Slide Dini Jurnal

8/16/2019 Slide Dini Jurnal

1/34


2/34

IntroductionIntroduction Levetiracetam (LEV) is a newer antiepileptic drug with better pharmacokinetic profile.

Currently, it is freuently used for the treatment of partial sei!ures. "he present study

was undertaken to compare the efficacy and safety of LEV and Carbama!epine

(C#$) in partial epilepsy. Methods. "his was a prospective, open labeled, randomi!ed

study. %t was conducted in participants suffering from partial sei!ures after the

approval of ethics committee and written informed consent."he first group received

"ab LEV (&'' to '''mgday) and the second group received "ab C#$ ('' to

*''mgday). "he primary outcomes were efficacy and safety. "he secondary outcome

was the +uality of Life (+L). Efficacy was assessed by comparing the sei!ure

freedom rates at the end of * months. -afety profile was evaluated by comparing the

adverse effects. +L was assessed by +L%E/' scale. Results. "he overall sei!ure

freedom rate at the end of * months was 0/.123 in C#$ group compared to 04.&03

in LEV group 5 '.2&26). #oth LEV and C#$ reported a similar incidence of adverse(

reactions. LEV group reported more behavioral changes like increased aggression

and an7iety. 8lso, it showed better +L compared to the C#$ group. Conclusion. LEV

monotherapy and C#$ monotherapy demonstrated similar efficacy for treatment of

partial epilepsy and were found to be well tolerated.


3/34

I. Introduction

Epilepsy is a chronic disorder characteri!ed by 2 or

recurrent sei!ures of cerebral origin. %t is the second most

common neurological condition after headache. "he

estimated average prevalence of epilepsy is *.4 per /'''people in 9-, &.& per /''' people in Europe, and /.& to /1

per /''' people in 8sia, respectively. Epilepsy is classified

based on the source of sei!ure into partial and generali!ed

sei!ures :/;.


4/34

"he mainstay of treatment of epilepsy is

pharmacological therapy with antiepileptic drugs

(8E>s). %n epilepsy, optimal treatment is important

as the condition is associated with increased

morbidity and mortality and une7pected deaths

without clear structural or pathological cause :&,

*;.8E>s are selected based on the nature of the

disease, the efficacy and tolerability of the agent,and the characteristics of the patient :0;.


5/34

"reatment options for epilepsy include the older 8E>s (carbama!epine,

ethosu7imide, phenytoin, phenobarbital, primidone, and valproic acid)

as well as several newer drugs (Levetiracetam, felbamate, gabapentin,

lacosamide, lamotrigine, o7carba!epine, pregabalin, rufinamide,

tiagabine, topiramate, vigabatrin, and !onisamide) :4;.Carbama!epine(C#$) is the preferred drug for the treatment of partial sei!ures but it

has the disadvantages of reuirement for freuent dosing, dose related

adverse reactions, and drug interactions. ?ecently, Levetiracetam

(LEV) has become one of the most freuently prescribed newer drugs

for the treatment of partial sei!ures. %t offers several advantages like

twice daily dosing, better safety profile, less drug interactions, and noreuirement of serum level monitoring. "his advantageous

pharmacologic profile makes LEV an attractive firstline or ad@unctive

therapy for epileptic sei!ures :6, /';.


6/34

2. Materials and Methods

2.1. Study Design and Setting.

"his was a randomi!ed, prospective, open label, comparative monotherapy

study. "he study was conducted in the >epartment of Aeurology at Vydehi

%nstitute of Bedical -ciences and ?esearch Center, #engaluru, %ndia. "he

institute is a /'''bed tertiary care hospital euipped with modern diagnosticand treatment facilities. atients visiting this hospital come from different

geographical regions including -outhern Darnataka, 8ndhra radesh, and


7/34

2.2. Selection of the Participants.

"he participants were included in the study after obtaining written

informed consent. "he study inclusion criteria included sub@ects of

age between /4 and *' years diagnosed newly with focal or partial

sei!ures with or without secondary generali!ation. "he e7clusion

criteria were pregnant and lactating mothers, patients withnonepileptic sei!ures, auras or absence of sei!ures, and patients

with acute symptomatic sei!ures occurring within /1 days of an acute

brain in@ury such as stroke and patients with history of psychiatric

illness.


8/34

2.3. ata Collection. -ub@ects who consented to participate were then interviewed and were

divided into two groups by the toss of a coin. Each group recruited '

participants.

Froup / participants were prescribed "ab LEV, /'''G '''

mgdayoralH and group 2 participants were prescribed "ab C#$, 1''G

/2''mgdayoral. "he participants were started with minimum dose,

&''mg of LEV and 2''mg of C#$, given twice daily after food and thentitrated depending on the sei!ure control. LEV dose was increased by

&'' mg twice daily every 2 weeks up to a ma7imum of '''mgday if

sei!ure control was not achieved. -imilarly, C#$ dose was increased by

2''mg twice daily up to a ma7imum of /2''mgday if sei!ure control

was not achieved. %n cases where the sei!ure was not controlled after

titration of drug dose, the participant was shifted to ad@uvant therapybased on the clinical condition. "he participant was also discontinued

from the study.


9/34

8ll the participants were given a diary and were asked to note down any

adverse effects (8E)."hey were advised to come after 1, /2, and 2* weeks

after the initiation of therapy for followup.

>uring followup visits, the participants were thoroughly e7amined, history of

breakthrough sei!ures was elicited, and any 8Es were noted. +L wasassessed by using the+L%E/' uestionnaire before initiation of the

treatment and after 2* weeks of therapy ://;.+L%E/' comprises seven

componentsI (/) sei!ureworry, (2)overall+L, () emotional wellbeing, (1)

cognitive function, (&) energyfatigue, (*) medication effectsI physical effects

and psychological effects, and (0) social functioningIwork, driving, and social

function. "he English version of +L%E/' was used for this study.


10/34

2.!. ata "nalysis.

"he baseline data like demography, efficacy, and

8Es were sub@ected to descriptive statistical

analysis and e7pressed as mean J ->,

freuencies, and percentages. "he +L%E/'scores were e7pressed as mean J -> scores. "he

categorical variables were compared using Chi

suare ( 2) test. Comparison of continuous

variables between groups was carried out usingunpaired -tudentKs test. -tatistical significance

was set at '.'&.


11/34

3. #esults

8 total of 06sub@ects were screened

for the study. ut of them, *' (0&.*3)

participants who fulfilled the eligibilitycriteria were randomi!ed into the two

study groups. Mollowing is the

summari!ation of the observed results.


12/34


13/34


14/34

8ll participants were followed up at 1, /2, and 2* weeks after

the initiation of monotherapy. 8t the 1th week of follow up, both

groups had eual sei!ure freedom of 4&.023 which is notstatistically significant value of /.'''). 8t /2 weeks of follow(

up, C#$ group had 46.263 of sei!ure freedom compared to LEV

group which had 6.13 sei!ure freedom which is not

statistically significant value, '.1&6&). "wentytwo (04.&03) of(

those taking LEV and 2' (0/.123) sub@ects on C#$ weresei!urefree for at least * months during the monotherapy

treatment, which is not statistically significant value, '.2&26).(


15/34


16/34


17/34

3.3. $reatment Safety.

articipants who e7perienced at least ne 8E constituted *.**3 in

C#$ group and 1'3 in the LEV group value, '.00/1), which is not(

statistically significant. ne participant (.3) on LEV therapy

discontinued the treatment due to 8E of increased nausea and

vomiting and 2 patients (*.**3) discontinued the treatment due to 8Eof di!!iness and increased nausea. %n LEV group, & participants

e7perienced behavioral changes like increased aggressive behavior, /

participant e7perienced suicidal tendency, participants had increased

an7iety, participants suffered from increased sleep, 2 participants

reportedweight gain of around G& kilograms in months of duration,

and 2 participants reported constipation. "he other 8Es reported weregiddiness, decreased sleep, nausea, itching, and vomiting. %n C#$

group, * participants e7perienced somnolence, and 1 patients reported

di!!iness. "he other adverse events reported were constipation,

itching, poor concentration, nausea, and vomiting.


18/34

3.!. %&L "ssessment.

%n clinical practice, +L%E/' score ranges from ' to /''. 8

total score range of less than &' indicates the poor uality of

life, a score from &' to 0' indicates the optimal +L, and a

score more than 0' implies better +L. +L assessment wasdone in the participants in both groups at ' weeks and at the

end of 21 weeks."he mean +L score inC#$ group at

'weekswas /./1J/.4 and in the LEV group it was 26.0* J

/.0/ value, '.&4*/) which is not statistically significant. "he(

mean +L score in C#$ group at the end of 2*th week was

&4.1/ J /.46 and the mean +L score inLEVgroup at the

endof 2*thweekwas *1.&4J2.'2 value of '.''2, '.'&)(

which was found to be statistically significant.


19/34


20/34

!. iscussion

"he aim of 8E> treatment is to achieve sei!ure freedom with minimal

or ideally no 8E and with an optimal +L. Aumerous 8E>s are

licensed as monotherapy for focal sei!ure in adults. "hese include

the older 8E> like C#$. Even though C#$ has many 8Es and

tolerability issues, it was considered as gold standard firstline drug totreat focal sei!ures from past many years. %n 2'/, %LE8 has

produced an updated review in epilepsy treatment, which highlighted

the fact that newer 8E>s like LEV and !onisamide have class /2

evidence to be used as monotherapy:2, /2;.


21/34

"ill date, there have been very few studies to compare the

efficacy and tolerability of LEV versus C#$ as monotherapy in

focal sei!ures all over the world. -ince the usage of LEV is

very high in %ndia, comparative study of efficacy andtolerability of LEV versus C#$ was e7pected to give more

confidence for the use of the drug. Evaluation of +L

outcomes has been increasingly adopted into the standard

management plan for epilepsy along with traditional measures

of sei!ure freuency and 8E.


22/34

!.2. Efficacy &utcome

%n this study, the efficacy was mainly assessed by sei!ure

freedomrate.8ccording to %L8E, a patient is considered as

sei!urefree following an intervention after a period without

sei!ures has elapsed eual to three times the longestpreintervention intersei!ure interval over the previous year

:/2;. %n this study, we assessed sei!ure freedom rate at 1, /2,

and 2* weeks.


23/34


24/34

articipants were asked to come for followup visits at 1, /2, and 2*

weeks after initiation of the 8t 1 weeks of followup, the sei!ure

freedom rate in both C#$ and LEV groups was the same (4&.023).

-ince the pretreatment sei!ure freuency in LEV group was high, the

sei!ure freedom at 1 weeks goes in the favor of LEV group. -imilarly,in LaLiBo trial, the sei!ure freedom at * weeks in LEV group was

4.*3 compared to 06.43 in Lamotrigine group 5 '.10) with no(

statistical significance :/2;. %n this study, both groups showed better

sei!ure freedom even though the results were not statistically

significant."he increased sei!ure freedom may be due to better drug

adherence.


25/34

%n most of the comparative studies of LEV versus

C#$, the main efficacy outcome was sei!ure

freedom rate at * months and /2months. -ince this

was time bound academic study,we could not followup the cases for long term.


26/34

"he final efficacy outcome was assessed on sei!ure freedom at the

end of * months. %n our study overall sei!ure freedom rate at the end

of *months was 0/.123in C#$ group compared to 04.&03 in LEV

group 5 '.2&26), which is not statistically significant. 8s per erry(

et al.Ks study, where they have compared LEV versus C#$ asmonotherapy for partial epilepsy, the efficacy outcome was sei!ure

freedom at *, /2, and 21 months."he sei!ure freedom rate at the end

of * months was 03 in LEV group compared to *&3 in C#$ group

5 '.&4) which showed no statistical significance like our study :/';.(

-imilarly, in DBE" trial, the authors compared LEV with C#$ in

newly diagnosed focal epilepsyH sei!ure freedom rate at *months forC#$ was *23which was comparatively higher than LEV which had

sei!ure freedom rate of &0.&3. "he results were not statistically

significant :/;.


27/34

!.3. Safety

"he ultimate goal of treatment of epilepsy is the fact that patients

should not have sei!ures, less 8E, and an optimal +L. %n this study,

both LEV and C#$ were well tolerated as initial monotherapy. nly

*.**3 of patients on C#$ and .3 of patients on LEV withdrew

from the study due to 8E.


28/34

%n this study, the participants taking C#$ mostly

reported 8Es like increased sleep (2'3) and

di!!iness (/.3) similar to the study conducted

by erry et al., where 1'3 of patients on C#$reported increased sleep and /'3 of patients

reported di!!iness.


29/34

%n this study, sub@ects assigned to the LEV group most

commonly (/0.4&3) reported behavioral changes in terms of

increased aggressive behavior, increased an7iety, and

suicidal tendency. -imilarly, in erry et al.Ks study, LEV was

associated with increased behavioral changes in terms of

irritability ('.&3). Bany of the case reports do suggest that

LEV is associated with increased behavioral changes :/1, /&;.


30/34

%n this study, 2 patients on LEV reported weight gain of G& kg in

months. "ill date, there have been reports of LEV induced weight

loss. =ere, weight gain can be correlated with improved +L. ther

8Es observed in this study were giddiness, increased sleep, itching,

and nausea. Long term 8Es of C#$ have been reported to beleukopenia, hyponatremia, disturbances of vitamin > metabolism,

agranulocytosis, and hepatitis. LEV is a comparatively new drug. "he

studies till date mention that the drug is well tolerated on long term

use."here are reports of discontinuation of the drug due to irritability

but this was related to previous history ofmood disorders :/0, /4;.

%n this regard, LEV appears to be a better option compared to C#$

for long term use. "o avoid the behavioral 8E, prescribers should

thoroughly evaluate a patient of past psychiatric illness.


31/34

!.!. %uality of Life.

"he +L evaluation is a relatively new measure to evaluate

patient related outcome of treatment for epilepsy. ?ecently,

other studies have tried to determine the effects of various

demographic and clinical variables on the overall +L among

patients with epilepsy :2;.


32/34


33/34

8mong both drugs, LEV has been shown to be

superior to C#$ in terms of +L, which can be due

to the fact that LEV was associated with increased

sei!ure freedom compared toC#$."his increasedsei!ure freuency can be correlated with decreased

+L in C#$ group. -imilarly, another study

conducted by"homas et al. -uggests that patients

on monotherapy have a significant better +L :2;.LEV thus demonstrated better +L after * months

of therapy compared to C#$.


34/34

Slide Dini Jurnal

Documents

Transcript of Slide Dini Jurnal