Special Issue "Anticoagulants"

Abstract: Management of anticoagulation in elderly patients represents a particularly challenging issue. Indeed, this patient population is at high thromboembolic risk, but also at high hemorrhagic risk. Assessment of the benefit-risk balance of anticoagulation is the key point when decisions are made about introducing and/or continuing such treatments in the individual elderly patient. In order to maximise the safety of anticoagulation in the elderly, some specific considerations need to be taken into account, including renal insufficiency, modified pharmacodynamics of anticoagulants, especially vitamin K antagonists, and the presence of multiple comorbidities and concomitant medications. New anticoagulants could greatly simplify and possibly increase the safety of anticoagulation in the elderly in the near future.

Abstract: This is a review of key factors for pharmacy and therapeutics committees to consider when developing a therapeutic interchange (TI) program for venous thromboembolism (VTE) prophylaxis. Recent patient safety initiatives aimed at reducing the incidence of hospital-acquired VTE may increase the prescribing of thromboprophylactic agents recommended in VTE management guidelines. As a result, more pharmacy and therapeutics committees may consider TI programs for parenteral anticoagulants. However, the TI of anticoagulants appears challenging at this time. Firstly, the therapeutic equivalence of the commonly prescribed parenteral anticoagulants, enoxaparin, dalteparin and fondaparinux, has not been established. Secondly, because of the wide range of clinical indications for these anticoagulants, a blanket agent-specific TI program could lead to off-label use. Use of an indication-specific TI program could be difficult to manage administratively, and may cause prescribing confusion and errors. Thirdly, careful dosing and contraindications of certain parenteral anticoagulants in special patient populations, such as those with renal impairment, further impact the suitability of these agents for inclusion in TI programs. Finally, although TI may appear to offer lower drug-acquisition costs, it is important to determine its effect on all cost parameters and ultimately ensure that the care of patients requiring VTE prophylaxis is not compromised.

Abstract: Dabigatran is an oral thrombin inhibitor which has been approved in several countries as an alternative to vitamin-K-antagonists for the prevention of stroke or embolism in atrial fibrillation patients. Dabigatran is introduced into clinical practice, although many issues regarding this drug are still unclear, like laboratory monitoring, use in elderly patients, drug- and food-interactions and use in patients with renal insufficiency. Additionally, there is no antidote for dabigatran. Thus, aim of the present review is to give an overview of concerns and unresolved issues concerning dabigatran.

Abstract: Dual antiplatelet therapy with acetylsalicylic acid and a thienopyridine, such as clopidogrel, is effective for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, but there is still a substantial residual risk of recurrence. Although anticoagulant therapy with a vitamin K antagonist (e.g. warfarin) in conjunction with antiplatelet therapy has been shown to reduce the risk of cardiovascular events, the rates of bleeding were increased with these combination therapies; hence, triple therapy with warfarin is currently only recommended in patients at low risk of bleeding. In addition, there are other limitations associated with vitamin K antagonist therapy, including the need for routine coagulation monitoring and dose adjustment to maintain the treatment within the therapeutic range. Rivaroxaban is an oral, direct Factor Xa inhibitor; in clinical practice, it is likely that rivaroxaban will be given to patients who also receive antiplatelet therapy, such as clopidogrel. This randomized, non-blinded, three-way crossover study investigated the effect of rivaroxaban on bleeding time when co­administered with clopidogrel. In addition, the influence of clopidogrel on the safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban was investigated. Of 27 healthy male subjects who received a single 300 mg dose of clopidogrel, 14 were identified as clopidogrel responders and were then randomized to the following three treatments: (A) two doses of clopidogrel on two consecutive days (300 mg on day 1; 75 mg on day 2); (B) one dose of rivaroxaban (15 mg); or (C) a combination of treatments A and B (rivaroxaban given on day 2). All treatments were well tolerated. Bleeding time with co­administration of rivaroxaban and clopidogrel was significantly prolonged in four subjects, compared with either drug alone: combination treatment increased the overall least squares-means to 3.77 times baseline (90% confidence interval [CI] 2.82–4.73), compared with 1.13 times baseline (90% CI 0.17–2.09) with rivaroxaban and 1.96 times baseline (90% CI 0.10–2.91) with clopidogrel. Co-administration of clopidogrel had no significant effect on the pharmacokinetics 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. As expected, owing to the mode of action of each study drug, the results of this study demonstrated that co­administration of the Factor Xa inhibitor rivaroxaban and the antiplatelet clopidogrel increased the bleeding time in healthy subjects without affecting other pharmacokinetic or pharmacodynamic parameters of each drug.

Abstract: Atrial Fibrillation (AF) is the most common sustained arrhythmia and 1/6 strokes is attributed to AF. The cornerstone of treatment remains maintaining sinus rhythm or appropriate ventricular rate control in addition to prevention of stroke. Oral anticoagulation therapy (OAC) with vitamin K antagonists (VKAs) has been the gold standard for almost 50 years and a significant reduction in the risk of stroke in patients with AF has been demonstrated. Nonetheless, only 50% of patients with guideline recommendations for OAC treatment actually receive VKAs and half of these will discontinue therapy within 3 to 5 years with only another half achieving therapeutic ranges more than 50% of the time. The aforementioned limitations in addition with frequent blood monitoring have prompted the development of a series of new OAC therapies. The present review focuses on the current pharmacological management for stroke prevention in patients with AF based on current and emerging evidence.

Abstract: Non-valvular atrial fibrillation is a recognized risk factor for stroke and systemic embolism. It has been clearly established that warfarin reduces the risk of stroke and systemic embolism in persons with atrial fibrillation and additional risk factors for stroke. The use of warfarin, however, requires frequent monitoring, and there is great variability in patient response to warfarin. Warfarin interacts with several medications and foods. In addition, warfarin use portends a significant risk of bleeding. For these reasons, warfarin is frequently not prescribed to persons for whom the drug would provide a clear benefit. Over the past decade, attempts have been made to develop drugs that are at least as safe and effective as warfarin for the treatment of atrial fibrillation that do not require monitoring nor have as many interactions. Initial studies of compounds in this regard ultimately failed due to safety concerns, but over the past two years two novel agents have been approved by the United States Food and Drug Association for anticoagulation in non-valvular atrial fibrillation, another drug is under review, and additional compounds are being studied. This article will review the use of warfarin and these new agents in the treatment of non-valvular atrial fibrillation.