list of newer antiarrhythmics

1. NEWER ANTIARRHYTHMICS
Dr D Sunil Reddy

2. • Antiarrhythmic drug therapy has been limited by both
incomplete efficacy and a substantial potential for
cardiac and extracardiac toxicity.
• As a result, only a few new antiarrhythmic agents have
successfully completed clinical development programs
and reached routine clinical usage over the past 20
years
• The drug therapy for atrial arrhythmias is often limited
by the drug’s simultaneous effects on the ventricles,
which has led to efforts to identify ionic channel targets
specific to or preferentially located in the atria

3. WILL DISCUSS …
• RANOLAZINE
• VERNAKALANT
• IVABRADINE
• CELIVARONE
• BUDIADARONE
• TECADENOSON

4. RANOLAZINE
• Ranolazine is a novel antianginal drug with multiple
ion channel blocking antiarrhythmic activity
• Ranolazine is an inactivated Na Ch blocker (blocks
late Na current) and is considered a Class IB agent
• Ranolazine also has effects on the delayed rectifier
current (I Kr) and prolongs APD at any given pacing
cycle length, with corresponding QT prolongation .
• It also inhibit s ryanodine receptor channel (RyR2)

5. • Atria show more depolarized resting membrane
potential than ventricular myocyte, the consequence
is an increased fraction of inactivated Na channels at
a given membrane potential
• Ranolazine produces a use-dependent depression of
several Na channels which can be found in human
atrial myocytes even at higher rates
• The principal mechanism underlying ranolazine’s
antiarrhythmic actions is thought to be primarily via
inhibition of late I Na in the ventricles, and via use-
dependent inhibition of peak I Na and I Kr in the atria

6. • In MERLIN-TIMI 36 study, ranolazine was shown
clinically to reduce arrhythmia episodes, including
NSVT, on ambulatory cardiac monitoring in pts
presenting with ACS and despite causing modest QT
prolongation, ranolazine use was not a/w an increased
risk of SCD compared with placebo
It has been used in the suppression of ectopic
ventricular activity and
 for the reduction in VT burden and prevention of shocks
in ICD recipients
 Kaliebe JW, Murdock DK. Suppression of nonsustained ventricular tachycardia
with ranolazine: WMJ. 2009;108:373–5
 Bunch TJ, Mahapatra S, Murdock D, et al.Ranolazine reduces ventricular
tachycardia burden and ICD shocks in patients with drug-refractory ICD
shocks. Pacing Clin Electrophysiol. 2011;34:1600–6

7. RANOLAZINE IN AF

8. • In a secondary analysis from the MERLIN-TIMI 36
trial, ranolazine treatment was associated with a 30%
reduction in new onset AF (p=0.08) as well as a
significant reductions of supraventricular
tachyarrhythmias (p<0.001)
• Ranolazine in particular works synergistically with
the Class III antiarrhythmic agents, most commonly
with amiodarone and can be used as an add-on
therapy in patients with recurrent VT events while on
a Class III antiarrhythmic agent

9. RAFFAELLO TRIAL
• Comparison of the efficacy of
3 doses of Ranolazine (low, intermediate & high)
versus placebo,
given for up to 16 weeks, in maintaining sinus rhythm
after successful DC cardioversion in patients with non-
permanent atrial fibrillation (AFib)
• Ongoing trial , results not yet published

10. HARMONY STUDY
• The purpose of this study is to evaluate whether
treatment with ranolazine or low dose dronedarone
reduces atrial fibrillation burden (AFB) in subjects
with paroxysmal atrial fibrillation (PAF)
• Whether combination therapy (ranolazine and low
dose dronedarone) is superior to individual drug
therapy in reducing AFB

11. VERNAKALANT
• Vernakalant is an atrial-selective, multiple ion
channel blocker being investigated for use in AF
• Vernakalant is an atrial repolarization-delaying agent
with its major target I Kur
• Vernakalant also blocks I to and INa, although there
is little effect on I Kr or Iks
• As I kur is present in higher density in the atria,
vernakalant is relatively atrial selective

12. • Vernakalant infusion dose-dependently prolongs
atrial ERP but has no significant effect on ventricular
ERP or QT intervalThe I Na inhibition is rate- and
voltage-dependent.
• Vernakalant has, therefore, a much greater effect in
fibrillating atria than in the ventricle and is less likely
to be proarrhythmic
• Most common side effects are hypotension ,
dysgeusia, sneezing, paresthesias, nausea due to Na
channel inhibition in CNS .

13. CLINICAL EFFICACY
TRIALS CONDUCTED SO FAR …
• Conversion of Rapid Atrial Fibrillation Trial [CRAFT]
• Atrial arrhythmia Conversion Trial [ACT]
 ACT I , II , III , IV
• AVRO
• Vernakalant was administered by a 10-minute
infusion of 3 mg/kg F/B a 15-min observation period
then a second 10-min infusion of 2 mg/kg if still in AF

15. VERNAKALANT FOR CONVERSION OF
AF TO NSR

16. • The lack of an oral formulation for long-term therapy
is an obvious limitation for the use of
intravenous vernakalant
• Results of clinical trials showed that the efficacy of
vernakalant decreases with the duration of AF
• The conversion rate was substantially lower in AF
lasting 3 to 7 days than 3 to 48 hours
• Longer-duration AF (8 to 45 days) rarely responded
to vernakalant
• Vernakalant appears less effective for acute
conversion of AF in association with HF and the
incidence of serious hypotension and ventricular
arrhythmia is higher in this patient population

17. IVABRADINE
• Ivabradine selectively inhibits the spontaneous
pacemaker activity of the sinus node by blocking the
If current
• This reduces the heart rate without altering
myocardial contractility or other hemodynamics
• Approved as a treatment for inappropriate sinus
tachycardia
• The blockage of the If current is dose dependent and
heart rate– dependent limiting the risks of
symptomatic bradycardia

18. • Some remodeling of the sinus node appears to occur
in response to ivabradine, but no rebound
tachycardia has been seen after discontinuing it
• Electrophysiological studies of Ivabradine in humans
have shown little effect on the conduction system or
on atrial and ventricular refractoriness
• The oral bioavailability is approximately 40%
• It takes 60 to 90 minutes to reach maximal plasma
concentrations. The half-life is approximately 2 hours

19. • In the BEAUTIFUL study there was no difference in the
primary end point of CVD or admissions for acute
infarction or heart failure
• In pts with BHR - 70 bpm, however, the secondary end
points of admission for fatal and nonfatal MI and the
need for revascularization were significantly reduced.
• Little trial data exists regarding the treatment of atrial
tachyarrhythmias with ivabradine
• Most side effects are dose-related.
• Ion channels in the retina that generate the Ih current
are also affected leading to phosgenes

20. CELIVARONE
• It is a noniodinated benzofuran derivative with EP
effects similar to amiodarone and dronedarone
• Its efficacy at 300- or 600-mg daily doses for
conversion of atrial fibrillation and flutter was
studied (CORYFEE )
• Dose ranging study compared Celivarone at 50,
100,200, or 300 mg once daily with amiodarone for
maintenance of sinus rhythm (MAIA)

21. • There was no significant difference in the rate of
spontaneous conversion to sinus rhythm between
the treatment and control groups.
• Celivarone does not appear to be efficacious in
the maintenance of sinus rhythm in AF/AFL
patients or for the conversion of AF/AFL patients
Khitri AR et al; Celivarone for maintenance of sinus rhythm and conversion of
atrial fibrillation/flutter;J Cardiovasc Electrophysiol. 2012 May;23(5):462-72

22. • Trials have shown the lowest rate of atrial fibrillation
recurrence at 50 mg dose with no enhanced efficacy
at the higher doses
• A 46% reduction in the number of sustained
ventricular arrhythmia episodes requiring ICD
therapy was noted in the 300 mg daily group, but
this reduction was not statistically significant
Kowey PR, Aliot E, Cappucci A, Connolly SJ, Crijns H, Hohnloser SH,Kulakowski P,
Roy D, Radzik D. Placebo-controlled double-blind dose ranging study of the
efficacy and safety of celivarone for the prevention of ventricular arrhythmia-
triggered ICD interventions.JAmColl Cardiol.2008;51:A2

23. BUDIODARONE
• Unlike dronedarone, budiodarone , retains 2 iodine
atoms in its molecular structure
• Budiodarone has electrophysiological properties
similar to amiodarone and has a shorter half-life than
amiodarone
• Ester modification of the compound changes its
metabolic pathways such that budiodarone
undergoes rapid degradation by plasma and tissue
esterases to an inactive compound
• There are as yet no published data on long-term
exposure to budiodarone, so its potential for chronic
toxicity is unknown

24. • In a study conducted in patients with paroxysmal AF
and a previously implanted dual-chamber
pacemaker , the percent change from baseline
AT/AFB over 12 weeks of treatment compared to
placebo was studied
• The median reduction of AT/AFB for the 400 and 600
mg BID groups vs. placebo was 54% and 74%
(p = 0.01 and 0.001), respectively.
• The budiodarone dose-response was statistically
significant (p < 0.001)
• Number and duration of AT/AF episodes were
reduced
Ezekowitz MD A randomized trial of budiodarone in paroxysmal atrial
fibrillation; J Interv Card Electrophysiol 2012 Jun;34(1):1-9

25. TECADENOSON
• Tecadenoson is a novel selective A1 adenosine
receptor agonist that is currently being evaluated for
the termination of SVT and rate control for atrial
fibrillation
• It is associated with fewer adverse effects such as
flushing, dyspnea, chest discomfort, and hypotension
than adenosine

26. • Tecadenoson also appears to be associated with a
lower incidence of atrial fibrillation following
conversion of PSVT compared to adenosine (15%)
• It causes significant prolongation of AV nodal
conduction and refractoriness without causing
hypotension or negative inotropic effects
• It has a longer half-life than adenosine (20 to 30
minutes)

27. • TEMPEST trial was done to evaluate tecadenoson in
the termination of SVT
• A multicenter,double-blinded, placebo-controlled trial
that randomly assigned 181 pts to receive placebo vs
one of several dose-escalating regimens of
tecadenoson for termination of SVT.
• The conversion rates were 73.5% in the tecadenoson-
treated pts and 6.7% in the placebo group.
• Rates of conversion did improve with dose escalation
and the side effects were relatively mild and increased
with dose escalation

28. FUTURE TARGETS FOR NOVEL
ANTIARRHYTHMIC DRUGS
• Specific acetylcholine-regulated K current inhibition
– Tertiapin
• Abnormal calcium handling
– RyR2 modulation ( ? Ranolazine )
– SERCa 2A modulation
• Gap junction modification
– Rotigaptide

29. • Na/Ca exchanger inhibition
– KBR-7943 and SEA-0400
• Stretch-induced or ischemia-induced ATP-sensitive K
current inhibitors
– HMR-1883, HMR-1098, HMR-1402, ?
Glibenclamide
• Gene and cellular therapy

30. THANK YOU

32. • Almokalant
• Almokalant
• Ibutilide
• Trecitilide
• Ambasilide
• Melperone
• Terikalant
• Azimilide
• Meobentine
• Nibentan
• Cardiocylide
• Pranolium
• Clofilium
• Chromanol
• Ranolazine
• Dofetilide
• Risotilide
• Sematilide
• Ersentilde
• Tedisamil
(blocks Ito)

33. • Atrial-selectiv e I Na Modulation
– Vernakalant
– Ranolazine
– Restoring Abnormal Ca2+ Handl ing
• Ranolazine
1. Atrial-selectiv e Ion-channel Modulation
1. Abnormal G ap Junction Conduction
1. rot igapt ide
2. danegapt ide

34. • Azimilide, a class III agent wit h bot h IKr-
and I Ks -blocking propert ies
• ALI VE [ AzimiLide post -I nf arct surViv al Ev
aluat ion - unpublished] t rial