Implementing vernakalant: a novel approach to cardioversion
evidence and practice    

Free Implementing vernakalant: a novel approach to cardioversion

Angela Hall Arrhythmia nurse specialist, Jersey General Hospital, St Helier, Jersey

Atrial fibrillation (AF) is the most common arrhythmia, and there is a one in four lifetime risk of developing the condition for people who are over the age of 40. Vernakalant, a new addition to intravenous antiarrhythmic drugs for cardioversion of AF, is the first atrial-specific antiarrhythmic drug for pharmacological cardioversion of recent onset AF and is more effective than placebo and amiodarone. The drug offers patients an alternative to other pharmacological agents for chemical cardioversion and avoids the risks associated with electrical cardioversion. Its main advantage is rapid conversion of AF, which potentially reduces atrial remodelling and it can be used in patients with little or no underlying cardiovascular disease and in those with moderate disease such as stable coronary and hypertensive heart disease. Post-marketing and clinical trials suggest a favourable rate of conversion to sinus rhythm. Jersey General Hospital was the first in the UK to obtain and introduce the drug in practice. This article describes the evidence and guidelines for its use and the local implementation process.

Emergency Nurse. doi: 10.7748/en.2018.e1902

Citation

Hall A (2018) Implementing vernakalant: a novel approach to cardioversion. Emergency Nurse. doi: 10.7748/en.2018.e1902

Peer review

This article has been subject to external double-blind peer review and has been checked for plagiarism using automated software

Correspondence

an.hall@health.gov.je

Conflict of interest

None declared

Published online: 11 December 2018

Introduction

Atrial fibrillation (AF) is the most common arrhythmia and prevalence increases with age (Camm et al 2010). Figures suggest there is a one in four lifetime risk of developing the arrhythmia for people who are over the age of 40 (Heeringa et al 2006). Epidemiological data suggest that more than six million people in Europe may have the arrhythmia and the projected number of those with AF is set to at least double in the next 40 years (Naccarelli et al 2009, Savelieva et al 2011).

Vernakalant is a novel choice of antiarrhythmic for use in recent onset AF in non-surgery adult patients with AF ≤ seven days duration or post-cardiac surgery patients with AF ≤ three days duration (Cardiome International 2015). It offers an alternative to other pharmacological agents for chemical cardioversion and avoids the risks associated with electrical cardioversion. Post-marketing and clinical trials suggest a favourable rate of conversion to sinus rhythm. This is echoed by data obtained through local use.

Key points

  • Vernakalant can be a valuable alternative to other antiarrhythmic agents or electrical cardioversion in patients with recent onset atrial fibrillation (AF) in acute settings

  • The drug can be offered to a broader patient population than other antiarrhythmics and results in more rapid conversion with consequent reduced hospital stay

  • Local audit data complements the findings of large randomised studies with high numbers of patients converting to sinus rhythm and being discharged home from the emergency department

  • The increasing number of people with AF requires a novel approach to treatments that support early and safe discharge

Background

AF has become an increasing public health problem and is associated with a substantially elevated risk of thromboembolic events and stroke (Blaauw and Crijns 2008, Camm et al 2010). There is also evidence that AF decreases quality of life; reduces exercise capacity; has a negative consequence on left ventricular function; increases hospitalisation and length of stay; and increases the risk of heart failure and even death (Blaauw and Crijns 2008, Camm et al 2010).

AF and atrial flutter are the most frequently encountered cardiac arrhythmias in emergency department (EDs) and AF represents more than one third of all dysrhythmia-based hospital admissions in the UK (Stellbrink 2010, Stiell et al 2017). Management of these patients follows either a rate or rhythm control approach and this can be multifactorial. Treatment may be determined by:

  • Duration of AF.

  • Patients’ age and co-morbidities.

  • Characteristics of the AF and whether it is paroxysmal, persistent or permanent.

Evidence does not suggest superiority of one approach over another in general management principles of AF (Opolski et al 2004, Roy et al 2008, Yildiz et al 2008), but rhythm correction should be considered when there is haemodynamic instability or if patients have distressing signs and symptoms.

Preventing treatment delay is vital to avoid further deterioration in signs and symptoms or to structural remodelling (Bash et al 2012). When rhythm control is the preferred option this may be through electrical cardioversion or pharmacological cardioversion using antiarrhythmic drugs. Until recently choice of antiarrhythmic drugs for pharmacological cardioversion was limited and some, for example flecainide, were only an option for highly selected patients (patients must have a structurally normal heart). Vernakalant is a new addition to intravenous (IV) antiarrhythmic drugs for cardioversion of AF (Camm et al 2012), is the first atrial-specific antiarrhythmic drug developed for pharmacological cardioversion of recent onset AF (Savelieva et al 2014) and has been shown to be more effective than placebo and amiodarone (Camm et al 2012).

The main advantage of vernakalant is rapid conversion of AF, which potentially reduces atrial remodelling. It can be used in patients with little or no underlying cardiovascular disease and in those with moderate disease, such as stable coronary and hypertensive heart disease. Vernakalant can also be given to those with mild heart failure and ischaemic heart disease providing they are not hypotensive or do not have severe aortic stenosis (Torp-Pederson et al 2013). Vernakalant has sodium and potassium channel blocking properties and blocks these channels in all phases of the action potential (Fedida et al 2005).

The drug is licensed for use in adults with an AF ≤ seven days duration or post-cardiac surgery patients with AF ≤ three days (Cardiome International 2015) but for reasons of clarity, safety and efficacy in terms of thromboembolic risk, uncertainty about duration of AF and effectiveness, most post-marketing use has centred on patients with clear onset of signs and symptoms and AF of ≤ 48 hours duration.

Evidence

Due to limitations of existing therapies, vernakalant was produced as an effective option for pharmacological cardioversion. The Atrio Arrhythmia Conversion trials (ACT) I and III showed vernakalant was significantly more effective than placebo in converting AF (51.7% compared to 4% and 51.2% compared to 3.6% respectively) (Roy et al 2008, Pratt et al 2010). ACT IV (Stiell et al 2010) demonstrated restoration of sinus rhythm in 50.9% of patients within 14 minutes after starting the infusion, while ACT II (Kowey et al 2009) examined post-cardiac surgery AF patients and found that 47% converted within 90 minutes of the start of treatment with a median conversion time of 12 minutes. A phase III superiority study of vernakalant vs amiodarone in subjects with recent onset atrial fibrillation (AVRO) (Camm et al 2011) compared vernakalant to amiodarone and 51.7% of subjects converted within 90 minutes compared to 5.2% treated with amiodarone.

In the pooled analysis, vernakalant was 8.4% more likely to convert AF to sinus rhythm than placebo or amiodarone without excess risk of adverse events (Bucceletti et al 2012). These studies generally included patients with a longer duration of AF, but post-marketing studies have identified conversion rates as high as 95% when the drug is administered within 48 hours of onset (Abidin et al 2012). Maintenance of sinus rhythm at seven days was also reported as high as 93% in ACT I, III and IV (Roy et al 2008).

Post-marketing studies have identified even higher numbers of patients who successfully cardioverted with vernakalant infusion when targeting those with acute onset (≤48 hours duration). Conversion was as high as 95% in Abidin et al’s (2012) study, 86% in an efficacy and safety study (Caballero-Requejo et al 2018) and 77.6% in a study evaluating its use in an ED (Dalman et al 2017).

Conversion times are also favourable when vernakalant is compared to other antiarrhythmic agents. Cardioversion speed was analysed in Bash et al’s (2012) systematic review of vernakalant and comparators and demonstrated amiodarone as the slowest with mean or median conversion times in the region of 8-12 hours. Flecainide was relatively quicker with conversion times averaging at 14-22 minutes and vernakalant the quickest with median conversion times equating to 8-11 minutes (Pratt et al 2010, Bash et al 2012).

A phase IIIb study (ACT V) in 2010 was stopped after a single serious case following infusion of vernakalant. It could not be certain that the drug was not involved therefore the study was discontinued and unpublished (Camm 2014). Supportive research has continued to demonstrate the effectiveness of vernakalant in practice, but it is important to note that the drug has not been implemented in the US due to safety concerns (Camm 2014).

Local implementation

Jersey was the first place in the UK to obtain and implement vernakalant in practice in 2016. The drug is widely used across Europe and was given a grade IA recommendation by the European Society of Cardiology in its guidelines on the management of AF when there is no structural heart disease (Kirchhof et al 2016). As a result of local implementation, protocols and policies written by the author have been shared with interested centres in the UK (Figure 1). There is gradual interest with wider applications reaching the relevant drugs committees which will hopefully result in the drug’s use in more acute settings.

Figure 1.

States of Jersey protocol for the administration of vernakalant

en.2018.e1902_0001.jpg

In Jersey General Hospital the process for obtaining vernakalant began following a conference presentation that the author attended at the Heart Rhythm Congress. As a novel approach to treating AF, the presentation and evidence were inspiring and intriguing and led me to make further enquiries. Following a review of the clinical trials and evidence to date I discussed introduction of the drug with the local cardiologist and applied to have vernakalant introduced locally through the hospital’s drugs and therapeutics committee. Initially there were complications in sourcing the drug, however these were overcome, and the committee approved unanimously its introduction following a presentation on its effectiveness. A robust local policy was supported with an algorithm and checklist, all written by the author, to enable safe application and patient selection. Implementation of a new and unfamiliar medicine can pose uncertainty and hesitation, therefore I spent time giving presentations and education and providing a presence in the relevant departments to try to reduce clinicians’ and nurses’ anxiety and promote confidence. This included medical staffing groups, governance groups and acute medical and emergency departments. Box 1 lists the main components of ensuring the change process was robust and implemented safely.

Box 1.

Implementing vernakalant at Jersey General Hospital

  • Interest in a novel antiarrhythmic drug first encountered at the Heart Rhythm Congress, Birmingham

  • Review of the evidence and trials to date

  • Discussion with local cardiologist

  • Evaluation of countries already using the drug, contacts and enquiries made

  • Review of guidelines on atrial fibrillation management (European Society of Cardiology)

  • Contact with the drug company

  • Liaison with the local Drugs and Therapeutics Committee about requirements when sourcing a new medicine

  • Protocol and policy for the implementation of vernakalant written

  • Review of new evidence and ongoing research compiled and discussed with consultant cardiologist, medical consultants and emergency department staff

  • Application approved for presentation at the drugs and therapeutics committee meeting

  • Simultaneous presentation of policy and protocol to local governance group

  • Presented with consultant cardiologist support with unanimous approval

  • Pharmacy liaison with drug company to obtain vernakalant, costings, delivery

  • Formal presentation and informal presence in the emergency department (and repeated)

  • Formal presentation to the medical staffing committee and sharing of policy and protocol to all acute medical areas and personnel who may encounter patients suitable for use

  • Frequent repetition of the above to ensure robust communication and as many personnel aware of the availability and appropriate use of vernakalant

  • Continuous audit of use and re-presentation of progress to using departments

  • Ongoing review of contemporary trials

  • Presentation back at the Heart Rhythm Congress demonstrating evidence and use as the first centre to be using vernakalant in the UK, sharing protocols and policy with interested UK centres (ten to date), and writing nursing and medical journal articles relating to this innovation

Stringency around safe medicine practice is essential and has contributed to a low incidence of complications and adverse reactions since local introduction of vernakalant. In the early days of administration, a senior cardiology doctor or I would visit the department concerned, but as experience has grown this has become less necessary as staff have become confident and competent in decision- making, prescriptions and administration. I also spoke informally with nursing staff to increase familiarity and awareness of vernakalant and shared practical components such as patient selection, how to administer the drug and the observations and monitoring required.

There is an ongoing local audit and the latest figures show an 87% success rate in converting patients from AF to sinus rhythm. One patient experienced sneezing, which is a known side effect, but there have been no other complications. All patients were discharged home after two hours of monitoring and at four-week follow-up patients who had received vernakalant were free of AF during this time.

Vernakalant is approved for marketing in Europe, Canada and several other countries, with a distribution network of more than 60 countries. In Europe it is approved for the rapid conversion of AF of onset of ≤ seven days or ≤ three days if AF occurs after cardiac surgery. IV vernakalant is not approved for use in the US, but is being re-presented in 2019 to the Food and Drug Administration without the need for additional evidence (Correvio 2018).

Patient selection and administration

Vernakalant is only available in IV form and must be given in an environment where continuous cardiac monitoring is available. Electrical cardioversion and defibrillation equipment must be easily accessible and close monitoring of vital signs is essential. Pre-existing hypotension or bradycardia excludes its use and patients should be adequately hydrated and haemodynamically optimised. Contraindications to receiving vernakalant are listed in Box 2 and the checklist (Box 3) must be strictly adhered to. Local practice is to administer a single dose of low molecular weight heparin, for example enoxaparin, at treatment dose (1.5mg/kg) unless there are contraindications. All patients must then be assessed using the CHA2DS2-VASc thromboembolism risk stratification tool (Box 4) and when the score is ≥1, patients should be consulted and prescribed anticoagulation with a direct oral anticoagulant where possible in line with European guidance (Kirchhof et al 2016).

Box 2.

Contraindications to the administration of vernakalant

  • Hypotension lower than 100mmHg

  • Recent (<30 days) acute coronary syndrome (NSTEMI, STEMI, unstable angina)

  • New York Heart Association classification III and IV heart failure

  • Severe aortic stenosis

  • QT interval prolongation (uncorrected QT at baseline >440msec)

  • Severe bradycardia

  • History of second or third-degree atrioventricular block in the absence of a pacemaker

  • In conjunction with intravenous class I and III antiarrhythmic drugs administered within four hours

(Source: ema.europa.eu/documents/product-information/brinavess-epar-product-information_en.pdf)

Box 3.

Checklist before administering vernakalant

Electrocardiogram ▭
Echocardiogram ▭
BRINAVESS (vernakalant) must NOT be given to patients with a ‘YES’ response below:
Does the patient have heart failure class New York Heart Association classification Ill or IV?YESNO
Has the patient presented with an acute coronary syndrome (including myocardial infarction) in the past 30 days?YESNO
Does the patient have severe aortic stenosis?YESNO
Does the patient have a systolic blood pressure < 100mmHg?YESNO
Does the patient have prolonged QT interval at baseline (uncorrected > 440 msec)?YESNO
Does the patient have severe bradycardia, sinus node dysfunction or second and third-degree heart block in the absence of a pacemaker?YESNO
Has the patient received an intravenous rhythm control antiarrhythmic drug (class I and/or class Ill) within four hours of the time when Brinavess will be infused?YESNO
Does the patient have hypersensitivity to the active substance or to any of the excipients?YESNO
Do NOT give other intravenous antiarrhythmic drugs for at least four hours after infusion of Brinavess
Box 4.

Thromboembolism and stroke risk stratification in atrial fibrillation

The CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes, stroke, vascular disease, age, sex) score
Risk factorScore
  • Congestive heart failure / left ventricular systolic dysfunction

1
  • Hypertension (treated or consistently above 140/90mmHg)

1
  • Age >75 years

2
  • Diabetes mellitus

1
  • Before stroke / TIA (trans-ischaemic attack)

2
  • Vascular disease (for example peripheral artery disease, myocardial infarction, aortic plaque)

1
  • Age 65-74 years

1
  • Sex category (female)

1
Total score0-9

Monitoring and further management

Patients should be closely observed and their blood pressure, pulse, oxygen saturations and respirations monitored during the infusion and for at least 15 minutes after completion. If there are adverse effects such as hypotension the infusion should be stopped (Figure 1). By stopping the infusion the adverse effects may stabilise but where intervention is necessary usual supportive measures should be undertaken, for example administration of IV fluids. Adverse effects have been reported more commonly in patients with pre-existing instability, hence the importance of adhering to the safety advice on contraindications and cautions. Continuous cardiac monitoring must be attached to patients throughout the infusion and they should be monitored for two hours after the start of the infusion and until clinical and ECG parameters have stabilised. If AF remains or develops into atrial flutter during the first infusion this should be continued followed by the 15-minute observation time. A second infusion will then be given and if AF or atrial flutter remains at this time alternative management should be adopted. This could include accepting the arrhythmia and achieving rate control. Beta blockers can be administered without waiting for the four hours necessary with alternative antiarrhythmics. Oral antiarrhythmic maintenance therapy can be resumed or initiated two hours after administration of vernakalant and anticoagulation must still be considered. Electrical cardioversion may be required but studies have not included electrical cardioversion within two hours of vernakalant administration, so outcomes are unknown.

The most commonly reported side effects include sneezing and dysgeusia and less commonly dizziness, headache, paraesthesia, bradycardia, hypotension, cough, nausea, vomiting and pruritus. There have been no reported adverse events since local implementation and vernakalant has been well tolerated. One patient experienced sneezing and one patient felt slightly dizzy.

Case study

A 62-year-old man with known paroxysmal atrial fibrillation (AF) attended an emergency department with a 20-hour history of palpitations, giddiness and chest pains. He had been investigated for palpitations two years before and found to have low-normal left ventricular function and mild mitral regurgitation on the echocardiogram. There were paroxysms of AF on ambulatory cardiac monitoring and the patient was taking bisoprolol and apixaban. He was an ex-smoker, who consumed around 12 units of alcohol a week and drank coffee. His heart rate was 112bpm initially on presentation, settling to 82bpm, AF. His blood pressure was 121/74mmHg and electrolytes were normal. The checklist (Box 3) was applied and there were no contraindications to vernakalant.

Vernakalant was prepared according to the patient’s weight (3mg/kg) and infused for more than ten minutes. The patient had taken his usual medicines earlier that day, including anticoagulation. Continuous cardiac monitoring was undertaken throughout the process with close observation of vital signs. No side effects were reported, and he converted to sinus rhythm at nine minutes. A further electrocardiogram (ECG) was obtained, and the patient was discharged home two hours after the start of the infusion and seen in the arrhythmia clinic for follow-up four weeks later. Figures 2 and 3 show the patient’s ECG before and after administration of vernakalant.

Figure 2.

Electrocardiogram before administration of vernakalant

en.2018.e1902_0002.jpg
Figure 3.

Electrocardiogram following cardioversion with vernakalant

en.2018.e1902_0003.jpg

Conclusion

Vernakalant offers a valuable alternative to traditional pharmacological agents or electrical cardioversion in acute hospitals managing patients with recent onset AF. The drug can be offered to broader patient populations than other antiarrhythmic medicines and results in more rapid conversion with reduced hospital stay. Local audit data complements the findings of large randomised studies with high numbers of patients converting to sinus rhythm, all of whom were discharged home from the ED. The rising numbers of people with AF requires novel approaches to treatments that support early and safe discharge.

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