The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.
BACKGROUND
Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify.


METHODS
SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748.


RESULTS
For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy.


CONCLUSIONS
Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.
Marson
Anthony G
AG
Division of Neurological Science, University of Liverpool, UK. a.g.marson@liv.ac.uk
Al-Kharusi
Asya M
AM
Alwaidh
Muna
M
Appleton
Richard
R
Baker
Gus A
GA
Chadwick
David W
DW
Cramp
Celia
C
Cockerell
Oliver C
OC
Cooper
Paul N
PN
Doughty
Julie
J
Eaton
Barbara
B
Gamble
Carrol
C
Goulding
Peter J
PJ
Howell
Stephen J L
SJ
Hughes
Adrian
A
Jackson
Margaret
M
Jacoby
Ann
A
Kellett
Mark
M
Lawson
Geoffrey R
GR
Leach
John Paul
JP
Nicolaides
Paola
P
Roberts
Richard
R
Shackley
Phil
P
Shen
Jing
J
Smith
David F
DF
Smith
Philip E M
PE
Smith
Catrin Tudur
CT
Vanoli
Alessandra
A
Williamson
Paula R
PR
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003362:Cost-Benefit Analysis; D004829:Epilepsy, Generalized / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D005260:Female; D005500:Follow-Up Studies; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D019057:Quality-Adjusted Life Years; D013997:Time Factors; D000077236:Topiramate; D017211:Treatment Failure; D014227:Triazines / Q000009:adverse effects / Q000627:therapeutic use*; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use*
D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid; D000077213:Lamotrigine