Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from...

Comparison of the efficacy and tolerabilityof new antiepileptic drugs: what can we learnfrom long-term studies?

In the last 15 years, several new antiepileptic drugs(AEDs) have become available in Europe and inthe US as add-on treatment for patients withepilepsy. As large comparative studies on these newAEDs have not yet been performed, specificselection criteria are still lacking. In this frame-work, a systematic review of the current evidencecan be useful, particularly as regards open-labelobservational studies.To assess the efficacy and/or tolerability of the

new AEDs, a number of meta-analyses have

explored the results reported in double-blindrandomized studies (1– 7). However, the transfer-ability of these findings to clinical practice islimited by several factors. First, the doses used inregulatory trials do not always reflect the dosesactually used in clinical practice. Second, thesemeta-analyses have used the response rate (per-centage of patients with 50% or greater reductionin seizure frequency compared with baseline) as theprimary efficacy index and have ignored importantclinically relevant end points such as the number of

Acta Neurol Scand 2006: 114: 157–168 DOI: 10.1111/j.1600-0404.2006.00705.x Copyright � Blackwell Munksgaard 2006

ACTA NEUROLOGICASCANDINAVICA

Zaccara G, Messori A, Cincotta M, Burchini G. Comparison of theefficacy and tolerability of new antiepileptic drugs: what can we learnfrom long-term studies?Acta Neurol Scand 2006: 114: 157–168. � Blackwell Munksgaard 2006.

Objective – A review of long-term open-label studies was performedwith the aim of detecting differences in efficacy and/or tolerability ofnew antiepileptic drugs (AEDs). Methods – From more than 500 openstudies conducted to evaluate the efficacy and tolerability ofgabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV),oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate(TPM) or zonisamide (ZNS), we selected all studies that reported orallowed us to calculate the number of patients who achieved seizurefreedom for 6 months and/or the number of patients withdrawing foradverse effects and/or the number or percentage of patients continuingtreatment after 1 year. Results – No studies were found in which thisinformation was available for OXC, PGB, TGB or ZNS. The numberof patients who achieved seizure freedom for 6 months was reported infour studies each for GBP and TPM, five studies for LTG, and eightstudies for LEV. The best efficacy profile using this end point wasfound for LEV, followed by TPM, LTG, and GBP. Twenty-two studiesreported the number of patients withdrawing due to adverse effects.LEV was the best-tolerated AED, a little ahead of LTG, andsignificantly better than GBP or TPM . TPM was by far the least well-tolerated drug. Information concerning patients continuing treatmentafter 1 year was reported in two GBP studies, two TPM studies, sixLEV studies and five LTG studies. GBP had a very low retention rate(between 20% and 25% of patients continued the drug), while TPMand LTG had a retention rate of 40–60% and LEV had a retention rateof 60–75%. Conclusion – One limitation of these rankings is that theirstatistical value is limited because of the indirect nature of thecomparisons. Anyhow, this review covers the main studies publishedthus far on this subject and provides full updated information on thecurrent literature about these drugs.

G. Zaccara1, A. Messori2,M. Cincotta1, G. Burchini2

1Unit of Neurology, S.M. Nuova Hospital, Florence, Italy;2Drug Information Centre, Careggi Hospital, Florence,Italy

Key words: epilepsy; antiepileptic drugs; long-termstudies; systematic review

Gaetano Zaccara, Unit� Operativa di Neurologia,Ospedale S.M. Nuova, Piazza S.M. Nuova 1, 50122Firenze, ItalyTel.: 00 390552758894Fax: 00 390552758291e-mail: [email protected]

Accepted for publication May 9, 2006

157

patients achieving seizure freedom. Third, theefficacy and safety profiles in patients enrolled inrandomized trials may differ strikingly from thoseof patients treated in everyday practice. Last butnot least, the follow-up periods in the main double-blind studies published thus far have been veryshort . For example, the mean duration of follow-up for the 29 double-blind studies analyzed byMarson et al. (1) was only 3.5 months.Patients with epilepsy must take their treat-

ment for years, often for their whole life. Howcan we be sure that a new treatment willmaintain its efficacy over months or years?How can we compare the long-term adverseeffects of these drugs? Well-designed long-termclinical trials with head-to-head comparisons arerequired to answer these questions. In theabsence of such studies, as much information aspossible should be sought from long-term open-label studies. Hundreds of these studies havebeen published, and some provide crucial infor-mation on the long-term effects of these treat-ments (8– 14). However, no attempt has yet beenmade to review these data with the aim ofassessing the new AEDs.Our review of the literature concentrates on

three markers of efficacy and tolerability: (i) thepercentage of patients achieving seizure freedom;(ii) the percentage of patients withdrawingbecause of adverse effects; and (iii) the percentageof patients continuing treatment. Freedom fromseizures is a simple measure of efficacy, but itsclinical relevance depends on the duration offollow-up. Some authors (15, 16) have reported aseizure-free patient when seizures were notobserved for the last 4 or 6 weeks of the study.Others have reported the number of patientswithout seizures for six consecutive months orfor 1 year (12). We chose the 6-month seizurefreedom criterion because, this information wasreported by the majority of the most recentstudies, and because this criterion tends to be lesssensitive to the type of population recruited. Wesearched all open-label studies in which gabap-entin (GBP), lamotrigine (LTG), levetiracetam(LEV), oxcarbazepine (OXC), pregabalin (PGB),tiagabine (TGB), topiramate (TPM) or zonisa-mide (ZNS) were added to the previous antiep-ileptic treatment in patients whose seizures werenot controlled. Among these studies, we selectedthose that had a follow-up of at least 6 monthsand reported at least one of the three markerspreviously described. We included both prospect-ive and retrospective studies. To ascertain poss-ible bias, we also performed a further analysiscomparing results only from prospective studies.

Methods

Study selection

In February 2006, a computer search of Medline(PubMed version) was conducted for human stud-ies published in English, Italian, French, or Span-ish from 1966 up to May 2005. The literaturedatabase was extracted (first MEDLINE search)using the following Boolean keyword syntax:(retention OR withdrawal OR discontinuationOR dropout) AND (gabapentin OR lamotrigineOR levetiracetam OR oxcarbazepine OR pregab-alin OR tiagabine OR topiramate OR zonisamide).In a second search, each drug was consideredseparately, using its name in a simple two-keywordquery (drug name AND epilepsy) with thePubMed limits of �clinical trial� and �human.� Thefirst MEDLINE search produced 507 articles. Thesecond search showed 73, 148, 52, 48, 7, 47, 100,and 31 articles for GBP, LTG, LEV, OXC, PGB,TGB, TPM, and ZNS respectively.From these articles, we selected the trials that

met each of the following criteria: (i) open-labelstudies performed in drug-resistant epilepticpatients in whom a new drug was added to aprevious treatment, (ii) adult patients (or at least90% aged over 18 years), (iii) studies which inclu-ded only patients affected by generalized seizureswere excluded, (iv) special populations (i.e. chil-dren, elderly, patients with mental retardation)were excluded, (v) the duration of the studyallowed for the evaluation of our outcome meas-ures (see below).

Outcome measures

Our analysis included all trials that had a follow-upperiod of at least 6 months and reported at leastone of the following three parameters:

1 The number of patients who achieved seizurefreedom for six consecutive months. We ascer-tained that in all of the selected studies, patientshad been followed for at least 6 months; so wedetermined whether any patients had experi-enced a 6-month period of seizure freedomduring the observation period.

2 The number of patients who withdrew becauseof adverse effects. Some studies reported separ-ate information for patients withdrawing onlyfor adverse effects and for patients withdrawingfor adverse effects and no efficacy. In these cases,in a first evaluation, we considered patientswithdrawing only for adverse effects. In asubsequent evaluation, we also performed asensitivity analysis with which we reported

Zaccara et al.

158

withdrawals due to adverse effects of any kind(including those associated with inefficacy).

3 The number or percentage of patients continuingtreatment after 1 year and, if available, aftertwo, three or more years of treatment.

For each drug, the number of patients seizure-free for 6 months and the overall number ofpatients enrolled were extracted from individualstudies and then summed up to generate �crude�totals and a �crude� percentage of the occurrence ofthis clinically favorable end-point. The same ana-lysis was carried out for the clinically unfavorableend point of drug withdrawal.

Statistical analyses

The 95% confidence intervals (CI) were calculatedto estimate the statistical variations of our end-points. Standard methods were used to calculate95%CI of means. In the case of proportions, thecalculations were based on the equations describedby Fleiss (17).

Results

One hundred and fifty four open-label studies wereselected in which one of the new AEDs had beenadded to the treatment of adults (or mainly adults)with refractory seizures (as in a few studies not allof the patients had refractory seizures, thesepopulations were included in our analysis providedthat the subgroup of refractory patients had beenevaluated separately). Only 23 studies (two ofwhich presented data from the same patientpublished twice) reported or allowed us to calculateat least one of the previously described outcomeparameters. No studies were found in which thisinformation was available for OXC, PGB, TGB,and ZNS. Therefore, this review was focused onfour drugs only: GBP, LEV, LTG, and TPM.Tables 1–4 show the main characteristics of the

studies selected for each AED, e.g. recruitmentinformation, patient characteristics at baseline anddisease severity. Fourteen studies were prospectiveand eight were retrospective.The number of patients who achieved 6 months

of seizure freedom was reported in five LTGstudies, eight LEV studies, and four studies eachfor GBP and TPM. All of the studies selectedreported the number of patients who withdrew dueto adverse events.Results for seizure freedom are shown in Fig. 1.

As the 95%CIs did not overlap, one can assumethat each drug was significantly different from theothers. The most efficacious drug was LEV,

followed by TPM, LTG, and GBP. Analysis fromthe selected prospective studies was possible forLTG, LEV and TPM. Results showed that totalpercentages of patients who experienced a 6-monthseizure freedom were 4.7% (95%CI: 3.0–6.3),13.2% (95%CI: 11.8–14.6), and 16.1% (95%CI:12.2–20.0), respectively.Results for withdrawal due to adverse events are

shown in Fig. 2. LEV was the best-tolerated AED,a little ahead of LTG, and significantly better thanGBP or TPM. TPM was by far the least well-tolerated drug. In this case, results from selectedprospective studies showed that patients withdraw-ing due to adverse effects were 3% (95%CI: 0.26–6.2), 12.9% (95%CI: 10.4–15.3), 14.5% (95%CI:13.0–15.9), and 23.5% (95%CI: 19.4–27.5) forGBP, LTG, LEV, and TPM, respectively. Addi-tionally, we also performed a sensitivity analysiscalculating all patients withdrawing for adverseeffects (patients withdrawing for adverse effectsand/or inefficacy). In this case, the percentageswere 23.5% (95%CI: 20.7–26.3), 17.6% (95%CI:15.9–19.1), 16.6% (95%CI: 15.3–17.8), and 34.4%(95%CI: 31.8–36.9) for GBP, LTG, LEV, andTPM, respectively.Information concerning patients �retained� after

1 year was reported in two GBP studies, two TPMstudies, six LEV studies, and five LTG studies.Although these studies generally reported Kaplan–Meier percentages of patients continuing treatmentafter 2, 3, 5, and also 8 years (see Tables 1–4),information on retention was methodologicallypoor in nearly all of these studies. In fact,information was generally lacking about the cen-soring process and about the absolute number ofpatients still on treatment at the various timepointsof the Kaplan–Meier curve. The knowledge ofthese data is crucial to understand whether the�right tail� of the Kaplan–Meier curve is stillinformative because it contains enough patientsor is virtually uninformative because only a fewpatients are still in the study. This prevented usfrom calculating (at the various times) the values ofoverall retention percentage across the studiesevaluating the same drug. For this reason, wehave reported only the percentages of patientscontinuing treatment after 1 year (Fig. 3).Fig. 3 suggests that the differences among the

four drugs might be clinically relevant. After 1 yearof treatment, GBP had a very low retention rate(between 20% and 25%), while TPM and LTGhad retention rates between 40% and 60% andLEV had rates ranging from 60% to 75%. Inter-estingly enough, even though very different trialswere examined (some were retrospective, othersprospective, patient populations were heterogene-

Comparing new AEDs from long-term studies

159

Tab

le1

Gaba

pent

inst

udie

s

Auth

orN

o.of

patie

nts

Type

ofst

udy

and

patie

ntre

crui

t-m

ent

Patie

ntch

arac

teris

tics

Dura

tion

offo

llow

-up

Perc

enta

geof

6M-S

Fpa

tient

sPe

rcen

tage

ofAE

Wpa

tient

sPe

rcen

tage

ofCT

patie

nts

Sive

nius

etal

.(18

)25

Pros

pect

ive.

Alls

ubje

cts

prev

ious

lyin

clud

edin

ado

uble

-blin

dst

udy

Loca

lizat

ion-

rela

ted:

100%

Med

ian

seizu

refre

quen

cy:8

mon

ths

Conc

omita

ntdr

ugs:

atle

ast

1M

ean

last

dosa

ge:1

350

mg/

d(n

on-re

spon

ders

),17

00m

g/d

(resp

onde

rs)

Med

ian:

54m

onth

s0%

(0/2

5)0%

(0/2

5)

Lang

anet

al.(

19)

260

Retro

spec

tive.

263

cons

ecut

ive

patie

nts

atte

ndin

gan

epile

psy

clin

icbe

twee

n19

93an

d199

7.Th

ree

patie

nts

excl

uded

(reas

onno

tgi

ven)

Loca

lizat

ion-

rela

ted:

88%

;gen

eral

ized:

4.9%

;un

dete

rmin

ed:6

.8%

Med

ian

seizu

refre

quen

cy:4

mon

ths

Med

ian

no.o

fco

ncom

itant

drug

s:2

(0–5

)M

ean

no.p

revi

ous

drug

s:6.

9(1

–16)

Med

ian

dose

:160

0m

g/d

Mea

n:6.

75m

onth

s(fr

om1

dto

47m

onth

s)2.

7%(7

/260

)27

%(7

2/26

0)

Won

get

al.(

8)36

1Re

trosp

ectiv

e.Al

lpat

ient

sst

artin

gth

edr

ugin

five

terti

ary

epile

psy

cent

ers.

Loca

lizat

ion-

rela

ted:

86%

;gen

eral

ized:

9%;

unde

term

ined

:4%

Case

reco

rds

from

5te

rtiar

yre

ferra

lepi

leps

yce

nter

s(s

eizu

reba

selin

eno

.not

spec

ified

)M

ean

max

imal

reco

rded

dose

:157

5m

g/d

Mea

n:14

mon

ths

0.8%

(3/3

61)

9.7%

(35/

361)

Tota

lAEW¼

21%

(77/

361)

1st

year¼

25%

2nd

year¼

6.6%

May

eret

al.(

20)

110

Pros

pect

ive.

123

patie

nts

enro

lled

from

ate

rtiar

yce

nter

for

epile

psy

(13

excl

uded

for

prot

ocol

viol

atio

n)

Loca

lizat

ion-

rela

ted:

100%

Med

ian

base

line

parti

alse

izure

frequ

ency¼

6.8

mon

ths

Conc

omita

ntdr

ugs:

1M

ean

no.p

revi

ous

drug

s:2.

5Da

ilydo

sage

:240

0m

gin

50%

and

2000

mg

in20

%of

patie

nts

6.5

mon

ths

Prot

ocol

Not

avai

labl

e3%

(4/1

10)

Tota

lAEW¼

7.3%

(8/1

10)

Lhat

ooet

al.(

10)

158

Retro

spec

tive.

Allp

atie

nts

star

ting

the

drug

atan

epile

psy

clin

icfro

mSe

pt19

96to

Dec

1996

Loca

lizat

ion-

rela

ted:

83%

;gen

eral

ized:

11%

;un

dete

rmin

ed:5

.6%

Refra

ctor

yep

ileps

ypa

tient

sfro

ma

terti

ary

refe

rral

cent

er(s

eizu

reba

selin

eno

.not

spec

ified

)M

ean

no.c

onco

mita

ntdr

ugs:

1.8

(in5

patie

nts

noco

ncom

itant

drug

s)M

ean

no.p

revi

ous

new

drug

s:1.

6M

ean

max

imal

reco

rded

dose

:144

0m

g/d

Mea

nor

med

ian:

not

repo

rted

0.6%

(1/1

58)

36.7

%(5

8/15

8)1s

tye

ar¼

23%

2nd

year¼

<10%

11/8

04¼

1.37

%16

9/91

4¼

18.5

%

6M-S

F,6-

mon

thse

izure

freed

om;A

EW,w

ithdr

ewbe

caus

eof

adve

rse

effe

cts;

CT,c

ontin

uing

treat

men

t;To

talA

EW,t

otal

num

ber

ofpa

tient

sw

ithdr

awin

gfo

rad

vers

eef

fect

s(s

umof

thos

epa

tient

sw

ithdr

awin

gfo

rad

vers

eef

fect

san

d/or

inef

ficac

y).

Zaccara et al.

160

Tab

le2

Lam

otrig

ine

stud

ies

Auth

orN

o.of

patie

nts

Type

ofst

udy

and

patie

nt's

recr

uitm

ent

Patie

ntch

arac

teris

tics

Dura

tion

offo

llow

-up

Perc

enta

geof

6M-S

Fpa

tient

sPe

rcen

tage

ofAE

Wpa

tient

sPe

rcen

tage

ofCT

patie

nts

Sand

eret

al.(

21)

125

Pros

pect

ive.

Patie

nts

enro

lled

intw

ote

rtiar

yce

nter

sfo

rep

ileps

y

Loca

lizat

ion-

rela

ted:

67%

;gen

eral

ized:

6%;

unde

term

ined

:28%

Atle

ast

4se

izure

s/m

onth

sM

ean

no.c

onco

mita

ntdr

ugs:

1.9

(1–3

)M

ean

dose

:367

mg/

d

11m

onth

s(ra

nge

3–27

)Pa

tient

sno

tw

ithdr

awin

g0%

(0/1

25)

15%

(19/

125)

1st

year¼

37.6

%(4

7/12

5)

Coci

toet

al.(

22)

16Pr

ospe

ctiv

e.Pa

tient

sen

rolle

din

one

cent

ers

for

epile

psy

Atle

ast

2se

izure

s/m

onth

sLo

caliz

atio

n-re

late

d:81

%;g

ener

alize

d:19

%At

leas

t2

seizu

res/

mon

ths

Mea

nno

.con

com

itant

drug

s:2

Dose

:400

mg/

d(p

atie

nts

indu

ced)

or20

0m

g/d

(pat

ient

sno

tin

duce

d)

15–3

8m

onth

s0%

(0/1

6)12

%(2

/16)

1st

year¼

62%

(10/

16)

Won

get

al.(

13,1

4)10

50Re

trosp

ectiv

eAl

lpat

ient

sat

tend

ing

the

outp

atie

ntcl

inic

sof

5te

rtiar

yep

ileps

yce

nter

s

Loca

lizat

ion-

rela

ted:

68%

;gen

eral

ized:

26%

;und

eter

min

ed:7

%Ca

sere

cord

sfro

m5

terti

ary

refe

rral

epile

psy

cent

ers(

seizu

reba

selin

eno

.not

spec

ified

)Pr

esum

ably

allp

atie

nts

had

the

new

drug

adde

dto

apr

evio

usth

erap

yM

ean

dose

:303

mg/

d

Mea

n:27

mon

ths

3%(3

1/10

50)

13.2

%(1

38/1

050)

Tota

lAEW

¼19

.2%

(202

/105

0)

1st

year¼

60%

5st

year¼

40%

8th

year¼

38%

Pim

ente

let

al.(

23)

61Pr

ospe

ctiv

ePa

tient

sat

tend

ing

one

cent

erfo

rep

ileps

y

Loca

lizat

ion-

rela

ted:

73%

;gen

eral

ized:

23%

;not

give

n:3%

Atle

ast

2se

izure

s/m

onth

sM

ean

no.c

onco

mita

ntdr

ugs:

1.8

Mea

ndo

se:2

05m

g/d

(pat

ient

sno

tin

duce

d)or

368

mg/

d(p

atie

nts

indu

ced)

25m

onth

sPr

otoc

olN

otre

porte

d6.

5%(4

/61)

1st

year¼

noda

ta2n

dye

ar¼

78%

(48/

61)

Lhat

ooet

al.(

10)

424

Retro

spec

tive.

Allp

atie

nts

star

ting

the

drug

atan

epile

psy

clin

icfro

mSe

pt19

96to

Dec

1996

Loca

lizat

ion-

rela

ted:

70.5

%;g

ener

alize

d:23

%;u

ndet

erm

ined

:6.6

%Re

fract

ory

epile

psy

patie

nts

from

ate

rtiar

yre

ferra

lcen

ter

(sei

zure

base

line

no.n

otsp

ecifi

ed)

Mea

nno

.con

com

itant

drug

s:1.

6(in

23pa

tient

sno

conc

omita

ntdr

ugs)

Mea

nno

.pre

viou

sne

wdr

ugs:

0.6

Mea

nm

axim

alre

cord

eddo

se:2

97m

g/d

Mea

nor

med

ian:

not

repo

rted

2%(1

4/42

4)22

%(9

3/42

4)1s

tye

ar¼

46%

3rd

year¼

29%

Arzim

anog

lou

etal

.(24

)56

6Pr

ospe

ctiv

ePa

tient

sat

tend

ing

seve

ral

cent

ers

for

epile

psy

25%

child

ren

Loca

lizat

ion-

rela

ted:

59%

;gen

eral

ized:

33%

;und

eter

min

ed:8

%Re

fract

ory

epile

psy

patie

nts

(sei

zure

base

line

no.n

otsp

ecifi

ed)

Mea

nno

.con

com

itant

drug

s:2.

2Do

sera

nge:

100–

200

mg/

d(p

atie

nts

not

indu

ced)

;200

–500

mg/

d(p

atie

nts

indu

ced)

48w

eek

Prot

ocol

5.8%

(33/

566)

13.1

%(7

4/56

6)1s

tye

ar¼

58%

(330

/566

)

78/2

181¼

3.6%

330/

2242¼

14.7

%

6M-S

F,6-

mon

thse

izure

freed

om;A

EW,w

ithdr

ewbe

caus

eof

adve

rse

effe

cts;

CT,c

ontin

uing

treat

men

t;To

talA

EW,t

otal

num

bero

fpat

ient

sw

ithdr

awin

gfo

radv

erse

effe

cts

(sum

ofth

ose

patie

nts

with

draw

ing

fora

dver

seef

fect

san

dof

thos

ew

ithdr

awin

gfo

rad

vers

eef

fect

san

din

effic

acy)

.


161

Tab

le3

Leve

tirac

etam

stud

ies

Auth

orN

o.of

patie

nts

Type

ofst

udy

and

patie

nt's

recr

uitm

ent

Patie

ntch

arac

teris

tics

Dura

tion

offo

llow

-up

Perc

enta

geof

6M-S

Fpa

tient

sPe

rcen

tage

ofAE

Wpa

tient

sPe

rcen

tage

ofCT

patie

nts

Krak

owet

al.(

12)

1422

Pros

pect

ive.

Allp

atie

nts

expo

sed

toLE

Vdu

ring

the

deve

lopm

enta

lpr

ogra

m(d

oubl

e-bl

ind

and

open

-labe

lstu

dies

)in

Euro

pean

dUS

Loca

lizat

ion-

rela

ted:

87%

;gen

eral

ized:

11%

;un

clas

sifia

ble:

1.6%

Allt

rials

wer

ead

d-on

stud

ies

Med

ian

base

line

seizu

refre

quen

cy:8

.7m

onth

sM

ean

no.c

onco

mita

ntdr

ugs:

1.7

Med

ian

dose

:300

0m

g/d

Med

ian:

13m

onth

s(1

dto

99m

onth

s)13

%(1

83/1

422)

15.8

%(2

25/1

422)

1st

year¼

60%

3rd

year¼

37%

5th

year¼

32%

Ben-

Men

ache

met

al.(

25)

98Pr

ospe

ctiv

e.Pa

tient

sre

crui

ted

from

asi

ngle

cent

erfo

rep

ileps

y

Loca

lizat

ion-

rela

ted:

79(8

0%);

gene

raliz

ed:1

6%;

Lenn

ox–G

asta

ut:1

%;m

yocl

onic

:1%

Mea

nse

izure

frequ

ency

:14

mon

ths

Mea

nno

.con

com

itant

drug

s:2.

1Do

sera

nge:

1000

–300

0m

g/d

1ye

ar*

14%

(14/

98)

17%

(17/

98)

1st

year¼

61%

(60/

98)

Bird

etal

.(26

)17

5Pr

ospe

ctiv

eCo

nsec

utiv

epa

tient

sfro

ma

sing

lece

nter

for

epile

psy

Loca

lizat

ion-

rela

ted:

87.4

%;g

ener

alize

d:12

.6%

;Re

fract

ory

patie

nts

(sei

zure

base

line

no.n

otsp

ecifi

ed)

Mea

nno

.con

com

itant

drug

s:2.

2Do

se:u

pto

3000

mg/

d

Atle

ast

6m

onth

s14

.3%

(25/

175)

10.3

%(1

8/17

5)To

talA

EW¼

16%

(28/

175)

Betts

etal

.(27

)11

9Re

trosp

ectiv

eAl

lpat

ient

sw

host

arte

dLE

Vat

anep

ileps

ycl

inic

betw

een

Oct

2000

and

Aug

2001

Perc

enta

geof

patie

nts

with

parti

alse

izure

sno

tsp

ecifi

edRe

fract

ory

epile

psie

s(s

eizu

reba

selin

eno

.not

spec

ified

)M

ean

no.c

onco

mita

ntdr

ugs:

not

spec

ified

Mea

ndo

seat

6m

onth

s(o

nly

seizu

refre

epa

tient

s):1

921

mg/

d

1ye

ar26

%(3

8/11

9)12

%(1

4/11

9)1s

tye

ar¼

77%

(92/

119)

Brod

tkor

bet

al.(

28)

184

Pros

pect

ive.

Cons

ecut

ive

patie

nts

from

two

cent

ers

for

epile

psy

Loca

lizat

ion-

rela

ted:

143

(77%

);ge

nera

lized

:22%

Refra

ctor

yep

ileps

ies

in16

6pa

tient

s(w

hoha

dat

leas

t1

seizu

re/m

onth

s).

Mea

nno

.con

com

itant

drug

s:1.

6M

ean

max

imal

dose

:220

5m

g/d

Mea

n:8.

1m

onth

s(1

–21

mon

ths)

10.2

%(1

7/16

6)�

6%(1

1/18

4)1s

tye

ar¼

69%

(128

/184

)

Moh

anra

jet

al.,

(29)

156

Pros

pect

ive

Cons

ecut

ive

patie

nts

from

one

cent

erfo

rep

ileps

y

Loca

lizat

ion-

rela

ted:

87%

Gene

raliz

ed:1

3%M

edia

nba

selin

ese

izure

frequ

ency

:5m

onth

sM

ean

no.c

onco

mita

ntdr

ugs:

1.6

Med

ian

no.o

fpr

evio

usan

tiepi

lept

icdr

ugs:

3M

edia

ndo

se:1

000

mg/

d(in

seizu

refre

epa

tient

s)or

1500

mg/

d(in

patie

nts

with

draw

ing)

or20

00m

g/d

(inpa

tient

sre

spon

ders

)

Not

spec

ified

26%

(40/

156)

17%

(27/

156)

Tota

lAEW¼

24.3

%(3

8/15

6)

Nic

olso

net

al.(

30)

354

Pros

pect

ive

Allp

atie

nts

who

star

ted

LEV

atan

epile

psy

clin

icbe

twee

nN

ov20

00an

dDe

c20

02

Loca

lizat

ion-

rela

ted:

80%

;gen

eral

ized:

18%

;un

clas

sifie

d:1.

1%Pr

esum

ably

refra

ctor

yep

ileps

ies

(sei

zure

base

line

no.n

otsp

ecifi

ed)

Mea

nno

.con

com

itant

drug

s:1.

7M

edia

ndo

se:1

799

mg/

d

Med

ian:

12.4

mon

ths

(1d

to30

mon

ths)

9.8%

(35/

354)

13.6

%(4

8/35

4)To

talA

EW¼

17,5

%(6

2/35

4)1s

tye

ar¼

74%

2nd

year¼

58%

Zaccara et al.

162

ous, etc.), no important differences were foundbetween studies performed with the same drug. Incontrast, differences were much more evidentbetween different drugs.In three small studies (one prospective LTG

study (22) and one retrospective (32) and oneprospective (33) TPM study), only 2-year retentiondata had been reported (Tables 2 and 4). In fourlarge studies – three retrospective and one pros-pective (8, 10, 12, 31)— percentages of patientscontinuing treatment also were reported after 3and 5 years, and in one case after 8 years oftreatment (Tables 1–4). However, as most of thesestudies did not indicate how many patients werestill on treatment at the time points of the follow-up, we could not place any reliance on the 3-yearretention data because only a very small number ofpatients might have been followed for so long.

Discussion

The first observation suggested by our analysis wasthat very few studies evaluated long-term out-comes. For OXC, PGB, TGB and ZNS, we couldnot find any long-term open-label studies ofpatients with refractory epilepsy, where theabove-mentioned parameters were evaluated.As far as the other four drugs were concerned,

some methodological limits weaken the results ofour review.Firstly, more than one third of the 23 selected

studies were retrospective (in particular, three ofthe five studies for GBP and two for LEV seeTables 1 and 3).Secondly, although we made every effort to

exclude studies with a selection bias in recruitment(see the details of the various studies reported inthe Tables), in some cases we could not calculatethe number of seizure-free patients simply becausethis information was lacking in the original study.Thirdly, while almost all studies included a large

majority of patients with partial epilepsies but alsoa small subgroup with generalized epilepsies (6–33%), a separate description of the results was notalways given. The presence of these small sub-groups with generalized epilepsies might havefavoured LTG, LEV and TPM which were alsoeffective against these forms of epilepsy. On theother hand, the percentage of patients with gener-alized epilepsies was very low (0–11%) in thestudies performed with GBP (see Tables 1– 4).We also found it distressing that the few studies

in which a Kaplan–Meier retention analysis wasperformed did not report crucial data such asabsolute numbers as opposed to mere percentages.This made it impossible to perform any reliableT

ab

le3

(Con

tinue

d.)

Auth

orN

o.of

patie

nts

Type

ofst

udy

and

patie

nt's

recr

uitm

ent

Patie

ntch

arac

teris

tics

Dura

tion

offo

llow

-up

Perc

enta

geof

6M-S

Fpa

tient

sPe

rcen

tage

ofAE

Wpa

tient

sPe

rcen

tage

ofCT

patie

nts

Depo

ndt

etal

.(31

)81

1Re

trosp

ectiv

eAl

lpat

ient

sw

host

arte

dLE

Vw

ithin

the

first

24m

onth

sof

mar

ketin

gat

anep

ileps

ycl

inic

Loca

lizat

ion-

rela

ted:

64%

Gene

raliz

ed:1

6%M

ixed

:19%

Pres

umab

lyre

fract

ory

patie

nts

from

ate

rtiar

yre

ferra

lcen

ter

(sei

zure

base

line

no.n

otsp

ecifi

ed)

Mea

nno

.con

com

itant

drug

s:1.

9M

ean

max

imal

reco

rded

dose

:226

7m

g/d

Mea

n:16

,7m

onth

s11

%(8

9/81

1)10

%(8

1/81

1)To

talA

EW¼

19%

(156

/811

)1s

tye

ar¼

74%

3rd

year¼

58%

441/

3301¼

13.4

%44

1/33

19¼

13.3

%

*Pat

ient

sw

ere

seizu

re-fr

eeaf

ter

titra

tion

for

1ye

ar.

�Pa

tient

sw

ithon

lyre

fract

ory

epile

psie

sw

ere

incl

uded

.6M

-SF,

6-m

onth

seizu

refre

edom

;AEW

,with

drew

beca

use

ofad

vers

eef

fect

s;CT

,con

tinui

ngtre

atm

ent;

LEV,

leve

tirac

etam

;Tot

alAE

W,t

otal

num

bero

fpat

ient

sw

ithdr

awin

gfo

radv

erse

effe

cts

(sum

ofth

ose

patie

nts

with

draw

ing

fora

dver

seef

fect

san

d/or

inef

ficac

y).


163

Tab

le4

Topi

ram

ate

stud

ies

Auth

orN

o.of

patie

nts

Type

ofst

udy

and

patie

nt's

recr

uitm

ent

Patie

ntch

arac

teris

tics

Dura

tion

offo

llow

-up

Perc

enta

geof

6M-S

Fpa

tient

sPe

rcen

tage

ofAE

Wpa

tient

sPe

rcen

tage

ofCT

patie

nts

Riba

coba

-Mon

tero

etal

.(32

)56

Retro

spec

tive.

Patie

nts

who

star

ted

TPM

betw

een

June

1519

97an

dDe

c20

00in

one

cent

erfo

rep

ileps

y

Alm

ost

alll

ocal

izatio

n-re

late

dRe

fract

ory

epile

psie

sTP

Mad

ded

toa

prev

ious

treat

men

t(s

eizu

reba

selin

eno

.not

spec

ified

)M

ean

no.p

revi

ousl

ypr

oven

AEDs

:7Do

sera

nge:

200–

400

mg/

d

Mea

n:27

mon

ths

(18–

44)

Not

repo

rted

12.5

%(7

/56)

Tota

lAEW¼

16.1

%(9

/56)

1st

year¼

noda

ta2n

dye

ar¼

80.4

%(4

5/56

)

Lhat

ooet

al.(

10,1

1)39

3Re

trosp

ectiv

e.Al

lpat

ient

sw

host

arte

dTP

Mat

anep

ileps

ycl

inic

from

Sept

1996

toDe

c19

96

Loca

lizat

ion-

rela

ted:

89%

;gen

eral

ized:

9%;

unde

term

ined

:1%

Refra

ctor

yep

ileps

ypa

tient

sfro

ma

terti

ary

refe

rral

cent

erM

ean

no.c

onco

mita

ntdr

ugs:

1.8

(in14

patie

nts

noco

ncom

itant

drug

s)(s

eizu

reba

selin

eno

.not

spec

ified

)M

ean

no.p

revi

ous

new

drug

s:2.

2M

ean

max

imal

reco

rded

dose

:308

mg/

d

15m

onth

s(1

to40

mon

ths)

3.56

%(1

4/39

3)40

%(1

57/3

93)

1st

year¼

52%

3rd

year¼

30%

Abou

-Kha

lilet

al.(

33)

292

Pros

pect

ive.

Patie

nts

recr

uite

dfro

mse

vera

lce

nter

sfo

rep

ileps

y

Parti

alse

izure

s:84

%;g

ener

alize

dse

izure

s:28

%M

edia

nba

selin

ese

izure

frequ

ency

:12

mon

ths

No.

ofco

ncom

itant

drug

spr

evio

usly

take

n:no

tkn

own

Mea

ndo

seat

last

visi

t:50

3m

g/d

Mea

n:13

.7m

onth

s(2

.8–2

6.8)

10%

(20/

196)

*32

.5%

(90/

277)

1st

year¼

noda

ta2n

dye

ar¼

39%

(114

/292

)

Step

hen

etal

.(34

)17

0Pr

ospe

ctiv

ePa

tient

sre

crui

ted

from

one

cent

erfo

rep

ileps

y

Parti

alse

izure

s:78

.8%

;gen

eral

ized:

21.2

%M

edia

nse

izure

frequ

ency

:4m

onth

s(ra

nge

2–12

0)M

ean

no.c

onco

mita

ntdr

ugs:

1.5

Mea

ndo

ses:

250

mg

(sei

zure

free

patie

nts)

,46

3m

g/d

(resp

onde

rs),

265

mg/

d(w

ithdr

awin

gpa

tient

s)

Tim

ere

quire

dto

reac

hse

izure

freed

omfo

r6

mon

ths

or>5

0%se

izure

redu

ctio

nor

AEW

23%

(39/

170)

8.8%

(15/

170)

Tota

lAEW¼

22.9

%(3

9/17

0)

Boot

sma

etal

.(35

)47

0Re

trosp

ectiv

e.Al

lpat

ient

stre

ated

with

TPM

betw

een

Sprin

g19

93an

dm

id-2

002

Loca

lizat

ion-

rela

ted:

75%

;gen

eral

ized:

20%

;un

dete

rmin

ed:4

.6%

Refra

ctor

yep

ileps

ypa

tient

sfro

ma

terti

ary

refe

rral

cent

er(s

eizu

reba

selin

eno

.not

spec

ified

)N

o.co

ncom

itant

drug

san

dof

drug

spr

evio

usly

take

n:no

tkn

own

Mea

ndo

se:2

17m

g/d

(at6

mon

ths)

,323

mg/

d(a

t24

mon

ths)

Mea

n:13

.8m

onth

s(S

D14

.9)

5.5%

�(2

6/47

0)23

.2%

(109

/470

)To

talA

EW¼

37.2

%(1

75/4

70)

1st

year¼

53.4

%2n

dye

ar¼

45.4

%3r

dye

ar¼

38.4

%

99/1

229¼

8.1%

378/

1366¼

27.7

%99

/122

9¼

8.1%

378/

1366¼

27.7

%

6M-S

F,6-

mon

thse

izure

freed

om;A

EW,w

ithdr

ewbe

caus

eof

adve

rse

effe

cts;

CT,c

ontin

uing

treat

men

t;TP

M,t

opira

mat

e;AE

D,an

tiepi

lept

icdr

ug;T

otal

AEW

,tot

alnu

mbe

rof

patie

nts

with

draw

ing

for

adve

rse

effe

cts

(sum

ofth

ose

patie

nts

with

draw

ing

for

adve

rse

effe

cts

and/

orin

effic

acy)

.*O

nly

patie

nts

com

plet

ing

6m

onth

sof

ther

apy.

�Pa

tient

sw

hoac

hiev

ed6-

mon

thse

izure

freed

omdu

ring

the

first

6m

onth

sof

TPM

ther

apy.

Zaccara et al.

164

meta-analysis about retention. Meta-analysis ofthe other two outcome measures was not feasiblebecause of heterogeneity.Although patients with epilepsy have to take

their medication for several years, no controlleddata existed on the chronic effects and on the long-term efficacy of these drugs. For this reason, wethought that every effort should be made tointerpret the data reported in the open studiespublished thus far, despite the important limita-tions of these studies.We identified a number of studies in which, after

the administration of GBP, LEV, LTG or TPM,some simple markers of efficacy and/or tolerabilityor a mixed parameter of efficacy and tolerability(e.g. the number of patients achieving seizurefreedom for 6 months; the number. of patientswithdrawing from the study because of adverse

effects; the percentage of patients continuingtreatment after 1 year with the new AED) couldbe calculated which provided interesting results.The percentage of patients who achieved six

consecutive months of seizure freedom might be amore robust indicator of efficacy than the responserate (percentage of patients with a 50% or greaterreduction in seizure frequency compared withbaseline), which had been used in all the previousmeta-analyses of double-blind studies. However,we felt that some factors must be considered inorder to interpret the results about this outcomemeasure correctly:

1 We could not rule out the possibility of a smallbias in our analysis. A few studies considered�seizure free� only those patients who had noseizures in the last 6 months of the study(terminal seizure freedom). In other studies,percentages were reported of patients who had a6-month period of seizure freedom during thestudy. We can imagine that drugs followed upfor longer time could be favoured (a patientwho is followed up for a longer time may have ahigher probability of experiencing, by chance, a6-month period of seizure freedom) comparedwith drugs for which only shorter studies wereavailable. However, from the inspection of the

0

2

4

6

8

10

12

14

16

GBP (804) LTG (2181) LEV (3301) TPM (1229)

% o

f 6M

-SF

pat

ien

ts (

95%

CI)

Figure 1. Total percentages (95% CI) of patients who achievedseizure freedom for 6 months (6M-SF) from all clinical studies.GBP, gabapentin; LTG, lamotrigine; TMP, topiramate; LEV,levetiracetam.

0

5

10

15

20

25

30

35

GBP (914) LTG (2242) LEV (3319) TPM (1366)

% o

f A

EW

pat

ien

ts (

95%

CI)

Figure 2. Total percentages (95% CI) of patients who with-drew from the antiepileptic drug because of adverse effects(AEW) from all clinical studies. GBP, gabapentin; LEV,levetiracetam; LTG, lamotrigine; TPM, topiramate.

10

20

30

40

50

60

70

80

0 1 2 3 4 5

GBP

Pts

on

tre

atm

ent

afte

r 1

year

(%

)

TPMLEV LTG

Figure 3. Percentage of patients still on treatment with gab-apentin (GBP), levetiracetam (LEV), lamotrigine (LTG), andtopiramate (TPM) after 1 year of treatment. Clinical studies.(n) Lhathoo et al. (10,11); (r) Wong et al. (8); (m) Sander et al.(21); (e) Cocito et al. (22); (h) Arzimanoglou et al. (24); (d)Krakow et al. (12); (+) Ben-Menachem et al. (25); (—) Bro-dtkorb et al. (28); ( ) Nicolson et al. (30); ( ) Betts et al. (27);(·) Depondt et al. (31); (-) Bootsma et al. (35).


165

duration of the studies included in our analysis(see Tables 1–4), it seemed that differences induration were not significant (with the possibleexception of GBP studies). In future studies,particularly those aiming at evaluating a verylong term outcome, it should be very clearlystated how this parameter was obtained and, ifpossible, both parameters should be calculated.

2 As all studies examined in our analysis wereuncontrolled, we could not rule out the possi-bility that some patients attained this seizurefree outcome not only as a direct effect of theexperimental drug but also because of othervariables such as the natural course of thedisorder or other drugs added subsequently.

3 We should bear in mind that only some of theselected long-term studies reported this outcomemeasure. It is conceivable that the studies thatdid not report seizure-free rates were also thestudies in which the seizure-free rates werelowest.

Our analysis showed that in long-term studies,differences can exist in the seizure-free outcome ofpatients treated with various AEDs (efficacy and/or tolerability). In fact, LEV was the most effectiveagent, followed by TPM and then by LTG andGBP. Analysis limited to prospective studiesshowed some differences. In the only study of thistype to assess, TPM, this drug had the highestpercentage of seizure-free patients, but the differ-ence between rates was not significant.Percentages of patients, attaining seizure free-

dom after the administration of the experimentaldrug, had also been reported in some double-blindstudies. In some cases these values were lower thanthose observed in our review. For example,between 3% and 5% of patients treated withLEV in two double-blind studies attained freedomfrom seizures (36, 37). While we do not have a clearexplanation for this discrepancy, some hypothesescan be made. For example, patients directlyrecruited in open studies may have milder formsof epilepsies than those enrolled in double-blindstudies. For these reasons, the percentages ofpatients acquiring seizure freedom in open studiesare not directly comparable to those obtained indouble-blind studies.The percentage of patients withdrawing because

of adverse effects has already been recognized to bea reliable marker of tolerability, and has also beenused in several meta-analyses of double-blindstudies (1, 2, 5, 6). This outcome measure providedslightly less clear results. LEV was the best-tolerated AED, a little ahead of LTG, and signi-ficantly better than GBP or TPM . TPM was by far

the least well-tolerated drug. However, the analysislimited to prospective studies showed that GBPhad the best profile although not significantly so.This tolerability outcome measure might be influ-enced by the duration of follow-up. A correlationbetween duration of follow-up and this outcomemeasure was not feasible because, in the studiesevaluated, the duration of follow-up was reportedusing different parameters (mean, median, orrange).Finally, the retention rate is a mixed measure of

efficacy and tolerability and has already been usedin numerous studies comparing traditional (38, 39)and new (40, 41) AEDs in patients with newlydiagnosed epilepsy.In Fig. 3, we reported only the retention rate at

the first year because, from inspection, it was onlypossible to calculate it for 1 year for the majorityof patients. Retention data for two, three and moreyears were much less robust.Although the populations studied were hetero-

geneous and the therapeutic protocols differedbetween the studies, similar retention rates wereobserved within trials performed with the samedrug (Fig. 3). GBP showed a very poor retentionrate, which was probably related to its lowefficacy. LTG and TPM had similar retentionvalues.A variety of factors might have influenced these

retention rates. For example, retention rates ofTPM after 1 year might reflect the drug’s poortolerability. On the other hand, retention ratesafter 3 and 5 years of TPM (see Table 4) showedthat patients who did not withdraw in the first yearwere unlikely to withdraw thereafter. Perhaps themost frequent adverse effects of this drug appearedrelatively early in treatment; if they did not appearearly, they were unlikely to appear during chronictreatment. However, too few patients were fol-lowed for three or more years, so no firm conclu-sions could be drawn.Retention rates of LTG might be related more to

efficacy outcomes than to tolerability, and LEVhad a 1-year retention rate that ranged from 60%to about 75%. These higher retention rates areprobably the consequence of a better efficacyassociated with good tolerability.We could speculate that, at least in part, the

retention rate was influenced by the sequence inwhich these drugs were introduced onto themarket. For example, patients treated with GBPmight have been withdrawn from treatmentbecause of the availability of new drugs (LTGor, more recently, TPM or LEV). We could alsoimagine that the latest AEDs were likely to be

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tested in a more refractory population ofpatients.Interestingly enough, the results of our review of

long-term open-label studies are similar to thosereported in several meta-analyses of double-blindstudies (1– 6) (where the proportion of responderswith respect to placebo has generally been used as amarker of efficacy). The most recently publishedmeta-analysis (7) showed that LEV was signifi-cantly more efficacious than GBP and LTG andwas more effective (but not significantly more so)than OXC, TGB, and ZNS. As far as tolerabilitywas concerned, LEV had a significantly lowerwithdrawal rate than OXC and TPM and a lower(but not significantly lower) withdrawal rate thanTGB and ZNS, while similar withdrawal rates wereobserved for LEV, LTG, and GBP.It is commonly thought that results from open-

label studies are of little clinical value. However,this might not be necessarily true. Large, long-termstudies (both prospective and retrospective) andthe use of robust parameters (such as those used inour analysis) might make results from open studiesmore valuable. In our review, the variability of theresults was more influenced by the drugs them-selves and less influenced by the different protocolsor the patient populations, supporting this hypo-thesis.We conclude that well designed, open-label,

long-term, and possibly randomized, add-on stud-ies should be encouraged in which two or moreAEDs are compared head to head. This is the firstattempt to compare new AEDs using data fromopen-label long-term studies. We think that, eventhough several biases might have affected ouranalysis, this is presently the only way to deriveinformation on the long-term therapeutic effect ofthese drugs.

Acknowledgement

This work was supported by a grant from the ��Ente Cassa diRisparmio di Firenze��, Florence, Italy. We wish to thankTonino Di Carlo for his valuable help. No sponsorship hasbeen received by the authors to conduct this study.

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