Direct oral anticoagulant reversal: how, when and issues faced.

INTRODUCTION: The number of atrial fibrillation (AF) patients requiring thrombo-prophylaxis with oral anticoagulation is greatly increasing. The introduction of non-vitamin K oral anticoagulants (NOACs) in addition to standard therapy with dose-adjusted warfarin has increased the therapeutic options for AF patients. Despite a generally better safety profile of the NOACs, the risk of major bleedings still persists, and the management of serious bleeding is a clinical challenge. Areas covered: In the current review, risk of major bleeding in patients taking NOACs and general approaches to manage bleeding depending on severity, with a particular focus on specific reversal agents, are discussed. Expert commentary: Due to short half-life of NOACs compared to warfarin, discontinuation of drug, mechanical compression, and volume substitution are considered to be sufficient measures in most of bleeding cases. In case of life-threatening bleeding or urgent surgery, hemostasis can be achieved with non-specific reversal agents (prothrombin complex concentrates) in patients treated with factor Xa inhibitor until specific antidotes (andexanet α and ciraparantag) will receive approval. Thus far, idarucizumab has been the only reversal agent approved for dabigatran.

Hypertension and Atrial Fibrillation: An Intimate Association of Epidemiology, Pathophysiology, and Outcomes.

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia found in clinical practice. AF rarely exists as a single entity but rather as part of a diverse clinical spectrum of cardiovascular diseases, related to structural and electrical remodeling within the left atrium, leading to AF onset, perpetuation, and progression. Due to the high overall prevalence within the AF population arterial hypertension plays a significant role in the pathogenesis of AF and its complications. Fibroblast proliferation, apoptosis of cardiomyocytes, gap junction remodeling, accumulation of collagen both in atrial and ventricular myocardium all accompany ageing-related structural remodeling with impact on electrical activity. The presence of hypertension also stimulates oxidative stress, systemic inflammation, rennin-angiotensin-aldosterone and sympathetic activation, which further drives the remodeling process in AF. Importantly, both hypertension and AF independently increase the risk of cardiovascular and cerebrovascular events, e.g., stroke and myocardial infarction. Given that both AF and hypertension often present with limited on patient wellbeing, treatment may be delayed resulting in development of complications as the first clinical manifestation of the disease. Antithrombotic prevention in AF combined with strict blood pressure control is of primary importance, since stroke risk and bleeding risk are both greater with underlying hypertension.

Antiplatelet and Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Coronary Stenting.

Stroke prevention is the main priority in the management cascade of atrial fibrillation. Most patients require long-term oral anticoagulation (OAC) and may require percutaneous coronary intervention. Prevention of recurrent cardiac ischemia and stent thrombosis necessitate dual antiplatelet therapy (DAPT) for up to 12 months. Triple antithrombotic therapy with OAC plus DAPT of shortest feasible duration is warranted, followed by dual antithrombotic therapy of OAC and antiplatelet agent, and OAC alone after 12 months. Because of elevated risk of hemorrhagic complications, new-generation drug-eluting stents, lower-intensity OAC, radial access, and routine use of gastric protection with proton pump inhibitors are recommended.

Effects of Aspirin on Endothelial Function and Hypertension.

PURPOSE OF REVIEW: Endothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension. RECENT FINDINGS: Emerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances. Aspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations.

Antithrombotic and Anticoagulant Therapy for Atrial Fibrillation.

As atrial fibrillation (AF) substantially increases the risk of stroke and other thromboembolic events, most AF patients require appropriate antithrombotic prophylaxis. Oral anticoagulation (OAC) with either dose-adjusted vitamin K antagonists (VKAs) (eg, warfarin) or non-VKA oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban) can be used for this purpose unless contraindicated. Therefore, risk assessment of stroke and bleeding is an obligatory part of AF management, and risk has to be weighed individually. Antiplatelet drugs (eg, aspirin and clopidogrel) are inferior to OAC, both alone and in combination, with a comparable risk of bleeding events.

Edoxaban for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

INTRODUCTION: Oral anticoagulation is central to the management of patients with atrial fibrillation (AF) and at least one additional stroke risk factor. For decades, the vitamin K antagonists (e.g. warfarin) remained the only oral anticoagulant available for stroke prevention in AF. The non-vitamin K oral anticoagulants (NOACs) are now available, and these drugs include the direct thrombin inhibitors and factor Xa inhibitors. The latter class includes edoxaban, which has recently been approved for stroke prevention in AF by the United States Food and Drug Administration and the European Medicine Agency. In line with other NOACs, edoxaban avoids the many limitations of warfarin associated with variability of anticoagulation effect and multiple food and drug interactions. AREAS COVERED: In this review, the currently available evidence on edoxaban in patients with non-valvular AF is discussed. The pharmacology, efficacy and safety, and current aspects of use of edoxaban in patients with non-valvular AF for stroke and thromboembolism prevention are reviewed. EXPERT OPINION: Phase III trials on edoxaban for stroke prevention in non-valvular AF confirms non-inferiority of edoxaban compared to well-managed warfarin both in terms of efficacy and safety. Currently ongoing and future trials as well as real-world data are warranted to confirm its effectiveness and safety for chronic anticoagulation and improve evidence in other areas which are lacking evidence where NOAC use remains controversial.

Cardiac Fibrosis in Patients With Atrial Fibrillation: Mechanisms and Clinical Implications.

Atrial fibrillation (AF) is associated with structural, electrical, and contractile remodeling of the atria. Development and progression of atrial fibrosis is the hallmark of structural remodeling in AF and is considered the substrate for AF perpetuation. In contrast, experimental and clinical data on the effect of ventricular fibrotic processes in the pathogenesis of AF and its complications are controversial. Ventricular fibrosis seems to contribute to abnormalities in cardiac relaxation and contractility and to the development of heart failure, a common finding in AF. Given that AF and heart failure frequently coexist and that both conditions affect patient prognosis, a better understanding of the mutual effect of fibrosis in AF and heart failure is of particular interest. In this review paper, we provide an overview of the general mechanisms of cardiac fibrosis in AF, differences between fibrotic processes in atria and ventricles, and the clinical and prognostic significance of cardiac fibrosis in AF.

Non-vitamin K oral anticoagulants in atrial fibrillation: Where are we now?

Atrial fibrillation (AF) confers increased risk of stroke and other thromboembolic events, and oral anticoagulation therefore is the essential part of AF management to reduce the risk of these complications. Until recently, the vitamin K antagonists (VKAs, e.g., warfarin) were the only oral anticoagulants available, acting by decreased synthesis of vitamin K-dependent coagulation factors (II, VI, IX, and X). The VKAs had many limitations: delayed onset and prolonged offset of action, variability of anticoagulant effect among patients, multiple food and drug interactions affecting pharmacological properties of warfarin, narrow therapeutic window, and obligatory regular laboratory control, which all made warfarin "inconvenient" both for patients and clinicians. The limitations of VKAs led to development of a new class of drugs collectively defined as non-VKA oral anticoagulants (NOACs), which included direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). The NOACs avoid many of the VKA drawbacks. In this review, we will focus on the current evidence justifying the use of NOACs in non-valvular AF.

Warfarin versus dabigatran etexilate: an assessment of efficacy and safety in patients with atrial fibrillation.

INTRODUCTION: Oral anticoagulation is the mainstay for stroke and thromboembolic event prevention in patients with atrial fibrillation (AF). Given limitations of warfarin therapy, non-vitamin K oral anticoagulants have been developed including direct thrombin inhibitors (i.e., dabigatran etexilate). Dabigatran etexilate has been tested thoroughly in terms of efficacy and safety in clinical trials and studies, involving 'real-world' cohorts. In this review, currently available evidence in patients with non-valvular AF is discussed. AREAS COVERED: The pharmacology, efficacy and safety, and current aspects of use of dabigatran etexilate in patients with non-valvular AF are reviewed in a comparative manner to warfarin both for chronic anticoagulation and in different clinical settings. EXPERT OPINION: Dabigatran etexilate appeared to have several pharmacokinetic and pharmacodynamic advantages over warfarin, as well as a favorable efficacy and safety profile being at least noninferior and often superior to warfarin in patients with non-valvular AF. The latter was shown in the clinical trials, meta-analyses and studies with 'real-world' data. Currently ongoing trials will expand the body of evidence on warfarin and will aid decision making in currently controversial areas. Important limitations of dabigatran etexilate include contraindications for its use in patients with prosthetic heart valves and end-stage chronic kidney disease.

Patients with atrial fibrillation undergoing percutaneous coronary intervention: current concepts and concerns: part II.

Atrial fibrillation (AF) and coronary artery disease (CAD) often present concomitantly. Given the increased risk of thrombotic complications with either of them but different pathogenesis of clot formation, combined antithrombotic therapy is necessary in patients developing acute coronary syndrome and/or undergoing percutaneous coronary intervention (PCI). Different antithrombotic regimens in this group of patients have been summarized and discussed earlier. Triple therapy remains the treatment of choice in these patients despite the increased risk of hemorrhagic complications. Given the absence of evidence from randomized controlled trials, balancing the risk of stroke and stent thrombosis against the risk of major bleeding is a challenge. Precise stroke and bleeding risk assessment is an essential part of the decision making process regarding antithrombotic management. Continuing the discussion of current concepts and concerns of antithrombotic management in AF patients undergoing PCI, we emphasize the importance of various strategies to reduce bleeding in the modern era, namely, radial access combined with careful selection of a P2Y12 receptor inhibitor, use of newer drug-eluting stents, and uninterrupted anticoagulation for patients undergoing procedures. We also focus on the role of the non-vitamin K oral anticoagulants (novel oral anticoagulants, eg, dabigatran, rivaroxaban, apixaban, and edoxaban) which are increasingly used for stroke prevention in AF. Finally, recent recommendations on the management of antithrombotic therapy in AF patients presenting with acute coronary syndrome and/or undergoing PCI as well as ongoing clinical trials and future directions are highlighted.

Patients with atrial fibrillation undergoing percutaneous coronary intervention. Current concepts and concerns: part I.

Atrial fibrillation (AF) and coronary artery disease (CAD) often coexist. Both conditions confer an increased risk of acute thrombotic complications. However, the pathogenesis of thrombus development in AF and CAD is different. Coagulation activation is the main pathway in AF, and platelet activation is the hallmark of coronary thrombosis. Antithrombotic prophylaxis is essential in both conditions. In patients with AF undergoing percutaneous coronary intervention (PCI), a combination of oral anticoagulation and antiplatelet therapy is required, which elevates the risk of major bleeding. This has to be balanced against the risk of stroke and stent thrombosis. In the first part of the present review, the prerequisites for antithrombotic management in AF patients undergoing PCI are discussed. We cover the epidemiology of concomitant presentation of AF and CAD as well as differences in the pathogenesis of thrombus formation in both conditions. We evaluate data regarding a variety of antithrombotic regimens including triple therapy in line with stroke and bleeding risk assessment. Overall, triple therapy is often warranted but should be for the shortest possible duration. Although much of the current guidance comes from observational data, well designed, adequately powered randomized clinical trials are emerging to further inform practice in this challenging area.  

Efficacy and safety of non-vitamin K antagonist oral anticoagulants vs. warfarin in Japanese patients with atrial fibrillation ­ meta-analysis.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOAC) have been developed as alternatives to warfarin. Until recently, the latter was the standard oral anticoagulant for patients with non-valvular atrial fibrillation (NVAF). The efficacy and safety of NOAC in Japanese patients with NVAF has been investigated in small trials or subgroups from global randomized control trials (RCT). METHODS AND RESULTS: We conducted a systematic review and meta-analysis of RCT, to compare the efficacy and safety of NOAC to those of warfarin in Japanese patients with NVAF. Published research was systematically searched for RCT that compared NOAC to warfarin in Japanese patients with NVAF. Random-effects models were used to pool efficacy and safety data across RCT. Three studies, involving 1,940 patients, were identified. Patients randomized to NOAC had a decreased risk for stroke and systemic thromboembolism (relative risk [RR], 0.45; 95% CI: 0.24-0.85), with a non-significant trend for lower major bleeding (RR, 0.66; 95% CI: 0.29-1.47), intracranial bleeding (RR, 0.46; 95% CI: 0.18-1.16) and gastrointestinal bleeding (RR, 0.52; 95% CI: 0.25-1.08). CONCLUSIONS: NOAC are more efficacious than warfarin for the prevention of stroke and systemic embolism in Japanese patients with NVAF. The present findings offer clinicians a more comprehensive picture of NOAC as a therapeutic option to reduce the risk of stroke in Japanese NVAF patients.

Antithrombotic and anticoagulant therapy for atrial fibrillation.

As atrial fibrillation (AF) substantially increases the risk of stroke and other thromboembolic events, most AF patients require appropriate antithrombotic prophylaxis. Oral anticoagulation (OAC) with either dose-adjusted vitamin K antagonists (VKAs) (eg, warfarin) or non-VKA oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban) can be used for this purpose unless contraindicated. Therefore, risk assessment of stroke and bleeding is an obligatory part of AF management, and risk has to be weighed individually. Antiplatelet drugs (eg, aspirin and clopidogrel) are inferior to OAC, both alone and in combination, with a comparable risk of bleeding events.

Stroke and bleeding risk in atrial fibrillation: navigating the alphabet soup of risk-score acronyms (CHADS2 , CHA2 DS2 -VASc, R2 CHADS2 , HAS-BLED, ATRIA, and more).

Stroke prevention is central to the management of patients with atrial fibrillation (AF). As effective stroke prophylaxis essentially requires oral anticoagulants, an understanding of the risks and benefits of oral anticoagulant therapy is needed. Although AF increases stroke risk 5-fold, this risk is not homogeneous. Many stroke risk factors also confer an increased risk of bleeding. Various stroke and bleeding risk-stratification schemes have been developed to help inform clinical decision-making. These scores were derived and validated in different study cohorts, ranging from highly selected clinical-trial cohorts to real-world populations. Thus, their performance and classification accuracy vary depending on their derivation cohort(s). In the present review, we provide an overview of currently available stroke and bleeding risk-stratification schemes. We particularly focus on the CHA2 DS2 -VASc and HAS-BLED schemes, as these are recommended by the latest European guidelines on AF management. Other risk-stratification schemes (eg, CHADS2 , R2 CHADS2 , ATRIA, HEMORR2 HAGES, QStroke) and their place in the decision-making are also considered.