Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04041778 |
| Other study ID # |
0689 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 25, 2019 |
| Est. completion date |
September 2024 |
Study information
| Verified date |
March 2023 |
| Source |
University of Leicester |
| Contact |
Ghulam Andre Ng, MBChB, PhD. |
| Phone |
0116 250 2438 |
| Email |
andre.ng[@]leicester.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Atrial fibrillation (AF) is the most common type of chronic heart rhythm disease worldwide,
with significant associated co-morbidities. Although there have been advances in
understanding the mechanisms of AF, the underlying cause of AF and factors which perpetuate
it remain incompletely understood. This is particularly the case for persistent AF (persAF).
Drug treatments for persAF have a role but can have undesirable side effects with relatively
limited efficacy. Furthermore, current invasive therapies for persAF remain suboptimal,
requiring significant resources, and with potentially serious complications for patients.
Catheter ablation is an effective treatment for paroxysmal AF. For persistent AF (persAF),
however, catheter ablation does not provide similar results. This is because there remains a
poor understanding of the electrophysiological mechanisms driving persAF. Part of this study
aims to further explore the specific locations that represent important substrates which
would guide more effective catheter ablation. There have been several different ablation
approaches explored in the past (see below), however, these did not improve the outcome post
procedure compared with pulmonary vein isolation alone. A pilot study has already been
carried out and I aim to expand this further with a larger cohort of patients (10-20) over 2
years. In this study the investigators want to explore whether stable high dominant frequency
(HDF) sites (with a high organisation index) act as potential drivers of Atrial Fibrillation.
Thus, targeting these sites may results in prolongation of the cycle length and thus possible
termination of the arrhythmia.
Description:
There are an estimated 1.4 million people in the UK with atrial fibrillation (AF), which
accounts for 2.4% of the adult population.1 It is well established that AF is a major
causative factor for ischaemic stroke and systemic embolism.2 In addition, strokes resulting
from AF carry the highest morbidity and mortality of any other form of stroke. AF is also
associated with increased morbidity in relation to heart failure.3,4,5 The UK 2016/7 Sentinal
Stroke National Audit Programme (SSNAP) reported that in 7,483 patients with known AF who
were not anticoagulated before their stroke, there was a 26% mortality and 45% were
discharged with moderate-severe disability.6 AF, therefore, is not only associated with
increased mortality and morbidity but also significant healthcare costs.
Broadly speaking AF is characterized by a rapid erratic depolarization of the atrial
myocardium which manifests clinically as an irregular pulse which can be rapid. This is
diagnosed initially on clinical suspicion by palpation of the pulse and then definitively by
an ECG which will show irregular intervals between the QRS complex and absence of a P-wave.
Clinically patients may be asymptomatic, however typical associated symptoms include
palpitations, (exertional) dyspnoea, syncope/presyncope and chest pains. The patient may
experience a variation of these symptoms.
The classification of AF is dependent on several factors: presentation, duration and
spontaneous termination. There are 5 defined patterns of AF: First diagnosed AF is that which
has not been previously diagnosed irrespective of duration and severity of AF-related
symptoms. Paroxysmal AF which self terminates, usually within 48 hours. This includes AF
episodes which are cardioverted within 7 days. Persistent AF, which lasts longer than 7 days.
Long standing persistent AF, continuous AF lasting >1 year when it is decided to adopt a
rhythm control strategy. Permanent AF implies that AF has been accepted by both the patient
and the physician, therefore there would be no further pursuit of rhythm control
intervention. [2016 ESC Guidelines for the management of atrial fibrillation].
The management of AF is two-fold. Where clinically indicated the patient should be
anticoagulated. Over the last seven years four non-VKA OACs (NOACs)-dabigatran, a direct
thrombin inhibitor and rivaroxaban, apixaban and Edoxaban, factor Xa inhibitors-have been
tested against warfarin in large randomised controlled trials.7-10 These NOACs have been
shown to be at least as effective as warfarin in stroke prevention, with a superior safety
profile, consistently reducing intracranial haemorrhage.11 Other practical advantages of the
NOACs include very few drug interactions and a predictable onset and offset that eliminates
the requirement for regular anticoagulation monitoring. This has led to the 2014 NICE AF
Guideline giving an equal first-line recommendation for NOACs alongside warfarin for stroke
prevention.12 NICE also recommends that the options for anticoagulation should be discussed
with the patient and the choice should be based on their clinical features and preferences.
The second treatment option is pursuit of either a rhythm or rate control strategy. Rate
control is achieved via drug therapy. When aiming for rhythm control the option are 1)
anti-arrhythmic drugs (AADs) or 2) Invasive catheter ablation.
At present, current AADs have limited efficacy in maintaining sinus rhythm in patients with
AF. In addition, there side effect profiles may prevent their long term use in some patients,
even where they are maintaining sinus rhythm.13 The most common drug used for maintenance of
sinus rhythm is Amiodarone which carries a significant side effect profile. In particular
there is a risk posed from long term use of thyroid dysfunction (hyper- or hypothyroidism),
liver cirrhosis and lung fibrosis.
Patients who have intolerable symptomatic AF which is not responding to medical therapy can
be offered invasive treatment in the form of an ablation. The two methods of ablation are
cryoablation and radiofrequency ablation. The procedure is carried out under sedation or
general anaesthesia. Catheters are introduced via sheaths placed in the femoral vein and
guided up to the right atrium. Catheters are usually placed at the level of the His and CS.
The patient is given heparin and a transeptal puncture is performed to gain access to the
left atrium. The pulmonary veins are located and radiofrequency energy or the cryoballoon is
applied to specific areas of the left atrial myocardium and around the pulmonary veins. The
patients cardiac rhythm is monitored via body surface ECGs and intracardiac electrograms
(EGMs). Piccini et al published a meta-analysis in 2009 which showed that PVI increased
freedom from AF at 1 year, compared with a non-ablation treatment strategy in those patients
with paroxysmal AF.14 Outcomes in persAF are less encouraging. Patients may require multiple
procedures to gain true symptom control. Catheter ablation is not without it risks. These
include Stroke, cardiac tamponade, diaphragmatic paralysis secondary to damage to the phrenic
nerve and oesophageal perforation. Appropriate patient selection is therefore incredibly
important.
Sustained AF perpetuates further AF. Simply put, this occurs because with sustained AF the
atria become fibrosed and therefore exhibit scar. Over time the atria become electrically and
structurally remodeled causing further perpetuation of the arrhythmia.
A paper by Haïssaguerre et al. in 1998 showed that when the atria and pulmonary veins were
mapped with intracardiac catheters isolated ectopic activity was a trigger for a pAF episode.
Theses site then underwent RF ablation. The pulmonary veins were found to be the predominant
sites of earliest activation and RF ablation at these sites prevented further pAF.15
Pulmonary vein isolation is now the cornerstone of therapy for patients with symptomatic drug
refractory pAF.
A better understanding of the mechanisms of persAF is still needed to improve catheter
ablation outcomes. Over the last decade, different ablation approaches have been proposed
including i) an anatomical one, with ablation lines mimicking the Cox Maze procedure, and ii)
electrical strategies which aim at identifying critical atrial sites with electrical
signatures that harbour areas of relevant remodeling believed to perpetuate or drive the
chaotic fibrillatory rhythm, whereby their ablation would terminate AF and prevent its
induction. Early results appeared promising ablating at sites where the recordings indicated
complex fractionated atrial electrograms (CFAEs) and also with a signal processing approach
to identify focal and /or rotor activity (FIRM mapping) but these results were proved to be
difficult to replicate and a more recent randomised study (STAR-AF II) showed that generic
linear and CFAE ablation did not improve the ablation outcome over and above pulmonary vein
isolation (PVI) alone.16
Also, heterogeneity in patient characteristics would explain the variable results and
precision medicine approaches are needed to design patient specific therapeutic strategies.
Better ways to identifying relevant atrial substrate are needed and to demonstrate that
targeting these locations improve ablation outcome.
Study Hypothesis
There are specific locations within the atria (left atrium specifically) which exhibit
electrical characteristics which act as drivers in persistent atrial fibrillation. These
sites can be analysed by non-contact mapping techniques which will more accurately guide
catheter ablation.
Proposal
The aim of USURP-II AF is to expand upon the work carried out in USURP-I and that is to be
able to determine driver characteristics and mechanisms of persistent atrial fibrillation.
The investigators still need to better understand the electrophysiological mechanisms
underlying persistent AF so that the investigators can have a guided approach to ablation in
persistent AF. Limitations of USURP-I included too shorter data analysis times (30 seconds
only from 5 minutes of exported data) purely due to lack of computer processing power. In
addition, only centre of gravity of DF clouds were analysed and no comparison of rotor
behaviour was done. The latter analysis is now possible. In the original study both
prolonging of the cycle length and termination of the arrhythmia were end points in
determining successful vs. unsuccessful ablation. Analysis of both DF and rotor behaviour at
successful vs. unsuccessful sites in longer recordings would allow refinement of the
characteristics and criteria for ablation which the investigators plan to apply prospectively
in this new study.
It should be noted that this is not a clinical trial and that I am studying the different
mechanisms of PersAF after applying the below ablation strategy, rather than outcomes. The
patients recruited will be on a standard care pathway and will not be recruited for the sole
purposes of the study. The following is broad overview of the how I intend to carry out the
clinical aspect of the study.
