(Brinavess) for the Treatment of Recent Onset Atrial Fibrillation May 2010

Vernakalant (IV) (Brinavess) for the treatment of recent onset atrial fibrillation

May 2010

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

May 2010

Vernakalant (IV) (Brinavess) for the treatment of recent onset atrial fibrillation

Target group • Atrial fibrillation (AF) - rapid conversion to normal sinus rhythm (NSR) in haemodynamically stable patients with recent onset AF (≤3 days post cardiac surgery, or ≤7 days otherwise).

Technology description Vernakalant (Brinavess, Kynapid, MK-6621, RSD-1235) is an atrial selective mixed sodium and potassium channel blocker with class I and III actions. It selectively prolongs the atrial refractory period and atrioventricular nodal conduction without inducing ventricular arrhythmias. Vernakalant is administered by peripheral intravenous infusion (IV) with 3mg/kg given over 10 minutes followed by an observation period of 15 minutes. If cardioversion is not achieved a second dose of 2mg/kg over 10 minutes may be administered.

An oral formulation of vernakalant is in phase II development for the treatment of chronic atrial fibrillation.

Innovation and/or advantages Vernakalant would provide an alternative to current pharmaceutical treatments for recent onset AF.

Developer MSD (Merk Sharpe & Dohme).

Availability, launch or marketing dates, and licensing plans Phase III clinical trials completed. Marketing Authorisation for the EU granted in September 2010.

NHS or Government priority area This topic is relates to the National Service Framework for Older People and Coronary heart Disease.

Relevant guidance • NICE technology appraisal in development. Dronedarone for atrial fibrillation and atrial flutter. Expected June 20101. 2 • NICE clinical guideline. The management of atrial fibrillation. 2006 . 3 • SIGN. Cardiac arrhythmias in coronary heart disease. 2007 . • American College of Cardiology (ACC), American Heart Association (AHA) and National Library for Health Guidance. Atrial fibrillation. 20074. 5 • Clinical Knowledge Summaries. Atrial fibrillation - management. 2007 . • European Society of Cardiology (ESC) guidelines. Guidelines for the management of patients with atrial fibrillation. 20066. • Clinical Knowledge Summaries. Cardiovascular risk - assessment and management. 20037.

Clinical need and burden of disease In 2008-09 there were 120,200 finished consultant episodes for atrial fibrillation and atrial flutter with people age 60+ years accounting for approximately 80% of this

2 May 2010

population. This represents 88,931 admissions, of which 55,522 were emergency admissions (I48)8. Atrial fibrillation is the most common cardiac arrhythmia and its prevalence increases with age from 0.5% at age 50-59 years to 9% at age 80-89 years. More than 46,000 new cases are diagnosed each year in the UK1.

Existing comparators and treatments In haemodynamically stable patients with AF without an acute identifiable precipitant (e.g. alcohol intake) which may revert spontaneously, a rhythm control strategy is preferred9, with:

Cardioversion to restore NSR2: • pharmacological cardioversion (PCV) – preferred strategy in very recent onset AF (<48 hours) o flecainide (IV). o amiodarone (IV, via central venous catheter). • electrical cardioversion (ECV) by cardiac pacing or direct current – preferred in more prolonged AF. Maintenance of NSR after cardioversion: • beta-blockers. • oral anti-arrhythmic agents e.g. sotalol, flecainide, propafenone, amiodarone.

Cardioversion is not always successful and follow-up studies show that approximately 50% of patients will be back in AF one year post conversion2.

Efficacy and safety Trial NCT00125320, 1235-0104, NCT00468767, 1235-0703, NCT00115791, 04-7-010, ACT 2; AF and atrial flutter ACT 1; short and long-term Cardiome 1235-0504, ACT (AFL) after heart surgery; AF; vernakalant vs placebo; 3; AF or AFL; vernakalant vernakalant vs placebo; phase III. vs placebo; phase III. phase III. Sponsor Astellas Pharma Inc. Astellas Pharma Inc. Astellas Pharma Inc. Status Published. Published. Trial complete and published in abstract. Source of Publication10, trial Publication12, trial Abstract14, trial registry15. information registry11. registry13.

Location EU, USA, Canada, Canada, USA, Denmark EU, USA, Canada, Argentina and India. and Sweden. Argentina, Chile, Mexico. Design Randomised placebo- Randomised, stratified, Randomised, stratified, controlled, unstratified. placebo-controlled. placebo-controlled. Participants n=190; adults; AF or AFL n=336; adults; stratified by n=276; adults; stratified by and schedule lasting 3-72 hours; after AF duration: 3 hours-7 days AF or AFL duration: 3 coronary artery bypass (short-term; n=237) or 8-45 hours-7 days (recent onset) surgery and/or valvular days (long-term). or 8-45 days. surgery; haemo- Randomised to vernakalant Randomised to vernakalant dynamically stable. 3mg/kg or placebo, with a 3mg/kg of placebo, with a Randomised to vernakalant second infusion of 2mg/kg second infusion of 2mg/kg 3mg/kg or placebo, with a or placebo if no conversion or placebo if no conversion second infusion of 2mg/kg to NSR observed after 15 to NSR observed after 15 or placebo if no conversion minutes. minutes. to NSR observed after 15 minutes. Follow-up Intense monitoring for 24 Intense monitoring for 24 30 days. hours; follow-up to day 30. hours; follow-up to day 30. 3 May 2010

Primary Conversion to NSR ≥1 Conversion to NSR ≥1 Conversion to NSR ≥1 outcome minute within 90 minutes minute within 90 minutes minute within 90 minutes (responders). (responders). (responders). Secondary For responders - time to For responders - time to For responders - time to outcomes conversion, time to conversion, NSR at 24 conversion. conversion for AF and AFL hours, proportion in NSR. sub-groups, NSR at 24 hours and 7 days, patient reported symptoms. Key results n=161 received therapy, of n=220 received therapy for n=190 received therapy for which 150 had AF. short-term AF. Conversion recent onset AF/AFL, of For vernakalant and to NSR in 51.7% with which 170 had AF. placebo respectively: vernakalant and 4% with For vernakalant and NSR conversion 44.9% vs. placebo (p<0.001). With placebo respectively: NSR 14.8% (p<0.001); for vernakalant, 76% converted conversion 47% and 3.3%. patients with AF NSR after a single dose, median Median time to conversion conversion 47% vs. 14% time to conversion 11 of 8 minutes. (p<0.001). minutes. 1 relapse to AF by For AF sub-group NSR Median time to conversion 24 hours. conversion: 52% and 3.6%. with vernakalant of 12 minutes, 75% responding to a single dose. 60% of responders in NSR at 24 hours, 57% at day 7. Adverse Serious AEs: 9.3% with Serious AEs: 13.1% with Severe AEs: 10% with effects vernakalant and 11.1% with vernakalant and 18.3% with vernakalant and 13% with (AEs) placebo. In first 24 hours 2 placebo. Most common placebo. Treatment related serious AEs reported with cardiac serious AE: serious AE in 3 patients vernakalant - hypotension recurrent AF requiring with vernakalant and 1 with and complete hospitalisation, 5.9% with placebo. 1 death with atrioventricular block. vernakalant and 12.2% with vernakalant. Most common Treatment emergent AEs placebo. Treatment AEs: transient dysgeusia within 24 hours: 38.4% emergent AEs with (22%) and sneezing (19%). with vernakalant and 31.5% vernakalant: hypotension with placebo; most and complete heart block in common were AF 8.4% vs. 3 patients. 9.3%, and nausea 5.6% vs. Rate of ventricular 3.7%. arrhythmias: 9.0% with Rate of ventricular vernakalant and 17.4% with arrhythmias similar in both placebo. groups; bradycardia events Most common AEs in the slightly more common with first 24 hours from vernakalant (6.3%) than vernakalant and placebo placebo (1.9%). respectively: dysgeusia (altered taste); 29.9%, 0.9%), sneezing (16.3%, 0%), paraesthesia (10.9%, 0%), nausea (9.0%, 0.9%), and hypotension (6.3%, 3.5%).

Trial NCT00281554, 05-7-012, NCT00668759, VERI-305- NCT00989001, 6517-CL- ACT 4; AF; vernakalant; AMIO, AVRO; AF; 0020, ACT V; AF; phase III. vernakalant vs amiodarone; vernakalant vs placebo; phase III. phase III.

4 May 2010

Sponsor Astellas Pharma Inc. Cardiome Pharma. Astellas Pharma Inc Status Trial complete and Trial complete and Ongoing. published in abstract. published in abstract. Source of Abstract16, trial registry17. Trial registry18, press Trial registry20, press information release19 release21. Location USA, Canada, EU, EU, Australia, Canada, USA, Canada, South Argentina and South Serbia and Ukraine. America and other Africa. countries. Design Uncontrolled, single arm. Randomised, double Randomised, placebo- placebo, active-controlled. controlled. Participants n=236; adults; symptomatic n=254; adults; symptomatic n=470 (planned); adults; and schedule AF for 3 hours - 45 days. AF for 3 - 48 hours. symptomatic AF for 3 Received vernakalant Randomised to vernakalant hours - 7 days; 3mg/kg with a second 3mg/kg with a second Randomised to vernakalant infusion of 2mg/kg if no infusion of 2mg/kg if no 3mg/kg or placebo, with a conversion to NSR conversion to NSR second infusion of 2mg/kg observed after 15 minutes. observed after 15 minutes; or placebo if no conversion or amiodarone 5mg/kg over to NSR observed after 15 60 minutes and 50mg over minutes. 60 minutes. Both with second placebo infusions. At 2 hours electrical cardioversion or rate control medication may be administered. Follow-up Intense monitoring for 24 Intense monitoring for 24 Intense monitoring for 24 hours; follow-up to 1 week. hours; follow-up to day 30. hours: follow-up to day 30. Primary Conversion to NSR ≥1 Conversion to NSR ≥1 Composite of hypotension, outcome minute within 90 minutes minute within 90 minutes ventricular arrhythmias and (responders). (responders). death, within two hours. Conversion to NSR ≥1 minute within 90 minutes (responders) Secondary Safety. For responders - time to Time to conversion, patient outcomes conversion within 90 reported symptoms 90 minutes, patient reported minutes after first exposure. symptoms 90 minutes after first exposure, quality of life at 2 hours, safety. Key results 50.9% of the patients with n=232 (received therapy). - recent onset AF (167 out of For vernakalant vs 236 patients who received amiodorane respectively: vernakalant) converted to responders, 51.7% vs 5.2% NSR within 90 minutes (p<0.0001); no AF after the start of the first symptoms at 90 minutes, Vernakalant infusion. 53.4% vs 32.8% Median time to conversion (p<0.0012); quality of life, with vernakalant was 14 vernakalant 10.9 vs 5.6 minutes among point increase (p<0.006). respondersa. Expected Publication in press Presentation on 14 May May 2011 (final data reporting (American Heart Journal)b. 2010 at Heart Rhythm collection for primary date Society conference, outcome). Denver, USA.

a Company provided information. 5 May 2010

Adverse Recorded adverse events; Recorded adverse events - effects 30 patients (13%) had total for vernakalant and (AEs) of 40 serious AEs. The amiodrane respectively most common were were; dysgeusia 6.9% vs recurrent AF (8 episodes), 0%; cough 3.4% vs. 1.7%; hypotension (5), and sneezing 3.4% vs. 0%; bradycardia (5). 6 patients atrial fibrillation 3.4% vs. had treatment-related 0%; nausea 2.6% vs. 1.7%; serious AEs including dizziness 2.6% for both dysgeusia, sneezing, groups and hypertension paraesthesia and 2.6% vs. 0%. hypotension.

Estimated cost and cost impact The cost of vernakalant is not yet known.

Drug Dose A single treatment course9b Amiodarone 5mg/kg over 20 minutes then up to 1.2g in 24 hours. Up to £50. Flecainide 2mg/kg over 10-30 minutes to a maximum of 150mg, if £4.40-£22. required 1.5mg/kg/hour for 1 hour then 100- 250µg/kg/hour for up to 24 hours not exceeding 600mg in 24 hours.

Claimed or potential impact – speculative

Patients Reduced mortality or increased Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use: peripheral rather Other: None identified than central IV infusion

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings: Other: Unknown comparative costs References

1 National Institute for Health and Clinical Excellence. Dronedarone for atrial fibrillation and atrial flutter. Technology appraisal in development. London: NICE; expected June 2010. 2 National Institute for Health and Clinical Excellence. The management of atrial fibrillation. Clinical guideline CG36. London: NICE; June 2006. 3 Scottish Intercollegiate Guidelines Network. Cardiac arrhythmias in coronary heart disease. 2007. Clinical guideline 94. Edinburgh: SIGN; February 2007. 4 National Library for Health. Guidance. Atrial Fibrillation. January 2007. http://cks.library.nhs.uk Accessed 28 July 2009. 5 Clinical Knowledge Summaries. Atrial fibrillation - management. January 2007. b Cost calculated based on an average body weight of 67.5kg. 6 May 2010

6 American College of Cardiology, American Heart Association and European Society of Cardiology guidelines. Guidelines for the management of patients with atrial fibrillation. 2006. 7 Clinical Knowledge Summaries. Cardiovascular risk - assessment and management. July 2003. 8 HES online. Hospital episode statistics, Inpatient data 2008-2009, primary diagnosis: 3 character table. http://www.hesonline.nhs.uk/Ease/servlet/ContentServer?siteID=1937&categoryID=203 Accessed 15 February 2010. 9 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; March 2010. 10 Kowey P R, Dorian P, Mitchell L B, et al. Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery. Circulation: Arrhythmia and Electrophysiology. 2009; 2:652-659. 11 ClinicalTrials.gov. Response to RSD1235 compared to placebo in subjects with atrial arrhythmia after heart surgery. http://www.clinicaltrials.gov/ct2/show/NCT00125320?term=NCT00125320&rank=1 Accessed 15 April 2010. 12 Roy D, Pratt C M, Torp-Pedersen C, et al, Vernakalant hydrochloride for rapid conversion of atrial fibrillation a phase 3, randomized, placebo-controlled trial. Circulation. 2008; 117: 1518-1525. 13 ClinicalTrials.gov. Phase III tolerance and efficacy study of RSD1235 in patients with atrial fibrillation (ACT I). http://www.clinicaltrials.gov/ct2/show/NCT00468767?term=NCT00468767&rank=1 Accessed 19 April 2010. 14 Pratt C, Roy D, Juul-Moller S, et al. Efficacy and tolerance of RSD1235 in the treatment of atrial fibrillation or atrial flutter: results of a phase III, randomised, placebo-controlled, multicenter trial. Journal of the American College of Cardiology 2006; 47 (4 Supple 1); A1-A36. Abstract 804-3. 15 ClinicalTrials.gov. Study to determine the response and effectiveness of RSD1235 in subjects with Atrial fibrillation or atrial flutter. http://www.clinicaltrials.gov/ct2/show/study/NCT00115791?term=NCT00115791&rank=1&show_locs=Y#lo cn. Accessed 15 April 2010. 16 Steill IG, Badenhost JCW, Kitt TM et al. A phase 3, multicenter, open-label safety study of vernakalant hydrochloride in patients with atrial fibrillation. European Heart Journal 2007;28 (abstract supplement); 809. 17 ClinicalTrials.gov. Study of RSD1235 to evaluate safety in patients with atrial fibrillation (ACT 4). http://www.clinicaltrials.gov/ct2/show/study/NCT00281554?term=nct00281554&rank=1&show_locs=Y#locn . Accessed 15 April 2010. 18 ClinicalTrials.gov. A phase III superiority study of vernakalant vs amiodarone in subjects with recent onset atrial fibrillation (AVRO). http://www.clinicaltrials.gov/ct2/show/NCT00668759?term=NCT00668759&rank=1 Accessed 15 April 2010. 19Cardiome Pharma Corporation. Merk and Cardiome announce phase III study results comparing investigational compound brinavesstm (vernakalant) intravenous to amiodrane injection in conversion of atrial fibrillation to normal sinus rhythm. Press release. 14 May 2010. 20 ClinicalTrials.gov. A phase 3b study of vernakalant injection in patients with recent onset symptomatic atrial fibrillation (AF) (ACT V). http://www.clinicaltrials.gov/ct2/show/NCT00989001?term=NCT00989001&rank=1 Accessed 30 March 2010. 21 Cardiome Pharma Corporation. Cardiome and Astellas announce initiation of patient enrolment in ACT 5 trial. Press release. 28 October 2009.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

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