rivaroxaban and Renal-Insufficiency

Patients with chronic kidney disease are at an increased risk of venous thromboembolism (VTE). The factor Xa inhibitor rivaroxaban has been shown to provide similar efficacy and a lower risk of bleeding compared with vitamin K antagonists for the treatment and prevention of VTE. Rivaroxaban has been studied in patients with varying degrees of renal impairment, and this review summarizes current knowledge supporting its use in patients with severe renal impairment (creatinine clearance [CrCl] of 15 to < 30 mL/min) for the prevention, treatment, or prophylaxis of VTE. Clinical pharmacology studies have demonstrated an increase in rivaroxaban systemic exposure, factor Xa inhibition, and prothrombin time with decreasing renal function. These changes reach a plateau with comparable increases in exposure among individuals with moderate or severe renal impairment and end-stage renal disease. The clinical development program for the treatment and prevention of VTE as well as prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery excluded patients with CrCl < 30 mL/min; however, a limited number of patients with severe renal impairment were enrolled. Efficacy outcomes in these patients with severe renal impairment were not meaningfully different from those of patients with higher levels of renal function. There was also no increase in the incidence of major bleeding with rivaroxaban in patients with CrCl < 30 mL/min. Taken together, these pharmacological and clinical data suggest that in patients with severe renal impairment, the approved dosages of rivaroxaban can be used in the treatment and prevention of VTE and for prophylaxis of DVT after hip or knee replacement surgery.

Topics: Anticoagulants; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Kidney; Renal Insufficiency; Rivaroxaban; Venous Thromboembolism

Rivaroxaban is a factor Xa inhibitor oral anticoagulant first approved for use in the United States in 2011. Under the drug class commonly termed direct oral anticoagulants, rivaroxaban is approved for the most indications within its class, 7 indications, which are: (1) reduction of risk of stroke and systemic embolism (SE) in nonvalvular atrial fibrillation, (2) treatment of deep vein thrombosis (DVT), (3) treatment of pulmonary embolism (PE), (4) reduction in the risk of recurrence of DVT and/or PE, (5) prophylaxis of DVT following hip or knee replacement surgery, (6) prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, and (7) reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Considering the relationship between cardiovascular disease, renal impairment, and the use of oral anticoagulants, the following targeted review was created. This review reports the results of the primary pharmacology, pharmacokinetic modeling, clinical safety and efficacy, and real-world postmarketing effectiveness and safety of rivaroxaban in patients with various degrees of renal impairment. Based on these data, rivaroxaban is a viable option for when anticoagulation is needed in patients who have both cardiovascular disease and renal impairment. However, as with any therapy, the benefits and risks of intervention should be carefully assessed and balanced. Patients treated with rivaroxaban for several of its approved indications should have their kidney function assessed prior to and during continued therapy to ensure consistency with the drug label.

Topics: Anticoagulants; Area Under Curve; Humans; Myocardial Infarction; Patient Acuity; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Renal Insufficiency; Rivaroxaban; Stroke; Thrombosis

Due to the high risk of ischemic and arterial or venous bleeding events in atrial fibrillation (AF) or venous thromboembolism (VTE) patients with renal impairment (RI), selection of appropriate anticoagulant regimen is important. Therefore, we systematically reviewed and compared the safety and effects of oral anticoagulants in AF and VTE patients with RI.. Eligible articles were identified through a literature search in PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library for studies published between January 2008 and November 2020. Network meta-analysis was conducted with STATA 14.0 to analyze the effects and safety of each drug with regard to different levels of renal function.. 15 studies including 82,931 patients (76,957 with AF and 5974 with VTE) were analyzed. Compared with those of warfarin, the risk ratios of effect and safety outcomes of apixaban were 0.70 (95% confidence interval [CI] 0.60-0.82) and 0.56 (95% CI 0.42-0.76) in AF patients and 0.33 (95% CI 0.19-0.59) and 0.95 (95% CI 0.68-1.34) in VTE patients. Apixaban had the first or second highest probability of being ranked first with respect to surface under the cumulative ranking curve (SUCRA) scores in the prevention of major bleeding events, while in the prevention of ischemic events, rivaroxaban showed a higher SUCRA score (0.78-0.92) in mild RI patients and dabigatran showed a higher SUCRA value (0.90-0.99) in moderate RI patients.. In the systematic review and meta-analysis, for AF or VTE patients with RI, direct oral anticoagulants performed comparably to or better than warfarin with regard to safety and effects. The network meta-analysis indicated that for patients with mild RI, apixaban might be safer for patients with a lower risk of ischemic events, while rivaroxaban might be suitable for patients with a lower risk of bleeding events. For patients with moderate RI, apixaban could reduce the risk of ischemic events without increasing the risk of bleeding events. For AF patients with severe RI, apixaban, rivaroxaban, and warfarin showed a similar effect. These results might provide suggestions for clinical arterial and venous thrombosis prevention.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Network Meta-Analysis; Renal Insufficiency; Rivaroxaban; Venous Thromboembolism; Warfarin

Traditionally, venous thromboembolism (VTE) resulting from major transient risk factors (e.g., surgery or trauma) or a major persistent risk factor such as cancer, has been defined as being provoked, whereas unprovoked VTE encompasses events without an identifiable cause. These categorizations influence anticoagulant treatment duration; unlike VTE provoked by major transient risk factors, extended anticoagulation beyond 3 months is advised for patients with cancer or unprovoked VTE due to risk persistence after treatment cessation. However, some patients with VTE provoked by minor transient or minor persistent risk factors may also be candidates for extended anticoagulation therapy due to the continuing risk of recurrence. In patients who require extended therapy, vitamin K antagonists (VKAs) are effective but are associated with an increased risk of bleeding and various treatment burdens (e.g., anticoagulation monitoring and dose adjustment). Evaluations of extended VTE treatment with the less-burdensome direct oral anticoagulants such as apixaban, dabigatran, edoxaban, and rivaroxaban show that they are at least as safe and effective as VKAs in a broad range of patients. In addition, apixaban and rivaroxaban offer more than one dosing option, allowing tailoring of treatment to the patient's specific risk factor profile. Analysis of more granular definitions for risk factor groupings has also yielded vital information on the most appropriate strategies for the treatment of patients with specific risk factors, highlighting that extended anticoagulation treatment may benefit those with minor transient and persistent environmental and nonenvironmental risk factors who commonly receive shorter-duration therapy.

Topics: Aged; Anticoagulants; Humans; Patient Selection; Precision Medicine; Pyrazoles; Pyridones; Renal Insufficiency; Risk Factors; Rivaroxaban; Venous Thromboembolism; Vitamin K; Withholding Treatment

The paper is a narrative review of the literature on the use of direct oral anticoagulants (DOACs) for the VTE treatment in challenging patients: senile age (≥75 years), impaired renal function (estimated glomerular filtration rate ≤50 ml/min), fragility (one of the previous characteristics and/or bodyweight ≤50 kg). The paper discusses the studies of EINSTEIN DVT and PE (rivaroxaban), AMPLIFY (apixaban), HOKUSAI-VTE (edoxaban), RE-COVER I and II (dabigatran) in the focus of the secondary analysis in the pre-specified patient's subgroups, as well as their pooled analyzes and meta-analyzes. Based on the results of this review, it was concluded that in a subgroup of senile age patients, dabigatran increases the risk of major bleeding by 4.8 times and has no advantages over vitamin K antagonists (VKA); rivaroxaban and apixaban retain superiority over VKA on the safety outcomes and reduce the risk of major bleeding by 73% and 77%. In the subgroup of patients with impaired renal function, the use of apixaban and dabigatran is associated with an increase in the risk of major bleeding by 6.5 and 7.3 times, and these DOACs do not have advantages over VKA; rivaroxaban retains its superiority over VKA and reduces the risk of major bleeding by 78%. For fragile patients, a secondary analysis is available only for rivaroxaban, which remains superior to VKA on safety endpoints and reduces the risk of major bleeding by 73%. In the absence of direct comparisons between the available DOACs, the presented data can be used as a rational approach for the choice of appropriate treatment for VTE in challenging patients.. Представлен классический описательный обзор литературы, посвященный проблемам использования прямых оральных антикоагулянтов (ПОАК) для лечения венозных тромбоэмболических осложнений (ВТЭО) у ослабленных пациентов: лиц старческого возраста (≥75 лет), пациентов с нарушенной функцией почек (СКФ ≤50 мл/мин), а также «хрупких» больных, имеющих один или оба из перечисленных признаков наряду с низкой массой тела (≤50 кг). Обсуждаются известные исследования EINSTEIN DVT и PE (ривароксабан), AMPLIFY (апиксабан), HOKUSAI-VTE (эдоксабан), RE-COVER I и II (дабигатран) в фокусе вторичного анализа результатов в искомых подгруппах пациентов, а также работы, объединившие их результаты, и метаанализы. Сделаны выводы, что у больных старческого возраста дабигатран увеличивает риск развития больших кровотечений в 4,8 раза и не имеет преимуществ перед антагонистами витамина К (АВК); ривароксабан и апиксабан сохраняют превосходство над АВК с позиции безопасности и снижают угрозу больших кровотечений на 73 и 77%. У пациентов с нарушенной функцией почек использование апиксабана и дабигатрана ассоциируется с увеличением риска больших кровотечений в 6,5 и 7,3 раза, названные ПОАК не имеют преимуществ перед АВК; ривароксабан сохраняется свое превосходство над АВК и снижает угрозу большого кровотечения на 78%. Для подгруппы «хрупких» пациентов вторичный анализ доступен только для ривароксабана, который сохраняется свое превосходство над АВК с позиции безопасности и снижает риск развития больших кровотечений на 73%. В отсутствие прямых сравнений между доступными ПОАК представленные данные могут использоваться с целью обеспечения рационального подхода к выбору препарата для антикоагулянтной терапии ВТЭО у ослабленных пациентов.

Topics: Administration, Oral; Age Factors; Aged; Antithrombins; Dabigatran; Frail Elderly; Humans; Pyrazoles; Pyridones; Renal Insufficiency; Rivaroxaban; Venous Thromboembolism

A recent survey on the use of direct oral anticoagulants (DOACs) revealed that 43% of patients with atrial fibrillation and renal impairment were potentially overdosed and had a hazard ratio for major bleeding of 2.19. In this review, we analyse and discuss the effect of renal failure on the pharmacokinetics and pharmacodynamics of DOACs and of strategies proposed to adjust doses according to the level of renal dysfunction. The pharmacokinetic characteristics of available DOACs (dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban) differ substantially as regards oral bioavailability, plasma protein binding and the relative involvement of renal and non-renal elimination. In this respect, 80% of dabigatran is excreted as an unchanged drug in urine, whereas edoxaban, rivaroxaban, apixaban and betrixiban are excreted unchanged by, respectively, 50, 33, 27 and 11% of the dose. Therefore, drug exposure (the area under the concentration-time curve, AUC) is expected to increase to differing extents, depending on the residual renal function and the contribution of the kidneys to the excretion of each drug. Our analysis found that the increased AUC in patients with severe renal dysfunction was greater than expected in the case of dabigatran, betrixaban and rivaroxaban, indicating that other pharmacokinetic parameters may be altered besides renal clearance. Although DAOC pharmacodynamics do not seem to be altered by renal diseases (the correlation between plasma levels and anticoagulant effects overlaps that of healthy subjects), renal failure per se is associated with an increased risk of bleeding and thromboembolism. Guidelines on dose adjustments in patients with renal dysfunction have been published by three National Drug Agencies (FDA, EMA, HC), but many of their items do not match one another, reflecting our substantial paucity of knowledge in advanced renal failure. Routine monitoring of DOAC anticoagulant effects or plasma concentrations is not recommended, since no validated therapeutic ranges have been established. However, this approach may be useful in emergency situations such as bleeding or thrombotic events, urgent surgery, pharmacokinetic interactions, etc. We conclude that more experimental work is needed to improve our knowledge of DOAC pharmacology in renal failure and to provide clinicians with valid tools to adjust therapy.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Renal Insufficiency; Rivaroxaban

Renal impairment increases risk of stroke and systemic embolic events and bleeding in patients with atrial fibrillation. Direct oral anticoagulants (DOACs) have varied dependence on renal elimination, magnifying the importance of appropriate patient selection, dosing, and periodic kidney function monitoring. In randomized controlled trials of nonvalvular atrial fibrillation, DOACs were at least as effective and associated with less bleeding compared with warfarin. Each direct oral anticoagulant was associated with reduced risk of stroke and systemic embolic events and major bleeding compared with warfarin in nonvalvular atrial fibrillation patients with mild or moderate renal impairment. Renal function decrease appears less impacted by DOACs, which are associated with a better risk-benefit profile than warfarin in patients with decreasing renal function over time. Limited data address the risk-benefit profile of DOACs in patients with severe impairment or on dialysis.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Pharmaceutical Research; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Risk Assessment; Rivaroxaban; Stroke; Therapeutic Equivalency; Thiazoles; Warfarin

Atrial fibrillation (AF) is an increasingly common cause of stroke and systemic embolism. While warfarin has been the mainstay of stroke prevention in patients with AF, newer novel oral anticoagulant medications are now available. Rivaroxaban, a direct factor Xa inhibitor with a rapid onset and offset after oral administration, offers potential advantages over warfarin, predominantly due to its predictable pharmacokinetics across wide patient populations. It requires no coagulation monitoring, and only two different doses are needed (20 mg daily for patients with normal renal function and 15 mg daily in those with reduced renal function). A large randomized trial (ROCKET AF) has shown non-inferiority to warfarin for preventing stroke or systemic embolism in the per-protocol population and superiority to warfarin in the on-treatment safety population. Several subanalyses confirm that the treatment effect of rivaroxaban is consistent across different patient subgroups, including those with reduced renal function. The tolerability of rivaroxaban appears similar to that of warfarin, with comparable overall bleeding rates in clinical trials. In ROCKET AF, significantly lower rates of fatal and intracranial bleeding were seen with rivaroxaban, while lower rates of gastrointestinal bleeding were seen with warfarin. Important contraindications to rivaroxaban include valvular AF, the presence of a prosthetic valve (mechanical or bioprosthetic) or valve repair, the need for concurrent dual antiplatelet therapy, and creatinine clearance <30 ml/min. Once-daily dosing and the lack of coagulation monitoring may increase utilization and adherence compared with warfarin, potentially decreasing the large burden of care associated with stroke secondary to AF. Overall, rivaroxaban offers a useful alternative to warfarin for stroke prevention in patients with AF.

Topics: Anticoagulants; Atrial Fibrillation; Creatinine; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency; Risk Factors; Rivaroxaban; Stroke

Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients.. Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Blood Coagulation Tests; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; International Normalized Ratio; Liver Failure; Metabolic Clearance Rate; Morpholines; Perioperative Care; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes; Thrombocytopenia; Thrombosis; Vitamin K

Recent reports suggest altered antithrombotic efficacy and higher risk of bleeding with new oral anticoagulants (NOACs) in patients with renal insufficiency. A meta-analysis was performed to evaluate the efficacy and safety with recommended doses of NOAC compared with conventional treatment in patients with renal insufficiency.. PubMed, Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases were searched from January 1, 2001 through March 23, 2014. Randomized controlled trials that compared NOACs (rivaroxaban, apixaban, and dabigatran) with comparators (vitamin K antagonist/warfarin, low molecular weight heparin, aspirin, placebo) were selected. We defined moderate renal insufficiency as creatinine clearance (estimated glomerular filtration rate [eGFR]) of 30-49 mL/min, and mild renal insufficiency as eGFR 50-79 mL/min.. There were 40,693 patients with renal insufficiency in 10 trials. Compared with other anticoagulants in patients with mild renal insufficiency there was significantly less major or clinically relevant nonmajor bleeding (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.72-0.90) and stroke or systemic embolism (OR, 0.70; 95% CI, 0.54-0.92) with NOACs. Using random effects meta-analysis, there was significantly less stroke or systemic embolism (OR, 0.72; 95% CI, 0.57-0.92) and a trend toward less major or clinically relevant nonmajor bleeding (OR, 0.82; 95% CI, 0.59-1.14) with the NOACs among patients with moderate renal insufficiency, and this became statistically significant when evaluated using a fixed effects model. NOACs showed efficiency comparable with conventional anticoagulants for prevention of venous thromboembolism or related mortality.. In patients with renal insufficiency, recommended doses of novel anticoagulants are noninferior and relatively safe compared with conventional anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Renal Insufficiency; Rivaroxaban; Stroke; Thiophenes; Thromboembolism

Rivaroxaban is a factor Xa inhibitor recently approved for use in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Older adults are at an increased risk for venous thromboembolism (VTE), and rivaroxaban offers an alternative to standard treatment including vitamin K antagonists. This review evaluates the literature supporting this new indication with a focus on the safety and efficacy in older adults as well as those with renal insufficiency and fragility, which the EINSTEIN-PE study defined as those older than 75 years of age, weighing 50 kg or less, or with a creatine clearance (Clcr) of less than 50 mL/min. Three large studies (EINSTEIN-PE, -DVT, -EXT) provide an evaluation of recurrent VTE and bleeding events with the use of rivaroxaban. EINSTEIN-DVT and EINSTEIN-PE showed rivaroxaban to be equivalent to standard treatment in the overall population as well as in older adults and those with renal insufficiency and fragility. Further, EINSTEIN-EXT showed benefit of rivaroxaban over placebo for extended VTE protection (i.e., longer than 6 to 12 months of treatment), both overall and in the subgroups of those older than 75 years of age and with a Clcr of 50 mL/min to < 80 mL/min..

Topics: Aged; Aged, 80 and over; Aging; Factor Xa Inhibitors; Humans; Kidney; Morpholines; Pulmonary Embolism; Recurrence; Renal Insufficiency; Rivaroxaban; Thiophenes; Venous Thromboembolism

The majority of patients with nonvalvular atrial fibrillation (AF) will require anticoagulation therapy for reducing the risk of stroke, the most devastating complication of AF. Although traditionally vitamin K antagonists have been used for this purpose, they have important limitations that interfere with their use in clinical practice. Different clinical trials have shown the benefits of new oral anticoagulants over warfarin, but patients included in the ROCKET-AF trial were found to be at a higher risk of AF-related complications. Moreover, rivaroxaban has been proven to be effective and safe in patients with AF and moderate renal dysfunction as well as in those with ischemic heart disease. Rivaroxaban is taken only once daily; this may improve medication adherence and, secondarily, it provides a higher protection and reduction in the risk of stroke. This article provides an extensive review of the available evidence about rivaroxaban, with a special focus on nonvalvular AF.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Humans; Ischemic Attack, Transient; Medication Adherence; Morpholines; Renal Insufficiency; Rivaroxaban; Severity of Illness Index; Stroke; Thiophenes; Thromboembolism; Vitamin K; Warfarin

Dabigatran, apixaban, and rivaroxaban have been approved for primary and secondary stroke prevention in patients with atrial fibrillation. However, questions have arisen about how to manage emergency situations, such as when thrombolysis would be required for acute ischemic stroke or for the managing intracranial or gastrointestinal bleedings. We summarize the current literature and provide recommendations for the management of these situations. Peak plasma levels of the direct oral anticoagulants (DOACs) apixaban, dabigatran, or rivaroxaban are observed about 2-4 h after intake. Elimination of dabigatran is mainly dependent on renal function. Consequently, if renal function is impaired, there is a risk of drug accumulation that is highest for dabigatran followed by rivaroxaban and then apixaban and thus dosing recommendations are different. To date, no bedside tests are available that reliably assess the anticoagulatory effect of DOACs, nor are specific antidotes available. We recommend performing the following tests if DOAC intake is unknown: dabigatran-associated bleeding risk is minimized or can be neglected if thrombin time, Hemoclot test, or Ecarin clotting time is normal. Apixaban and rivaroxaban effects can be ruled out if findings from the anti-factor Xa activity test are normal. High plasma levels of DOAC are also mostly excluded if PTT and PTZ are normal four or more hours after DOAC intake. However, normal values of global coagulation tests are not sufficient if thrombolysis is indicated for treating acute stroke. The decision for or against thrombolysis is an individual decision; in these cases, thrombolysis use is off-label. In case of bleeding, prothrombin complex concentrates seems to be the most plausible treatment. For severe gastrointestinal bleeding with life-threatening blood loss, the bleeding source needs to be identified and treated by invasive measures. Use of procoagulant drugs (antifibrinolytics) might also be considered. However, there is very limited clinical experience with these products in conjunction with DOAC.

Topics: Administration, Oral; Animals; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Dose-Response Relationship, Drug; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes

The new oral anticoagulants (NOAs) dabigatran, rivaroxaban, and apixaban have proved effective and safe when used in clinical trials, without a need to adjust the dose in response to laboratory testing. This demonstrated efficacy does not necessarily mean that the laboratory, considered the mainstay for the management of the old anticoagulants, will no longer play a role in treatment with NOAs.. Laboratories are involved in the management of anticoagulants in 2 ways. The first, monitoring, implies laboratory testing to assess the drug's effect and to adjust the dosage to maintain anticoagulation within the therapeutic interval. This consideration applies to the old drugs. The second way, measurement, implies laboratory evaluations of drug effect to determine whether patients are under- or over-anticoagulated, information that can be useful for decision-making in special circumstances. The latter applies to NOAs.. Measurements of the effect of NOAs are indicated in several situations: (a) patients with adverse events (i.e., thrombotic/hemorrhagic), particularly those who present with overdosage owing to excessive drug intake or decreased clearance; (b) patients undergoing surgical procedures for ensuring that no residual drug remains in the circulation; (c) patients requiring anticoagulation reversal because of life-threatening hemorrhage; (d) patients with renal insufficiency, who are likely to accumulate the drug in the circulation; (e) patients with liver failure, because NOAs are metabolized by the liver; (f) patients taking other drugs that might increase/decrease the effects of NOAs via drug-drug interactions. The choice of tests is based on such characteristics as availability, linearity of the dose-response curve, standardization, and responsiveness to increasing drug dosage. Practitioners need to be aware that NOAs can interfere with the measurement of common hemostasis parameters.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Hemostasis; Humans; Liver Diseases; Morpholines; Pyrazoles; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes

Novel oral anticoagulants that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are currently available for prevention of venous thromboembolism (VTE) after orthopaedic surgery, treatment of acute VTE, and prevention of arterial thromboembolism in non-valvular atrial fibrillation. These agents offer advantages over VKAs, including rapid onset, shorter half-lives, fewer drug interactions, and lack of need for routine monitoring. However, there are no established agents to reverse their anticoagulant effect. We review the risk of bleeding with the novel oral anticoagulants and the limitations of conventional coagulation assays for measuring anticoagulant effect. We provide an approach to the management of patients with bleeding complications with evidence for various interventions for reversal, where available.

Topics: Acute Disease; Administration, Oral; Aged; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Morpholines; Plasma; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Renal Dialysis; Renal Insufficiency; Risk Factors; Rivaroxaban; Thiophenes

The new oral anticoagulants are now a reality and are available to clinicians. Although a large number of patients have been included in the many clinical trials of these drugs, there is one population that is always underrepresented - called special populations - such as those aged more than 75 years old, the obese, and patients with renal impairment. This review aims to analyze differences in the efficacy and safety in these special populations recruited in the various trials.

Topics: Administration, Oral; Age Factors; Anticoagulants; Benzimidazoles; Contraindications; Dabigatran; Embolism; Humans; Morpholines; Obesity; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Stroke; Thiophenes; Thrombosis

The mechanism of action, pharmacodynamics, pharmacokinetics, efficacy in clinical trials, interactions, adverse effects and toxicity, and place in therapy of rivaroxaban are reviewed.. Rivaroxaban, the first oral, direct factor Xa (FXa) inhibitor to reach Phase III trials, inhibits thrombin generation by both the intrinsic and the tissue factor pathways. It has shown predictable, reversible inhibition of FXa activity, and it may have the ability to inhibit clot-bound FXa. Rivaroxaban is being evaluated for prevention of venous thrombosis in patients undergoing hip or knee arthroplasty, treatment of venous thrombosis, long-term use for secondary prevention of venous thrombosis, and prevention of stroke in atrial fibrillation. To date, only short-term trials have been reported, but rivaroxaban's safety and efficacy appear to be at least equivalent to those of traditional anticoagulants. The results of four studies of primary prevention of venous thrombosis in patients undergoing orthopedic surgery suggest that rivaroxaban 10 mg daily is a promising alternative to low-molecular-weight heparins. Rivaroxaban appears to have a low potential for drug-drug or drug-food interactions. It offers the advantages of a fixed oral dose, rapid onset of action, and predictable and consistent anticoagulation effect, precluding the need for routine monitoring of anticoagulation.. Rivaroxaban is a promising alternative to traditional anticoagulants for the prevention and treatment of venous thromboembolism and for stroke prevention in atrial fibrillation; it offers once-daily oral administration without the need for routine monitoring.

Topics: Aging; Antithrombin III; Clinical Trials as Topic; Drug Interactions; Fibrinolytic Agents; Hepatic Insufficiency; Humans; Morpholines; Obesity; Prothrombin Time; Renal Insufficiency; Rivaroxaban; Thiophenes; Venous Thromboembolism

Patients with symptomatic lower extremity peripheral artery disease (LE-PAD) experience an increased risk of major vascular events. There is limited information on what clinical features of symptomatic LE-PAD prognosticate major vascular events and whether patients at high risk have a greater absolute benefit from low-dose rivaroxaban and aspirin.. To quantify the risk of major vascular events and investigate the response to treatment with low-dose rivaroxaban and aspirin among patients with symptomatic LE-PAD based on clinical presentation and comorbidities.. This is a subanalysis of a previously reported subgroup of patients with symptomatic LE-PAD who were enrolled in a large, double-blind, placebo-controlled randomized clinical trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]) in 602 centers in 33 countries from March 2013 to January 2020. Data analysis was completed from May 2016 to June 2020.. A combination of low-dose rivaroxaban and aspirin compared with aspirin alone.. Thirty-month incidence risk of myocardial infarction, stroke and cardiovascular death (MACE), major adverse limb events (MALE) including major vascular amputation, and bleeding.. The COMPASS trial enrolled 4129 patients with symptomatic LE-PAD (mean [SD] age, 66.8 [8.8] years; 2932 men [71.0%]). The 30-month Kaplan-Meier incidence risk of MACE or MALE, including major amputation, was 22.6% in those with prior amputation (this outcome was observed in 54 patients), 17.6% (n = 15) in those with Fontaine III or IV symptoms, and 11.8% (n = 142) in those with previous peripheral artery revascularization, classifying these features as high-risk limb presentations. The 30-month incidence risk of MACE or MALE, including major amputation, was 14.1% (n = 118) in those with kidney dysfunction, 13.5% (n = 67) in those with heart failure, 13.4% (n = 199) in those with diabetes, and 12.8% (n = 222) in those with polyvascular disease, classifying these features as high-risk comorbidities. Among patients with either high-risk limb presentations or high-risk comorbidities, treatment with rivaroxaban and aspirin compared with aspirin alone was associated with an estimated 4.2% (95% CI, 1.9%-6.2%) absolute risk reduction for MACE or MALE, including major amputation, at 30 months. Although the estimated absolute risk increase of major bleeding was higher with rivaroxaban and aspirin in combination than aspirin alone (2.0% [95% CI, 0.5%-3.9%]) for patients with either high-risk limb presentation or high-risk comorbidity, the estimated absolute risk increase of fatal or critical organ bleeding was low in this high-risk group (0.4% [95% CI, 0.2%-1.8%]), such that the net clinical benefit was estimated to be 3.2% (95% CI, 0.6%-5.3%).. Patients with LE-PAD with high-risk limb presentations or high-risk comorbidities had a high incidence of major vascular events. For these patients, treatment with rivaroxaban and aspirin in combination compared with aspirin alone led to a large absolute reduction in vascular risk.

Topics: Aged; Amputation, Surgical; Aspirin; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Double-Blind Method; Factor Xa Inhibitors; Female; Heart Failure; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prognosis; Renal Insufficiency; Rivaroxaban; Severity of Illness Index; Stroke

Topics: Aged; Factor Xa Inhibitors; Female; Humans; Male; Peripheral Arterial Disease; Renal Insufficiency; Rivaroxaban; Vascular Surgical Procedures

Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P-glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age-matched controls with normal renal function were studied concurrently. Subjects' overall mean age was 59 years. Mean creatinine clearance values in the 2 groups were 105 and 71 mL/min. After single 20-mg oral doses, rivaroxaban area under the curve (AUC) was increased by a factor of 1.11 (ratio of geometric means [RGM]) in mild renal insufficiency compared to controls. Verapamil coadministration independently increased AUC to the same extent in both the mild renal insufficiency and control groups (RGM, 1.39 and 1.43). Concurrent mild renal insufficiency and verapamil produced additive inhibition compared to controls without verapamil (RGM, 1.58). Prothrombin time (PT) prolongation and Factor Xa inhibition tracked plasma rivaroxaban, and were enhanced by verapamil. Concentration-response relationships for PT (linear) and Factor Xa inhibition (hyperbolic) were unaffected by renal function or verapamil. The absolute and relative increases in rivaroxaban AUC caused by verapamil in mild renal insufficiency subjects are potentially associated with an increased bleeding risk. Modification of recommended dosage may be required in this combination of circumstances to reduce risk to patients.

Topics: Adult; Aged; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Prothrombin Time; Renal Insufficiency; Rivaroxaban; Verapamil

Current dosing recommendations for rivaroxaban advocate dosage reduction in patients with moderate to severe renal impairment and avoidance of concomitant strong inhibitors of CYP3A or P-glycoprotein. However, rivaroxaban dosing in patients with mild renal impairment taking concomitant moderate inhibitors of CYP3A and P-glycoprotein is not addressed. To quantify the impacts of concomitant verapamil administration and renal impairment on rivaroxaban pharmacokinetics, a minimal physiologically based pharmacokinetic model system was developed and used to evaluate potential increases in rivaroxaban exposure and the consequent increase in risk of major bleeding. Data from a phase 1, drug-drug interaction study were used to qualify the minimal physiologically based pharmacokinetic model system. Model-based simulations indicate that coadministration of rivaroxaban with verapamil substantially increases rivaroxaban exposure across all renal function categories, resulting in an exponential increase in bleeding risk. Reduction of the daily rivaroxaban dose to 10 to 15 mg reduces the major bleeding risk below the designated 4.5% threshold in the majority of patients with normal or mildly impaired renal function. A reduction to 10 mg daily in patients with moderate to severe renal impairment provides additional risk reduction so that 90% of those patients fall below the 4.5% threshold. A risk threshold of 4.5% was selected because it is the median predicted risk in patients treated concomitantly with ketoconazole, which is contraindicated for use with rivaroxaban. Patients taking both rivaroxaban and verapamil should take a reduced daily dose of rivaroxaban to minimize bleeding risk.

Topics: Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Factor Xa Inhibitors; Hemorrhage; Humans; Middle Aged; Models, Biological; Renal Insufficiency; Risk; Rivaroxaban; Verapamil

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Blood Coagulation; Double-Blind Method; Factor Xa; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Models, Biological; Morpholines; Prothrombin Time; Renal Insufficiency; Rivaroxaban; Thiophenes

Two previously conducted rivaroxaban studies showed that, separately, renal impairment (RI) and concomitant administration of erythromycin (P-glycoprotein and moderate cytochrome P450 3A4 [CYP3A4] inhibitor) can result in increases in rivaroxaban exposure. However, these studies did not assess the potential for combined drug-drug-disease interactions, which-in theory-could lead to additive or synergistic increases in exposure. This study investigated rivaroxaban pharmacokinetics and pharmacodynamics when co-administered with steady-state (SS) erythromycin in subjects with either mild or moderate RI. Similar to previous studies, rivaroxaban administered alone in RI subjects, or when co-administered with SS erythromycin in normal renal function (NRF) subjects, increased rivaroxaban exposure. When combined, the co-administration of rivaroxaban 10 mg with SS erythromycin in subjects with mild or moderate RI produced mean increases in rivaroxaban AUC∞ and Cmax of approximately 76% and 56%, and 99% and 64%, respectively, relative to NRF subjects, with PD changes displaying a similar trend. No serious adverse events occurred and no persistent adverse events were reported at the end of study. Although these increases were slightly more than additive, rivaroxaban should not be used in patients with RI receiving concomitant combined P-glycoprotein and moderate CYP3A4 inhibitors, unless the potential benefit justifies the potential risk.

Topics: Aged; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Erythromycin; Factor Xa; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Morpholines; Partial Thromboplastin Time; Prothrombin Time; Renal Insufficiency; Rivaroxaban; Thiophenes

In the Japanese Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) study, rivaroxaban 15 mg once daily was given to patients with creatinine clearance (CrCl) ≥ 50 ml/min (preserved renal function), and was reduced to 10mg once daily in patients with CrCl 30-49 ml/min (moderate renal impairment). The aim of this subanalysis was to assess the safety and efficacy of the adjusted dose of rivaroxaban compared with warfarin in a cohort with moderate renal impairment.. Compared with patients with preserved renal function, those with moderate renal impairment (22.2% of all randomized patients) had higher rates of bleeding and stroke events irrespective of study treatment. Among those with moderate renal impairment, the principal safety endpoint occurred at 27.76%/year with rivaroxaban vs. 22.85%/year with warfarin (hazard ratio [HR], 1.22; 95% confidence interval [CI]: 0.78-1.91) and the rate of the primary efficacy endpoint was 2.77%/year vs. 3.34%/year (HR, 0.82; 95% CI: 0.25-2.69), respectively. There were no significant interactions between renal function and study treatment in the principal safety and the primary efficacy endpoints (P=0.628, 0.279 for both interactions, respectively).. The safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and preserved renal function.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Asian People; Atrial Fibrillation; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Japan; Kidney; Male; Middle Aged; Morpholines; Renal Insufficiency; Reproducibility of Results; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Warfarin

Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages.. We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban.. Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Double-Blind Method; Embolism; Female; Hemorrhage; Humans; Male; Morpholines; Renal Insufficiency; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Warfarin

Increased bleeding risk was found associated with concurrent prescription of rivaroxaban and amiodarone. We previously recommended dose adjustment for rivaroxaban utilizing a physiologically based pharmacokinetic (PBPK) modeling approach. Our subsequent in vitro studies discovered the pivotal involvement of human renal organic anion transporter 3 (hOAT3) in the renal secretion of rivaroxaban and the inhibitory potency of amiodarone. This study aimed to redefine the disease-drug-drug interactions (DDDI) between rivaroxaban and amiodarone and update the potential risks.. Prospective simulations were conducted with updated PBPK models of rivaroxaban and amiodarone incorporating hOAT3-related parameters.. Simulations to recapitulate previously explored DDDI in renal impairment showed a higher bleeding tendency in all simulation scenarios after integrating hOAT3-mediated clearance into PBPK models. Further sensitivity analysis revealed that both hOAT3 dysfunction and age could affect the extent of DDDI, and age was shown to have a more pivotal role on rivaroxaban in vivo exposure. When amiodarone was prescribed along with our recommended dose reduction of rivaroxaban to 10 mg in moderate renal impaired elderly people, it could result in persistently higher rivaroxaban peak concentrations at a steady state. To better manage the increased bleeding risk among such a vulnerable population, a dose reduction of rivaroxaban to 2.5 mg twice daily resulted in its acceptable in vivo exposure.. Close monitoring of bleeding tendency is essential for elderly patients with moderate renal impairment receiving co-prescribed rivaroxaban and amiodarone. Further dose reduction is recommended for rivaroxaban to mitigate this specific DDDI risk.

Topics: Aged; Amiodarone; Hemorrhage; Humans; Kidney; Renal Insufficiency; Rivaroxaban

Despite potential enzyme- and transporter-mediated drug-drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N-desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations.. The middle-out development of our PBPK model combined literature-derived or in-house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4- and P-glycoprotein-mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban-specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P-glycoprotein were incorporated into the PBPK-DDI model for prospective dronedarone-rivaroxaban DDI simulation.. Dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto-inactivation on dose nonlinearities. Following successful model validation, nondose-adjusted rivaroxaban-dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration-time curve up to 24 h fold change greater than dose exposure equivalence (0.70-1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban-ketoconazole DDI.. Our PBPK-DDI model predicted clinically significant dronedarone-rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban.

Topics: ATP Binding Cassette Transporter, Subfamily B; Dronedarone; Drug Interactions; Humans; Models, Biological; Renal Insufficiency; Rivaroxaban

In atrial fibrillation (AF) patients on vitamin K antagonists, a progressive deterioration of renal function is common but there is limited evidence with long-term use of rivaroxaban. Herein, we investigated the change in renal function in AF patients after 2 years of rivaroxaban treatment.. The EMIR registry is an observational and multicentre study including AF patients treated with rivaroxaban for at least 6 months prior to inclusion. Changes in analytical parameters were recorded during 2 years of follow-up. Renal function was estimated using the Cockroft-Gault equation.. 1433 patients (638, 44.5% women, mean age of 74.2 ± 9.7 years) were included. Creatinine clearance (CrCl) was available at baseline and at 2 years in 1085 patients. At inclusion, 33.2% of patients had impaired renal function (CrCl <60 ml/min). At 2 years, we were not able to find changes in the proportion of patients with impaired renal function, which increased to 34.6% (p = 0.290). However, the baseline mean CrCl was 76.0 ± 30.5 ml/min and slightly improved at 2 years (77.0 ± 31.8 ml/min; p = 0.014). Overall, the proportion of patients with CrCl <60 ml/min at baseline that had CrCl ≥60 ml/min at 2 years was significantly higher compared to that of patients with CrCl ≥60 ml/min at baseline and CrCl <60 ml/min after (22.2% vs. 13.1%; p < 0.001) CONCLUSIONS: In AF patients on long-term rivaroxaban therapy, a decrease in renal function was not observed. We even observed a slight improvement in the patients with renal impairment. These results reinforce the idea that rivaroxaban may be a safe option even in patients with renal impairment.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Registries; Renal Insufficiency; Rivaroxaban; Stroke

The non-vitamin K antagonist oral anticoagulant rivaroxaban is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug-drug interactions. This physiologically based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease-specific parameters, and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild to moderate renal impairment had a minor effect on area under the concentration-time curve and maximum plasma concentration of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters vs normal renal function. Area under the concentration-time curve and maximum plasma concentration increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and C

Topics: Anticoagulants; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; Computer Simulation; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Hepatic Insufficiency; Humans; Metabolic Clearance Rate; Models, Biological; Patient Acuity; Renal Insufficiency; Rivaroxaban

To evaluate the current interpretation of the lower doses of direct oral anticoagulants (DOAC) dabigatran, apixaban, edoxaban and rivaroxaban in nonvalvular atrial fibrillation.. A questionnaire of 14 statements to which the possible answers were fully agree/partially agree/partially disagree/fully disagree or yes/no was prepared within the board of the Italian Atherosclerosis, Thrombosis and Vascular Biology Study Group and forwarded to individual Italian physicians.. A total of 620 complete questionnaires were received from nearly all the Italian regions and physicians of various medical specialists, either enabled or not for the prescription of DOAC. A wide agreement was found as regards the pharmacological, as well as clinical consequences of the administration of the lower dose of factor-Xa inhibitors both in patients with and without clinical and/or laboratory criteria requiring dose reduction. Wide agreement was also found as regards the presence of moderate kidney insufficiency in selecting the dose of DOAC. Instead, more debated were issues regarding the proportionality between dabigatran dose and plasma concentration and selection of dabigatran dose, as well as the role of measuring drug plasma concentration and/or determine the anticoagulant activity of factor-Xa inhibitors when used at the lower dose.. The interpretation of the lower doses of DOAC in current Italian clinical practice appears largely correct and shared. Because of the persistence of some residual uncertainties, essentially regarding dabigatran, however, continuous educational effort still appears warranted.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Italy; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Surveys and Questionnaires; Thiazoles; Thrombosis; Treatment Outcome

Factor-Xa inhibitors (FXaIs) are widely used for the treatment of non-valvular atrial fibrillation (NVAF). Although we have previously reported the distribution of the anti-factor Xa activity (AXA) values of three different FXaIs in NVAF patients, the differences in the distribution of AXA values among the different FXaIs in patients with renal impairment (RI) have not been fully elucidated.. Trough and peak AXA values were measured in 94 patients taking rivaroxaban, 124 patients taking apixaban, and 66 patients taking edoxaban. Of them, we identified 26 patients with moderate RI [creatinine clearance (CrCl) 30-49 mL/min] and 17 patients with severe RI (CrCl 15-29 mL/min) in the rivaroxaban cohort, 37 patients with moderate RI and 17 patients with severe RI in the apixaban cohort, and 21 patients with moderate RI and 9 patients with severe RI in the edoxaban cohort. AXA values were measured using chromogenic AXA assays. Both trough and peak AXA values were compared between patients with moderate RI and those with severe RI in each cohort, and differences in the peak-to-trough ratio among the different drugs were assessed.. In the rivaroxaban cohort, the peak AXA value was significantly higher in patients with severe RI than in those with moderate RI. In the apixaban cohort, neither the trough nor peak AXA values significantly differed between patients with moderate RI and those with severe RI. In the edoxaban cohort, the trough AXA value was significantly higher in patients with severe RI than in those with moderate RI, and peak AXA tended to be higher in patients with severe RI. The peak-to-trough ratio of AXA values was significantly lower in patients taking apixaban than in those taking rivaroxaban and edoxaban.. Among Japanese NVAF patients with RI, the peak or trough AXA values were higher in patients with severe RI than in those with moderate RI when taking rivaroxaban and edoxaban, whereas both the peak and trough AXA values were similar between patients with severe RI and those with moderate RI when taking apixaban. The peak-to-trough ratio of AXA values was the lowest in patients taking apixaban.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Cohort Studies; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiazoles

Rivaroxaban (Xarelto; Johnson & Johnson Services, Inc) is a direct oral anticoagulant (DOAC) that works by directly inhibiting the active site of factor Xa (FXa). Rivaroxaban is metabolized and cleared via the kidney and liver. The results of various studies have shown that patients with severe renal impairment should receive reduced dosages of rivaroxaban or another anticoagulant due to impaired clearance. Although it is not required, monitoring rivaroxaban is useful in some conditions; however, the assays required for such monitoring are not readily available. Herein, we present a case of a 68-year-old Caucasian male patient who was receiving rivaroxaban (20 mg/day) for atrial flutter and had mild renal impairment. The patient was found to have increased effect of rivaroxaban due to further impairment of renal clearance caused by several renally cleared medications. This case highlights the importance of closely examining the renal function of and medication list for a patient before starting DOACs such as rivaroxaban.

Topics: Aged; Atrial Flutter; Factor Xa Inhibitors; Hemorrhage; Humans; Male; Metabolic Clearance Rate; Prothrombin Time; Renal Insufficiency; Rivaroxaban

Background and Purpose- Although rivaroxaban 15 mg (R15) was only given to patients with creatinine clearance (CrCl) ≤50 mL/min in the pivotal clinical trial, this dose has been commonly prescribed in Asian patients with nonvalvular atrial fibrillation regardless of renal function. There is a paucity of information on the clinical outcomes of R15 compared with rivaroxaban 20 mg (R20) in patients with CrCl ≥50 mL/min. This study aimed to examine the effectiveness and safety of 2 doses of rivaroxaban in Asian patients with atrial fibrillation and CrCl ≥50 mL/min. Methods- Using the Korean National Health Insurance Service database, patients with atrial fibrillation and normal or mildly impaired renal function (CrCl ≥50 mL/min) and naive to rivaroxaban or warfarin were included from January 2014 to December 2016. Three separate 1:1 propensity score-matched cohorts were conducted: R20 versus warfarin (n=15 584), R15 versus warfarin (n=11 554), and R20 versus R15 (n=10 392). Hazard ratios for ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, major bleeding, all-cause death, and composite clinical outcome were analyzed. Results- Compared with warfarin, both R20 and R15 showed significantly lower risk for ischemic stroke, major bleeding (mainly through reduction of intracranial hemorrhage), and all-cause death. Compared with R15, R20 showed better results for the composite clinical outcome (hazard ratio, 0.852; 95% CI, 0.735-0.988). This benefit was consistently observed in patients aged ≥80 years and those <50 kg. R20 was associated with higher risk of major bleeding than R15 in patients with marginal CrCl (50-60 mL/min). Conclusions- Among Asians with atrial fibrillation and CrCl ≥50 mL/min, both R20 and R15 were associated with reduced risk of ischemic stroke, intracranial hemorrhage, major bleeding, and all-cause death without significantly increased risk of gastrointestinal bleeding compared with warfarin. In patients with CrCl ≥50 mL/min, on-label R20 showed better results for the composite clinical outcome compared with off-label R15.

Topics: Aged; Aged, 80 and over; Asian People; Atrial Fibrillation; Cohort Studies; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Renal Insufficiency; Republic of Korea; Retrospective Studies; Rivaroxaban

Rivaroxaban is a direct oral anticoagulant administered to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was a prospective, observational, post-marketing surveillance study that examined the safety and effectiveness of rivaroxaban in routine clinical practice. This sub-analysis of the XAPASS investigated the outcomes of patients with worsening renal function (WRF).. The XAPASS included 11,308 patients with NVAF who began treatment with rivaroxaban. Of 9578 patients who completed 1-year follow-up, the 7509 patients, for whom the change in creatinine clearance could be assessed, were included in the present analysis. Patients with WRF were those with a decrease in creatinine clearance of ≥20% from enrollment to any time point; patients with stable renal function (SRF) were those without such a decrease. Outcomes in patients with WRF versus SRF were compared at 1 year.. No association between WRF and occurrence of any bleeding, major bleeding, and stroke/systemic embolism/myocardial infarction was observed in patients with AF on rivaroxaban treatment during 1-year follow-up in real-world clinical practice. Clinicaltrials.gov: NCT01582737.

Topics: Aged; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Japan; Male; Middle Aged; Myocardial Infarction; Product Surveillance, Postmarketing; Proportional Hazards Models; Prospective Studies; Renal Insufficiency; Rivaroxaban; Stroke; Treatment Outcome

Non-vitamin K antagonist direct oral anticoagulants (DOACs) are fixed-dose regimens indicated for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients. Dose adjustment is necessary among patients with renal insufficiency to optimize efficacy and safety.. To assess DOAC dosing appropriateness and its effect on clinical outcomes in NVAF patients.. Adult NVAF patients with ≥1 DOAC pharmacy claim (January 1, 2013, to December 31, 2014), continuous enrollment for ≥12 months post-index DOAC claim, and documented creatinine clearance within 3 months preindex date in the Optum/Humedica SmartFile database were eligible. DOAC dosage was classified as inappropriate or appropriate by level of renal function, age, and body weight per US prescription information. Cox proportional models were used to assess the risks of bleeding and stroke associated with inappropriate DOAC dosage.. Of the 388 eligible patients, 69 (17.8%) were inappropriately dosed, and rivaroxaban had the highest inappropriate dosing rate. Most inappropriately dosed patients were underdosed. Inappropriately dosed patients were more likely to be older, female, and have a body weight of ≤60 kg; they also had higher mean CHA. Inappropriate dosing occurred among patients with normal and insufficient renal function. The consideration of clinical factors beyond renal function is necessary to reduce bleeding risk associated with DOAC therapy.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Renal Insufficiency; Rivaroxaban; Stroke; Young Adult

Clinical practice guidelines recommend regular kidney function monitoring in atrial fibrillation patients on nonvitamin K oral anticoagulants (NOAC); however, information regarding compliance with these recommendations in daily life conditions is scarce. We sought to determine the compliance with kidney function monitoring recommendations in nonvalvular atrial fibrillation (NVAF) patients starting NOAC and its implication on the appropriateness of NOAC dosage.. This study involves the retrospective analysis of a multicentre registry including consecutive NVAF patients who started NOAC (n = 692). Drug dosage changes and serum creatinine determinations were recorded during 1-year follow-up. European Heart Rhythm Association criteria were used to define the appropriateness of kidney function monitoring as well as adequate NOAC dosage.. During the follow-up (334 ± 89 days), the compliance with kidney function monitoring recommendations was 61% (n = 425). After multivariate adjustment, age (OR × year: 0.92 (CI 95%: 0.89-0.95) P < .001), creatinine clearance (OR × mL/min: 1.02 (CI 95%: 1.01-1.03) P < .001) and adequate NOAC dosage at baseline (OR: 1.54 (CI 95%: 1.06-2.23), P = .024) were independent predictors of appropriate kidney function monitoring. Compliance with kidney function monitoring recommendations was independently associated with change to appropriate NOAC dose after 1 year (OR: 2.80 (CI 95%: 1.01-7.80), P = .049).. Noncompliance with kidney function monitoring recommendations is common in NVAF patients starting NOAC, especially in elderly patients with kidney dysfunction. Compliance with kidney function monitoring recommendations was associated with adequate NOAC dosage at 1-year follow-up. Further studies are warranted to evaluate the implication of kidney function monitoring on prognosis.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Creatinine; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Female; Guideline Adherence; Humans; Kidney Function Tests; Male; Multivariate Analysis; Odds Ratio; Practice Guidelines as Topic; Pyrazoles; Pyridones; Registries; Renal Insufficiency; Retrospective Studies; Rivaroxaban; Stroke

Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice.. A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction. Hepatic clearance and drug-drug interactions (DDI) were estimated by in vitro in vivo extrapolation (IVIVE) based on parameters obtained from in vitro experiments. To validate the model, observed concentrations were compared with predicted concentrations, and the impact of special scenarios was investigated.. The PBPK model successfully predicted the pharmacokinetics for healthy subjects and patients as well as DDIs. Sensitivity analysis shows that age, renal, and hepatic clearance are important factors affecting rivaroxaban pharmacokinetics. The predicted fold increase of rivaroxaban AUC values when combined administered with the inhibitors such as ketoconazole, ritonavir, and clarithromycin were 2.3, 2.2, and 1.3, respectively. When DDIs and hepatic dysfunction coexist, the fold increase of rivaroxaban exposure would increase significantly compared with one factor alone.. Our study using PBPK modeling provided a reasonable approach to evaluate exposure levels in special patients under special scenarios. Although further clinical study or real-life experience would certainly merit the current work, the modeling work so far would at least suggest caution of using rivaroxaban in complicated clinical settings.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Clarithromycin; Computer Simulation; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Factor Xa Inhibitors; Humans; Ketoconazole; Liver Diseases; Male; Models, Biological; Renal Insufficiency; Ritonavir; Rivaroxaban

Topics: Adult; Aged; Amiodarone; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Rivaroxaban; Vasodilator Agents; Young Adult

Dose reduction of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in patients with atrial fibrillation (AF) with renal impairment. Failure to reduce the dose in patients with severe kidney disease may increase bleeding risk, whereas dose reductions without a firm indication may decrease the effectiveness of stroke prevention.. The goal of this study was to investigate NOAC dosing patterns and associated outcomes, i.e., stroke (ischemic stroke and systemic embolism) and major bleeding in patients treated in routine clinical practice.. Using a large U.S. administrative database, 14,865 patients with AF were identified who initiated apixaban, dabigatran, or rivaroxaban between October 1, 2010, and September 30, 2015. We examined use of a standard dose in patients with a renal indication for dose reduction (potential overdosing) and use of a reduced dose when the renal indication is not present (potential underdosing). Cox proportional hazards regression was performed in propensity score-matched cohorts to investigate the outcomes.. Among the 1,473 patients with a renal indication for dose reduction, 43.0% were potentially overdosed, which was associated with a higher risk of major bleeding (hazard ratio: 2.19; 95% confidence interval: 1.07 to 4.46) but no statistically significant difference in stroke (3 NOACs pooled). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed. This underdosing was associated with a higher risk of stroke (hazard ratio: 4.87; 95% confidence interval: 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban-treated patients. There were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication.. In routine clinical practice, prescribed NOAC doses are often inconsistent with drug labeling. These prescribing patterns may be associated with worse safety with no benefit in effectiveness in patients with severe kidney disease and worse effectiveness with no benefit in safety in apixaban-treated patients with normal or mildly impaired renal function.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Pyrazoles; Pyridones; Renal Insufficiency; Retrospective Studies; Rivaroxaban; Stroke; Time Factors; Treatment Outcome; United States; Vitamin K; Young Adult

Compared with vitamin K antagonists, direct-acting oral anticoagulants (DOACs) have fixed dosing, limited drug interactions, and do not require therapeutic drug level monitoring. Dose adjustments are recommended for moderate renal dysfunction, low body weight, and select drug interactions.. The aim of our study is to determine if DOAC dose reductions were appropriate based on the manufacturer labeling recommendations for each agent. We also followed patients' treatment outcomes.. We retrospectively reviewed patients administered a DOAC at a reduced dose between January 2011 and August 2014. The primary outcome was adherence to current manufacturer dose recommendations. The secondary outcome measures were the incidence of thromboembolic events or any bleeding episodes, regardless of severity, while on therapy.. Of 224 patients included in the analysis, 43.3% of patients fit criteria for a dose adjustment according to manufacturer recommendations. Only 3 of 28 (10.7%) patients treated with apixaban met 2 out of 3 clinical criteria required for a dose reduction per manufacturer recommendations. Only 54.7% of rivaroxaban-treated patients and 32.2% of dabigatran-treated patients had renal insufficiency requiring a dose reduction. Half of our patient population received aspirin therapy, with 6.3% of patients on triple antithrombotic therapy (dual antiplatelet agents plus an anticoagulant). A past medical history significant for bleeding was prevalent in patients treated with a reduced-dose DOAC (32.1%, 20.4%, and 25.4% of patients in the apixaban-, rivaroxaban-, and dabigatran-treated groups, respectively). Thromboembolic events occurred in 10.7%, 3.6%, and 5.1% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively. Frequency of bleeding complications, regardless of severity, was 17.9%, 18.2%, and 23.7% of patients in the apixaban, rivaroxaban, and dabigatran groups, respectively.. We found that dose-adjusted DOAC therapy was often prescribed in a dose that was lower than package insert recommendations.

Topics: Aged; Aged, 80 and over; Antithrombins; Aspirin; Atrial Fibrillation; Comorbidity; Creatinine; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Renal Insufficiency; Retrospective Studies; Rivaroxaban; Stroke; Venous Thromboembolism

The direct oral anticoagulants (DOAC) are increasingly used for primary and secondary stroke prophylaxis in atrial fibrillation, although their use in patients with renal failure is problematic.. In an 82-years old female with recurrent strokes and atrial fibrillation, the vitamin-K-antagonist was changed to rivaroxaban because of "unstable international normalized ratio (INR) values". Because of renal failure with a creatinine clearance of 32ml/min, a dosage of rivaroxaban 10mg/d was chosen. Eleven days after initiation of rivaroxaban, she was re-hospitalized because of acute onset of right-sided weakness of the upper and lower limbs.. In cases of stroke, renal failure and inadequate anticoagulation it is not useful to change from vitamin-K-antagonists to "low dose" DOAC. Diligent investigations for the cause of INR-instability and continuation of vitamin-K-antagonist therapy seem to be more effective and safer since there is the opportunity of monitoring therapy and to avoid under- as well as over-dosage.

Topics: Aged, 80 and over; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Morpholines; Recurrence; Renal Insufficiency; Rivaroxaban; Stroke; Thiophenes

Topics: Acenocoumarol; Administration, Oral; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Drug Monitoring; Drug Substitution; Epistaxis; Factor Xa Inhibitors; Female; Frail Elderly; Humans; Medication Therapy Management; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Renal Insufficiency; Rivaroxaban; Stroke

Topics: Anticoagulants; Asian People; Atrial Fibrillation; Female; Humans; Male; Morpholines; Renal Insufficiency; Rivaroxaban; Stroke; Thiophenes

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Double-Blind Method; Humans; Morpholines; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Renal Insufficiency; Rivaroxaban; Secondary Prevention; Severity of Illness Index; Stroke; Thiophenes; Treatment Outcome; Warfarin

This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor.. Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) ).. Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively.. Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Cohort Studies; Creatinine; Factor Xa Inhibitors; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Morpholines; Renal Insufficiency; Rivaroxaban; Thiophenes