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 II activity 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 prolonged atrial and ventricular refractory periods. As well as inhibition of conduction along any bypass tract inboth directions.

Pharmacology It is a noncardioselective. water-soluble (hydrophilic), nonprotein-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 not teratogenic 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, paroxysmal supraventricular 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 sinus rhythm,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 dose at 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.

STUDIES ABOUT CLINICAL USES OF SOTALOL

SAFE-T

SOTALOL OR AMIODARONE FOR AF RECURRENCE PREVENTION DRUG VS ICD IN PREVENTION OF VT , VF SOTALOL VS CLASS 1 DRUGS IN VT SOTALOL OR AMIODARONE SOTALOL OR AMIODARONE AMIODARONE ,SOTALOL ,BETA BLOCKER IN ICD SHOCK AF AFTER CABG SOTALOL INCREASES MORTALITY THAN PLACEBO

P<0.001 AMIODARON>SOTA LOL ICD> DRUGS SOTALOL>CLASS 1 SOTALOL=AMIODAR ONE SOTALOL> AMIODARONE AMIODARONE+BET A BLOCKER >SOTALOL AMIODARONE>SOT ALOL SOTALOL= PLACEBO P=.623 P=.05

AVID EVSM CHRONIC VT NOT DUE TO ISCHEMIA CHRONIC VT DUE T0 ISCHEMIA OPTIC

P<0.001

REDUCE SOTALOL ON MORTALITY

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 implantable cardioverter-defibrillator is superior to amiodarone or sotalol . the benefit conferred by device therapy was not confirmed for patients with well-preserved left ventricular 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 I agents

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 on sotalol. When the results are analysed by intention to treat there was no significant difference in antiarrhythmic efficacy or in the incidence of sideeffects . There was an increase in left ventricular ejection fraction in those treated with sotalol.

Comparison of sotalol with amiodarone for long-term treatment of spontaneous sustained ventricular tachyarrhythmia based on coronary artery disease(3)

Patients (n=75) with spontaneous, sustained ventricular tachyarrhythmias secondary to remote myocardial infarction were studied.

At 36 months, 75% of those allocated sotalol remained free of ventricular tachyarrhythmia compared with 38% of those allocated amiodarone (P=005). On multivariate analysis the risk of recurrence of ventricular tachyarrhythmia for patients on amiodarone was 59 times higher (P=0008) than that for patients on 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 ~2 mg/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 implantable cardioverter 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) and sotalol (HR 0.43; 95% CI 0.22-0.85; P = 0.02).

Tachycardia: sotalol decreased implantabledefibrillator first shocks.(7) Clinical bottom line (level 1b) Patients with ventricular tachycardia and an implantable-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 Cardiovascular Arrhythmic 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 TORSADES DE POINTES 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 the QT-interval

The ESVEM study demonstrate that dofetilide and sotalol have equal efficacy (9)

but that dofetilide has a lower rate of adverse events with shortterm 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, Atwood JE, Jacobson AK, Lewis HD Jr, Raisch DW,Ezekowitz MD; Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861 1872. 2. . Kovoor, V. Eipper, K. Byth, M.J. Cooper, J.B. Uther, and D.L. Ross Comparison 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 and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and 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