sotalol,2010,anti arrhythmic drugs
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Weekly drug presentation
sotalol
Dr .Navojit chowdhury MD (Thesis) student
NICVD
NATIONAL INSTITUTE OF CARDIOVASCULAR
DISEASES ,DHAKA,BANGLADESH
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Sotalol was first licensed for control of severe ventricular arrhythmias.
It is now licensed also for maintenance of
sinus rhythm in patients with recurrent
atrial fibrillation or atrial flutter,who are
symptomatic.
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Sotalol is a racemic mixture of dextro- and levoisomers,
Both have comparable class III activity, the class IIactivity arises from l sotalol.
In humans, class II effects are sinus and AV node
depression.Class III effects are prolongation of the action
potential in atrial and ventricular tissue and prolongedatrial and ventricular refractory periods.
As well as inhibition of conduction along any bypass
tract inboth directions.
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Pharmacology
It is a noncardioselective. water-soluble (hydrophilic), non-
protein-bound agent, excreted solely by the kidneys, with a
plasma half-life of 12 hours.
When given in two divided doses, steady-state plasma
concentrations are reached in 2 to 3 days
In patients with renal impairment or in the elderly, or
when there is a risk factors for proarrhythmia, the dose
should be reduced and the dosing interval increased.
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In pregnancy, the drug is category B.It is notteratogenic but does cross the placenta and
may depress fetal vital functions.
Sotalol is also excreted in mother's milk.
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USES
Because of its combined class II and class
III properties,sotalol is theoretically active
against a wide variety of tachycardia,
including sinus tachycardia, paroxysmalsupraventricular tachycardia,WPW
arrhythmias with either antegrade or
retrograde conduction,recurrence of atrial
fibrillation, ischemic ventricular
arrhythmias,and recurrent sustained
ventricular tachycardia or fibrillation.
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Dosing
For atrial fibrillation and atrial flutter, currently in sinusrhythm,320 mg/day (two doses) may give the ideal ratio
between effects and side effects(torsades).
The risk is 0.3% at 320 mg/day, but goes up to 3.20/0 at
higher doses.
For ventricular arrhythmias, the dose range is 160 to 640
mg/day given in two divided doses. Keeping the daily doseat 320mg or lower lessens side effects,including torsades
de pointes. Yet doses of 320 to 480mg may be needed to
prevent recurrent VT or VF.
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SAFE-T SOTALOL OR
AMIODARONE FOR AF
RECURRENCE
PREVENTION
AMIODARON>SOTA
LOL
P<0.001
AVID DRUG VS ICD IN
PREVENTION OF VT , VF
ICD> DRUGS
EVSM SOTALOL VS CLASS 1
DRUGS IN VT
SOTALOL>CLASS 1
CHRONIC VTNOT DUE TO
ISCHEMIA
SOTALOL ORAMIODARONE SOTALOL=AMIODARONE
CHRONIC VT
DUE T0
ISCHEMIA
SOTALOL OR
AMIODARONE
SOTALOL>
AMIODARONE
P=.05
OPTIC AMIODARONE ,SOTALOL,BETA BLOCKER IN ICD
SHOCK
AMIODARONE+BETA BLOCKER
>SOTALOL
P<0.001
REDUCE AF AFTER CABG AMIODARONE>SOT
ALOL
SOTALOL ONMORTALITY
SOTALOL INCREASESMORTALITY THAN
SOTALOL= PLACEBO P=.623
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Sotalol Amiodarone Atrial Fibrillation Efficacy Trial
(SAFE-T)(1)
this double-blind, placebo-controlled trial, randomly assigned 665
patients to receive amiodarone(267 patients), sotalol (261 patients),
or placebo (137 patients) and monitored them for 1 to 4.5 years.
The median times to recurrence was 809, 209, and 13 days,
respectively, according to treatment received. Amiodarone
was superior to sotalol (P<0.001) and to placebo (P<0.001), and
sotalol was superior to placebo (P<0.001).(intention to treat analysis)
In patients with ischemic heart disease, the median time
to a recurrence of atrial fibrillation was 569 days with amiodarone
therapy and 428 days with sotalol therapy (P=0.53)
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AVID study showed that in survivors of ventricular
fibrillation or in patients with sustained ventricular
tachycardia causing severe symptoms, the implantablecardioverter-defibrillator is superior to amiodarone or
sotalol .
the benefit conferred by device therapy was not
confirmed for patients with well-preserved leftventricular ejection fraction.EF>40%
These points are of particular importance
in countries where the actual cost of
implantable cardioverter-defibrillators has limited the
number of implanted devices.
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In ventricular arrythmias, the major outcome study
with sotalol was the ESVEM trial
SOTALOL 400mg daily was better at decreasing death
and ventricular arrhythmias than any of six class Iagents
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Multicentre randomized trial of sotalol vs amiodarone
for chronic malignant ventricular tachyarrhythmias(2)
open randomized multicentre study of patients with VT and VF not
associated with acute myocardial infarction, refractory to or intolerant of
Class I drugs. 16 of 30 patients treated with amiodarone completed 12
months on therapy,Sixteen of 29 patients completed 12 months onsotalol.
When the results are analysed by intention to treat there was no
significant difference in antiarrhythmic efficacy or in the incidence of side-
effects .
There was an increase in left ventricular ejection fraction in those treated
with sotalol.
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Atrial tachycardias in young adults and adolescents with
congenital heartdisease: Conversion using single dose oral
Sotalol (4)
adults and adolescents with CHD and hemodynamically
stable atrial tachyarrhythmias ,conversion with sotalol at ~2mg/kg generally occurred within 2 h. Vigilance for
thromboembolism must be maintained as well as caution for
those with bradycardia without pacemakers.
There are theoretical and practical advantages of sotalol
over cardioversion.
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EFFECT OF SOTALOL ON MORTALITY: A META-ANALYSIS OF
RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIALS (5)
Of the total of 2,426 patients combined from these studies, 1,468
patients had been randomized to sotalol & 940 to placebo. Patient
characteristics
included age ranging from 53-67 years & a mean left ventricular
ejection fraction ranging from 49-56%. 78 % of the patients were
men,68% had IHD or had a history of MI. Other patient
characteristics betweenthe 2 groups did not differ. The crude
mortality rate was 5.3% (n=79) in the sotalol arm & 5.8% (n=55) in
the placebo arm.
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OPTIC study; Beta-blocker, amiodarone plus beta-blocker,
or sotalol for shock prevention from implantablecardioverter defibrillators (6)
Shocks occurred in 41 patients (38.5%) receiving beta-blocker, 26 (24.3%)
receiving sotalol, and 12 (10.3%) receiving amiodarone plus beta blocker.
A reduced risk of shock was observed with amiodarone plus beta blocker
and sotalol vs beta blocker alone (HR 0.44; 95% CI 0.28-0.68; P<0.001).
Amiodarone plus beta blocker significantly reduced the risk of shock
compared with beta blocker alone (HR 0.27; 95% CI 0.14-0.52; P<0.001) andsotalol (HR 0.43; 95% CI 0.22-0.85; P = 0.02).
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Tachycardia: sotalol decreased implantable-
defibrillator first shocks.(7)
Clinical bottom line (level 1b)
Patients with ventricular tachycardia and animplantable-defibrillator who were given sotalol,
were less likely to have a first shock from the
defibrillator than those given placebo (NNT = 5
at 12 months) .
Patients given sotalol had no clear difference in
death than those given placebo
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Amiodarone Versus Sotalol for the Treatment of Atrial
Fibrillation After Open Heart Surgery: The Reduction
in Postoperative CardiovascularArrhythmic Events (REDUCE) Trial (8)
The incidence of AF did not differ significantlybetween the patients
treated with amiodarone (17%) and sotalol (25%).
The mean duration of AF was significantly shorter in the
Amiodarone group (2.8 h) than in the sotalol
group (8.1 h).
Markedly shorter duration of AF in the amiodaroAne
group favors the use of amiodarone over sotalol after
open-heart surgery.
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SIDE EFFECTS
These are those of beta-blockade. including fatigue (20%)and
bradycardia (13%), added to which is the risk of torsades de
Pointes.
Bronchospasm may be precipitated.
For the initial treatment in patients with recurrent atrial
fibrillation or flutter, the patient should be hospitalized and
monitored for 3 days while the dose is increased The drug
should be avoided in patients with serious conduction
defects(unless there is a pacemaker), and when there are
evident risks of proarrhythmia.
The drug is contraindicated when creatinine clearance, below
40ml/minute
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PRECAUTION ABOUT T ORSADES DE POINT ES
Torsades de pointes is more likely
when sotalol dose is high, exceeding 320 mg/day,
when there is bradycardia,
when the baseline QT exceeds 450 milliseconds , or in severe LV failure, or
in the female gender or in the congenitallong-QT syndrom
Co-therapy with class IA drugs, amiodarone or other drugs prolonging theQT-interval
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The ESVEM study demonstrate that dofetilide and sotalol have
equal efficacy (9)
but that dofetilide has a lower rate of adverse events with short-
term therapy sotalol was the most effective drug in ESVEM and did
not differ from amiodarone in another study
Sotalol, in its currently used racemic form, did not differ from
placebo in a post-infarction mortality trial
Although dofetilide had a neutral effect on survival in the
DIAMOND study, the major concern in the use of any Ikr
blocker remains the risk of torsades de pointes
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references
� 1. Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, Fletcher RD,Sharma SC, AtwoodJE, Jacobson AK, Lewis HD Jr, Raisch DW,Ezekowitz MD; Sotalol Amiodarone Atrial FibrillationEfficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial fibrillation.
� N Engl J Med 2005;352:18611872.
� 2. . Kovoor, V. Eipper, K. Byth, M.J. Cooper, J.B. Uther, and D.L. RossComparison of sotalol with amiodarone for long-term treatment of spontaneous sustained
ventricular tachyarrhythmia based on coronary artery disease
� 3. G. Boriani, A. Lubinski, A. Capucci, P. Niederle, Z. Kornacewicz-Jack, A.M. Wnuk-Wojnar, M.Borggrefe, J. Brachmann, M. Biffi, G.S. Butrous, et al.A multicentre, double-blind randomized crossover comparative study on the efficacy andsafety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardiaand ischaemic heart disease
Eur. Heart J., December 1, 2001; 22(23): 2180 - 2191� 4 N. Saoudi, J.P. Rinaldi, K. Yaici, and M. Bergonzi
Dofetilide: what role in the treatment of ventricular tachyarrhythmias?Eur. Heart J., December 1, 2001; 22(23): 2141 2143
� continued