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FEBRUA RY 16,1 998 'tlpy PerspectiveS For Rational Drug Use and Diseaset'iIaoogmgzent VO LUME 11. NO.3 ISSN 111'2-0360 CONTENTS New drugs and disease management 1 Ibutilideterminates atrial fibrillationlflutter - but watch for proarrhythmia 6 Donepe zil: a stepforward compared with tac rinefor Alzheimer's diseas e? 9 Viral involvement dictates tr eatment for ne crotising vasculitides Drug economics and quality of life 13 Avoid amputation if possible in patients with diabeticfoot ulcers Practical issues and updates 8 Alzheimer's treatment guidelines from the UKand US au-IS INTERNA TIONAL A Wolters Kluwer Company Ibutilide terminates atrial fibrillation/flutter - but watch for proarrhythmia _ Ibutilide is the first pure class ill antiarrhythmic, that is indicated for the rapid conversion of recent-onset atrial flutter or fibrillation. In clinical trials, ibutilide mg/kg or Img) successfully cardioverted 27 to 58% of patients. Ibutilide is more effective than the class Ia agent procainamide or the class II/Ill agent sotalol. Ibutilide has minimal haemodynamic effects and causes few noncardiovascular adverse events. However, ibutilide can cause nonsustained and sustained polymorphic ventricular tachycardia (including torsade de pointes). Patients receiving ibutilide must be carefully monitored to allow detection and prompt treatment of proarrhythmic events. Atrial fibrillation and atrial flutter are the most common arrhythmias that require medical attention. The aim of treating these arrhythmias is to reduce symptoms and prevent complications. Restoration of sinus rhythm may help to achieve these goals.Ul Electrocardioversion is often the most effective and rapid means of restoring sinus rhythm in patients with atrial fibrillation and flutter. However, electrocardioversion causes severe discomfort to the patient. This necessitates sedation or anaesthesia, which can be associated with extra cost and a risk of complications. Thus, pharmacological cardioversion may be preferred in some situations.lU First 'pure' class III antiarrhythmic Cardioversion can be achieved with class la, Ie or III antiarrhythmics. Ibutilide is the first of the so-called 'pure' class III antiarrhythmics (see table 1). As such, ibutilide acts fundamentally by prolonging myocardial action potential duration without any other significant electrophysiological effects. Ibutilide has a unique ionic mechanism of action that appears to

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Page 1: Ibutilide terminates atrial fibrillation/flutter —but watch for proarrhythmia

FEBRUA RY 16,1998

'tlpy PerspectiveS™For Rational Drug Use and Diseaset'iIaoogmgzent

VO LUME 11. NO.3

ISSN 111'2-0360

CONTENTS

New drugs anddisease management

1 Ibutilide terminatesatrial fibrillationlflutter­but watch for proarrhythmia

6 Donepezil: a stepforwardcomparedwith tacrineforAlzheimer's disease?

9 Viral involvement dictatestreatment for necrotisingvasculitides

Drug economics andquality of life

13 Avoidamputation ifpossible inpatients with diabeticfoot ulcers

Practical issues andupdates

8 Alzheimer's treatment guidelinesfrom the UKand US

L~.au-ISINTERNA TIONAL

A Wolters Kluwer Company

Ibutilide terminates atrial fibrillation/flutter ­but watch for proarrhythmia

_ Ibutilide is the first pure class ill antiarrhythmic,that is indicated for the rapid conversion of recent-onset atrial

flutter or fibrillation. In clinical trials, ibutilide (~O.Ol mg/kg orImg) successfully cardioverted 27 to 58% of patients. Ibutilide ismore effective than the class Ia agent procainamide or the classII/Ill agent sotalol.

Ibutilide has minimal haemodynamic effects and causes fewnoncardiovascular adverse events. However, ibutilide cancause nonsustained and sustained polymorphic ventriculartachycardia (including torsade de pointes). Patients receivingibutilide must be carefully monitored to allow detection andprompt treatment of proarrhythmic events.

Atrial fibrillation and atrial flutter are the most common arrhythmiasthat require medical attention. The aim of treating these arrhythmias is toreduc e symptoms and prevent complications. Restoration of sinus rhythmmay help to achieve these goals.Ul

Electrocardioversion is often the most effective and rapid mean sof restoring sinus rhythm in patients with atrial fibrillation and flutter.However, electrocardioversion causes severe discomfort to the patient.This necessitates sedation or anaesthesia, which can be associated with extracost and a risk of complications . Thu s, pharmacological cardioversion maybe preferred in some situations. lU

First 'pure' class III antiarrhythmicCardioversion can be achieved with class la , Ie or III antiarrhythmi cs.

Ibutilide is the first of the so-called ' pure' class III antiarrh ythmi cs (seetable 1). As such, ibutilide acts fundamentally by prolonging myocardialaction potential duration without any other significant electrophysiologicaleffects. Ibutilide has a unique ionic mechanism of action that appears to

Page 2: Ibutilide terminates atrial fibrillation/flutter —but watch for proarrhythmia

-Drugs & Therapy Perspectives

Editor: lison J. ForbeAssociate Editor: Claire BerkahnEditorial Secretary: Carol Milligan

Director. Content Creation: Paul Chrisp

President: Chris Mellor

International Editorial Board

D.R. hernethy, Washillgtoll, DC. USA: C. P.Alderman.Adelaide. SA. All arali a: C.D. Bayliff, Loudon, Cantu la;

E.J . Begg, Christchurch, Nell' Zealand: T. Bergan. Oslo,

No/way: G. Bianchi Porro, Mi lan, ltalv; C. Bruter,lndianap olis, IN. USA: A. I. Breckenridge. Liver pool, UK:

W.W. Busse. Madison, WI, USA: .G. Carruthers, London.

Canada; G. Carstens, Hanovet; Germany:.I.AJ.lI. Critchley.Hong Kong: R.O. Day, Sydnev. NS \V. Australia:

I. .G. Dukes. So rborg, Denm ark: . Ebihuru, Tochigi-kcn,

Japan; L. Ereshefsky, S(III Anto nio, TX. liSA: • Erill,Barcelona, Spain: . Eru. h, Philadelphia. PA. USA : P. Fuller,Paris. France; .I. Feely, Dublin. Ireland: R.G. Finch.No ttingham, UK: S. Frias. Madrid, Spain; W.H. Frishman.Bronx. NY. USA: S.T. Garner, No tting ham, UK:

D..I. Greenblatt. Bosto n, MA . USA: R. Gugler, Karl sruhe,

Germany; «~D. Hart. l.rnulon, UK: D.A. Henry. Newcastle.

SW Australia: I. Hindmarch, Godalming. UK: Tc lshizaki,Tokyo , Japan: R. Janknegt, Sittard. The Netherlands:

G.t. Kearns. Kansa ' City, MO. USA ; .I. Kenyon. Auckland.

Nell' Zealand: .K. Lam, Hong Kong; M. Le Duff, Rennes,France: 1\1. Levy, Je rusalem, Israel : \ ~J. Louis. Heidelberg,

Vic. Australia; H.1. Iaibach, Stili Francisco. CA, USA:

G. Mancla, MOII:a, ltal»; A. Mcl .eun, Melb ourne. Vic.

Australia ; P.A. 'li tenko, Nanaimo. Canada; D. ash.Phi/a delphia. PA, USA: 1\1.0. ielsen, Hump, Denmark:

P.L. ielsen, Frederikshavn. Denmark: L.P. Opie, Capt!

TOII'I/. South Africa: I. Packer, Nell' York. NY. USA:

R. Pauwels. Ghent, Belgium: P. Persson . Stockholm. Sweden:

J. Schentag, Huffa lo, N)~ USA : D-R. ohn, Chonan, Korea ;

Dc K. Sommer, Pretoria. OIl1hAfrica: . Terragno,Buenos Aires, Argentina: M. Thomas, H!llorre. Ind ia:

J-P. Tillement, Creteil, France: G. Tognoni. Milan, Italy:

.I.H. Toogood, Londo n, anada; C. Tugwell, London. UK:

T. ernatsu, Gifu , Japan: C~I . van Boxtel, Amsterdam.

TI/e Netherlands; R.E. Vestal. Boi 'C'. !D. USA: II.B. Wong.Singaporr

All mat erial prepared by Adis Ed itors

See back cover Ior sub scription detailE-mail address:d&tp@adis .co.nz

Vol. 11, No. 3; February 16, 1998

involve activation of a late inward sodium current, aswell as interaction with potassium channe ls .I U

Terminates sustained atrial flutter/fibrillationIntravenous ibutilide is more effective than placebo

in terminating sus tained atrial flutter or fibrilJ ation in

haemodynamically stable patients. Cardioversion was

successful in 33 to 49 % of patients given an ade qua tedo se of ibutilide (~O .O 1 mglkg or Img ), compa redwith 2 to 3% of placebo recipients, in 2 tri als in vol ving

439 patients with arrhythmias of ~3 hours ' durati on(mean 12 to 60 days) .[2,3]

Wlten using ibutil ide, tlte risk ofpro arrlujtlnnic events must be toeiglted

against the benefits of ibutilide therapy

In patients who developed atria l flutter or fibri lla tio n

after coronary artery byp ass g raft or cardiac va lve

surgery. 2 dose s of intravenous ibutilide 1mg we resignificantly more effecti ve than placebo (c ard iovers ionrates of 57 vs 15%).14] Ibutilide al so facil itates atri aloverdrive pacing-induced termination of atria l flutter.l']

Better in flutterAs with other class III agents. ibutilide is ge nera lly

more effective in patients with atr ia l flutter than thosewith fibrillation (see figure I) . Efficac y is al so greate rwhen atria] flutter or fibrillati on is of sho rte r durat ion

(e.g . <7 days) . On average. sinus rhythm is restoredwithin 30 minutes of treatment initiation and arrhy thmiadoes not recur within 24 hours in most parient s.Ul

More effective than sotalol or procainamideIbutilide has shown superiority over the class IIIIII

agent sotalol and the class Ia agent procainamide .Cardioversion rates were 27 % with ibuti lide Img, 48 %with ibutilide 2mg and 12% with sota lol 1.5 mg/kg in319 evaluable patients with atrial fib rillation or flutter.U!

Similarly. cardioversion rates were 45 and 58% withibutilide (0 .005 to 0 .025 mg/kg or 2mg) and 3 and 18%with procainamide (12 to 15 mglkg or 1200mg) in 2 studiesinvolving a total of 187 patients.l 6,7]

Potential for ventricular tachycardia.Ad verse events ass oc iated with ibutilide treatment are

predominantly cardiovascular (see figure 2).11] Th e drug is

generally well tolerated and ha s minimal haem od ynamiceffects . However, ibutilide ha s the potential to inducepolymorphic ventricular tachycardia (VT).

1172-03601981003-002/$01,00 "Adis Int ernationat Limited. A ft right s reserved

Page 3: Ibutilide terminates atrial fibrillation/flutter —but watch for proarrhythmia

&~~~~h~ 3-Table 1. Vaughan-Williams classification ofantiarrhythmic drugs[1]

Prescribing and formulary considerationsIbutilide is indicated for the rapid conversion of recent­

onset atrial flutter or fibrillation . Very preliminary datasuggest that ibutilide is cost effective compared withelectrocardioversion.U 0] amiodarone, procainamide,sotalol or quinidine,l II] and decreases hospitalisationcosts compared with procainamide.l l-l The efficacy rateof ibutilide, particularly in patients with sustained atrialfibrillation, appears to be less than would be expectedwith electrocardioversion.Hl Nonetheless, ibutilide is

that prolong the corrected QT interval. Ibutilide shouldnot be used in patients who have previously developedpolymorphic VT. Hypokalaemia and hypomagnesaemiashould be corrected before ibutilide treatment is initiated.l'il

Patients who have been in atrial fibrillation for >2 daysmust receive an adequate course of anticoagulant therapyfor at least 3 weeks before conversion to sinus rhythmwith ibutilide is atternpted.Ul It is recommended thatpatients with abnormal liver function are monitored bytelemetry for more than the standard 4-hour monitoringperiod.[9]

Sotalol ,atenolol,metoprolol

Ibutilide, sotalol,

arniodarone" .bretyliurn!

Verapami l,dilt iazem ,nifedipin e

Flecain ide,encainide t,propafenone

Lidocaine(lignocaine),

mexiletine,morac izine t

Quinid ine,disopyramide,proca inamide

Examples·

IV

Block sodium channels and delayrepolarisation, thereby increasingthe duration of the act ion potential.Moderately slow conduction

Block sodium channels andaccele rate repolarisation, therebydecreasing the duration of theaction potential

Block sodium channels but havelittle effect on repolarisation.Depress phase 0 depolarisat ionand slow conduction

Block ~-ad renocepto rs. Reducehyperactivity of the sympatheticnervous system and depressphase 4 depolarisation

Increase the duration of the actionpotential and effective refractory

period

Block calcium channels . Slowconduct ion through calciumchannel- dependent tissues(e.g. the sinoatrial andatrioventricular nodes)?

t Moracizine, encainide and bretylium are not available in Spain.a Drugs may fit into more than one classification.b Also has class I, II and IV properties.c Niledipine may increase atrioventricular conduction.

II I

II

Ie

lb

la

Class Action s

Adis Evaluation

. . . so monitor for proarrhythmiaBecause of the risk of proarrhythmia, all patients

should be monitored by electrocardiogram for at least4 hours after ibutilide treatment, or until the correctedQT interval has returned to the baseline level.

Appropriate equipment and personnel trained in thedetection and treatment of these types of arrhythmiasshould be available. Prompt treatment is essential.Treatment involves discontinuation of ibutilide,correction of electrolyte abnormalities, and overdrivecardiac pacing, electrocardioversion or defibrillation.Magnesium sulfate may also be administered.I''l

CLINICAL BENEFITS

• More effective than sotalol or procainamide• Particularly effective in terminating atrial flutter

• Minimal haemodynamic effects• Causes few noncardiovascular adverse events

Key points in the overall evaluation of ibutilidein terminating atrial flutter and fibrillation

The incidence of sustained polymorphic VT (primarilytorsade de pointes) was 1.7% in clinical trials overall,and a further 2.7% of ibutilide recipients experiencednonsustained polymorphic VT.[l] However, much higherincidences of nonsustained polymorphic VT have beenreported from some individual studies.[3,8]Almost allreported cases of polymorphic VT have developed within40 minutes of the initiation of treatment. The risk of thispotentially fatal complication must be weighed againstthe benefit of ibutilide for each individual patient.

POTENTIAL LIMITATIONS

• Less effective when arrhythmia has been presentfor >7 days

• Can induce polymorphic ventricular tachycardia

. . . and be alert for risk factorsGeneral risk factors for torsade de pointes include:

• bradycardia• varying heart rate

• hypokalaemia• a prolonged QT interval.l''l

Heart failure, low ventricular ejection fraction, femalegender and non-White race may also be risk factors forpolymorphic ventricular tachycardia with ibutilide, assuggested by clinical trial data.[1,9]The risk may beincreased in patients who are also receiving other drugs

1172-03601981003-0031$0I.()()cAdis International Limited. All rights reserved Vol. II, No.3; February 16,1998

Page 4: Ibutilide terminates atrial fibrillation/flutter —but watch for proarrhythmia

Fig. 1. Cardioversion rates with ibutilide in patients with atrialflutter or fibriliationPl 242 evaluable patients with atrial flutter orfibrillation of >3 hours' and <45 days' duration received placeboor intravenous ibutilide 1mg (0.01 mg/kg in patients weighing lessthan 60kg) plus an additional 0.5 or 1mg (0.005 or 0.01 mg/kg) ifthe arrhythmia persisted for >10 minutes after the first dose.Results for placebo recipients were not reported separately foratrial flutter and atrial fibrillation.Symbols: • p s 0.05 vs placebo; •• p < 0.01 vs atrial fibrillation.

a reasonable option if the decision is made to usepharmacological therapy rather than electrocardioversion,e.g. because of patient preference, cost considerations,or lack of suitable facilities and/or personnel.

Ibutilide has greater efficacy than procainamide orsotalol. However, whether ibutilide is more effectivethan other potentially useful agents, e.g. flecainide andamiodarone, is unknown. These agents are compared in theDifferential features table. The rapid effect of intravenousibutilide (on average <30 minutes) is advantageouscompared with the I to 3 days that may be required forconversion with oral agents such as quinidine.Ul

Careful patient selection necessaryCareful patient selection increases the likelihood of

successful cardioversion with ibutilide. For instance,ibutilide restores sinus rhythm more readily in atrialflutter than in atrial fibrillation, whereas class I agentshave very limited efficacy in atrial flutter.IU

How ibutilide fits into the overall management ofpatients with atrial fibrillation or flutter has yet to bedetermined. Once sinus rhythm has been restored, somepatients will require prophylactic antiarrhythmic therapy.Presumably ibutilide does not affect the long-termresponse to such therapy, but this requires confirmation.Whether ibutilide is effective in more seriously ill patients(e.g. those who are haemodynamically unstable, have arapid ventricular response and/or have serious symptomssuch as significant hypotension, unstable angina oruncontrolled heart failure) is also unknown .Ul

Ibutilide

o Placebo

2 3 4 5 6

Incidence (%)

o

Headache~~~~~~Nonsustained poly-VT ~

Tachycardia~+~~

Hypotension -IE=~Nausea~~~

Bundle branch block .iiI.Sustained poly-VT

AV block

Ventricular extrasyst ,c::::;:==:;;::;;::=~

Nonsustained mono-VT~~:~iiiI~~~

Fig. 2. Tolerability of ibutilide.[11lncidence of adverse eventsoccurring in ~1.5% ibutilide recipients and with greater frequencyin ibutilide than placebo recipients. Data are from 586 patientswho received ibutilide 0.005 to 0.035 mg/kg and 127 whoreceived placebo in phase II and III clinical trials of atrialfibrillation and flutter.

Abbreviations: AV = atrioventricular; extrasyst = extrasystoles;mono-VT =monomorphic ventricular tachycardia;poly-VT = polymorphic ventricular tachycardia.

ReferencesI . Foster RH, Wilde MI, Markham A. Ibutilide : a review of its

pharmacological properties and clinical potential in the acutemanagement of atrial flutter and fibrillation. Drugs 1997 Aug;54 (2): 312-30

2. Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy ofintravenous ibutilide for rapid termination of atrial fibrillation andatrial flutter: a dose-response study. J Am Coli Cardiol 1996 Jul;28: 130-6

3. Starnbier BS, Wood MA, Ellenbogen KA, et al. Efficacy and safetyof repeated intravenous doses of ibutilide for rapid conversion ofatrial flutter or fibrillation . Circulation 1996 Oct I ; 94: 1613-21

4. News from the 46th Annual Scientific Sessions of the AmericanCollege of Cardiology . Anaheim , US, March 1997. Ibutilide forarrhythmia termination after cardiac surgery. Inpharma 1997Apr 12; (1082) : 12

5. Stambler BS, Wood MA, Ellenbogen KA. Comparative efficacy ofintravenous ibutilide versus procainamide for enhancing terminationof atrial flutter by atrial overdrive pacing . Am J Cardiol 1996May I; 77: 960-6

6. Stambler BS, Wood MA, Belz MK, et al. Electrophysiologicdeterminants of pharmacologic conversion of human atrialfibrillation and flutter : enhanced efficacy of ibutilide a newclass III antiarrhythmic drug [abstract] . Circulation 1993 Oct;88 Suppl. (Pt 2): 445

7. Yolgman AS, Stambler BS, Kappagoda C, et al. Comparisonof intravenous ibutilide versus procainamide for the rapidtermination of atrial fibrillation or flutter [abstract]. Pace 1996Apr ; 19 (Pt II): 608

8. Johns TE, Hancock WW, Lopez LM. Does intravenous ibutilidecause ventricular tachycardia? [abstract no. 5J. Pharmacotherapy1997; 17 (5): 1080-1

9. Pharmacia & Upjohn Inc. Corvert" prescribing information.Kalamazoo, USA, 1996

10. Zarkin GA, Bala MY, Calingaert B, et al. Cost-effectiveness ofa stepped treatment regimen of ibutilide followed by electricalcardioversion in the treatment of atrial fibrillation and flutter[abstract C02J . Am J Manage Care 1997 Mar; 3 (3 Suppl.) : S43

PlaceboIbutilidelmg + 1mg

Ibutilidelmg + 0.5mg

.. DAII patients

,-- Atrial flutter

D Atria l fibrillation..~ .. c--

c--

l-

I-

.....---.

~80

Q)

~c 600'§Q)>0

'Etll 40o

20

0

Vol. 11, No.3; February 16, 1998 1/72-0360/98/003-004/$01.00 eAdis International Limited. All rights reserved

Page 5: Ibutilide terminates atrial fibrillation/flutter —but watch for proarrhythmia

-Feature Ibutilide' Procainamide Flecainide

Class" III ta Ie

Adverse effects

Proarrhythmic I!! I! !I!potential

Haemodynamic I! !I!effects

GI disturbance III I!

Other signi ficant Lupus- like Vision disturbance,adverse events syndrome dizziness

Dose? IV 1mgd (repeatedto max 2mg)

IV 100mg(repeated to

max 19)

IV 2 mg/kg (max 150mg)then 1.5 mg/kg/h for 1 hourthen 100-250 J.lg/kg/h(max 600mg in 24 hours)

Sotalol

11/111

!I!

!I!

Dyspnoea,fatigue,

asthenia,headache

IV 20-120mg(repeated6 hourly)

Am iodarone

IIlb

!!

!ll

Pulmonary toxicity,hepatotoxicity,hyper/hypothyroidism,ocular effects,dermatologicaleffects, neuropathy

IV S5 mg/kg(repeated to max1,2g in 24 hours)

1.50 (150mg)

68.75 (150mg)

1.76 (40mg)

IV NA

Acquisition cost

IntheUK(£) NA 1.90 (lg) 4.95 (150mg)

In the US ($) NA 4.00-36.44 (lg) IV NA

t Ibutilide is not available in Canada, France, Spain and The Netherlands.a Vaughan-Williams classification for antiarrhythmic drugs (see table 1).b Also has class I II and IV properties.c Intravenous rather than oral doses are shown to facilitate comparison with ibutilide; cardioversion is generally achieved more rapidly with

intravenous administration. As most of these drugs are not officially approved for cardioversion of atrial fibrillationlfluller, the doses shownare not specifically for this indication.

d 0.01 mg/kg for patients weighing <60kg.Abbreviations and symbols: GI =gastrointestinal; IV =intravenous; max =maximum total dose; NA =not available; ! =low frequency/significance; !! =moderate frequency/significance; !I! =high frequency/significance; - =none reported to date.

II. Singletary TJ, Malone DC, Wortman Gc. Cost-effectivenessanaly sis of pharmacologic cardioversion for ambulatory atrialarrhythmias [abstract no. 162). Pharmacotherapy 1997;17 (5): 1106

12. Zack PM, Grimm MF, Choo EB, et al. Intravenous ibutilide forconversion of atria l fibrillation and atria l flutter : reduction induration and cost of hospitalization [abstract) . J Invest Med 1997Mar ; 45 (3): 211A

13. Geraet s DR, Kienzle MG. Atrial fibrillation and atria l flutter .Clin Pharm 1993 Oct ; 12: 721-35

14. Briti sh National Formulary No. 34. London: The PharmaceuticalPress, 1997 Sep

15. Gill J, Heel RC, Fitton A. Amiodarone: an overview of itspharmacological properties,and review of its therapeutic usein cardiac arrhythmias. Drugs 1992; 43 ( 1): 69-110

16. Filion A, Sorkin EM. Sotalol : an updated review of itspharmacological properties and therapeutic use in cardiacarrhythmias. Drugs 1993 Oct; 46: 678-719

17. 1997 Mosby's complete drug reference. Physicians GenRx ®.7th ed . St Louis, Missouri : Mosby-Year Book, Inc., 1997

Aims and scope of Drugs & Therapy Perspectives:• To provide timely overviews of new drugs , incorporating comparative data with established agents• To report on new developments and international consensus on drug use in disease management• To advise on the avoidance and management of adverse drug reactions and interactions• To inform readers of developments in pharmacoeconomics and outcomes research that have a bearing

on clinical practice

Key features of the publication include:• Differential features tables - to provide a basis for formulary compa risons of products• Patient care guidelines - for use in disease management and drug usage evaluation• Adis evaluation tables - for a rapid appraisal of the benefits and limitations of drugs and drug classes

// 72-0360/98/003-005/$0/.00 0Adis International Limited. All rights reserved Vol. 11, No.3; February 16, 1998