolic and lacunar stroke. Its prognostic role still remains unclear, due to conflicting data. D-dimer could be also an useful screening test for excluding CSVT in patients presenting with acute headache, making the presence of cerebral thrombosis unlikely with low plasma levels. In this clinical setting sensitivity and negative predictive value are comparable to that reported in the diagnosis of acute thromboembolic disease. However, more studies are needed to confirm these recent findings as well as management studies to correctly introduce D-dimer measurement in clinical daily practice of ischemic stroke and CSVT.
  Seminars in Vascular Medicine 12/2005; 5(4):379-86.
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  Article: D-dimer testing in pregnancy.

  Sabine Eichinger
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  ABSTRACT: Normal pregnancy is associated with alterations of the hemostatic system toward a hypercoagulable state. Elevated markers of coagulation and fibrinolytic system activation, such as D-dimer, indicate increased thrombin activity and increased fibrinolysis following fibrin formation throughout pregnancy. Testing for D-dimer in pregnant women could be useful for the diagnosis and prediction of a venous thromboembolic event or pregnancy-related complications and for monitoring antithrombotic treatment. This approach, however, is hampered by the fact that even an uncomplicated pregnancy in healthy women is accompanied by a substantial increase of D-dimer. Thus, prior to clinical application reference values of D-dimer according to gestational age need to be validated. A substantial increase of D-dimer during pregnancy is seen despite thromboprophylaxis with low-molecular-weight heparin (LMWH), indicating that further studies are needed to evaluate monitoring of LMWH during pregnancy and to investigate the optimal beginning and dose of LMWH thromboprophylaxis in pregnant women.
  Seminars in Vascular Medicine 12/2005; 5(4):375-8.
• Article: The role of qualitative D-dimer assays, clinical probability, and noninvasive imaging tests for the diagnosis of deep vein thrombosis and pulmonary embolism.

  Philip S Wells
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  ABSTRACT: Recent advances in the management of patients with suspected venous thromboembolism have both improved diagnostic accuracy as well as made management algorithms safer and more accessible. It is now clear that determination of clinical probability prior to diagnostic testing will improve patient management. D-dimer testing can be employed to decrease the need for imaging tests. Patients at low risk with a negative qualitative D-dimer can avoid imaging tests. Imaging test interpretation benefits from consideration of pretest probability also as this helps clinicians determine when a test may be falsely negative or falsely positive. Diagnostic strategies should include pretest clinical probability, D-dimer assays, and noninvasive imaging tests.
  Seminars in Vascular Medicine 12/2005; 5(4):340-50.
• Article: The harmonization of quantitative test results of different D-dimer methods.

  P Meijer, C Kluft
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  ABSTRACT: Nowadays D-dimer testing is frequently applied in the diagnosis of venous thromboembolism. However, the test results of different quantitative D-dimer tests can differ significantly. The background of this variability, which is mainly caused by the variety of fibrin degradation products in plasma, the specificity of D-dimer assays, and the calibrators used in the test, is summarized here. Because D-dimer is not a single entity in plasma but a mixture of heterogeneous fibrin degradation products, method standardization is in principle impossible. Efforts undertaken in the past to standardize D-dimer methods are summarized. All these projects failed and it was concluded that only harmonization of D-dimer test results seems to be feasible. The results of a large field study on which a new approach to the harmonization of quantitative D-dimer methods will be based is summarized in this article. This approach seems to be an adequate solution for overcoming the practical problem of variation of test outcome in different D-dimer assays.
  Seminars in Vascular Medicine 12/2005; 5(4):321-7.
• Article: Comparability of D-dimer assays in clinical samples.

  Geneviève Freyburger, Sylvie Labrouche
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  ABSTRACT: D-dimers (DD) have shown sufficient proof of their efficiency in the last 10 years to play an important role in hemostasis laboratories for excluding thromboembolic events. Numerous reagents are available on the market but their performances differ. This overview takes stock of the methods used to evaluate the performances of DD assays, the results published in the literature, the technical parameters influencing assay performance, the difficulties caused by the lack of harmonization of DD units, and the attempts to tackle this problem. It raises the issue of the potential optimization of their use with regard to better adaptation to multidisciplinary diagnostic strategies and to target patient populations.
  Seminars in Vascular Medicine 12/2005; 5(4):328-39.
• Article: Fibrin D-dimer and cardiovascular risk.

  Gordon D O Lowe
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  ABSTRACT: Fibrin D-dimer, the most commonly used clinical assay for detection of coagulation activation and in vivo fibrin formation and lysis in circulating blood, has been associated with risks of cardiovascular diseases in studies published over the past 15 years. This review discusses, in turn, analytic and preanalytic considerations; associations with risk factors; and associations with coronary heart disease, atrial fibrillation, stroke and cerebrovascular disease, peripheral arterial disease, and venous thromboembolism. These associations suggest that activated coagulation and in vivo fibrin formation and lysis may play a role in arterial, intracardiac, and venous thromboembolism. The potential clinical utility of D-dimer in prediction of cardiovascular risk, in indicating patient groups for prophylactic anticoagulation and in monitoring of anticoagulation, requires further study. Harmonization of results from different assays would increase clinical utility.
  Seminars in Vascular Medicine 12/2005; 5(4):387-98.
• Article: D-dimer levels, constitutional thrombophilia, and venous thrombosis prediction: clinical aspects and implications.

  M M Samama, M H Horellou, I Elalamy, V Mathieux, E Ombandza-Moussa, J Conard
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  ABSTRACT: The negative predictive value of D-dimers in the diagnosis of a recent venous thromboembolism (VTE) episode is well established. The plasma level of D-dimer is usually increased in hypercoagulable states. The measurement of D-dimer could be of clinical interest in patients with constitutional thrombophilia as there is no close relationship between the clinical expression and the genotype indicating the existence of a hypercoagulable state. Moreover, the predictive value of D-dimer testing in patients with thrombophilia has been questioned. The review of the literature and results of a recent study of our group are presented. Decreased levels of D-dimer are observed in patients receiving an oral anticoagulant treatment versus untreated patients. In contrast, no significant difference was observed between those with and those without thrombophilia among treated or untreated patients. Patients with constitutional thrombophilia are supposed to have an increased risk of postoperative VTE. The review of the existing literature could not confirm this opinion but this could be due to the fact that most patients receive a prophylactic treatment. Thus, there is an indirect evidence of its efficacy in these patients.
  Seminars in Vascular Medicine 12/2005; 5(4):371-4.
• Article: Validation, calibration, and specificity of quantitative D-dimer assays.

  Carl-Erik Dempfle
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  ABSTRACT: Assays for D-dimer antigen are based on monoclonal antibodies reactive with epitopes found on fibrin fragment D-dimer but not on fibrinogen fragment D, other fibrinogen degradation products, or native fibrinogen. The antibodies react with conformational epitopes generated by factor XIII-induced linkage of the C-terminal appendages of the fibrin gamma-chains of adjacent D-domains within a fibrin polymer. For some monoclonal antibodies, degradation of the cross-linked fibrin compound by plasmin is an additional requirement for the generation of the epitope. In clinical plasma samples, D-dimer antigen assays detect an array of fibrin compounds of different molecular weights, including fibrin fragment D-dimer as well as higher-molecular-weight fibrin degradation products and fibrin X-oligomers. Most D-dimer antigen represents cross-linked soluble fibrin present in circulation rather than degradation products from particulate clots. Due to differences in epitope reactivity, harmonization of D-dimer antigen assays can only be achieved with standard preparations containing a similar variety of cross-linked fibrin compounds. Assay technologies include manual latex agglutination assays, automated latex-enhanced light-scattering immunoassays, enzyme-linked immunoassays, and others.
  Seminars in Vascular Medicine 12/2005; 5(4):315-20.
• Article: D-dimer, oral anticoagulation, and venous thromboembolism recurrence.

  Benilde Cosmi, Gualtiero Palareti
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  ABSTRACT: Venous thromboembolism (VTE) requires prolonged treatment to prevent late recurrences. However, the optimal duration of vitamin K antagonist (VKA) therapy is still controversial. More recently, D-dimer (D-d) has emerged as a predictive factor for recurrences. D-d has been evaluated both during and after VKA treatment. Some patients with DVT of the lower limbs have persistently high D-d during anticoagulation and this could reflect insufficient anticoagulation despite apparently adequate antithrombotic treatment. Altered D-d during anticoagulation is more frequent in patients with idiopathic or cancer-associated VTE than in those with secondary VTE. In subjects with an unprovoked VTE event, the time spent at near normal international normalization ratio (INR) values (< 1.5) during the first 3 months of treatment is associated with higher D-d during and after VKA treatment and with a higher risk for late recurrences. Moreover, the combination of altered D-d and inherited thrombophilia, and not residual venous obstruction, is associated with a significantly higher hazard ratio for recurrence. Preliminary results of a management study, the PROLONG study, indicate that subjects with normal D-d at 1 month after VKA withdrawal have a low risk of recurrence, and those with altered D-d have a significantly higher risk and deserve prolonged treatment.
  Seminars in Vascular Medicine 11/2005; 5(4):365-70.
• Article: Screening for deep vein thrombosis and pulmonary embolism in outpatients with suspected DVT or PE by the sequential use of clinical score: a sensitive quantitative D-dimer test and noninvasive diagnostic tools.

  Jan Jacques Michiels, Alain Gadisseur, Marc van der Planken, Wilfried Schroyens, Marianne De Maeseneer, Jan T Hermsen, Paul H Trienekens, Henk Hoogsteden, Peter M T Pattynama
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  ABSTRACT: The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1% during 3-month follow-up. The negative predictive value (NPV) during 3 months of follow-up is 98.1 to 99% after a normal venogram, 97 to 98% after a normal compression ultrasonography (CUS), and > 99% after serial CUS testing. Serial CUS testing is safe but 100 CUS must be repeated to find one or two CUS positive for deep vein thrombosis (DVT), which is not cost-effective and indicates the need to improve the diagnostic workup of DVT by the use of clinical score assessment and D-dimer testing. The NPV varies from 97.6 to 99.4% for low clinical score followed by a negative SimpiRED test, indicating the need for a first CUS. The NPV is 98.4 to 99.3% for a normal rapid enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer test result (< 500 ng/mL) irrespective of clinical score. The NPV is more than 99% for a negative CUS followed by either a negative SimpiRED test or an ELISA VIDAS test result of < 1000 ng/mL without the need to repeat a second CUS within 1 week. The sequential use of a sensitive, rapid ELISA D-dimer and clinical score assessment will safely reduce the need for CUS testing by 40 to 60%. Large prospective outcome studies demonstrate that with one negative examination with complete duplex color ultrasonography (CCUS) of the proximal and distal veins of the affected leg with suspected DVT, it is safe to withhold anticoagulant treatment, with a negative predictive value of 99.5%. This may indicates that CCUS is equal to serial CUS or the combined use of clinical score, D-dimer testing, and CUS. Pulmonary angiography is the gold standard for segmental pulmonary embolism (PE) but not for subsegmental PE. A normal perfusion lung scan and a normal rapid ELISA VIDAS D-dimer test safely excludes PE. Helical spiral computed tomography (CT) detects all clinically relevant PE and a large number of alternative diagnoses in symptomatic patients with suspected PE and can replace both the ventilation perfusion scan and pulmonary angiography to safely rule in PE and to rule out PE with an NPV of > 99%. The combination of clinical assessment, a rapid ELISA VIDAS D-dimer, followed by CUS will reduce the need for helical spiral CT by 40 to 50%.
  Seminars in Vascular Medicine 11/2005; 5(4):351-64.
• Article: A step change in oral anticoagulation: lack of coagulation monitoring with ximelagatran.

  Stefan C Carlsson, Sam Schulman
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  ABSTRACT: 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.
  Seminars in Vascular Medicine 09/2005; 5(3):259-65.
• Article: Ximelagatran in the clinic: practical management of patients.

  Sam Schulman, Gregory Y H Lip
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  ABSTRACT: 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.
  Seminars in Vascular Medicine 09/2005; 5(3):301-7.
• Article: Prevention of cardiovascular events after acute coronary syndrome.

  Lars Wallentin
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  ABSTRACT: Given the pivotal role of thrombin in the pathogenesis of acute coronary syndromes (ACS) and its persistent activation at the site of arterial lesions, antithrombin agents are essential for the prevention of coronary events. Antiplatelet agents are used routinely in the prevention of ACS, but their inability to prevent thrombin generation might contribute to the remaining high rates of recurrent ischemic events after intense antithrombotic treatment in the acute phase. Combination treatment with antiplatelet agents and anticoagulants, such as low-molecular-weight heparins (LMWH) and vitamin K antagonists, provides improved efficacy in the secondary prevention of ACS but these agents have limitations that prevent widespread adoption of their use for long-term treatment. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors (DTIs) and has considerable therapeutic potential in ACS. The DTIs are able to inhibit free and fibrin-bound thrombin by directly binding to the thrombin catalytic site. Furthermore, the oral administration and predictable pharmacokinetics of ximelagatran mean that it can be used at a fixed dose without coagulation monitoring and is convenient for long-term therapy. The efficacy of ximelagatran in the prevention of coronary events has been investigated in patients with recent myocardial infarction (MI) in the phase II Efficacy and Safety of the Oral Direct Thrombin inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial. Ximelagatran (24 to 60 mg twice daily) added to aspirin (160 mg once daily) reduced the risk of the composite end point of death, MI, and severe recurrent ischemia by 24% versus aspirin alone, with no significant increase in major bleeding. Elevated serum transaminase enzymes developed during the first 1 to 6 months of treatment in a proportion of patients given ximelagatran. These elevations usually abated without clinical sequelae whether or not treatment was continued. The ESTEEM results highlight the potential for ximelagatran as an efficacious and well-tolerated long-term treatment for the prevention of arterial thrombotic events.
  Seminars in Vascular Medicine 09/2005; 5(3):293-300.
• Article: Ximelagatran as a new oral anticoagulant for thrombosis.

  Ola E Dahl, Jan Jacques Michiels
  Seminars in Vascular Medicine 09/2005; 5(3):223-5.
• Article: Discovery of ximelagatran in an historical perspective.

  David Gustafsson
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  ABSTRACT: The oral direct thrombin inhibitor ximelagatran is the first oral anticoagulant since the introduction of the vitamin K antagonists in the early 1940s. A comparison of the discovery and early clinical development of the two classes of oral anticoagulants reveals some similarities but also several differences that illustrate the change in drug discovery over the last half century.
  Seminars in Vascular Medicine 09/2005; 5(3):227-34.
• Article: Low potential for interactions between melagatran/ximelagatran and other drugs, food, or alcohol.

  Michael Wolzt, Troy S Sarich, Ulf G Eriksson
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  ABSTRACT: Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of melagatran, and the main route of elimination of melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of ximelagatran to melagatran. No significant pharmacokinetic interactions have been observed when oral ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral ximelagatran. Increases of mean melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.
  Seminars in Vascular Medicine 09/2005; 5(3):254-8.
• Article: Treating patients with venous thromboembolism: initial strategies and long-term secondary prevention.

  Menno V Huisman, Henri Bounameaux
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  ABSTRACT: Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a candidate for both acute and chronic therapy. The Thrombin Inhibitor in Venous Thromboembolism (THRIVE) clinical trial program has demonstrated that this agent has a favorable benefit-risk profile compared with standard therapy for the initial treatment (6 months) and secondary prevention (up to 18 months) of VTE. However, in a substantial proportion (6 to 13%) of patients given extended ximelagatran therapy, elevated serum transaminase enzymes developed, typically in the first 2 to 4 months of treatment. Even though these elevations usually abated without clinical sequelae whether or not treatment was continued, their clinical relevance remains unclear. In addition, locally reported coronary events occurred more frequently in ximelagatran-treated patients during the initial 6 months of treatment, the reason for which is yet unclear. The consistent anticoagulant response and fixed oral dosing without coagulation monitoring allows ximelagatran to overcome many of the limitations inherent to current treatment options for VTE treatment and secondary prevention, provided the problem of liver enzyme elevation and coronary events is resolved.
  Seminars in Vascular Medicine 09/2005; 5(3):276-84.
• Article: Mechanism of action of the oral direct thrombin inhibitor ximelagatran.

  Christer Mattsson, Troy C Sarich, Stefan C Carlsson
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  ABSTRACT: Thrombin plays a central role in thrombus formation through its conversion of fibrinogen to fibrin and activation of platelets as well as amplifying its own generation by feedback activation via factors V, VIII, and XI. Consequently, thrombin represents a logical and promising target for therapeutic interventions against arterial and venous thromboembolic disorders. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors and is rapidly absorbed and bioconverted to the active moiety, melagatran, which inhibits fluid-phase and clot-bound thrombin with similar high potency. Binding to the active site of thrombin is direct and competitive and does not require the presence of co-factors. Inhibition of thrombin generation and platelet activation has been demonstrated in vitro with melagatran as well as ex vivo after oral administration of ximelagatran to healthy human volunteers. Oral ximelagatran dose dependently reduced the total thrombus area in an ex vivo flow chamber model of arterial thrombosis, reflecting the cumulative effect of inhibition of thrombin activity, thrombin generation, and platelet activation. Melagatran has also been shown to reduce thrombin-mediated inflammation in vitro. The combination of antithrombotic and anti-inflammatory activity with the practicality of oral dosing provided by ximelagatran represents an important new option for the treatment of arterial and venous thromboembolic disorders.
  Seminars in Vascular Medicine 09/2005; 5(3):235-44.
• Article: Prevention of stroke in patients with atrial fibrillation.

  S Bertil Olsson, Jonathan L Halperin
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  ABSTRACT: Nonvalvular atrial fibrillation (AF) is an independent risk factor for stroke that becomes increasingly prevalent as populations age. More than half a dozen clinical trials have demonstrated that anticoagulation with the vitamin K antagonist warfarin is the most effective therapy for stroke prophylaxis in AF. The narrow therapeutic index of warfarin requires that the intensity of anticoagulation be maintained within the international normalized ratio (INR) range of 2.0 to 3.0 to optimize efficacy while minimizing bleeding risk. The pharmacokinetics of warfarin are subject to variability due to interactions with multiple drugs and foods, making maintenance of the INR within this range difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustments. Current guidelines recommend oral anticoagulation for high-risk individuals with AF but these inherent limitations lead to substantial underprescribing, particularly in elderly patients at greatest risk. This has stimulated the development of new agents with improved benefit-risk profiles, such as ximelagatran, the first of the oral direct thrombin inhibitors, which has a wider therapeutic margin and low potential for drug interactions, allowing fixed dosing without anticoagulation monitoring. Ximelagatran has been evaluated for stroke prevention in AF in the Stroke Prevention using an Oral Direct Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) program, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials of ximelagatran in AF, SPORTIF III and V, found a fixed oral dose of ximelagatran (36 mg twice daily) comparable to dose-adjusted warfarin (INR 2.0 to 3.0) in preventing stroke and systemic thromboembolic complications among high-risk patients with AF. Results from the population of over 7000 patients in SPORTIF III and V demonstrate noninferiority of ximelagatran compared with warfarin. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin of 1.6% per year versus 2.3% per year, respectively ( P = 0.10). SPORTIF V further supports noninferiority between the two agents with an absolute risk reduction of 0.45%, well within the predefined noninferiority margin (95% confidence interval -0.13, 1.03; P = 0.13). Although event rates for major bleeding did not differ significantly with ximelagatran versus warfarin in either study, combined rates for major and minor bleeding were significantly reduced with ximelagatran. The overall net clinical benefit, taking into account effects on stroke or systemic embolic events, major bleeding, and death, was also greater with ximelagatran compared with warfarin in both studies. Elevated serum transaminase enzymes were observed in approximately 6% of patients given ximelagatran in these trials. These typically occurred 1 to 6 months after initiating treatment and usually abated without clinical sequelae whether or not treatment was continued. Given the consistency of response, the favorable overall benefit-risk ratio and the convenience of fixed oral dosing, ximelagatran may increase the number of patients with AF eligible for anticoagulation and amplify the potential for prophylaxis against stroke.
  Seminars in Vascular Medicine 09/2005; 5(3):285-92.