New Oral Anticoagulants

Overall View On NOACs.

http://www.cec.health.nsw.gov.au/__data/assets/pdf_file/0007/326419/noac_guidelines.pdf

https://www.medscape.com/viewarticle/876322

https://academic.oup.com/eurheartj/article/35/28/1888/529307

https://www.escardio.org/The-ESC/Press-Office/Press-releases/ESC-guide-on-new-oral-anticoagulant-drugs

AF Management

Principles of AF management: key points

• Assessment of thromboembolic risk and antithrombotic treatment for patients at risk
• A choice of:
  • Restoration and maintenance of sinus rhythm (rhythm control)
    • – using electrical cardioversion, drugs, ablation, or surgery may be particularly useful in younger patients with structurally normal hearts and paroxysmal AF, or persistent AF of recent onset
    • – surgery suitable even in long standing AF, but associated with substantial morbidity and mortality
  • Acceptance of the arrhythmia and control of the ventricular rate (rate control)
    • – using drugs (usually β or calcium channel blockers with or without digoxin), or occasionally atrioventricular node ablation and implantation of a permanent pacemaker
    • – may be more appropriate in elderly patients with hypertension or structural heart disease and persistent or permanent arrhythmia, especially if this can be tolerated symptomatically
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AF is a common and increasingly prevalent arrhythmia that is associated with substantial morbidity and mortality. Because of the limited efficacy of catheter based treatments, especially for patients with persistent AF, and the substantial morbidity and mortality associated with surgery for the arrhythmia, pharmacological therapy remains the mainstay of treatment for the majority of patients. The optimum treatment strategy for patients with persistent AF remains controversial, with some clinicians favouring rhythm control and others rate control. Ultimately, treatment needs to be individualised, based on symptomatology and the likelihood of maintenance of sinus rhythm. Regardless of these controversies in arrhythmia management, anticoagulation or antiplatelet therapy for stroke prevention form an integral part of treatment of patients with AF and risk factors for thromboembolism.

The predominant focus of recent developments in pharmacological therapy for AF has been the development of novel class III antiarrhythmic agents, each with characteristic effects on potassium channels. In general, these agents have proven moderately efficacious but carry a significant risk of proarrhythmia. While research in this field continues, other drugs such as specific serotonin receptor antagonists continue to be developed. Further developments in catheter ablation technologies may greatly facilitate safe isolation of multiple pulmonary veins for patients with predominantly paroxysmal AF, whereas improvements in linear catheter ablation technologies, accompanied by three dimensional atrial mapping and catheter navigation, may facilitate creation of linear left atrial lesions, which appear to be critical for the successful treatment of patients with persistent arrhythmia.

The pathophysiological science of atrial fibrillation

Atrial Fibrillation

The prevalence of atrial fibrillation (AF), already the most common sustained cardiac arrhythmia, is constantly rising, even after adjusting for age and presence of structural heart disease. AF increases the risk of stroke sixfold and is associated with a twofold increase in mortality, which remains above 1.5-fold after adjusting for co-morbidity, predominantly caused by cerebrovascular events, progressive ventricular dysfunction, and increased coronary mortality. The adverse haemodynamic effects of AF are well described and relate not only to loss of atrial contraction, but also to the accompanying rapidity and irregularity of ventricular contraction. Although AF may be asymptomatic, up to two thirds of patients report that the arrhythmia is disruptive to their lives. Finally, the treatment of AF and its associated complications creates a significant and increasing economic burden. This article focuses predominantly on the pathophysiology of the arrhythmia and its pharmacological treatment. Anticoagulation for prevention of thromboembolism, a fundamental principle in the management of this arrhythmia, electrical cardioversion, percutaneous ablation techniques, and surgery for AF are not discussed in any detail.

PATHOPHYSIOLOGY AND MECHANISMS

Hypertensive, valvar, ischaemic, and other types of structural heart disease underlie most cases of persistent and permanent AF, whereas lone AF accounts for approximately 15% of AF cases. Familial AF is well described, although at present considered rare. A region on chromosome 10 (10q22-q24) was originally identified as containing the gene responsible for AF in families in which the arrhythmia segregated as an autosomal dominant trait. However, familial AF appears to be a heterogeneous disease. A family with a mutation in the gene encoding the pore forming α subunit of the cardiac I_Ks channel on chromosome 11 that results in increased function of this channel, with affected members developing persistent AF probably caused by a reduction in refractoriness, has more recently been described.

The pathogenesis of AF is now thought to involve an interaction between initiating triggers, often in the form of rapidly firing ectopic foci located inside one or more pulmonary veins, and an abnormal atrial tissue substrate capable of maintaining the arrhythmia. Although structural heart disease underlies many cases of AF, the pathogenesis of AF in apparently normal hearts is less well understood. Although there is considerable overlap, pulmonary vein triggers may play a dominant role in younger patients with relatively normal hearts and short paroxysms of AF, whereas an abnormal atrial tissue substrate may play a more important role in patients with structural heart disease and persistent or permanent AF.

Focal initiators of AF

It is now known that foci of rapid ectopic activity, often located in muscular sleeves that extend from the left atrium into the proximal parts of pulmonary veins, play a pivotal role in the initiation of AF in humans. Less frequently, focal initiation of AF may be result from ectopic activity that arises from muscular sleeves in the proximal superior vena cava, from the ligament of Marshall, or other parts of the right and left atria. Initiation of AF by rapid focal activity has been demonstrated not only in patients with structurally normal hearts and paroxysmal AF, but also during the process of reinitiation of persistent AF after electrical cardioversion, both in the presence and absence of associated structural heart disease.

Muscular sleeves that extend into the proximal pulmonary veins are present in the normal heart. The mechanisms involved in the production of ectopic activity by these sleeves in patients with AF, as well as the exact mechanism of initiation of AF by the rapid activity, remain to be elucidated. Proposed mechanisms for generation of abnormal focus activity include increased automaticity, triggered activity, and micro-reentry. Changes in autonomic tone around the time of initiation of AF paroxysms, with an increase in sympathetic activity followed by an abrupt change to parasympathetic predominance, have also recently been demonstrated.

Tissue substrate capable of maintaining AF

Both experimental and human mapping studies have demonstrated that persistent AF is generally characterised by the presence of multiple wavelets of excitation that propagate around the atrial myocardium. However, there is considerable variability in the observed patterns of activation, both between patients and between the two atria of individual patients. Perpetuation of AF is facilitated by the existence or development of an abnormal atrial tissue substrate capable of maintaining the arrhythmia, with the number of meandering wavelets that can be accommodated by the substrate determining the stability of AF. Re-entry within the atrial myocardium is facilitated by conduction slowing and shortening of the refractory period. Both have been demonstrated in animal models and patients with AF, with increased dispersion of refractoriness further contributing to arrhythmogenesis. Shortening of the atrial action potential, reduced expression of L type calcium channels, and microfibrosis of the atrial myocardium have also been demonstrated.

Electrophysiological remodelling

        AF in itself can cause progressive changes in atrial electrophysiology such as substantial refractory period shortening, which further facilitate perpetuation of the arrhythmia. In animal studies, changes in ion channel function and shortening of refractory periods start within minutes of AF onset and, by 24 hours, sufficient atrial remodelling has occurred to increase the likelihood of AF persisting. However, restoration of sinus rhythm in this animal model, even after two weeks of persistent AF, results in a rapid reversal of the electrophysiological remodelling.

The science of atrial fibrillation

Contemporary theories of the mechanism of atrial fibrillation require an understanding of re-entry as a mechanism of arrhythmogenesis. Re-entry, which is not a disorder of impulse formation but rather a disorder of impulse propagation, occurs when an impulse travels around an abnormal circuit repetitively. Consider 2 distinct areas of tissue (Fig. 1), where area A is excited by a depolarizing wavefront. Once excited, cells in area A cannot be excited again until their cell membranes have repolarized and the cells have recovered; the depolarizing wavefront has left the cells in its wake refractory to further stimulus. A premature stimulus activating area B cannot excite area A if it occurs when the intervening tissue is still refractory. However, if that depolarizing wavefront travels to area A by an alternate route, allowing sufficient time for tissue in area A to recover, then area A may be re-excited. Under the right circumstances, areas A and B can then re-excite each other, which leads to sustained “re-entry.” Thus, re-entry requires an appropriately timed stimulus (trigger) that is able to find its way into a circuit (substrate) where its depolarizing wavefront never encounters refractory tissue.

(Fig 1)

 Re-entry. a) A sinus impulse activates area A. b) A premature beat arising in area B fails to reach area A because the intervening tissue remains refractory from the preceding sinus beat. c) The premature stimulus travels slowly via an alternative route back to area A, allowing enough time for area A to recover and be excited. d) Area A re-excites area B, and the cycle sustains itself. This particular example illustrates the mechanism of typical atrial flutter. Photo: Christine Kenney

Anatomic versus functional re-entry. In anatomical re-entry, circuit size is determined by fixed anatomic obstacles (left). In functional re-entry (middle), circuit size = conduction velocity х refractory period (length of the refractory tail). If the wavefront travels too quickly, or its refractory period is too long, its leading end would “bite its tail” and extinguish itself (right). Thus, these properties determine the smallest possible circuit size. Photo: Christine Kenney

Action potential duration: normal versus after atrial fibrillation. The action potential duration and refractory period are shortened as the calcium current is reduced. Photo: Christine Kenney