Special Issue "Anticoagulants"

Guest Editor
Prof. Dr. Sam Schulman
Department of Medicine, McMaster University, Hamilton, ON, Canada
Website: http://www.fhs.mcmaster.ca/medicine/hematology/faculty_member_schulman.htm
E-Mail:

Dear Colleagues,

After 60 years with warfarin and heparins as the only commonly used anticoagulants, the past 20 years have provided an impressive row of new agents. Low-molecular-weight heparins resulted in the first change of paradigm by enabling outpatient care of many patients with venous thromboembolism. The next shift should be the obviated need for routine laboratory monitoring and frequent dose adjustments of the oral anticoagulant. The purpose of this special issue is to assess the current status of the array of new anticoagulants at advanced stages of clinical trials. There are, however, still hurdles on the way, for example the question of reversal of such agents in emergency situations and how the higher cost of any new drug can be justified to the payers in view of the very inexpensive vitamin K antagonists, keeping in mind the considerable management costs associated with the latter.

Prof. Sam Schulman, MD
Guest Editor

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• dabigatran
• rivaroxaban
• apixaban
• betrixaban
• edoxaban
• otamixaban
• AVE5026
• bleeding
• health economy

Title: Per-protocol versus Intention-to-treat Evaluation of Dabigatran Effects in the RE-LY Study
Authors: Claudia Stöllberger, Josef Finsterer
Affiliation: Krankenanstalt Rudolfstiftung, Juchgasse 25, A-1030 Wien, Österreich, Austria; E-Mail: claudia.stöllberger@chello.at
Abstract: Dabigatran is a new oral thrombin-inhibitor which has been approved by the FDA advisory committee in September 2010 to prevent stroke/embolism in patients with non-valvular atrial fibrillation (AF), and it is expected that dabigatran will also be approved in other countries. Approval of dabigatran was based on the RE-LY study which was supported by Boehringer Ingelheim, the manufacturer of dabigatran. RE-LY, designed as a noninferiority trial, compared fixed doses of dabigatran – 110 mg or 150 mg twice daily - with adjusted-dose warfarin in 18,113 AF patients. The duration of follow-up was 2.0 years. The primary outcome was stroke or systemic embolism. Yearly rates of stroke/embolism were 1.69% with warfarin, 1.53% with 110 mg dabigatran and 1.11% with 150 mg dabigatran. Yearly rates of major bleeding were 3.36% with warfarin, 2.71% with 110 mg dabigatran and 3.11% with 150 mg dabigatran. Yearly rates of hemorrhagic stroke were 0.38% with warfarin, 0.12% with 110 mg dabigatran and 0.10% with 150 mg dabigatran.[1] Although the authors present dabigatran as a drug with a similar effect to warfarin for stroke prevention but with a lower complication rate, we are not convinced by their data. We have the following concerns: In the publication of the RE-LY study, the events are only analyzed according to the intention-to-treat principle, however, the rates of discontinuation differed significantly: They were for 110 mg of dabigatran, 150 mg of dabigatran, and warfarin 14.5%, 15.5%, and 10.2%, respectively, at 1 year and 20.7%, 21.2%, and 16.6% at 2 years. Rates of discontinuation at 1 and 2 years were higher with dabigatran than with warfarin (<0.001).[1] It remains uncertain if discontinuation was counted as an outcome event. It would be interesting to re-analyse the data on a per-protocol principle, since it can be assumed that patients were under active treatment with dabigatran during a shorter time than on warfarin, and that might explain that lower bleeding- and stroke-rates in the dabigatran- compared to the warfarin-treated patients. The second concern relates to drug- and food interactions of dabigatran. Dabigatran is a substrate of the intestinal P-glycoprotein transport-system. A variety of drugs and food-components affect the P-glycoprotein system, thus influencing serum levels of these drugs. It has been shown that P-glycoprotein-affecting drugs are prescribed to 42% of hospitalized AF-patients.[2] The relevance of these drug- and food-interactions are unknown. Thus, there is an urgent need to collect data on this issue, a task which will be impeded by the lack of easily available laboratory testing of antithrombotic effects. The third concern relates to the long-term effects of thrombin-generation inhibition, which seem to be unknown. Thrombin plays an important role in infection, immune response, angiogenesis, tumor growth and endothelial function.[3] Side-effects of dabigatran reported in the RE-LY study were restricted to hemorrhagic, gastrointestinal and vascular events but did not consider conditions like cancer, sepsis, dementia, neurodegenerative diseases or infection.
Overall, there is an urgent need to clarify these unsolved issues in order not to expose patients to a treatment, of which the effects and side-effects were underestimated.
Keywords: atrial fibrillation, oral anticoagulation, dabigatran, vitamin K antagonist

Type of Paper: Article
Title: Rivaroxaban – An Oral, Direct Factor Xa Inhibitor – Has No Clinically Relevant Interaction with Clopidogrel in Healthy Subjects
Authors: D. Kubitza *, Michael Becka, Wolfgang Mück and Stephan Schwers
Affiliation: Clinical Pharmacology, Bayer HealthCare AG, Wuppertal, Germany; Email: Dagmar.Kubitza@bayer.com
Abstract: In clinical practice, co-administration of the oral, direct Factor Xa inhibitor rivaroxaban with the antiplatelet agent clopidogrel is likely. The aim of this randomized, non-blinded, three-way crossover study was to investigate the influence of clopidogrel on the safety, tolerability, pharmacodynamics and pharmacokinetics (PK) of rivaroxaban. Of 27 healthy male subjects who received a single dose of clopidogrel 300 mg, 14 showed clopidogrel-induced inhibition of platelet aggregation (>40% of baseline) and were randomized to the following three treatments: A) two doses of clopidogrel on 2 consecutive days (300 mg day 1 and 75 mg day 2); B) one dose of rivaroxaban (15 mg); C) a combination of A and B (rivaroxaban given on day 2). All treatments were well tolerated. Co-administration of clopidogrel had no effect on the PK of rivaroxaban and when compared with rivaroxaban alone had no further effects on Factor Xa activity or prothrombin time. Inhibition of ADP-stimulated platelet aggregation by clopidogrel was not affected by rivaroxaban. Bleeding time with the combination treatment was significantly prolonged in four subjects, compared with either drug alone: combination treatment increased the overall least-squares-means to 3.77 times baseline (tb) (90% confidence interval 2.82–4.73], compared with 1.13 tb (0.17–2.09) with rivaroxaban and 1.96 tb (0.10–2.91) with clopidogrel. Significantly prolonged bleeding times have also been observed in some subjects in a study assessing co-administration of clopidogrel and acetylsalicylic acid in healthy subjects. Co-administration of clopidogrel and rivaroxaban may be a viable alternative to current treatment strategies and is currently under evaluation in clinical trials.