Pharmacokinetic Comparison of Subcutaneous and Intravenous Nadroparin Administration for Thromboprophylaxis in Critically Ill Patients on Vasopressors.

INTRODUCTION: Critically ill patients are exposed to a high risk of developing thromboembolism. Moreover, standard prophylaxis with subcutaneous (SC) heparin is less efficient in patients requiring vasopressors. The aim is a comparison of pharmacokinetics between SC and intravenous (IV) applied nadroparin. METHODS: Thirty-eight ventilated ICU patients requiring vasopressor support were randomized into a single dose of nadroparin 3,800 IU (0.4 mL) subcutaneously (SC group) or 1,900 IU (0.2 mL) intravenously (IV group). Anti-factor Xa activity (anti-Xa) was observed over 24 h; data are stated as median (IQR). RESULTS: Peak anti-Xa was significantly higher in the IV group 0.42 (0.39-0.43) IU/mL than in the SC group 0.16 (0.09-0.18) IU/mL (p < 0.001). There was a trend towards higher area under the curve (AUC) of anti-Xa in the SC group 1.41 (0.41-1.80) IU/mL × h than in the IV group 1.04 (0.93-1.13) IU/mL × h (p = 0.08). In the SC group, there was a negative correlation between anti-Xa AUC and both capillary refill time Xa (r = -0.86) and norepinephrine dose (r = -0.68). In the IV group, anti-Xa decrease half-life was 1.6 (1.4-2.0) h. CONCLUSIONS: IV administration of 1,900 IU of nadroparin led to a predictable effective peak anti-Xa. After SC administration, anti-Xa was heterogeneous and significantly influenced by peripheral perfusion.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting.

Effect of major gastrointestinal tract surgery on the absorption and efficacy of direct acting oral anticoagulants (DOACs).

Direct-acting oral anticoagulants (DOACs) have been introduced as alternatives to warfarin for stroke prevention in non-valvular atrial fibrillation and for treatment of venous thromboembolism. Many patients undergoing major gastrointestinal resections or bypass receive anticoagulants for various indications, including the treatment of thrombotic complication of surgery and prevention of visceral vessels events recurrence. DOACs have a wide therapeutic range that allows fixed dosing determined based on studies conducted in healthy subjects with normal absorptive capacity. Patients with significantly altered gastrointestinal tracts were not included in the Phase II and III studies that assessed DOAC efficacy and safety. The aim of this article is to review clinical data on DOACs use in patients with major surgical resection or bypass. MEDLINE and EMBASE were searched to identify studies and case reports of DOAC use in this population. Prescribing information for the four approved DOACs was also reviewed. The only types of available literature identified were case series and isolated case reports. Patients who underwent major distal intestinal resection were successfully anticoagulated with rivaroxaban, dabigatran was not effective. There is uncertainty about the efficacy of rivaroxaban and dabigatran in patients requiring anticoagulation after Roux-en-Y gastric bypass. Avoidance of rivaroxaban therapy in patients undergoing gastrectomy is advised Data are lacking regarding anticoagulation using apixaban and edoxaban in patients with major gastrointestinal resection or bypass is lacking. Clinicians should be aware of these limitations when using DOACs in this group of patients.

Anticoagulation Therapy in Patients with Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are at increased risk for both thrombotic events and bleeding. The early stages of CKD are mainly associated with prothrombotic tendency, whereas in its more advanced stages, beside the prothrombotic state, platelets can become dysfunctional due to uremic-related toxin exposure leading to an increased bleeding tendency. Patients with CKD usually require anticoagulation therapy for treatment or prevention of thromboembolic diseases. However, this benefit could easily be offset by the risk of anticoagulant-induced bleeding. Treatment of patients with CKD should be based on evidence from randomized clinical trials, but usually CKD patients are excluded from these trials. In the past, unfractionated heparins were the anticoagulant of choice for patients with CKD because of its independence of kidney elimination. However, currently low-molecular-weight heparins have largely replaced the use of unfractionated heparins owing to fewer incidences of heparin-induced thrombocytopenia and bleeding. We undertook this review in order to explain the practical considerations for the management of anticoagulation in these high risk population.

Laboratory Monitoring: A Turning Point in the Use of New Oral Anticoagulants.

Large clinical trials have demonstrated that new oral anticoagulants (NOACs) are at least as efficient as vitamin K antagonists (VKAs) in preventing thromboembolic events, while providing a better safety profile. The relatively stable pharmacokinetics and pharmacodynamics, the reduced reports on food and drug interactions, and the wide therapeutic windows of NOACs appear to provide a more predictable anticoagulant effect than that observed with VKAs, enabling the use of fixed doses without the need for monitoring. However, the safe implementation of NOACs may require additional judgment, and one should not have the erroneous impression that NOACs are free from interactions or that inter- and intra-individual variability is absent with NOACs. In fact, a consensus seems to have been reached concerning the usefulness of "circumstantial" testing in certain clinical scenarios. Recent data also suggest that factors such as intercurrent diseases, drug interactions, and inexplicable variability may occasionally alter the anticoagulant effect of NOACs. Furthermore, the issue of nonadherence, already high in VKA-treated patients, may represent an even greater clinical concern with NOACs, given their short half-lives. This review aims to underline the main arguments that support the need for NOAC monitoring, at least in selected categories of patients. Additionally, an overview of classic coagulation assays and novel laboratory techniques that may provide a tool for NOAC monitoring is also provided.

Why develop antidotes and reversal agents for non-vitamin K oral anticoagulants?

Over the past several years, non-vitamin K oral anticoagulants (NOACs) have been introduced into clinical practice for the treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Clinical trials have shown these agents to have similar or less risk of major bleeding as compared to warfarin therapy. Moreover, when patients do experience a major bleeding event administration of advanced factor products is rare, and post-bleed outcomes are similar in those receiving a NOAC compared to those receiving warfarin. However, there are situations where urgent reversal of NOAC anticoagulation would be desirable. The following review focuses on the outcomes and management strategies for patients experiencing a major bleed with warfarin or NOAC agents and describes the rationale for the development of therapies capable of targeted NOAC-reversal.

A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment.

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.

Acenocoumarol: A Review of Anticoagulant Efficacy and Safety.

Anticoagulant treatment is required for the treatment and prevention of thromboembolic disorders. Vitamin K antagonists are commonly used oral anticoagulants worldwide. Acenocoumarol is mono-coumarin derivative with racemic mixture of R (+) and S (-) enantiomers. Efficacy and safety of acenocoumarol has been evaluated in atrial fibrillation, cardiac valve replacement, after myocardial infarction, treatment of deep vein thrombosis, after major surgeries and after critical illness requiring prolonged hospitalization. Acenocoumarol is effective and safe in all age groups. It offers an advantage over warfarin in terms of better stability of anti-coagulant effect. Due to its economic advantage acenocoumarol may be suitable oral anticoagulant for long term use in countries like India.

The new or non-vitamin K antagonist oral anticoagulants: what have we learned since their debut.

One of the major advances in the management of thrombosis is arguably the introduction of the new non-vitamin K antagonist oral anticoagulants (NOACs). These are small molecules, designed to directly inhibit specific steps in the coagulation pathway, with dabigatran (Pradaxa), inhibiting thrombin and rivaroxaban (Xarelto), apixiban (Eliquis), edoxaban (Lixiana), and betrixaban being factor Xa inhibitors. They have several advantages over vitamin K antagonists such as warfarin, with more predictable bioavailability, fewer drug interactions, and improved safety, especially intracranial hemorrhage. Yet, since their debut, several issues have arisen with their increasing usage, with concerns over monitoring and reversal, being predominant. Issues addressed in this article include their efficacy, bleeding risk, and the recognition of a vulnerable population where monitoring is needed. The current approach to reversing the drug action is updated. The change in the approach to future drug design is also discussed.

Pros and cons of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants.

Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, "novel" or non-vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs.

Management of Anticoagulant and Antiplatelet Medications in Adults Undergoing Percutaneous Interventions.

OBJECTIVE: Many radiologists are unfamiliar with the new antithrombogenic medications and how to modify patient management before nonvascular percutaneous procedures performed in a radiology department. In this article, we review the indications for use, mechanism of action, pharmacokinetics, dosing, and recommendations for periprocedural management of patients using these medications. CONCLUSION: To improve patient safety, radiologists involved in percutaneous procedures should have knowledge of the antithrombotics that will be encountered routinely in clinical practice.

A systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency.

PURPOSE: Although therapeutic dosages of most low-molecular-weight heparins (LMWHs) are known to accumulate in patients with renal insufficiency, for the lower prophylactic dosages this has not been clearly proven. Nevertheless, dose reduction is often recommended. We conducted a systematic review to investigate whether prophylactic dosages of LMWH accumulate in renal insufficient patients. METHODS: A comprehensive search was conducted on 17 February 2015 using Embase, Medline, Web of Science, Scopus, Cochrane, PubMed publisher, and Google scholar. The syntax emphasized for LMWHs, impaired renal function, and pharmacokinetics. The search yielded 674 publications. After exclusion by reading the titles, abstracts, and if necessary the full paper, 11 publications remained. RESULTS: For dalteparin and tinzaparin, no accumulation was observed. Enoxaparin, on the other hand, did lead to accumulation in patients with renal insufficiency, although not in patients undergoing renal replacement therapy. Bemiparin and certoparin also did show accumulation. No data were available for nadroparin. CONCLUSIONS: In this systematic review, we show that prophylactic dosages of tinzaparin and dalteparin are likely to be safe in patients with renal insufficiency and do not need dose reduction based on the absence of accumulation. However, prophylactic dosages of enoxaparin, bemiparin, and certoparin did show accumulation in patients with a creatinine clearance (CrCl) below 30 ml/min, and therefore, dose reduction is required. The differences in occurrence of accumulation seem to depend on the mean molecular weight of LMWHs.

[Direct oral anticoagulant, useful pharmacological characteristics in clinical practice]. / Données pharmacologiques utiles pour une bonne utilisation des anticoagulants oraux directs.

Direct oral anticoagulants offer an alternative to vitamin K antagonist drugs in the prevention and treatment of thromboembolic events. Unlike the latter, they inhibit directly and specifically coagulation factors (Xa, IIa). Their pharmacological properties allow a fixed dose administration and no biological monitoring for the majority of patients. However, their pharmacokinetics dependent of membrane transporters (P-gp) and cytochrome P450 (CYP3A4) expose them to significant drug-drug interactions. Dose adjustment may then become necessary as in some clinical situations, such as kidney and liver failure. However, some questions remain open, particularly on the optimal handling of these molecules in some population (elderly patients, renal and hepatic impairment or polymedicated).

Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa).

AIMS: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. METHODS AND RESULTS: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin. CONCLUSION: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.

Interactions between antiepileptic drugs and direct oral anticoagulants for primary and secondary stroke prevention.

INTRODUCTION: Direct oral anticoagulants (DOAC) are the guideline-recommended therapy for prevention of stroke in atrial fibrillation (AF) and venous thromboembolism. Since approximately 10% of patients using antiepileptic drugs (AED) also receive DOAC, aim of this review is to summarize data about drug-drug interactions (DDI) of DOAC with AED by using data from PubMed until December 2023. AREAS COVERED: Of 49 AED, only 16 have been investigated regarding DDI with DOAC by case reports or observational studies. No increased risk for stroke was reported only for topiramate, zonisamide, pregabalin, and gabapentin, whereas for the remaining 12 AED conflicting results regarding the risk for stroke and bleeding were found. Further 16 AED have the potential for pharmacodynamic or pharmacokinetic DDI, but no data regarding DOAC are available. For the remaining 17 AED it is unknown if they have DDI with DOAC. EXPERT OPINION: Knowledge about pharmacokinetic and pharmacodynamic DDI of AED and DOAC is limited and frequently restricted to in vitro and in vivo findings. Since no data about DDI with DOAC are available for 67% of AED and an increasing number of patients have a combined medication of DOAC and AED, there is an urgent need for research on this topic.

New aspects on efficient anticoagulation and antiplatelet strategies in sheep.

BACKGROUND: After addressing fundamental questions in preclinical models in vitro or in small animals in vivo, the translation into large animal models has become a prerequisite before transferring new findings to human medicine. Especially in cardiovascular, orthopaedic and reconstructive surgery, the sheep is an important in vivo model for testing innovative therapies or medical devices prior to clinical application. For a wide variety of sheep model based research projects, an optimal anticoagulation and antiplatelet therapy is mandatory. However, no standardised scheme for this model has been developed so far. Thus the efficacy of antiplatelet (acetylsalicylic acid, clopidogrel, ticagrelor) and anticoagulant (sodium enoxaparin, dabigatran etexilate) strategies was evaluated through aggregometry, anti-factor Xa activity and plasma thrombin inhibitor levels in sheep of different ages. RESULTS: Responses to antiplatelet and anticoagulant drugs in different concentrations were studied in the sheep. First, a baseline for the measurement of platelet aggregation was assessed in 20 sheep. The effectiveness of 225 mg clopidogrel twice daily (bid) in 2/5 sheep and 150 mg bid in 3/5 lambs could be demonstrated, while clopidogrel and its metabolite carboxylic acid were detected in every plasma sample. High dose ticagrelor (375 mg bid) resulted in sufficient inhibition of platelet aggregation in 1/5 sheep, while acetylsalicylic acid did not show any antiplatelet effect. Therapeutic anti-factor Xa levels were achieved with age-dependent dosages of sodium enoxaparin (sheep 3 mg/kg bid, lambs 5 mg/kg bid). Administration of dabigatran etexilate resulted in plasma concentrations similar to human ranges in 2/5 sheep, despite receiving quadruple dosages (600 mg bid). CONCLUSION: High dosages of clopidogrel inhibited platelet aggregation merely in a low number of sheep despite sufficient absorption. Ticagrelor and acetylsalicylic acid cannot be recommended for platelet inhibition in sheep. Efficient anticoagulation can be ensured using sodium enoxaparin rather than dabigatran etexilate in age-dependent dosages. The findings of this study significantly contribute to the improvement of a safe and reliable prophylaxis for thromboembolic events in sheep. Applying these results in future translational experimental studies may help to avoid early dropouts due to thromboembolic events and associated unnecessary high animal numbers.

Reversal of target-specific oral anticoagulants.

The target-specific oral anticoagulants represent the first new oral anti-thrombotic therapy in over 50 years and have the potential to make therapy easier and hence more accessible to many patients. Like any new therapy, the potential benefits must be weighed against the potential challenges and one of the most concerning aspects of the new target-specific oral anticoagulants is the lack of a proven method to reverse their effect. Unlike the vitamin K antagonist, i.e. warfarin, there is no specific antidote for these medications. This paper will review the limited data on the use of non-specific therapies to reverse anticoagulation for the new agents. We hope to prepare clinicians who are faced with a patient who has serious bleeding or needs emergent surgery while taking dabigatran, rivaroxaban or apixaban.

Practical issues, limitations, and periprocedural management of the NOAC's.

The recent introduction of new oral anticoagulants or novel target specific oral anticoagulants (TSOA's) is likely to have a major impact in the years ahead. Many large clinical trials have been published in the past few years showing these agents are generally safe and effective in several clinical settings including acute venous thromboembolic disease, prophylaxis in the postoperative setting, prevention of thromboembolism in patients with atrial fibrillation, and in the management of acute coronary syndromes. Reported rates of overall and intracranial bleeding are lower compared to oral vitamin K antagonists. Other major advantages of oral direct thrombin inhibitors (dabigatran) and Xa inhibitors (rivaroxaban and apixaban) include rapid onset and offset of action and predictable pharmacodynamics with relatively wide therapeutic window allowing for unmonitored drug use. The relatively short half-life, rapid onset of action, and predictable pharmacokinetics should simplify periprocedural use of these agents. In this review we focus on some practical issues related to TSOA's including some limitations, potential complications, considerations to be made for certain patient populations, periprocedural management and issues pertaining to transition to and from these novel agents.