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Clinical Articles, Featured

News from the ESC 2016


Clinical Articles, Lead Article

ENSURE AF: edoxaban allows prompt cardioversion in AF

The study also showed that newly diagnosed non-anticoagulated AF patients can start edoxaban as early as two hours prior to their cardioversion procedure if they have access to transoesophageal echocardiography (TEE) or three weeks prior to the procedure without.

ENSURE-AF (Edoxaban versus Enoxaparin/Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation), the largest randomised clinical trial of anticoagulation for cardioversion in AF patients, involved 239 study sites in 19 countries in Europe and the US, and included 2,199 patients with non-valvular AF.

At the discretion of the physician, patients either received delayed cardioversion  (non-guided TEE stratum) or early cardioversion (TEE stratum).  They were then randomised equally into two anticoagulation treatments groups per stratum receiving either edoxaban (60/30 mg once daily) or enoxaparin and warfarin (INR 2.0–3.0).  Some 1,095 patients were randomised to receive edoxaban and the remaining 1,104 received enoxaparin/warfarin.

Primary efficacy outcomes (a composite of stroke, systolic embolic event, myocardial infarction and cardiovascular death) were not significant being reached in 0.5% patients (n=5) in the edoxaban arm versus 1.0% (n=11) in the enoxaparin and warfarin arm.

Safety outcomes showed no increased risk of major or clinically relevant non-major bleeding, which were similarly low between the two arms.

Net clinical outcome showed a trend to better outcome in the edoxaban arm but this was not significant.

The study presenter Dr Andreas Goette (St Vincenz Hospital, Paderborn, Germany) said while conventional anticoagulation works well, it has a major limitation in that it requires regular monitoring and dose adjustment to ensure that patients reach anticoagulation targets, which means cardioversion can sometimes be delayed for several weeks.

“Edoxaban,” he continued “may allow prompt cardioversion to be performed following the start of anticoagulation.”

Discussant of the study at the hotline session, Dr Riccardo Cappato (Policlinico San Donato, Milan, Italy) said: “Edoxaban administered at the maximally tolerated single daily dose in the peri-procedural phase of elective AF cardioversion can be considered a safe and effective alternative to VKA therapy”.

The study was simulataneously published in The Lancet (doi: 10.1016/S0140-6736(16)31474-X) on August 30th 2016.


Clinical Articles, Lead Article

Commentary on ENSURE-AF

ENSURE-AF is a multinational phase 3 study, which evaluated the efficacy and safety of the oral, once-daily direct factor Xa-inhibitor edoxaban compared to enoxaparin/warfarin for the prevention of stroke, and other thrombotic complications, in patients with non-valvular atrial fibrillation (NVAF) undergoing electrical cardioversion. Dr Joseph discusses the implications for practice.


Clinical Articles, Lead Article

ANNEXA 4: reversal agent shows efficacy in acute bleeding

ANNEXA-4 (Andexanat Alfa, a Novel Antidote to the Anticoagulation Effects of FXA inhibitors) is the first study to look at andexanet in acutely bleeding patients.  The study was not randomised for ethical reasons and interim results in 67 patients, who required urgent reversal of acute major bleeding within 18 hours of receiving either a direct or indirect factor Xa inhibitor, were given andexanet alfa in a bolus over 15-30 minutes followed by a two-hour infusion.

An efficacy assessment carried out in 47 patients showed an 89% decrease in anti-factor Xa activity from baseline to end of bolus for those exposed to rivaroxaban  (n=26 ) and 93% for those exposed apixaban (n=20).   At 12 hours, clinical haemostatic efficacy was rated as good to excellent in 79% of patients.

Thrombotic events occurred in 18% of patients during the 30-day follow up. “This rate of events is not unexpected considering the thrombotic potential of the patients and the fact that in most of them anticoagulation was discontinued at the time of bleeding and not restarted,” said Dr Stuart J Connolly (McMaster University, Hamilton, Ontario, Canada) speaking at the ESC hotline session where the data was presented.


Clinical Articles, Lead Article

New ESC/EACTS guidelines for the management of AF

In addition, the guidelines deal with long-term challenges in the management of AF patients, with recommendations on what to do when patients develop complications on anticoagulation, re-initiation of anticoagulation after a bleed, how to manage bleeds, and how to manage patients who have an ischaemic stroke on anticoagulation.

Key new recommendations are summarised (table 1). Free smartphone tools are provided for patients with AF and their healthcare professionals via the ESC Pocket Guidelines App.

Table 1. What’s new in the ESC-EACTS guidelines on AF?

Table 1. What’s new in the ESC-EACTS guidelines on AF?


1. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016.


Clinical Articles, Lead Article

‘True’ costs of NOACs assessed

The investigators looked at 14,024 patients in the ENGAGE AF-TIMI 48 study and compared hospitalization rates. Rates (per 100 patient-years) of cardiovascular-related admissions, including haemorrhagic and ischaemic stroke, were lower with edoxaban (60/30 mg) than warfarin (12.8 vs. 13.9; p<0.0001). Rates of total non-stroke bleeding-related admissions were also lower with edoxaban (60/30 mg)  (2.38 vs. 2.45; p<0.0001), due to fewer subdural/epidural haematomas (0.10 vs. 0.23; p<0.0001) and extracranial bleeding complications (1.08 vs. 1.14; p<0.0001). Overall, total cardiovascular bleeding hospitalisation costs were US$147/patient-year less with edoxaban (60/30 mg) compared to warfarin (p=0.0004).

This “may to some extent offset increased drug treatment costs associated with edoxaban versus warfarin,”  said Dr Magnuson.


1. Magnuson E at al. Hospitalization-related costs among patients with atrial fibrillation treated with the factor Xa inhibitor edoxaban vs warfarin: results from the ENGAGE AF-TIMI 48 trial. Abstract P4970. Eur Heart J 2016;37(Abstract supplement):1007.


Clinical Articles, Lead Article

Smartphone monitoring detects atrial fibrillation

A low-cost application (app) has been developed that uses the phone’s own accelerometer and gyroscope to check for AF.

The study he presented tested the ability of a smartphone to detect AF without any add-on hardware. The study included 16 AF patients from the Turku Heart Centre. In addition, 20 recordings from healthy people were used as a control group data to validate the developed algorithm. To detect AF, a smartphone was placed on the chest of the patient, and accelerometer and gyroscope recordings were taken. Patients were advised to lie in a prone or supine position during the measurements.

Using this technology the investigators detected AF with a sensitivity and specificity of more than 95%.“We measure the actual motion of the heart via miniature accelerometers and gyroscopes that are already installed in today’s smartphones,” said Mr Koivisto. “No additional hardware is needed and people just need to install an app with the algorithm we developed.”

Mr Koivisto concluded: “This is a low cost, non-invasive way to detect atrial fibrillation that people can do themselves without any help from medical staff. Given the widespread use of smartphones, it has the potential to be used by large populations worldwide”.


1.  Koivisto T et al. Detecting atrial fibrillation via existing smartphones without any add-ons. Abstract 4237. Eur Heart J 2016;37 (Abstract supplement):825-6.


Clinical Articles, Lead Article

Historic Papal visit to Congress


Clinical Articles, Featured

Expert suggests there is ‘no absolute age cut-off for anticoagulation’

Antiplatelet, anticoagulant, and fibrinolytic drugs can prevent, postpone, or attenuate the severity of thrombotic events – such as stroke, and myocardial infarction (MI), and retard cardiovascular and all-cause death, particularly in elderly patients, but at the cost of increased bleeding. The critical conundrum is whether, in the older patient, the benefits outweigh the bleeding risks, in the view of the paper’s authors.

To avoid older people being denied antithrombotic drugs because of unjustified concerns, or conversely being inappropriately over-treated, this patient oriented consensus document has focused on age-specific risks and benefits of antithrombotic drugs tested in phase III trials and provides recommendations

Professor Felicita Andreotti (Catholic University, Rome, Italy)

Professor Felicita Andreotti (Catholic University, Rome, Italy)

BJC Arrhythmia Watch interviewed the lead author, of the paper Professor Felicita Andreotti, Institute of Cardiology, Catholic University, Rome, Italy, who summarises many of the key recommendations.

Is this the first such paper which focuses on the elderly?

“This is the first paper to focus on antithrombotic therapy in the elderly in a systematic and comprehensive way. The paper reports age-stratified thrombotic and bleeding event rates extracted from the major randomised trials of oral or parenteral antithrombotic drugs for both arterial and venous diseases. For the first time, a table of recommendations is provided.

There are sections on non-vitamin K antagonist oral anticoagulants, fibrinolysis, how to prevent and manage bleeding, and discussion of clinical cases. The whole document is supported by a European and partly North American panel of experienced clinician-scientists”.

Integrating age in to thrombosis and bleeding risk appears to be challenging. Is there now a case for all patients over a certain age (>65 years) to have a CHA2DS2-VASC and HAS-BLED assessment prior to commencing anticoagulation?

“We believe the scores should be used regardless of age whenever antithrombotic therapy is being considered. These two scores – assessing thromboembolic and bleeding risk in a semi-quantitative way – were developed for patients with atrial fibrillation but can be applied to other patient groups and to antithrombotic agents other than anticoagulants. Both scores include age as an essential component. Other items of the scores, such as hypertension, concomitant intake of drugs that affect haemostasis, alcohol abuse, and suboptimal INR, can potentially be modified to reduce the risk of adverse events.”

Is such assessment feasible/suitable for the primary care (i.e. GP) setting?

“The simplicity and broad applicability of these scores make them feasible and suitable for all care settings including primary care”.

Are there other risk engines for the elderly in the pipeline or in current use?

“Most risk calculators for thrombosis, bleeding or early death consider age. In the setting of acute coronary syndromes, for instance, the GRACE 2 and TIMI scores, that estimate the probability of short-term death, both include age, while the CRUSADE score, that predicts rates of in-hospital major bleeds, integrates age indirectly through the Cockcroft-Gault formula and through the presence or absence of diabetes, anaemia, vascular disease and heart failure, which are all more prevalent in the elderly”.

Is there any absolute age cut-off beyond which anticoagulation should not be introduced or is it more a component of biological versus chronological age?

“There is no absolute age cut-off for anticoagulation. In fact, none of the recent anticoagulation trials in atrial fibrillation excluded patients because of advanced age. In older patients, however, lower doses of dabigatran (in Europe), apixaban (if combined with either poor renal function or low body weight) and enoxaparin are recommended.

For those aged 75 or above we also recommend caution with glycoprotein IIb/IIIa inhibitors and with fibrinolysis, avoidance of a clopidogrel bolus with fibrinolysis, and half dose tenecteplase with the pharmacoinvasive strategy.

The patient’s history, particularly of prior stroke/TIA and especially of intracranial haemorrhage, may represent an absolute contraindication for strong antiplatelet agents, for fibrinolysis, or for prolonged dual or triple antithrombotic therapy.

Renal function needs to be assessed to dose-reduce or avoid drugs that are mainly renally cleared, such as low molecular weight heparins, fondaparinux, dabigatran, bivalirudin, eptifibatide and tirofiban.

The greatest challenge is that age and other predictors of thrombosis overlap with predictors of bleeding, pointing at an overall vascular vulnerability of the older individual.

As the growing global population ages, there is a special need for randomised evidence to guide and refine antithrombotic therapy in the elderly”.


1. Andreotti F, Rocca B, Husted S, et al. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Euro Heart J 2015;36:3238–49.


Clinical Articles, Lead Article

Syncope – improving approaches to diagnosis and treatment

Syncope is a common medical problem that can be debilitating and is associated with high healthcare costs. There is wide variation in practice of syncope evaluation, and wide variation in adoption of recommendations from published guidelines. The absence of a systematic approach to transient loss of consciousness(T-LOC) incurs higher health and social care costs, unnecessary hospitalisations, and diagnostic procedures, as well as prolongation of hospital stays, lower diagnostic rates, and higher rates of symptom recurrences, according to the new document.

Therefore, a systematic approach, set out in this new document, by a dedicated service (an SU), equipped to evaluate and manage this common problem may ensure better management of T-LOC, from risk stratification to diagnosis, therapy and follow-up

Professor Michele Brignole (Ospedali del Tigullio, Italy)

Professor Michele Brignole (Ospedali del Tigullio, Italy)

Patients with syncope may often present in primary as well as secondary care. There are many causes of syncope, some common and some rare. Reflex Syncope is the most common cause of blackouts. However, many people, including medical professionals, are unaware that some everyday activities can be the cause of many reported fainting attacks (see:

Despite the recommendation from the ESC, SUs are not widely established in clinical practice in the UK and other European countries. Possible reasons for this include:

- Lack of awareness of the benefits of an SU due to inadequate research trials comparing SUs to normal practice

- Underestimation of consequences of syncope

- Lack of awareness of benefit of an SU on quality-of-life

- Low numbers of syncope specialists

- Lack of formal syncope training programmes

Professor Rose Anne Kenny (Trinity College, Dublin)

Professor Rose Anne Kenny (Trinity College, Dublin)

BJC Arrhythmia Watch interviewed, Professor Michele Brignole, Head of Department, 
Arrhythmology Centre, Department of Cardiology,
 Ospedali del Tigullio, Lavagna, Italy, and Professor Rose Anne Kenny, Professor of Medical Gerontology, Trinity College, Dublin, the co-chairpersons of the Position Paper  about the concept of an SU and why barriers exist to their wider adoption.

A number of barriers to establishing a SU have been identified. Why do you think there are so few specialists, is this possibly due to some ‘political rivalry’ between care of the elderly, neurologists, cardiologists, cardiac electrophysiologists, or mainly that it is not a recognised sub-specialty, and what is being done to address this?

“Syncope is not a recognised sub-speciality by most. The EHRA consensus document is aimed at achieving that”

Who ‘owns’ these patients i.e. who should primarily care for the syncopal patient?

“Syncope is a symptom, not a disease. Depending on the different aetiology of syncope, cardiologists, neurologists, internists, geriatricians, should take care of these patients. Most syncope has unexplained aetiology. The final results are that nobody ‘owns’ syncope patients.”

Professor Kenny commented:

The consensus was that there was no evidence for superiority of one specialty over another for managing syncope – the leadership could come from any interested specialty provided that the SU could deliver the multidisciplinary approach recommended”.

Are investigations such as tilt testing available in many general cardiology units in the UK or other European countries or is it under-provided and only seen in highly specialist centres?

“I believe that tilt testing is performed in many general hospitals in the UK and Europe, not necessarily in cardiology departments. However, specialised, structured units, i.e. syncope units, are rare”.

How many units are there in Italy, for example?

“There are 72 Gruppo Italiano Multidisciplinare per lo Studio della Sincope [GIMSI] certified units in Italy”.

Professor Kenny added:

In order to deliver a structured training program the Royal College of Physicians in Ireland has developed a diploma course in ‘Syncope and related disorders’. This is a year long course of lectures/workshops, digital curriculum and practical sessions. This is its second year. Participants are predominantly from British and Irish Isles and to a lesser extent to date, other European centres.

Syncope – Arrhythmia Alliance UK 2016 Cardiac Update Meetings

‘Setting up a T-LOC/syncope clinic’ will be one of the topics covered in the series of Regional Cardiac Update meetings organised by the Arrhythmia Alliance throughout 2016:

The meetings are intended for healthcare professionals involved in the management and treatment of arrhythmias. The meetings also provide a platform for education and networking and sharing best practice on related topics, such as syncope.

Further information is available from:


1. Kenny RA, et al. Syncope Unit: rationale and requirement – the European Heart Rhythm Association position statement endorsed by the Heart Rhythm Society. Europace 2015;17:1325–40.

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