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



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.



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.



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.



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.



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.



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.





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



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)



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.



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



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.





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.



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.



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).



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



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.



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



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



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



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

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sotalol,2010,anti arrhythmic drugs