Michiel Coppens

Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials

In the last 4 years, 6 phase 3 trials including a total of 27,023 patients with venous thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K antagonists (VKAs). To aid the clinician in assessing the amount of information, we address frequently raised clinical questions in a review of combined trial results. We included the phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of DOAC recipients compared with 2.2% in VKA recipients (relative risk [RR] 0.90, 95% confidence interval [CI] 0.77-1.06). Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ≥100 kg, moderate renal insufficiency, an age ≥75 years, and cancer. In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of major bleeding.

The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy

AIMS The CHA(2)DS(2)-VASc score is a modification of the CHADS(2) score that aims to improve stroke risk prediction in patients with atrial fibrillation (AF) by adding three risk factors: age 65-74, female sex, and history of vascular disease. Whereas previous evaluations of the CHA(2)DS(2)-VASc score included all AF patients, the aim of this analysis was to evaluate its discriminative ability only in those patients for whom recommendations on antithrombotic treatment are uncertain (i.e. CHADS(2) score of 1). METHODS AND RESULTS We selected all patients with a CHADS(2) score of 1 from the AVERROES and ACTIVE trials who were treated with acetylsalicylic acid with or without clopidogrel and calculated the incidences of ischaemic or unspecified stroke or systemic embolus (SSE) according to their CHA(2)DS(2)-VASc score. Of 4670 patients with a baseline CHADS(2) score of 1, 26% had a CHA(2)DS(2)-VASc score of 1 and 74% had a score of ≥ 2. After 11 414 patient-years of follow-up, the annual incidence of SSE was 0.9% (95% CI: 0.6-1.3) and 2.1% (95% CI: 1.8-2.5) for patients with a CHA(2)DS(2)-VASc score of 1 and ≥ 2, respectively. The c-statistic of the CHA(2)DS(2)-VASc score was 0.587 (95% CI: 0.550-0.624). Age 65 to <75 years was the strongest of the three new risk factors in the CHA(2)DS(2)-VASc score. CONCLUSION The CHA(2)DS(2)-VASc score reclassifies 26% of patients with a CHADS(2) score of 1 to a low annual risk of SSE of 1%. This risk seems low enough to consider withholding anticoagulant treatment.

New oral anticoagulants in elderly patients.

The new oral anticoagulants (NOACs) dabigatran etexilate, rivaroxaban, and apixaban have been extensively studied for prevention and treatment of venous thromboembolic disease and for stroke prevention in atrial fibrillation. Elderly patients have the highest incidence of thrombotic complications but also have the highest risk of anticoagulant associated bleeding. In this review we critically examine the balance between risks and benefits of NOACs compared with vitamin K antagonists in elderly patients enrolled in phase 3 randomized controlled trials for the management of venous thrombosis and stroke prevention in atrial fibrillation. Results show that the favourable balance between risks and benefits of NOACs is preserved in the elderly population.

The risk of venous and arterial thrombosis in hyperhomocysteinaemia is low and mainly depends on concomitant thrombophilic defects

As homocysteine-lowering treatment has not reduced the risk of recurrent thrombosis in recent clinical trials, we hypothesized that mild hyperhomocysteinaemia is an epiphenomenon or associated with a low absolute risk of thrombosis. In this retrospective study, we enrolled 478 evaluable first-degree relatives of consecutive patients with venous thrombosis or premature atherosclerosis, and hyperhomocysteinemia. Absolute risks of thrombosis and effects of concomitant thrombophilic defects were compared. Relative risks were adjusted for clustering in families, age, sex, and atherosclerotic risk factors, where appropriate. Annual incidence of venous thrombosis was 0.16% (95% confidence interval [CI], 0.08-0.30) in hyperhomocysteinemic relatives versus 0.11% (CI, 0.05-0.20) in normohomocysteinemic relatives; adjusted relative risk 1.6 (CI, 0.6-4.5). Annual incidences of arterial thrombosis were 0.34% (CI, 0.21-0.52) and 0.24% (CI, 0.15-0.37) in hyperhomocysteinemic and normohomocysteinemic relatives, respectively; adjusted relative risk 1.5 (CI, 0.6-3.5). Concomitance of multiple thrombophilic risk factors increased the risk of venous thrombosis in hyperhomocysteinemic relatives 20 fold, but a comparable effect was demonstrated in normohomocysteinemic relatives. We conclude that hyperhomocysteinaemia is associated with a low absolute risk of venous and arterial thrombosis. Concomitant thrombophilic defects are probably main determinants on the risk of venous thrombosis, rather than hyperhomocysteinaemia itself.

Translational Success Stories Development of Direct Thrombin Inhibitors

Anticoagulants are the cornerstone of therapy for conditions associated with arterial and venous thrombosis. Direct thrombin inhibitors (DTIs) are anticoagulants that bind to thrombin and block its enzymatic activity. The bivalent parenteral DTIs hirudin and bivalirudin were based on the observation that the salivary extracts of medicinal leeches prevented blood from clotting. Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care.

Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study

Elevated levels of factor VIII:c (elevated FVIII:c) are associated with an increased risk for venous thromboembolism (VTE) and arterial vascular events, and are at least in part determined genetically. We prospectively followed 192 asymptomatic individuals with elevated FVIII:c (>150%) and 340 with normal levels for an average duration of 31 months (range 7 to 56 months) to investigate the risk of VTE and arterial vascular events. Participants were first degree relatives of consecutive patients with elevated FVIII:c and VTE or arterial vascular events before the age of 50 years. The incidences of VTE were 1.25% (0.46-2.73) per year in the subjects with elevated FVIII:c, versus 0.23% (0.03-0.82) in those with normal levels (OR 5.5 [1.1-27.3]). The annual incidences of arterial vascular events were 1.04% (0.34-2.42) and 0.23% (0.03-0.82) in relatives with and without elevated levels of FVIII:c, respectively (OR: 4.5 [0.9-23.5]). After adjustment for age, smoking, known diabetes mellitus, hyperlipidemia, and hypertension, the odds ratio for any event was 3.7 (1.1-13.1). In conclusion, asymptomatic individuals with elevated FVIII:c levels and a positive family history of VTE or arterial vascular events before the age of 50 appear to have a high annual incidence of first VTE and arterial vascular events. Elevated FVIII:c may be a common risk factor for both clinical entities.

Current practise of testing for inherited thrombophilia

About half of all episodes of venous thromboembolism (VTE,i.e.deepveinthrombosisandpulmonaryembolism)areelicitedby an acquired clinical risk factor, such as recent surgery,immobilization or pregnancy [1]. Before the discovery ofantithrombin deficiency in 1965, the other half remainedunexplained [2]. In the decades thereafter, we have witnessedthe emergence of numerous mainly inherited coagulationabnormalities, such as deficiencies of protein S and proteinC, the factor (F) V Leiden mutation (APC resistance), theprothrombin 20210A mutation and elevated levels of clottingFVIII [3]. These thrombophilias can be identified in at least50% of cases with idiopathic VTE, thereby providing anexplanation for a previously poorly explained disease [3].However, despite strong associations between thrombophiliaand a first VTE, thrombophilia is, at best, a weak predictor forrecurrent VTE [4].Probably encouraged by the high incidence in VTE, testingfor inherited thrombophilia was also performed in manystudies on arterial thrombosis such as myocardial infarctionand ischemic stroke. Although some studies have foundassociations between thrombophilia and arterial events at ayounger age [5], thrombophilia was not associated with thesediseases in unselected patient groups [6].Finally, the hypercoagulable state induced by inheritedthrombophilia, has been linked to an increased risk ofunexplained recurrent miscarriage, stillbirth and other preg-nancy-related vascular complications such as pre-eclampsiaand the HELLP syndrome [7,8].At present, there are no clinical trials that comparedifferent management strategies for patients with thrombo-philia and vascular events or an estimated high risk ofvascular events. Therefore, management recommendationsfor patients with inherited thrombophilia, such as in the 7thACCP Guideline for Antithrombotic Therapy for VenousThromboembolic Disease [9], are usually graded level 2,meaning that individual patients (or physicians) values maylead to different choices. This can lead to different and,frequently, contradicting hospital guidelines on whom to testand on the management consequences of the test results. Inthis study, we have investigated t he current practise of testingfor inherited thrombophilia in the Netherlands; in particular,who orders the tests, what are the reasons for testing, andwhat are the management decisions made on the basis of thetest results?Two thousand consecutive patients were identified in whomtests for APC resistance, FV Leiden, prothrombin 20210Amutation, antithrombin, protein C or protein S activity wereordered between November 2003 and March 2004. These testswere performed in the laboratory of a non-profit organizationthat provides nationwide specialized diagnostic facilities forregional or hospital laboratories (Sanquin Diagnostic Services,Amsterdam,theNetherlands).Thetestsoftheselectedpatientsoriginated from 61 mainly non-academic hospitals or regionaldiagnostic centres throughout the Netherlands. For eachpatient, a short multiple-choice questionnaire was sent to theordering physician, which included questions regarding theirmedical specialty, reasons for testing and presence and natureof management decisions made in that particular individual.The study was approved by the institutional Medical EthicsCommittee.Of a total of 2000 sent questionnaires, 63% was returned.One hundred and thirty-five returned questionnaires could notbe analyzed because it was unclear which physician hadactually ordered the tests or because only antithrombin wasdetermined as a measure of liver synthesis capacity. Of theremaining 1134 tested patients, 64% were women [median age38 years, inter-quartile range (IQR) 30–50] and 36% were men(median age 51 years, IQR 41–59).Venous thromboembolism was the reason for testing in42% of patients; 20% had had a single episode of deepvein thrombosis or pulmonary embolism, 4% had had asingle episode in combination with a familial thromboticpredisposition and 8% had had recurrent VTE (Table 1).Twenty-three per cent of patients were tested because ofa history of arterial thrombotic disease. Of those, 46% wereaged over 50 years at the time of testing. Pregnancy-relatedvascular events and a familial predisposition for VTE inasymptomatic patients was the reason for testing in 17 and16%, respectively. Table 1 provides further details of thereasons for testing.

Pregnancy-related venous thromboembolism: Risk and the effect of thromboprophylaxis

Venous thromboembolism (VTE) is a leading cause of maternal mortality and morbidity during pregnancy in developed countries. The incidence of VTE per pregnancy-year increases about 4-fold during pregnancy and at least 14-fold during the puerperium. Risk factors include a personal history of VTE, presence of inherited or acquired thrombophilia, a family history of VTE and general medical conditions, such as immobilisation, overweight, varicose veins, some haematological diseases and inflammatory disorders. VTE is considered potentially preventable with the prophylactic administration of anticoagulants, but there are no high quality randomized clinical trials that compared different strategies of thromboprophylaxis in pregnant women. Balancing the absolute risk of VTE against the risks of exposure to anticoagulants, this review provides advice regarding which women may benefit from thromboprophylaxis during and after pregnancy.

Duration of anticoagulant therapy for venous thromboembolism: balancing benefits and harms on the long term

Venous thromboembolism (VTE) is effectively treated with anticoagulant therapy. After an initial treatment phase, extended treatment is effective to prevent recurrence after a first event but this is at the expense of a continued risk of bleeding. Ideally, patients at a high risk of recurrence and low risk of bleeding continue anticoagulant therapy, and for those at low risk of recurrence the duration of treatment can be limited. Identifying these patients, however, is difficult. Duration of treatment after a first VTE provoked by a transient risk factor should be limited to 3 months. Although guidelines suggest extended treatment for all patients after unprovoked VTE unless bleeding risk is high, we emphasize that the long‐term risks of recurrent VTE off anticoagulation are uncertain whereas the risk of bleeding associated with anticoagulant therapy increases with age. In the absence of evidence of replaced mortality or improved quality of life with extended anticoagulant treatment, we suggest a limited duration for most patients after a first VTE. Extended treatment can be considered, based mainly on patient preference.

Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent.

The results of early trials evaluating the tolerability, efficacy,and safety of specific antidotes for the DOACs are promising (Table 2), but none of these agents are as yet approved for clinical use. Until they are approved, clinicians attempting to reverse the anticoagulant effects of DOACs will be limited to the use of general hemostatic agents, such as(activated) PCCs or rFVIIa,3-12 and to hemodialysis or hemofiltration for removal of DOACs that are not highly protein-bound.The overall goal of using reversal agents is to prevent morbidity and mortality.23 Even without specific antidotes, the randomized trials have demonstrated that DOACs compared with standard therapies are associated with similar or lower rates of major bleeding and lower rates of intracranial bleeding,2,24 with similar or lower mortality rates after bleeding.25,26 In order to be approved for clinical use, future trials with specific antidotes will need to demonstrate their efficacy in clinical studies involving patients treated with DOACs. At this stage however, it is unclear whether regulatory agencies will require evidence of control of bleeding or whether demonstration of reversal of anticoagulant effects of DOACs will be sufficient for their approval. Demonstration of hemostatic efficacy will be challenging because bleeding of sufficient severity to require reversal of DOACs is uncommon, the half-life of DOACs are short, creating a limited window to administer the antidote, and the appropriate outcome measure for such studies is uncertain.However, because the overall goal of reversal agents is to prevent morbidity and mortality rather than to normalize prolonged coagulation tests, demonstration of hemostatic efficacy will be essential to establish that specific antidotes for DOACs can also make a clinically important difference.