The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or...

The SANAD study of effectiveness of carbamazepine,gabapentin, lamotrigine, oxcarbazepine, or topiramate fortreatment of partial epilepsy: an unblinded randomisedcontrolled trial

Anthony G Marson, MD,Division of Neurological Science, University of Liverpool, UK

Asya M Al-Kharusi, MBBCh,Southport and Formby District General Hospital, Merseyside, UK

Muna Alwaidh, MBBCh,St Helens and Knowsley Hospital NHS Trust, Whiston Hospital, Liverpool, UK

Richard Appleton, MA[Oxon],Roald Dahl EEG Unit, Department of Neurology, Royal Liverpool Children's NHS Trust (AlderHey), Liverpool, UK

Gus A Baker, PhD,Division of Neurological Science, University of Liverpool, UK

David W Chadwick, DM,Division of Neurological Science, University of Liverpool, UK

Celia Cramp, MBBCh,Royal Shrewsbury Hospital, Shrewsbury, UK

Oliver C Cockerell, MD,Royal London Hospital, London, UK

Paul N Cooper, DM,Royal Bolton Hospital, Bolton, UK

Julie Doughty, MSc,School of Population and Health Sciences, University of Newcastle, UK

Barbara Eaton,Division of Neurological Science, University of Liverpool, UK

Carrol Gamble, PhD,Centre for Medical Statistics and Health Evaluation, University of Liverpool, UK

Peter J Goulding, MD,Leeds General Infirmary, Leeds, UK

Stephen J L Howell, DM,Royal Hallamshire Hospital, Sheffield, UK

Adrian Hughes, MBChB,Arrowe Park Hospital, Wirral, UK

Margaret Jackson, MD,Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK

Ann Jacoby, PhD,

Europe PMC Funders GroupAuthor ManuscriptLancet. Author manuscript; available in PMC 2007 November 19.

Published in final edited form as:Lancet. 2007 March 24; 369(9566): 1000–1015. doi:10.1016/S0140-6736(07)60460-7.

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Division of Public Health, University of Liverpool, UK

Mark Kellett, MD,Royal Bolton Hospital, Bolton, UK

Geoffrey R Lawson, MB ChB,Sunderland Royal Hospital, Sunderland, UK

John Paul Leach, MD,Southern General Hospital, Glasgow, UK

Paola Nicolaides, MBChB,Great Ormond Street Hospital, London, UK

Richard Roberts, DPhil,Ninewells Hospital, Dundee, UK

Phil Shackley, PhD,School of Population and Health Sciences, University of Newcastle, UK

Jing Shen, MSc,School of Population and Health Sciences, University of Newcastle, UK

David F Smith, MD,The Walton Centre for Neurology and Neurosurgery NHS Trust, Liverpool, UK

Philip E M Smith, MD,University Hospital of Wales, Cardiff, UK

Catrin Tudur Smith, PhD,Centre for Medical Statistics and Health Evaluation, University of Liverpool, UK

Alessandra Vanoli, MSc, andSchool of Population and Health Sciences, University of Newcastle, UK

Paula R Williamson, PhD on behalf of the SANAD Study groupCentre for Medical Statistics and Health Evaluation, University of Liverpool, UK

SummaryBackground—Carbamazepine is widely accepted as a drug of first choice for patients withpartial onset seizures. Several newer drugs possess efficacy against these seizure types butprevious randomised controlled trials have failed to inform a choice between these drugs. Weaimed to assess efficacy with regards to longer-term outcomes, quality of life, and healtheconomic outcomes.

Methods—SANAD was an unblinded randomised controlled trial in hospital-based outpatientclinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to bestandard treatment, and they were randomly assigned to receive carbamazepine, gabapentin,lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, andtime to 12-months remission, and assessment was by both intention to treat and per protocol. Thisstudy is registered as an International Standard Randomised Controlled Trial, numberISRCTN38354748.

Findings—For time to treatment failure, lamotrigine was significantly better than carbamazepine(hazard ratio [HR] 0·78 [95% CI 0·63–0·97]), gabapentin (0·65 [0·52–0·80]), and topiramate (0·64[0·52–0·79]), and had a non-significant advantage compared with oxcarbazepine (1·15 [0·86–1·54]). For time to 12-month remission carbamazepine was significantly better than gabapentin(0·75 [0·63–0·90]), and estimates suggest a non-significant advantage for carbamazepine againstlamotrigine (0·91 [0·77–1·09]), topiramate (0·86 [0·72–1·03]), and oxcarbazepine (0·92 [0·73–

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Lancet. Author manuscript; available in PMC 2007 November 19.

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1·18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportionachieving a 12-month remission (lamotrigine-carbamazepine) is 0 (−8 to 7) and 5 (−3 to 12),suggesting non-inferiority of lamotrigine compared with carbamazepine.

Interpretation—Lamotrigine is clinically better than carbamazepine, the standard drugtreatment, for time to treatment failure outcomes and is therefore a cost-effective alternative forpatients diagnosed with partial onset seizures.

IntroductionEpilepsy is a common disorder worldwide (50 per 100 000 people; 0·5–1%).1 Studies of thenatural history of the condition indicate that as many as 70% of patients enter long-termremission shortly after starting drug therapy.2,3 Carbamazepine is currently recommendedas the first-line antiepileptic drug treatment for patients with partial onset seizures.4,5 Thisrecommendation is based largely on the results of randomised controlled trials comparingcarbamazepine and valproate, a meta-analysis of which provided evidence thatcarbamazepine was the better treatment for the outcomes of time to first seizure and time to12-month remission.6

The past decade and a half has seen the licensing and introduction of several newantiepileptic drugs. These have all been licensed initially on the basis of add-on randomisedcontrolled trials in patients with refractory partial epilepsy. Aggregate data meta-analyses ofthese trials7,8 indicate by indirect comparisons that some agents could be more effectivethan others. Some comparative randomised trials of the new drugs compared withcarbamazepine9-19 or other standard drugs20-23 have appeared. Such trials comparingcarbamazepine with tiagabine,16 vigabatrin,13 and remacemide17 indicate that these drugsare not as effective as carbamazepine and should not be investigated further as possible first-line treatments. For gabapentin, lamotrigine, oxcarbazepine, and topiramate, randomisedcontrolled trials suggest efficacy as monotherapy, but for several reasons these trials fail toinform clinical practice or policy, an issue that has been highlighted in NICE appraisals.24,25 Firstly, the trials were too short to measure important clinical outcomes of longer-termseizure control.26 Secondly, existing randomised controlled trials have not systematicallyaddressed quality of life outcomes, and have not been structured to assess health economicissues. Despite these limitations, there has been a steady rise in the prescribing of newantiepileptic drugs from 0·1% of total antiepileptic prescriptions in 1991 to 20% in 2002,where new drugs accounted for 69% of the total costs of such drugs to the UK NationalHealth Service (NHS; GBP£99 million of £142 million).24

Because most patients who develop epilepsy are treated with one type of drug and mightcontinue to take them for many years, standard and new drugs need to be compared so as toestablish which should, in the future, be first choice for appropriate groups of patients. Wehave therefore undertaken two concurrent unblinded randomised controlled trials comparingStandard and New Antiepileptic Drugs (SANAD), which examine seizure control,tolerability, quality of life, and health economic outcomes. Arm A of SANAD is reportedhere and compares carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate.

SANAD was commissioned by the Health Technology Assessment Programme of NHSResearch and Development. It received appropriate multicentre and local ethics and researchcommittee approvals, and was managed according to the Medical Research Council's GoodClinical Practice Guidelines.27 Patients gave informed written consent to inclusion and tolong-term follow-up.

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MethodsPatients and procedures

Patients were included in arm A of SANAD if they had a history of two or more clinicallydefinite unprovoked epileptic seizures in the previous year and if carbamazepine wasdeemed the better standard treatment option, compared with valproate, by the recruitingclinician. This allocation allowed inclusion of patients with newly diagnosed epilepsy,patients who had failed treatment with previous monotherapy (as long as the drug failure didnot include one of the drugs present in the randomisation), and patients who had entered aperiod of remission from seizures but had relapsed after withdrawal of treatment. Patientswere excluded if the clinician or patient felt that treatment was contraindicated, if all theirseizures had been acute symptomatic seizures (including febrile seizures), they were aged 4years or younger, or if there was a history of progressive neurological disease.

Information recorded at entry to the study included patient demographics, a history oflearning disability or developmental delay, neurological history including head injury,stroke, intra-cerebral infection and acute symptomatic seizures, and a history of epilepsy in afirst degree family member. Clinicians were asked to classify seizures and epilepsysyndromes by International League Against Epilepsy classifications28,29 as far as waspossible, at least to differentiate between partial onset (focal) or generalised onset seizures.However, where there was uncertainty, patients were recorded as having unclassifiedconvulsive or other unclassified seizures. Results of any electroencephalography or brainimaging around the time of randomisation were documented.

Participants were randomly allocated to treatment in a ratio of 1:1:1:1:1. However, fewerpatients were randomised to oxcarbazepine, since it was only included in this randomisationafter June 1, 2001. To randomise a patient, the clinician telephoned a central randomisationservice, and provided patient identifying information as well as the clinical factors used forstratification of randomisation, which were centre, sex, and treatment history (newlydiagnosed and untreated, treated with ineffective monotherapy, relapse after remission ofepilepsy). The central randomisation centre then allocated patients using a computerprogramme that used a minimisation procedure. Although choice of drug was randomised,drug dose and preparation was that used by the clinician in their everyday practice. The rateof titration, initial maintenance dose, and any subsequent increments or decrements weredecided by the clinician aided by guidelines (webtable 1). The aim of treatment was tocontrol seizures with a minimum effective dose of drug. This treatment necessitated dosageincrements if further seizures happened as is usual clinical practice.

Patients were to be seen for follow-up at 3 months, 6 months, 1 year, and at successiveyearly intervals from the date of randomisation. If clinically indicated, more frequentfollow-up was undertaken. At every visit, details of the occurrence of seizures, adverseevents, hospital admissions, and antiepileptic drug treatment were documented. For adverseeffects, clinicians were asked to indicate whether they were clinically important. Wherepatients ceased attending hospital clinics, follow-up was obtained from general practitioners,or directly from the patient via a telephone interview.

There were two primary outcome measures: the time from randomisation to treatmentfailure (stopping the randomised drug due either to inadequate seizure control or tointolerable side-effects, or both, or the addition of other antiepileptic drugs, whichever wasthe earliest); and the time from randomisation to the achievement of a 1 year period ofremission of seizures. Secondary clinical outcomes were: the time from randomisation to afirst seizure (an efficacy outcome that is to some degree dependent on choice of the initialdrug dose); time to achieve a 2-year remission; the incidence of clinically important adverse

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events and side-effects emerging after randomisation. Additionally, quality of life outcomesand cost-effectiveness of the different drugs were assessed.

The calculations of sample size were based on the two primary outcomes and informed by ameta-analysis of individual patient data comparing valproate and carbamazepine.30 Wewished to establish that the lower 95% confidence limit for the treatment comparisonsbetween old and new drugs exceeded −10% (non-inferiority), rather than establishingequivalence within 10%. With α=0·05 and β=10%, giving a 95% CL of 10% around anoverall 1 year remission rate of 70% and a retention rate of 70% (ie, treatment failure rate of30%) at a median of 2·5 years follow-up with power 90% (β=0·10), needed 445 patients pertreatment group.

Details of methods used in assessing quality of life and health economic outcomes aredetailed in the webappendix, webfigure 1, and webtables 2 and 3. For both adults andchildren, the quality of life assessment involved use of several previously validated genericand epilepsy-specific measures. For adults, we used the Newly Diagnosed Epilepsy Qualityof Life battery, for which the included measures have been previously validated. For healtheconomic assessment, patients' use of resources was categorised under three generalheadings: consumption of antiepileptic drugs; resource use associated with the managementof adverse events requiring hospitalisation; and other health care and social servicesresource use.

Because oxcarbazepine was added to arm A only after the trial had been running for sometime, two separate analyses are presented: (1) a comparison of carbamazepine withgabapentin, lamotrigine, and topiramate using patient data from the entire trial period; and(2) a comparison of oxcarbazepine with gabapentin, lamotrigine, carbamazepine, andtopiramate using data from patients recruited after June 1, 2001.

Statistical analysisInitial analyses of time-to-event data used log-rank tests and Cox proportional hazardmodels. For analysis of the primary clinical outcomes, we planned to undertake both anintention-to-treat analysis and a per-protocol analysis. Intention-to-treat analysis would bemost conservative for tests of differences between drugs, but per-protocol analysis would bemost conservative when considering issues of equivalence. The populations for these twoanalysis approaches are described in figure 1. For the per-protocol analyses, the clinical andstatistical issues of informative censoring have been identified. The problem arises for theremission outcomes as follows: patients who have a treatment failure before achieving aperiod of remission will be censored at the date of treatment failure, and the log-rankanalysis assumes that time to achieve a remission for an individual is independent of thereason for censoring. However, patients with a poor prognosis of remission would morelikely be withdrawn from a drug for inadequate seizure control, leading to selection bias in alog-rank analysis. For this reason, the log-rank analysis is not considered appropriate hereand the cumulative incidence analysis is preferred; however, the p values from the log-rankanalysis are presented for consistency. For time to treatment failure, further analyses wereundertaken to assess the two main reasons for treatment failure—inadequate seizure controlor unacceptable adverse effects. To allow for possible dependence between the differentwithdrawal risks, cumulative incidence analyses are presented, the analysis which does notassume that censoring is non-informative.

This study is registered as an International Standard Randomised Controlled Trial, numberISRCTN38354748.

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Role of the funding sourceSANAD was funded by the Health Technology Assessment Programme, with an additional20% of resources coming from companies with products assessed. The funding sources hadno role in study design, data collection, analysis, interpretation of data, or in writing thisreport. All authors had full access to the data. The corresponding author had full access tothe data and had final responsibility for the decision to submit for publication.

ResultsThe first patient was randomised into the study on Dec 1, 1999, and randomisationcontinued up to Aug 31, 2004. Attempts were made to follow-up all patients to, at the latest,a point in time between May 1, 2005, and Aug 31, 2005, although some follow-up data wasobtained up to Jan 13, 2006. 1721 patients were randomised: 378 to carbamazepine; 377 togabapentin; 378 to lamotrigine; 210 to oxcarbazepine; and 378 to topiramate. The treatmentgroups were well balanced for demographic and clinical factors (table 1), with 88% ofpatients classified as having a cryptogenic or symptomatic partial epilepsy and 10%classified as having an unclassified epilepsy. 49 patients were excluded from all analyses(figure 1), 44 because the diagnosis of epilepsy was subsequently changed, and five forother reasons. During the course of the study 38 patients declined further follow-up and onepatient left the country; these 39 patients contributed to the analysis up to the time of theirlast follow-up.

Follow-up in arm A was 94% complete, with 5406 patient years of follow-up, comparedwith 5762 years that could have been expected had follow-up been complete. Of the 71deaths, ten were judged as related to epilepsy (including accidental deaths caused byseizures, status epilepticus, and all sudden deaths), one to carbamazepine, two to gabapentin,four to lamotrigine, three to oxcarbazepine, and none to topiramate. The remaining 61deaths were from other causes. Because of the pragmatic nature of the trial design and theabsence of blinding, we needed to assess the doses of drugs used and consider the degree towhich the full dose ranges were explored before treatment failure events (table 2).

There is satisfactory evidence that clinicians did explore a full dosing range before acceptingtreatment failure because of inadequate seizure control. As might be expected, dosesassociated with unacceptable adverse events were consistently lower than those associatedwith inadequate seizure control.

Treatment failure for unacceptable side-effects was largely limited to the early post-randomisation period, whereas the timing of withdrawal for inadequate seizure control (withor without unacceptable adverse events) was later because upward titration of dose is neededbefore withdrawal for inadequate seizure control could have taken place; the median numberof days to failure (25th–75th centile) for unacceptable adverse events was 84 (26–215) andfor inadequate seizure control was 313 (152–642).

For time to treatment failure for any reason (inadequate seizure control or unacceptableadverse events; table 3) there are significant overall differences, although inevitably there issome reduction in power in the analysis using data from June 1, 2001, onwards. Whencomparisons are made across the whole duration of the trial, lamotrig ine is better than allother drugs for pairwise comparisons (figure 2). Carbamazepine and oxcarbazepine are intermediate between these options and appear broadly similar, although the CI is wide andshould not be taken to imply equivalence between the two drugs. Gabapentin and topiramateare the poorest performing drugs. Sensitivity analyses (not shown) indicate that includingonly patients with definite partial seizures or including patients subsequently withdrawn as“not epilepsy” does not affect the results.

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The reasons for treatment failure vary according to drug (webtable 4). The cumulativeincidence analysis shows that carbamazepine (lamotrigine:carbamazepine 0·62 [0·46–0·83])and topiramate (lamotrigine: topiramate 0·62 [0·46, 0·84]) are most frequently associatedwith treatment failure for unacceptable adverse events, and lamotrigine and gabapentin(gabapentin:carbamazepine 0·60 [0·44–0·81]) are least likely to produce this treatmentfailure (webfigure 2). By contrast, gabapentin is most likely to be associated with treatmentfailure due to inadequate seizure control and carbamazepine the least likely(gabapentin:carbamazepine 2·45 (1·81–3·32). Carbamazepine was also better thantopiramate (topiramate: carbamazepine 1·43 [1·03–1·98]), with no significant differencebetween lamotrigine and carbamazepine (lamotrigine:carbamazepine 1·17 [0·84–1·64];webfigure 3). When examining estimates for the proportion of patients with treatment failureevents (table 4), compared with carbamazepine, lamotrigine is 10–11% better for treatmentwithdrawal for adverse events and statistically different at all time points between 1 and 6years. Lamotrigine is similar to carbamazepine for incidence of treatment failure due toinadequate seizure control, with point estimates varying between 1% superiority at 6 yearsand 6% inferiority at 4 years. For this efficacy outcome, examination of the lower 95% CIfor differences in withdrawal rates indicates that we have excluded any inferiority oflamotrigine greater than 12% (years 4 and 5). At other time points, non-inferiority limits(according to the lower 95% CI) were 4% at 1 year, 8% at 2 years, and 9% at 6 years. Thisresult lends support to the non-inferiority for efficacy of lamotrigine compared withcarbamazepine.

For oxcarbazepine, analyses including patients randomised after June 1, 2001, indicate thatoverall treatment failure rates for oxcarbazepine and carbamazepine are similar(oxcarbazepine:carbamaze-pine 1·04 [0·78–1·39]), but oxcarbazepine might be less likelythan carbamazepine to fail because of adverse effects (oxcarbazepine: carbamazepine 0·85[0·59–1·24]), but more likely to fail because of inadequate seizure control (oxcarbazepine:carbamazepine 1·33 [0·82–2·15]). Point estimates for differences in the proportion offailures due to inadequate seizure control vary between 4% inferiority for oxcarbazepineversus carbamazepine (years 1–3) and 6% at 4 years, but examination of the CIs indicatesthat we cannot exclude oxcarbazepine being between 9% inferior at 1 year and 17% inferiorat 4 years. This finding would not seem to support a claim for non-inferiority ofoxcarbazepine compared with carbamazepine for this efficacy outcome, although this couldbe due to reduced power because of the fewer patients available for this analysis. Results fortime to 12-month remission of seizures are presented in table 4, figure 3, and webfigure 4.

The intention-to-treat analysis shows that times to achieve a 12-month remission arestatistically different across drugs and identify gabapentin and topiramate as the leastfavoured options (figure 3). For gabapentin the differences from carbamazepine (and indeedoxcarbazepine and lamotrigine) are significant and of likely clinical importance, though thedifferences for topiramate from these drugs are less and are not significant. The standarddrug, carbamazepine, seems to be the preferred treatment for this outcome in all pair-wisecomparisons, although differences between lamotrigine and oxcarbazepine are smaller(figure 3). Restricting analyses to patients with partial onset seizures produces nosubstantive differences.

In intention-to-treat analyses, follow-up data after a treatment failure have been included.Thus some patients achieve a 1-year remission on drug regimens other than the one to whichthey were randomised, and still contribute to outcome for the drug to which patients wereoriginally randomised. In examining data for intention to treat for time to 12-monthremission, understanding how clinicians chose to switch treatment after treatment failureevents becomes important. After failure on one of the newer drugs (except oxcarbazepine),remission would probably happen after switching to carbamazepine, but failure on

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carbamazepine then switching to lamotrigine was most commonly associated with achievingremission (webtable 5).

For these reasons, a per-protocol analysis is also presented (table 4, webfigure 4), in whichobservations were censored at the point of treatment failure (a 1-year remission is onlycounted as an event for patients achieving remission on the drug to which they wererandomised). Overall, the best performing drugs result in around 50% of patients achieving a1-year remission on the drug to which they were randomised, compared with around 75%remission rates for the best performing drugs in the intention-to-treat analyses (at 5 yearsafter randomisation). For the comparisons across the whole treatment period, differencesbetween carbamazepine and lamotrigine seem small. Although the point estimates suggest a4% inferiority for lamotrigine at 1 year, there is no difference at 2 years, and lamotrigine isbetter at 4–5 years. Examination of the lower 95% CI around point estimates indicates thatthere is sufficient power in these comparisons to exclude lamotrigine being any more than11% inferior to carbamazepine at 1 year, 8% at 2 years, 4% at 3 years, 3% at 4 years, and5% at 5 years after randomisation. These estimates might be sufficient to support non-inferiority of lamotrigine compared with carbamazepine for this primary efficacy outcome.This per-protocol analysis is the most conservative when assessing issues of non-inferiority.When the per-protocol analysis for the period after inclusion of oxcarbazepine is considered,oxcarbazepine produces similar 12-month remission rates but the CIs do not exclude thedrug varying between 12% (at 1 year) and 17% (at 2 years) inferior to carbamazepine. Thereis insufficient evidence of non-inferiority.

Intention-to-treat analyses for time to 2-year remission are shown in table 4. Overall,carbamazepine is better than all other drugs and statistically so compared with gabapentin(HR gabapentin:carbamazepine 0·72 [0·58–0·91]) and topiramate(topiramate:carbamazepine 0·80 [0·64–1·00]). For the period after the addition ofoxcarbazepine, this drug seems statistically better than gabapentin (1·51 [1·05–2·18]). Forthis period, carbamazepine remains the preferred option but the differences in pair-wisecomparisons between oxcarbazepine and carbamazepine, lamotrigine and topiramate werenot significant.

Data for time to first seizure outcomes are shown in table 4. Gabapentin seems leasteffective in preventing first seizures, with carbamazepine being most effective. Topiramateand lamotrigine are intermediate. Pair wise comparisons for the entire period showcarbamazepine to be statistically better than both gabapentin (1·35 [1·14, 1·60]) andlamotrigine (1·23 [1·04, 1·45]), but not topiramate (1·05 [0·89, 1·25]). Results for the periodafter addition of oxcarbazepine suggest carbamazepine and oxcarbazepine are similar, butthe CI is wide (1·06 [0·84, 1·33]).

For the primary outcomes, regression models were used to assess the effect of age and toinvestigate an age-treatment interaction. For time to treatment failure, children (youngerthan 16 years) were significantly more likely to have treatment failure (1·25 [1·00–1·56]),whereas the older age-group (65 years or older) were significantly less likely to havetreatment failure (0·72 [0·55–0·94]) than the middle age-group (16–65 years). For time to12-month remission, children and the older age-group had a significantly better chance ofremission than the middle age-group (1·22 [1·01–1·48] and 1·70 [1·39–2·09], respectively).There was no evidence of an age-treatment interaction for either outcome, hence we have noevidence that the relative treatment effects differ across these age-groups.

During follow-up, clinicians recorded adverse events described by patients, and indicatedwhether they judged the events to be clinically important. Table 5 summarises intention-to-treat rates of adverse events judged as clinically important. An intention-to-treat approach

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summarises adverse events associated with the randomised policy, but since patients mighthave had their treatment changed during follow up, this approach does not clearly presentadverse events attributable to specific drugs. We therefore present both intention-to-treat andper-protocol rates for adverse events (table 5).

Notably, around 50% of patients reported adverse events at some point in the study and thatthe differences between drugs were not great. For the intention-to-treat population,lamotrigine was the drug with the least number of patients reporting adverse events (45%intention to treat, 37% per protocol) with topiramate the most (53% intention to treat, 49%per protocol).

For the individual symptoms reported, tiredness, headache, and fatigue were the mostcommon symptoms, though these did not seem specific to any individual drug. Depression,memory disturbance, and various psychiatric symptoms were common and particularlyassociated with topiramate. Rash was a common non-CNS symptom, especially withcarbamazepine and oxcarbazepine. Rates of rash were lower with lamotrigine. Gabapentin'sparticular adverse event profile was characterised by a high rate of dizziness, ataxia, andweight gain, topiramate by psychiatric symptoms, including anxiety, weight loss, andparaesthesiae. The profiles of lamotrigine and oxcarbazepine were non-specific. Theseprofiles were consistent across intention-to-treat and per-protocol summaries. Overall, themost common adverse effect associated with treatment failure was rash (7% of patientsallocated carbamazepine), which accounted for 21% of carbamazepine treatment failures.Similarly 6% of patients had a rash on oxcarbazepine which accounted for 19% of theoxcarbazepine treatment failures. The overall rash rate on lamotrigine was 3% of patientsand rash accounted for 14% of treatment failures. We should note that in the study neitherpatients nor clinicians were masked to drug treatment, which might have affected thesymptoms reported to the clinicians and their assessment of the clinical importance.

The quality of life analysis was confined to adult patients only (although quality of life datawere obtained for children younger than 16 years, the numbers eligible were small and themeasures used were different from those for adults). 1345 randomised adults were sentbaseline quality-of-life questionnaires. The overall response rate in this group of the trialwas 84% at baseline and 75% at 2-year follow-up (webtable 6) and there were no significantdifferences between the drugs. Comparison of responders and non-responders to the baselineand 2-year follow-up assessments revealed that there were important differences betweenthem, with potential to create bias in the interpretation of the results of the quality of lifestudy. Women were more likely to respond to the questionnaires than men, and the medianage for responders was higher than for non-responders.

Of adult participants who returned a questionnaire at baseline, there were differencesbetween those who subsequently returned a 2-year follow-up questionnaire and those whodid not for the quality of life measures defined as primary: anxiety, depression,neurotoxicity, other adverse effects of antiepileptic drugs, EQ-5D scores, and self-ratedglobal quality of life. Non-responders at 2 years reported worse baseline levels of anxietyand depression, higher neurotoxicity and adverse events, poorer EQ-5D scores, and poorerglobal quality of life. 2-year non-responders were also less likely to have achieved a 12-month remission of seizures before the 2-year follow up; 21% of those who achieved a 12-month remission were non-responders at 2 years compared with 32% of those who had not(p<0·0001). Similarly, non-responders were more likely to have had a treatment failure onthe randomised drug; 23% of those without treatment failure were non-responders comparedwith 31% of those who had treatment failure (p<0·0002).

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Few significant differences in quality of life between treatment groups at 2 years wereidentified (webtable 7), although some trends in the data with regard to direction oftreatment effects were evident. Thus, based both on mean scores and caseness (ie, whether apatient was classified as clinically anxious), the likelihood of anxiety was reduced fortopiramate (despite this symptom being commonly reported to clinicians by patients takingthe drug), compared with carbamazepine and gabapentin (though the size of the reductionwas small and the CIs relatively wide); and there was a non-significant reduction in risk fortopiramate compared with lamotrigine or oxcarbazepine. Likewise, based both on meanscores and caseness (ie, whether the patient was classified as clinically depressed) there wasa trend for reduced risk of depression for lamotrigine compared with the other antiepilepticdrugs; and the difference was significant for lamotrigine compared with gabapentin (thoughagain the difference was small and the CIs relatively wide). There were no importantdifferences or trends for scores on the Adverse Events Profile, the Neurotoxicity Scale, theEQ-5D, or for global quality of life. The lack of differences between treatment groups mightindicate that those with the poorest quality of life outcomes failed to return a 2-yearquestionnaire, so that important effects were diluted or missed.

By contrast, there were several significant differences both for achieving a positive (ie,remission of seizures) and a negative (ie, treatment failure of the original randomised drug)clinical outcome (webtable 8). Thus, achieving a 12-month remission by 2-year follow-upwas associated with a decreased risk of anxiety and depression (measured both by meanscores and caseness), a decreased risk of cognitive (neurotoxicity) and other antiepilepticdrug adverse effects, and a reduced likelihood of scoring negatively for global quality oflife. There was also a small but significant improvement for quality of life as measured byscores on the EQ-5D. Treatment failure on the randomised drug by 2-year follow-up wasassociated with increased risk of anxiety and depression, increased risk of cognitive andother antiepileptic drug adverse effects, poorer quality of life as measured by EQ-5D score,and an increased likelihood of scoring negatively for global quality of life.

The cost per quality adjusted life year (QALY) analysis was restricted to adults, because theEQ-5D (from which QALYs were derived) had not been validated for completion bychildren or by proxy. Since the estimation of QALYs and resource use were dependent onpatients returning completed questionnaires, results could have been subject to response biasas outlined above. Two analyses are presented, the first compared carbamazepine,gabapentin, lamotrigine, and topiramate and included all 636 patients who were randomisedto one of these drugs and provided complete EQ-5D responses. Tables 6 and 7 show thepoint estimates of the incremental cost-effectiveness ratios, which were estimated using thelowest costs for carbamazepine and lamotrigine. Disaggregated costs are presented inwebtable 9.

Gabapentin has a positive incremental cost and a negative incremental QALY gain and istherefore dominated by lamotrigine. Because lamotrigine has a lower incremental cost-effectiveness ratio than topiramate, topiramate is ruled out on the grounds of extendeddominance. The incremental cost-effectiveness ratio for lamotrigine relative tocarbamazepine is £11 851. Bootstrapping methods (webappendix) were used to generatecost effectiveness acceptability curves, and table 8 summarises the probabilities that each ofthe new antiepileptic drugs is cost-effective at ceiling ratios of £10 000, £30 000, and £50000 per QALY.

The second analysis compared carbamazepine, gabapentin, lamotrigine, oxcarbazepine,topiramate and included the 414 adults who provided complete EQ-5D responses. Bothtopiramate and gabapentin have positive incremental costs and negative incremental QALYgains and are therefore dominated by oxcarbazepine and lamotrigine, respectively (table 6).

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For cost per seizure avoided analysis in adults and children, two analyses were undertaken,the first comparing carbamazepine, gabapentin, lamotrigine, and topiramate, and included823 children and adults for whom we had data for both numbers of seizures and resourceuse. Topiramate and gabapentin have positive incremental costs and a negative incrementalnumber of seizures avoided, and are therefore dominated by carbamazepine and lamotrigine,respectively. Topiramate is dominated by carbamazepine, hence the incremental cost-effectiveness ratio for lamotrigine presented in table 7 (£80) has been recalculated relative tocarbamazepine.

The second analysis compared carbamazepine, gabapentin, lamotrigine, oxcarbazepine, andtopiramate, and was based on 547 adults and children (table 6). Lamotrigine, topiramate, andgabapentin have positive incremental costs and negative incremental seizures avoided andare therefore dominated by oxcarbazepine. The incremental cost-effectiveness ratio foroxcarbazepine relative to carbamazepine is £35 (table 7).

DiscussionFor patients with partial onset seizures that need monotherapy, we have found lamotrigine tobe significantly better for time to treatment failure than the current standard treatment,carbamazepine, and the newer drugs gabapentin and topiramate. For time to 12-monthremission from seizures, lamotrigine was non-inferior to carbamazepine.

SANAD was designed as a pragmatic trial to assess whether any of the newly licensedantiepileptic drugs should become first-choice treatment and replace the existing first-lineagents, carbamazepine or valproate. If there were clinical or quality of life benefits fromthese new drugs, we wished to assess the incremental costs associated with such benefits.

Because epilepsy is a chronic disorder, we wished to assess treatments over a relevantamount of time. Therefore, several decisions were made about the methods used that shouldbe considered when assessing the results. We wished the trial to have strong externalvalidity so that results could be applied to everyday clinical practice. Entry criteria weretherefore as inclusive as possible and clinicians were encouraged to use their everydayclinical practice in the management of patients. We provided some guidelines for initialtarget drug dosing, but allowed clinicians to vary the dose on clinical grounds as they saw fitthroughout the course of the study to ensure as far as possible that patients receivedoptimum doses for seizure control on the one hand and avoidance of adverse effects on theother.

The study was unmasked because this situation is closer to clinical practice and because itgreatly reduced the cost of the study, while increasing practicability. For a five-waycomparison of drugs (in arm A), we would have been unable to provide a single matchingtablet for all treatment options, and patients would have had to take an active treatment aswell as one or more placebo tablets to match the remaining treatment options. Thisrestriction, in addition to the central provision of drug supplies that would be needed todeliver medications formulated specifically for the trial and for protracted periods of follow-up, would have presented unfeasible logistical problems and have been prohibitivelyexpensive. For a long study, there would have been practical difficulties in maintainingmasking for drugs that have differing interactions with important treatments such as the oralcontraceptive or warfarin. Similarly, management of women in the child-bearing yearswould have been greatly complicated. All these decisions, especially the lack of blinding,could be seen as compromising the internal validity of the study, and we cannot exclude thepossibility that the use of some of the drugs might not have been optimum as far as dosingand the use of modified-release preparations are concerned. To compensate for these

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concerns, we have been able to randomise more than 1721 patients and achieve a high levelof follow-up, something that would have been impossible with a more explanatory shorterclinical trial.

Previous comparative drug studies in similar patients had shown differences in tolerability,but had failed to show differences in efficacy. We therefore felt that the possibility ofequivalence, or at least non-inferiority for efficacy outcomes, should be addressed. Thus, if anew antiepileptic drug showed better tolerability to its standard comparator, we wished tohave power to exclude clinically important differences in efficacy, before accepting the drugas being first choice according to clinical outcomes. This decision resulted in powercalculations needing 445 patients per treatment group. Although we were unable to recruitthis many patients, we were able to extend the length of the study, with an increase in thenumber of outcome events and corresponding protection of power. We have presented twoanalyses of seizure-outcome results. In the intention-to-treat analyses, clinical data after atreatment failure on the randomised drug are included. Thus these analyses are of a policy ofinitial treatment with the randomised drug followed by, where necessary, switching to analternative regimen, which was usually monotherapy with the standard drug or, if thestandard drug failed, with lamotrigine. By contrast, the per-protocol analyses censoredobservations at the time of a treatment failure, so that only information while on therandomised drug is included. The intention-to-treat analyses should be regarded as mostconservative, but when assessing possible equivalence or non-inferiority then per-protocolanalyses are more conservative and should be given greatest weight.31

SANAD is the only large comparative drug study to our knowledge that includes quality oflife and health economic assessments alongside clinical assessments. Our findings ofdifferences between responders and non-responders for baseline quality of life profile andtrial clinical outcomes accord with previous research showing that responders to surveys arelikely to make favourable reports and to be more successful in their current status than non-responders.32,33 The implications of this responder bias for interpretation of the quality oflife data and calculation of QALYs must therefore be considered when interpreting results.We can, however, be confident that the measures used are sensitive in view of the fact thatthere are clear quality of life benefits from achieving 12-month remission and harms fromtreatment failure.

The health economics analysis was done with two distinct incremental cost-effectivenessratios, namely cost per QALY gained and cost per seizure avoided. Although number ofseizures is an important clinical outcome, it constitutes a narrow measure of benefit in aneconomic assessment because it focuses on only one aspect of patient outcome. By contrast,the QALY is a much broader measure of benefit because it measures health-related qualityof life, which is affected by not only the various clinical outcomes, but also other factors,such as the consequences of drug side-effects on patients' health.

Analysis of the clinical primary outcomes provides results with some precision. Lamotriginehas the lowest incidence of treatment failure and is better for this outcome than all drugsexcept oxcarbazepine (when this comparison is restricted to patients randomised after June1, 2001). The differences are clinically important, with 12% and 8% fewer patients havingtreatment failure on lamotrigine than carbamazepine at 1 year and 2 years afterrandomisation, respectively. Competing risks analysis shows that lamotrigine is betterbecause of its tolerability advantage over carbamazepine, since carbamazepine has fewestcontributions to treatment failure from inadequate seizure control and is better thanlamotrigine for the secondary efficacy outcome of time to first seizure. The differencebetween lamotrigine and carbamazepine for time to 12-month remission is small comparedwith the difference in tolerability and is not significant. Indeed, the CIs around comparisons

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between carbamazepine and lamotrigine for treatment failure due to inadequate seizurecontrol and time to 12-month remission are sufficiently small to infer non-inferiority oflamotrigine for these outcomes (varying between 5–12% for both per protocol analyses).Carbamazepine is better than lamotrigine for time to first seizure, but this efficacy outcomemight be dependent on initial dosing and could indicate that initial lamotrigine dosing in thetrial was conservative, which would favour better tolerability outcomes, but detract from itsefficacy early in the study. This inference is supported by the way in which per-protocolanalysis of time to 12-month remission shows lamotrigine catching up with and eventuallyovertaking carbamazepine. There is also a lower rate of rash in patients randomised tolamotrigine in this arm of the study than might have been expected, a further potentialconsequence of conservative initial dosing.34,35

One further issue that might affect the lamotrigine-carbamazepine comparison is the choiceof prescribing carbamazepine as either a standard preparation or as modified release. We didnot obtain information systematically on this prescribing, but most collaborating cliniciansindicated that they routinely prescribe the modified rather than the standard release versionsof the drug. We feel that prescribing of ordinary release carbamazepine is unlikely to haveadversely affected carbamazepine assessment in the study.

Our study recruited across a wide range of ages, which allowed us to assess whether theresults from arm A were as applicable to children and to people older than 65 years as theywere to those between the extremes of age. Although age itself does affect outcomes, thereis no evidence of an interaction between age and drug treatment groups, which indicates thatindividual drug results are applicable through life. These findings do not accord with thoseof Rowan and colleagues,36 who studied older patients with epilepsy and reported that bothlamotrigine and gabapentin were preferred to carbamazepine in this age-group.

Although there might be circumstances where other drugs are preferred (consideration ofteratogenicity, bone health, drug interactions), the better tolerability seen in lamotrigine thancarbamazepine, with non-inferiority of longer-term efficacy outcomes, lends support tolamotrigine as first choice treatment for most patients with partial epilepsy. Although theimproved clinical outcomes are not indicated by improvements for individual core domainsof quality of life with the exception of depression, there is no evidence from such data thatwould detract from the clinical conclusion. The economic analysis lends support tolamotrigine being preferred to carbamazepine in terms of both cost per seizure avoided andcost per QALY gained. There seems to be a high probability that lamotrigine is a cost-effective alternative to carbamazepine at what might be considered affordable (to the NHS)values of the ceiling ratio (λ). The National Institute for Health and Clinical Excellenceshould now reconsider its guidance about the first-line antiepileptic drug for patients withpartial onset seizures.

We see no reasons to prefer gabapentin or topiramate to the standard drug carbamazepine,except where there might be individual mitigating factors. Both are associated with a higherrisk of treatment failure that are not significant, gabapentin because of poor efficacy andtopiramate because of poor tolerability and lesser efficacy than carbamazepine. The healtheconomic assessment supports this view. For all clinical outcomes, there is some similaritybetween carbamazepine and oxcarbazepine, but the smaller numbers of patients available tothe comparison reduce the statistical power and we could not conclude that they areequivalent. The economic analysis that included oxcarbazepine provides some evidence thatit is preferred to carbamazepine. The point estimates of the incremental cost per seizureavoided are low, ranging between £31 and £35. In the cost per QALY analysis, theprobability that oxcarbazepine is a cost-effective alternative to carbamazepine is high acrossthe range of ceiling ratio values (λ). Indeed, data from this period of the study suggest than

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oxcarbazepine is the most cost-effective of the drugs assessed. However, in the absence offirm conclusions about oxcarbazepine's clinical effectiveness, further data for both clinicaland health economic outcomes are needed before the drug can be accepted or rejected as afirst-line treatment.

Other studies have compared lamotrigine with carbamazepine in similar populations, thoughover much shorter periods, and a meta-analysis of individual patient data has beenundertaken.26 This meta-analysis showed that lamotrigine was better tolerated, and lesslikely to be associated with treatment failure, in agreement with our results. Time to firstseizure also agreed with SANAD in indicating that time tended to be longer forcarbamazepine, but SANAD is the first study to our knowledge that has allowedexamination of the more clinically important time to 12-month remission efficacy outcome,where the difference between the two drugs is much smaller. Two studies have comparedlamotrigine and gabapentin in elderly and adult patients, respectively, and recorded littledifference.36,37 They were, however, too short to allow meaningful comparison of efficacyoutcomes, so that the treatment failure outcomes reported in the studies were dominated bythe drugs' similar and good tolerability.

The SANAD study has successfully shown the feasibility of doing large pragmatic epilepsystudies in the NHS in a way that would be difficult in many other health-care systems. Sinceits design, three further new antiepileptic drugs have been licensed in the UK: levetiracetam,pregabalin, and zonisamide. The same questions that applied to gabapentin, lamotrigine,oxcarbazepine, and topiramate, now apply to these drugs, though for partial epilepsies theywill now need to be compared with lamotrigine and possibly oxcarbazepine, rather thancarbamazepine. SANAD has shown that we have a robust method to answer these questions.

FootnotesCorrespondence to: Dr A G Marson, Division of Neurological Science, University of Liverpool, Clinical SciencesBuilding, Lower Lane, Fazakerley, Liverpool L9 7LJ, UK [email protected]

SANAD Study Group membersClinical Coordinator: D Chadwick (Liverpool); Assistant Clinical Coordinator: A G Marson (Liverpool); Quality ofLife Study Coordinator: A Jacoby (Liverpool); Health Economics Team: P Shackley (coordinator), A Vanoli, JShen (Newcastle); Statistical Team: P R Williamson (coordinator), C Tudur Smith, C Gamble (Liverpool);Neuropsychology Study Coordinator: G Baker (Liverpool); DNA Bank Coordinator: M R Johnson (Imperial); TrialAdministration Liverpool: B Eaton, T Ball, H Crone; Quality of Life Study Administration Newcastle: J Doughty, JDryburgh, P Potts, V Swain-Dixon, L Wake; DNA Bank Administration: C Middleditch; Liverpool RandomisationCentre from Sept 1, 2003, to Aug 31, 2004: P R Williamson; Manchester Randomisation Centre from Jan 1, 1999,to Aug 31, 2003: Paola Dey.

CollaboratorsA D Kindley (Aberdeen); D Briley (Aylesbury); J Horn, M Perry (Bangor); H Angus-Leppan, S J Laurent (Barnet);M Manford (Bedford); T Esmonde, K Pang (Belfast); D Nichol (Birmingham); P Martin (Bishops Stortford); PTidswell (Blackburn); P Cooper, E Hawkins, M Kellett, J Liddle (Bolton); V Antao (Caerphilly); M Manford(Cambridge); N Moran, L Nashef, (Canterbury); P E M Smith, S Steward (Cardiff); G N Fuller (Cheltenham); P MPreece, M Reuber (Chesterfield); S J L Howell (Doncaster); D Davidson, S Macdonald, R Roberts, K White(Dundee); C Lueck, G Stewart, A Zeman (Edinburgh); J Taylor (Enfield); O C Cockerell (Epping); J P Leach(Glasgow); O K Kurian (Greenock); O C Cockerell, R W H Walker (Harlow); S Gupta (Hartlepool); B E Dafalla, CThompson (Huddersfield); Ms M Peachey, S J Wroe, (Ipswich); C S Nanayakkara (Kettering); P A Gibson, SIreland, C A Ramesh, J Sandhu (Lancaster); Ms J Geldard, P Goulding, S Jamieson (Leeds); R J Abbott, MLawden, Y Rajabally (Leicester); B Sharrack (Lincoln); N Adab, R Appleton, Prof D W Chadwick, A Curran, MDoran, G Hart;Nurse Specialist—V Leach, B Lecky, A G Marson, K Mohamed, P Nicolaides, C Owen, L Owen, D Smith, GVeling-Warnke, U C Wieshmann, J Winterbottom (Liverpool); J Bowler, J Bucknall, H Cock, O C Cockerell, REvans, A Goddard, D Gurtin, N Lessof, A Lloyd-Evans, M Rose, S Shorvon, R Sood, J Von Oertzen (London); J ROwens (Macclesfield); R H A Campbell, P Cooper, S Duncan, O Ismayl, M Kellett, H Lewis, T R Martland, R WNewton (Manchester); M J Maguire (Merthyr Tydfil); P J W McKee, G Young (Middleborough); P H Rowlandson(Newport Isle of Wight); P Burt, M J Jackson, A Knowles (Newcastle upon Tyne); J Hewertson (Northampton); JHorsley (Ormskirk); Y Hart (Oxford); D Davidson (Perth); M Alwaidh, G Litherland, P Nicholaides, M J Steiger

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(Prescot); L North, P Tidswell (Preston); R P Gregory (Reading); M Doran, R Lauder, S Lewis, D Smith (Rhyl); PBaxter, R A Grunewald, S J L Howell, M Reuber, C Rittey (Sheffield); C Cramp (Shrewsbury); G Okugbeni (SouthShields); C R Kennedy, C Laidlaw, A Nathwani, M C Prevett, A Waggott (Southampton); A M Al-Kharusi(Southport); J Davidson, S Ellis, S Puri, R P Singh (Stoke-on-Trent); S Bruce, P G Cleland, G R Lawson, MLinsley, L McCoy (Sunderland); I M S Sawnhey (Swansea); C Cramp, F R J Hinde (Telford); A Hughes, J Stewart(Upton); A S N Al-Din (Wakefield); M Doran, N Silver (Warrington); M R Johnson (Windsor); R N Corston(Wolverhampton); A K Garg (Worthing); M Doran, B Harrington, R Lauder, P Minchom, N Nelhans, G G Owens,D Smith (Wrexham); P M Crawford (York).DMEC members—A L Johnson (MREC Biostatistics Unit, Cambridge); A Richens; C Warlow (Dept of ClinicalNeurosciences, University of Edinburgh).TSC members—P Sandercock (Dept of Clinical Neurosciences, University of Edinburgh); R Appleton (RoyalLiverpool Children's Hospital); Prof G Baker (Dept of Neurological Science, University of Liverpool); Prof D WChadwick (Dept of Neurological Science, University of Liverpool); B Eaton (Dept of Neurological Science,University of Liverpool); J Greener (Consumer Representative); Prof A Jacoby (Dept of Primary Care, Universityof Liverpool); M R Johnson (Imperial College, London); M Knapp (Personal Social Services Research Unit,London School of Economics); C Tudur Smith (Centre for Medical Statistics and Health Evaluation, University ofLiverpool); M Wadsworth (MRC National Survey, University College London Medical School); T Walley (Dept ofPharmacology and Therapeutics, University of Liverpool); P R Williamson (Centre for Medical Statistics andHealth Evaluation, University of Liverpool);Management group members—G Baker (Dept of Neurological Science, University of Liverpool); T Ball (Dept ofNeurological Science, University of Liverpool); D W Chadwick (Dept of Neurological Science, University ofLiverpool); B Eaton (Dept of Neurological Science, University of Liverpool); C Gamble (Centre for MedicalStatistics and Health Evaluation, University of Liverpool); A Jacoby (Dept of Primary Care, University ofLiverpool); A G Marson (Dept of Neurological Science, University of Liverpool); P Shackley (Centre for HealthServices Research, University of Newcastle upon Tyne); D Smith (The Walton Centre for Neurology andNeurosurgery, Liverpool); C Tudur Smith (Centre for Medical Statistics and Health Evaluation, University ofLiverpool); P R Williamson (Centre for Medical Statistics and Health Evaluation, University of Liverpool).

Conflict of interest statement

AGM has received fees and reimbursement for attending conferences from Jannsen Cilag, GlaxoSmithKline,

Novartis, Pfizer, and Sanofi Synthelabo, and research funding from Pfizer; AMA-K has received speaker fees and

reimbursement for attending conferences from Jannsen Cilag, GlaxoSmithKline, Novartis, Pfizer, and Sanofi

Synthelabo; RA has received consultancy fees, speaker fees, and reimbursement for attending conferences from

Jannsen Cilag, GlaxoSmithKline, and Sanofi Synthelabo; GAB has received research funding, speaker fees, and

reimbursement for attending conferences from Jannsen Cilag, Glaxo SmithKline, Novartis, Pfizer, and Sanofi

Synthelabo; DWC has received consultancy fees, speaker fees, and reimbursement for attending conferences from

Jannsen Cilag, GlaxoSmithKline, and Sanofi Synthelabo; PNC has received speaker fees from Jannsen Cilag,

reimbursement for attending conferences from Jannsen Cilag, GlaxoSmithKline, Novartis, Pfizer, and Sanofi

Synthelabo, and research funding from Sanofi Synthelabo; PJG, has received speaker fees and reimbursement for

attending conferences from Eisai, GlaxoSmithKline, Jannsen Cilag, Pfizer, Cyberonics, and UCB; SJLH has

received reimbursement for attending conferences from Jannsen Cilag, GlaxoSmithKline, Novartis, Pfizer, and

Sanofi Synthelabo, and payment for research from Jannsen Cilag and GlaxoSmithKline; AH has received

reimbursement for attending conferences from Jannsen Cilag and GlaxoSmithKline; MJ has received speaker fees

and reimbursement for attending conferences from GlaxoSmithKline, Pfizer, and Jannsen Cilag; AJ has received

funding from SanofiSynthelabo, GlaxoSmithKline, and Jannsen Cilag, and has acted as a research consultant to

Johnson and Johnson Pharmaceuticals; MK has received speaker fees and reimbursement for attending conferences

from Jannsen Cilag, GlaxoSmithKline, and Pfizer; GRL has received speaker fees and reimbursement for attending

conferences from UCB and Jannsen Cilag; JPL has received speaker fees and reimbursement for attending

conferences from Jannsen Cilag, GlaxoSmithKline, Pfizer, Eisai, UCB, and Sanofi Synthelabo, and research

funding from GlaxoSmithKline; PN has received speaker fees and reimbursement for attending conferences from

Jannsen Cilag, GlaxoSmithKline, Pfizer, and Sanofi Synthelabo; RR has received consultancy fees, speaker fees,

and reimbursement for attending conferences from GlaxoSmithKline, Jannsen Cilag, Novartis, and Pfizer; DFS has

received speaker fees and reimbursement for attending conferences from Jannsen Cilag, GlaxoSmithKline,

Novartis, Pfizer, and Sanofi Synthelabo, and research funding from GlaxoSmithKline; PEMS has received speaker

fees, consultancy fees, and reimbursement for attending conferences from UCB Pharma, Pfizer, Eisai, Novartis, and

GlaxoSmithKline, and research funding from UCB Pharma and GlaxoSmithKline; the other authors declare no

conflict of interest.

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AcknowledgmentsThe study was supported by a grant from the Health Technology Assessment Programme of the NHS. There werefurther contributions from GlaxoSmithKline, Janssen-Cilag, Novartis Pfizer, Sanofi-Synthelabo, and the WellcomeTrust that supported related studies.

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21. Christe W, Kramer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepineversus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res. 1997; 26:451–60.[PubMed: 9127726]

22. Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial ofoxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res. 1997;27:205–13. [PubMed: 9237055]

23. Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnoseduntreated epilepsy: a double-blind comparison with phenytoin. Epilepsia. 1999; 40:601–07.[PubMed: 10386529]

24. Newer drugs for epilepsy in adults. London: National Institute for Clinical Excellence; 2004.Technology Appraisal Guidance 76

25. Newer drugs for epilepsy in children. London: National Institute for Clinical Excellence; 2004.Technology Appraisal Guidance 79

26. Gamble CL, Williamson PR, Marson AG. Lamotrigine versus carbamazepine monotherapy forepilepsy. Cochrane Database Syst Rev. 2006; 1:CD001031. [PubMed: 16437428]

27. Medical Research Council. Guidelines for good clinical practice in clinical trials. London: MRC;1998.

28. Commission on Classification and Terminology of the International League Against Epilepsy.Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989; 30:389–99. [PubMed: 2502382]

29. Commission on Classification and Terminology of the International League Against Epilepsy.Proposal for revised clinical and electroencephalographic classification of epileptic seizures.Epilepsia. 1981; 22:489–501. [PubMed: 6790275]

30. Williamson P, Hutton J, Marson A, Chadwick D. Individual patient data meta-analyses for time toevent outcomes: an example from epilepsy. Control Clin Trials. 1997; 18(3 suppl 1):S184.

31. Jones B, Jarvis P, Lewis JA, Ebutt AF. Trials to assess equivalence; the importance of rigorousmethods. BMJ. 1996; 313:36–39. [PubMed: 8664772]

32. Donald MN. Implications of non-response for the interpretation of mail questionnaire data. PublicOpin Q. 1960; 24:99–114.

33. Goyden, J. The Silent Minority: non-respondents to sample surveys. Cambridge: Polity Press;1987.

34. Messenheimer JA, Guberman AH. Rash with lamotrigine: dosing guidelines. Epilepsia. 2000;41:488. [PubMed: 10756418]

35. Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skinrash. Ann Pharmacother. 1999; 33:1037–42. [PubMed: 10534214]

36. Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study ofgabapentin, lamotrigine, and carbamazepine. Neurology. 2005; 64:1868–73. [PubMed: 15955935]

37. Brodie MJ, Chadwick DW, Anhut H, et al. Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia. 2002; 43:993–1000. [PubMed:12199724]

Marson et al.


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Figure 1.Study flow diagram for SANAD arm A*Three patients did not take drug but did not have seizure data.

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Figure 2.Time to treatment failure for whole recruitment period (A) and recruitment after June, 2001(B)*HR greater than 1 indicates that failure takes place more rapidly on drug compared withbaseline.†Analysis for oxcarbazepine use data only from patients randomised after June 1,2001.

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Figure 3.Time to 12-month remission for whole recruitment period (A) and recruitment after June,2001 (B)*HR greater than 1 indicates that failure takes place more rapidly on drug compared withbaseline.†Analysis for oxcarbazepine use data only from patients randomised after June 1,2001.

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Tabl

e 1

Bas

elin

e de

mog

raph

ic a

nd c

linic

al c

hara

cter

istic

s fo

r ar

m A

Car

bam

azep

ine

(n=3

78)

Gab

apen

tin

(n=3

77)

Lam

otri

gine

(n=

378)

Oxc

arba

zepi

ne (

n=21

0)T

opir

amat

e (n

=378

)T

otal

(n=

1721

)

Sex,

n (

%)

Men

208

(55·

0)20

7 (5

4·9)

208

(55·

0)11

1 (5

2·9)

208

(55·

0) 9

42 (

54·7

)

Wom

en17

0 (4

5·0)

170

(45·

1)17

0 (4

5·0)

99

(47·

1)17

0 (4

5·0)

779

(45

·3)

Tre

atm

ent

hist

ory,

n (

%)

Unt

reat

ed30

9 (8

1·8)

306

(81·

2)30

8 (8

1·5)

181

(86·

2)30

8 (8

1·5)

1412

(82

·1)

Mon

othe

rapy

(no

t opt

imum

trea

tmen

t) 6

0 (1

5·9)

60

(15·

9) 6

1 (1

6·1)

25

(11·

9) 6

0 (1

5·9)

266

(15

·5)

Rec

ent s

eizu

res

afte

r re

mis

sion

9

(2·4

) 1

1 (2

·9)

9

(2·4

)

4 (1

·9)

10

(2·7

)

43 (

2·5)

His

tory

, n (

%)

Lea

rnin

g di

sabi

lity

20

(5·3

) 1

7 (4

·5)

23

(6·1

)

4 (1

·9)

21

(5·6

)

85 (

4·9)

Neu

rolo

gica

l def

icit

34

(9·0

) 2

8 (7

·4)

32

(8·5

) 1

5 (7

·1)

30

(7·9

) 1

39 (

8·1)

Neu

rolo

gica

l dis

orde

r, n

(%

)

Stro

ke/c

ereb

rova

scul

ar 3

2 (8

·5)

27

(7·2

) 2

0 (5

·3)

10

(4·8

) 1

9 (5

·0)

108

(6·

3)

Intr

acra

nial

sur

gery

13

(3·4

) 1

7 (4

·5)

15

(4·0

)

2 (1

·0)

24

(6·4

)

71 (

4·1)

Hea

d in

jury

12

(3·2

) 1

7 (4

·5)

18

(4·8

) 1

0 (4

·8)

26

(6·9

)

83 (

4·8)

Men

ingi

tis/e

ncep

halit

is

4 (1

·1)

7

(1·9

) 1

2 (3

·2)

3

(1·4

)

8 (2

·1)

34

(2·

0)

Oth

er 2

8 (7

·4)

24

(6·4

) 2

9 (7

·7)

11

(5·2

) 3

2 (8

·5)

124

(7·

2)

His

tory

of

seiz

ures

, n (

%)

Febr

ile c

onvu

lsio

ns 2

7 (7

·1)

16

(4·2

) 2

5 (6

·6)

7

(3·3

) 1

7 (4

·5)

92

(5·

4)

Any

oth

er a

cute

sym

ptom

atic

sei

zure

s

6 (1

·6)

15

(4·0

) 1

8 (4

·8)

8

(3·8

) 1

3 (3

·4)

60

(3·

5)

Epi

leps

y in

fir

st d

egre

e re

lativ

es 3

9 (1

0·3)

44

(11·

7) 3

8 (1

0·1)

24

(11·

4) 3

4 (9

·0)

179

(10

·0)

Epi

leps

y sy

ndro

me,

n (

%)

*

Idio

path

ic p

artia

l

4 (1

·1)

5

(1·3

)

6 (1

·6)

3

(1·4

)

6 (1

·6)

24

(1·

4)

Sym

ptom

atic

or

cryp

toge

nic

part

ial

338

(89·

4)33

3 (8

8·6)

330

(88·

0)18

0 (8

5·7)

322

(85·

4)15

03 (

87·6

)

Idio

path

ic g

ener

alis

ed

3 (0

·8)

3

(0·8

)

4 (1

·1)

5

(2·4

)

7 (1

·9)

22

(1·

3)

Oth

er s

yndr

ome

2

(0·5

)

0 (0

)

0 (0

)

1 (0

·5)

1

(0·3

)

4 (

0·2)

Unc

lass

ifie

d 3

1 (8

·2)

35

(9·3

) 3

5 (9

·3)

21

(10·

0) 4

1 (1

0·9)

163

(9·

5)

Med

ian

inte

rval

bet

wee

n fi

rst a

nd m

ost r

ecen

t

seiz

ure

(25t

h–75

th c

entil

e), d

ays†

465

(162

–172

0)44

6 (1

56–2

195)

492

(165

–176

5)46

3 (1

55–1

470)

488

(153

–194

9) 4

67 (

156–

1889

)


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Marson et al.

Car

bam

azep

ine

(n=3

78)

Gab

apen

tin

(n=3

77)

Lam

otri

gine

(n=

378)

Oxc

arba

zepi

ne (

n=21

0)T

opir

amat

e (n

=378

)T

otal

(n=

1721

)

Med

ian

inte

rval

bet

wee

n m

ost r

ecen

t sei

zure

and

rand

omis

atio

n (2

5th–

75th

cen

tile)

, day

s‡ 1

3 (4

–37)

13

(3–3

7) 1

4 (3

–38)

14

(4–4

1) 1

2 (3

–33)

13

(3–

37)

Med

ian

num

ber

of s

eizu

res

(25t

h–75

th c

entil

e)§

12

(4–6

5) 1

2 (4

–70)

12

(4–6

0) 1

1 (4

–51)

12

(4–8

0)

12 (

4–63

)

Mea

n ag

e (S

D),

yea

rs 3

9·2

(18·

3) 3

7·8

(17·

9) 3

6·8

(18·

3) 4

0·1

(18·

0) 3

8·4

(18·

6)

38·3

(18

·3)

* Mis

sing

dat

a fo

r ep

ileps

y sy

ndro

me

for

one

indi

vidu

al o

n ga

bape

ntin

, thr

ee in

divi

dual

s on

lam

otri

gine

, and

one

indi

vidu

al o

n to

pira

mat

e.

† Mis

sing

dat

es f

or s

eizu

res

for

one

indi

vidu

al o

n to

pira

mat

e.

‡ Mis

sing

dat

a fo

r da

tes

of s

eizu

res

for

one

indi

vidu

al o

n to

pira

mat

e.

§ Mis

sing

num

ber

of s

eizu

res

for

one

indi

vidu

al o

n to

pira

mat

e.


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Tabl

e 2

Dos

e ta

ken

by a

dults

at w

ithdr

awal

or

last

fol

low

-up

Car

bam

azep

ine

Gab

apen

tin

Lam

otri

gine

Top

iram

ate

Oxc

arba

zepi

ne *

Inad

equa

te s

eizu

re c

ontr

oln=

33n=

83n=

42n=

40n=

15

991

(347

); 4

00–1

800

2414

(89

9); 3

00–4

800

355

(175

); 8

5–80

029

1 (1

68);

50–

600

1480

(52

5); 3

00–2

100

Una

ccep

tabl

e ad

vers

e ev

ents

n=50

n=35

n=30

n=68

n=29

546

(189

); 2

00–1

000

1366

(63

6); 4

00–3

000

178

(113

); 2

5–55

013

7 (7

7); 2

5–40

0 8

95 (

351)

; 300

–210

0

Inad

equa

te s

eizu

re c

ontr

ol a

nd u

nacc

epta

ble

adve

rse

even

tsn=

18n=

23n=

9n=

16 n

=9

711

(323

); 2

00–1

400

1878

(87

5); 6

00–3

600

219

(178

); 5

0–55

021

8 (1

10);

75–

400

1150

(52

5); 4

50–1

950

Oth

er r

easo

n fo

r w

ithdr

awal

n=13

n=14

n=19

n=14

n=

7

569

(317

); 2

00–1

200

1314

(46

6); 3

00–2

100

184

(62)

; 50–

300

189

(103

); 7

5–50

0 8

14 (

285)

; 600

–120

0

Rem

issi

on o

f se

izur

esn=

14n=

12n=

9n=

13 n

=7

614

(337

); 2

00–1

400

1475

(66

3); 3

00–2

700

158

(92)

; 50–

300

133

(57)

; 50–

200

771

(29

3); 3

00–1

200

Still

on

rand

omis

ed d

rug

n=14

0n=

120

n=16

8n=

126

n=87

662

(311

); 1

00–2

000

1496

(66

9); 3

00–3

600

249

(136

); 2

0–80

018

1 (1

08);

25–

600

1019

(46

7); 3

00–2

850

Dat

a ar

e m

ean

(SD

); r

ange

.

* Figu

res

in th

is c

olum

n us

e da

ta o

nly

for

patie

nts

rand

omis

ed a

fter

Jun

e 1,

200

1.


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Tabl

e 3

Tre

atm

ent f

ailu

re (

all e

vent

s)

Yea

r

12

34

56

Any

rea

son

Num

ber

at r

isk

Car

bam

azep

ine

225

160

106

65

26

7

Gab

apen

tin19

513

3 8

7 5

1 2

4

8

Lam

otri

gine

266

178

121

84

42

11

Top

iram

ate

207

136

81

54

24

7

Oxc

arba

zepi

ne11

8 7

3 2

9

3

Perc

enta

ge s

till o

n dr

ug (

95%

CI)

Car

bam

azep

ine

65

(61

to 7

0) 5

7 (5

2 to

62)

53

(47

to 5

8) 5

0 (4

4 to

56)

45

(38

to 5

2) 4

0 (3

1 to

49)

Dif

fere

nce

in p

erce

ntag

e w

ithou

t fai

lure

com

pare

d w

ith c

arba

maz

epin

e (9

5% C

I)

Gab

apen

tin −

8 (−

15 to

−1)

−8

(−16

to −

1)−

10 (

−18

to −

2)−

11 (

−19

to −

3) −

7 (−

16 to

2)

−4

(−15

to 7

)

Lam

otri

gine

12

(6 to

19)

8

(1 to

15)

6

(−2

to 1

3)

4 (−

4 to

12)

6

(−4

to 1

5) 1

1 (1

to 2

0)

Top

iram

ate

−5

(−12

to 2

) −

9 (−

16 to

−2)

−8

(−16

to −

1) −

8 (−

16 to

0)

−5

(−14

to 4

) −

4 (−

16 to

7)

Oxc

arba

zepi

ne −

2 (−

11 to

8)

−1

(−11

to 9

) −

1 (−

13 to

10)

−1

(−14

to 1

2)

For

una

ccep

tabl

e ad

vers

e ev

ents

Perc

enta

ge w

ithou

t fai

lure

(95

% C

I)

Car

bam

azep

ine

74%

(70

to 7

9) 7

0% (

65 to

75)

69%

(64

to 7

4) 6

9% (

64 to

74)

68%

(63

to 7

3) 6

8% (

63 to

73)

Dif

fere

nce

in p

erce

ntag

e w

ithou

t fai

lure

com

pare

d w

ith c

arba

maz

epin

e (9

5% C

I)

Gab

apen

tin

9 (3

to 1

5) 1

1 (4

to 1

7) 1

1 (4

to 1

7) 1

1 (4

to 1

7) 1

2 (5

to 1

8) 1

2 (5

to 1

8)

Lam

otri

gine

10

(4 to

16)

11

(4 to

17)

10

(4 to

17)

11

(4 to

17)

10

(3 to

17)

10

(3 to

17)

Top

iram

ate

0

(−6

to 6

)

0 (−

7 to

7)

−1

(−8

to 6

)

0 (−

7 to

7)

1

(−7

to 8

) −

2 (−

10, 7

)

Oxc

arba

zepi

ne*

3

(−6

to 1

1)

4 (−

5 to

13)

4

(−6

to 1

3)

5 (−

5 to

15)

For

inad

equa

te s

eizu

re c

ontr

ol

Perc

enta

ge w

ithou

t fai

lure

(95

% C

I)

Car

bam

azep

ine

92

(55

to 9

5) 8

7 (4

1 to

91)

84

(33

to 8

8) 8

2 (2

8 to

86)

77

(20

to 8

3) 7

3 (1

5 to

81)

Dif

fere

nce

in p

erce

ntag

e w

ithou

t fai

lure

com

pare

d w

ith c

arba

maz

epin

e (9

5% C

I)

Gab

apen

tin−

17 (

−22

to −

11)

−19

(−25

to −

13)

−21

(−

27 to

−14

)−

21 (

−29

to −

14)

−18

(−

27 to

−10

)−

15 (

−26

to −

4)


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Yea

r

12

34

56

Lam

otri

gine

0

(−4

to 4

) −

2 (−

8 to

3)

−4

(−10

to 2

) −

6 (−

12 to

1)

−3

(−12

to 5

)

1 (−

9 to

12)

Top

iram

ate

−4

(−9

to 0

) −

8 (−

14 to

−3)

−7

(−13

to 0

) −

7 (−

14 to

0)

−5

(−13

to 4

) −

2 (−

13 to

9)

Oxc

arba

zepi

ne*

−4

(−9

to 2

) −

4 (−

11 to

4)

−4

(−14

to 5

) −

6 (−

17 to

5)

* Figu

res

in th

is r

ow u

se d

ata

for

oxca

rbaz

epin

e an

d ca

rbam

azep

ine

only

fro

m p

atie

nts

rand

omis

ed a

fter

Jun

e 1,

200

1.


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Tabl

e 4

Seiz

ure

outc

omes

by

drug

Eve

nts/

tota

lY

ear

1Y

ear

2Y

ear

3Y

ear

4Y

ear

5Y

ear

6

Tim

e to

12-

mon

th r

emis

sion

—in

tent

ion

to t

reat

Num

ber

at r

isk

Car

bam

azep

ine

25

4/36

234

712

073

41 1

6 6

Gab

apen

tin

215/

359

337

141

7645

25

7

Lam

otri

gine

24

5/36

535

612

659

36 1

9 4

Top

iram

ate

22

5/35

833

812

674

50 2

4 5

Oxc

arba

zepi

ne

128/

200

189

58

21 3

Perc

enta

ge o

f 12

-mon

th r

emis

sion

(95

% C

I)

Car

bam

azep

ine

25

4/36

2 3

6 (3

1 to

41)

60

(55

to 6

6) 6

9 (6

3 to

74)

77 (

72 to

82)

82

(77

to 8

7)85

(79

to 9

1)

Dif

fere

nce

in p

erce

ntag

e of

12-

mon

th r

emis

sion

com

pare

d w

ith c

arba

maz

epin

e (9

5% C

I)

Gab

apen

tin

215/

359

−12

(−

19 to

−5)

−9

(−16

to −

1)−

6 (−

13 to

2)

−6

(−14

to 1

) −

9 (−

17 to

−1)

−9

(−18

to 0

)

Lam

otri

gine

24

5/36

5 −

7 (−

13 to

0)

−3

(−11

to 4

) 3

(−

4 to

11)

−1

(−8

to 7

) −

3 (−

10 to

5)

−2

(−11

to 7

)

Top

iram

ate

22

5/35

8 −

3 (−

10 to

4)

−5

(−13

to 2

)−

2 (−

10 to

5)

−6

(−14

to 1

) −

7 (−

14 to

1)

−4

(−14

to 6

)

Oxc

arba

zepi

ne

128/

200

−1

(−11

to 9

) −

3 (−

13 to

7)

−1

(−12

to 9

)−

2 (−

15 to

10)

Tim

e to

12-

mon

th r

emis

sion

—pe

r pr

otoc

ol

Num

ber

at r

isk

Car

bam

azep

ine

16

4/35

222

2 4

726

13

5

Gab

apen

tin

126/

351

194

42

16 8

5

Lam

otri

gine

17

0/35

826

4 6

625

16

6

Top

iram

ate

13

8/35

320

3 4

015

5

3

Oxc

arba

zepi

ne

80/1

9511

7 2

5 6

Perc

enta

ge o

f 12

-mon

th r

emis

sion

(95

% C

I)

Car

bam

azep

ine

16

4/35

2 2

9 (2

4 to

34)

44

(39

to 5

0)48

(42

to 5

3)50

(44

to 5

5) 5

3 (4

7 to

58)

Dif

fere

nce

in p

erce

ntag

e of

12-

mon

th r

emis

sion

com

pare

d w

ith c

arba

maz

epin

e (9

5% C

I)

Gab

apen

tin

126/

351

−9

(−16

to −

3) −

9 (−

17 to

−2)

−9

(−17

to −

1)−

9 (−

17 to

−1)

−12

(−

20 to

−4)

Lam

otri

gine

17

0/35

8 −

4 (−

11 to

3)

0

(−8

to 7

)

4 (−

4 to

12)

5 (

−3

to 1

2)

3 (−

5 to

11)

Top

iram

ate

13

8/35

3 −

4 (−

11 to

3)

−6(

−13

to 2

)−

6 (−

14 to

1)

−6

(−14

to 2

) −

8 (−

16 to

0)

Oxc

arba

zepi

ne

80/1

95 −

2 (−

12 to

7)

−7(

−17

to 4

) −

5 (−

16 to

6)

Tim

e to

24

mon

ths

rem

issi

on—

inte

ntio

n to

tre

at


Europe PM

C Funders A

uthor Manuscripts

Europe PM

C Funders A

uthor Manuscripts

Marson et al.

Eve

nts/

tota

lY

ear

1Y

ear

2Y

ear

3Y

ear

4Y

ear

5Y

ear

6

Num

ber

at r

isk

Car

bam

azep

ine

16

8/36

229

511

671

28

8

Gab

apen

tin

132/

359

283

125

7436

8

Lam

otri

gine

15

5/36

529

612

067

30

9

Top

iram

ate

14

0/35

828

412

480

41 1

2

Oxc

arba

zepi

ne

68/2

0013

8 3

9 5

Perc

enta

ge o

f 24

mon

th r

emis

sion

(95

% C

I)

Car

bam

azep

ine

16

8/36

2 3

2 (2

7 to

37)

50

(44

to 5

6)57

(51

to 6

3)65

(58

to 7

2)69

(61

to 7

8)

Dif

fere

nce

in p

erce

ntag

e of

24

mon

th r

emis

sion

com

pare

d w

ith c

arba

maz

epin

e (9

5% C

I)

Gab

apen

tin

132/

359

−13

(−

20 to

−6)

−12

(−

21 to

−4)

−7

(−16

to 2

)−

7 (−

17 to

4)

−8

(−20

to 4

)

Lam

otri

gine

15

5/36

5 −

6 (−

13 to

1)

−7

(−15

to 1

)−

1 (−

9 to

8)

−3

(−13

to 6

)−

5 (−

17 to

6)

Top

iram

ate

14

0/35

8 −

5 (−

12 to

3)

−7

(−16

to 1

)−

6 (−

15 to

3)

−11

(−

21 to

−2)

−8

(−20

to 4

)

Oxc

arba

zepi

ne

68/2

00 −

4 (−

15 to

7)

−6

(−19

to 6

) 0

(−

18 to

17)

Tim

e to

fir

st s

eizu

re—

inte

ntio

n to

tre

at

Num

ber

at r

isk

Car

bam

azep

ine

25

9/36

212

692

5334

17 4

Gab

apen

tin

288/

359

83

5339

18 7

1

Lam

otri

gine

29

0/36

510

676

4829

10 5

Top

iram

ate

26

8/35

811

276

5033

13 4

Oxc

arba

zepi

ne*

14

4/20

0 6

742

11

Perc

enta

ge o

f fi

rst s

eizu

re (

95%

CI)

Car

bam

azep

ine

25

9/36

2 6

3 (5

8 to

68)

69 (

64 to

73)

73 (

68 to

78)

73 (

68 to

78)

74 (

69 to

79)

78 (

69 to

87)

Dif

fere

nce

in p

erce

ntag

e of

fir

st s

eizu

re c

ompa

red

with

car

bam

azep

ine

(95%

CI)

Gab

apen

tin

288/

359

12

(5 to

19)

11 (

4 to

17)

8 (

1 to

14)

9 (

3 to

16)

11 (

3 to

18)

6 (

−4

to 1

7)

Lam

otri

gine

29

0/36

5

7 (1

to 1

4) 6

(0

to 1

3) 7

(0

to 1

3) 8

(2

to 1

5)10

(3

to 1

7) 5

(−

5 to

15)

Top

iram

ate

26

8/35

8

4 (−

3 to

11)

5 (

−2

to 1

1) 3

(−

4 to

9)

5 (

−2

to 1

2) 4

(−

3 to

11)

0 (

−10

to 1

0)

Oxc

arba

zepi

ne*

14

4/20

0

1 (−

8 to

10)

1 (

−8

to 1

0) 5

(−

4 to

15)

* Figu

res

in th

is r

ow f

or u

se d

ata

for

oxca

rbaz

epin

e an

d ca

rbam

azep

ine

only

fro

m p

atie

nts

rand

omis

ed a

fter

Jun

e 1,

200

1.


Europe PM

C Funders A

uthor Manuscripts

Europe PM

C Funders A

uthor Manuscripts

Marson et al.

Tabl

e 5

Freq

uenc

y of

clin

ical

ly im

port

ant a

dver

se e

vent

s Car

bam

azep

ine

Gab

apen

tin

Lam

otri

gine

Oxc

arba

zepi

neT

opir

amat

eT

otal

Num

ber

rand

omis

ed37

837

737

821

037

817

21

Tot

al n

umbe

r (%

) of

pat

ient

s w

ith a

t lea

st o

ne a

dver

se e

vent

183

(48%

)17

8 (4

7%)

169

(45%

)10

0 (4

8%)

200

(53%

)83

0 (4

8%)

Tir

edne

ss/d

row

sine

ss/f

atig

ue/le

thar

gy 4

8 [3

6] 4

6 [3

4] 3

1 [1

7] 2

2 [1

6] 4

3 [3

3]19

0 [1

36]

Dep

ress

ion

14

[8]

18

[10]

20

[13]

7

[5]

29

[24]

88

[60]

Hea

dach

e 2

1 [9

] 2

0 [1

5] 2

1 [1

3]

9 [6

] 1

7 [1

1] 8

8 [5

4]

Alle

rgic

ras

h 3

8 [3

2] 1

3 [4

] 1

7 [1

5] 2

0 [1

6] 1

7 [8

]10

5 [7

5]

Mem

ory

prob

lem

s 2

0 [1

2] 2

2 [1

9] 1

3 [1

0] 1

3 [8

] 2

6 [1

9] 9

4 [6

8]

Diz

zine

ss/v

ertig

o 1

4 [1

0] 2

3 [1

5] 1

5 [9

] 1

3 [1

2] 1

5 [8

] 8

0 [5

4]

Oth

er p

sych

iatr

ic 1

6 [7

] 1

7 [9

] 1

1 [7

]

7 [5

] 3

7 [3

1] 8

8 [5

9]

Wor

seni

ng o

f se

izur

es 1

7 [5

] 2

2 [1

3] 1

7 [1

2]

3 [1

] 1

7 [8

] 7

6 [3

9]

Oth

er n

euro

logi

cal

9

[6]

21

[14]

15

[9]

8

[5]

18

[12]

71

[46]

Oth

er g

ener

al 1

3 [6

] 1

9 [1

1] 1

9 [1

3]

9 [6

] 1

6 [1

2] 7

6 [4

8]

Beh

avio

ur/p

erso

nalit

y ch

ange

/agg

ress

ion

12

[4]

9

[6]

12

[7]

2

[1]

24

[19]

59

[37]

Ata

xia

9

[6]

24

[12]

14

[9]

8

[6]

9

[3]

64

[36]

Con

fusi

on/d

iffi

culty

thin

king

/dis

orie

nted

9

[9]

16

[15]

8

[4]

8

[6]

22

[19]

63

[53]

Anx

iety

/agi

tatio

n/ne

rvou

snes

s

7 [7

] 1

5 [1

1]

8 [5

]

7 [6

] 1

5 [1

2] 5

2 [4

1]

Wei

ght l

oss

2

[1]

4

[2]

4

[2]

3

[1]

29

[27]

42

[33]

Dip

lopi

a

5 [2

] 1

1 [4

]

4 [2

]

8 [6

]

6 [3

] 3

4 [1

7]

Nau

sea

9

[6]

7

[3]

9

[6]

15

[13]

4

[4]

44

[32]

Wei

ght g

ain

9

[7]

15

[12]

4

[1]

1

[0]

5

[4]

34

[24]

Acc

iden

tal i

njur

y

7 [2

] 1

1 [6

] 1

2 [8

]

3 [1

]

8 [3

] 4

1 [2

0]

Pins

and

nee

dles

/dys

aest

hesi

a

4 [1

]

5 [1

]

3 [1

]

0 [0

] 2

6 [2

4] 3

8 [2

7]

Slee

p di

stur

banc

e

5 [2

]

4 [4

]

9 [8

]

4 [2

]

9 [8

] 3

1 [2

4]

Oth

er e

vent

s*10

8 [7

1]11

3 [7

3]11

0 [7

0] 4

6 [3

8]10

3 [6

4]48

0 [3

16]

For

adve

rse

even

ts, d

ata

outs

ide

brac

kets

are

inte

ntio

n to

trea

t and

insi

de b

rack

ets

are

per

prot

ocol

.

* Sort

ed b

y de

scen

ding

tota

l fre

quen

cy: o

ther

car

diac

or

vasc

ular

; oth

er s

kin

and

appe

ndag

es; a

bdom

inal

pai

n, d

yspe

psia

; oth

er g

astr

oint

estin

al; o

ther

vis

ual d

istu

rban

ce; o

ther

ren

al tr

act o

r ge

nita

l;di

arrh

oea;

trem

or; a

ches

and

pai

ns; c

onst

ipat

ion;

infe

ctio

n; m

outh

or

gum

pro

blem

; oth

er r

espi

rato

ry o

r pu

lmon

ary;

isch

aem

ic h

eart

dis

ease

or

myo

card

ial i

nfar

ct; o

ther

hae

mat

olog

ical

; oth

erm

uscu

losk

elet

al; v

omiti

ng; i

mpo

tenc

e or

libi

do p

robl

ems;

alo

peci

a; w

ord

find

ing

diff

icul

ty; s

tatu

s ep

ilept

icus

; str

oke—

infa

rctio

n; d

iabe

tes

mel

litus

; hea

ring

pro

blem

or

tinni

tus;

hyp

erte

nsio

n; a

nore

xia;

brui

sing

; flu

like

sym

ptom

s; h

aem

orrh

age;

mal

igna

ncy;

sho

rt o

f br

eath

; vag

inal

ble

edin

g; a

rthr

itis;

ecz

ema;

pep

tic u

lcer

atio

n; a

sthm

a; o

ther

hep

atob

iliar

y; u

rina

ry r

eten

tion;

abn

orm

al li

ver

func

tion

test

s;


Europe PM

C Funders A

uthor Manuscripts

Europe PM

C Funders A

uthor Manuscripts

Marson et al. an

aem

ia; c

hild

bir

th; m

yalg

ia; o

ther

end

ochr

ine;

pso

rias

is; u

pper

res

pira

tory

trac

t inf

ectio

n, c

atar

rh, s

inus

itis,

rhi

norr

hoea

; uri

nary

trac

t inf

ectio

n; f

aint

s; h

allu

cina

tions

; hep

atiti

s; p

ancr

eatit

is; p

sych

osis

;tr

ansi

ent i

scha

emic

atta

ck; t

achy

card

ia; t

hyro

id d

isea

se; v

enou

s th

rom

bosi

s.


Europe PM

C Funders A

uthor Manuscripts

Europe PM

C Funders A

uthor Manuscripts

Marson et al.

Tabl

e 6

Incr

emen

tal c

ost-

effe

ctiv

enes

s ra

tios—

cost

per

QA

LY

Cos

t (£

)Q

AL

Ys

Incr

emen

tal

cost

(£)

Incr

emen

tal

QA

LY

sIn

crem

enta

l cos

t-ef

fect

iven

ess

rati

o (£

/QA

LY

)

Com

pari

son

excl

udin

g ox

carb

azep

ine

Car

bam

azep

ine

1226

1·47

7

.. .

...

Top

iram

ate

2009

1·50

178

3 0

·024

Ext

ende

d do

min

ance

Lam

otri

gine

2257

1·56

424

8 0

·063

1185

1

Gab

apen

tin25

611·

491

304

−0·

073

Dom

inat

ed

Com

pari

son

incl

udin

g ox

carb

azep

ine

Car

bam

azep

ine

1095

1·49

1

.. .

...

Oxc

arba

zepi

ne18

391·

611

744

0·1

262

00

Top

iram

ate

1930

1·54

1 9

1−

0·07

Dom

inat

ed

Lam

otri

gine

2078

1·56

314

8 0

·022

Ext

ende

d do

min

ance

Gab

apen

tin25

731·

480

495

−0·

083

Dom

inat

ed


Europe PM

C Funders A

uthor Manuscripts

Europe PM

C Funders A

uthor Manuscripts

Marson et al.

Tabl

e 7

Incr

emen

tal c

ost-

effe

ctiv

enes

s ra

tios—

cost

per

sei

zure

avo

ided

Cos

t (£

)Se

izur

esIn

crem

enta

lco

st (

£)In

crem

enta

lse

izur

es a

void

edIn

crem

enta

l cos

t-ef

fect

iven

ess

rati

o (£

/sei

zure

avo

ided

)

Com

pari

son

excl

udin

g ox

carb

azep

ine

Car

bam

azep

ine

1266

52·6

..

..

..

Top

iram

ate

2008

63·1

742

−10

·5D

omin

ated

Lam

otri

gine

2134

41·7

126

21·

480

Gab

apen

tin24

9469

·836

0−

28·1

Dom

inat

ed

Com

pari

son

incl

udin

g ox

carb

azep

ine

Car

bam

azep

ine

1151

50·9

..

..

..

Oxc

arba

zepi

ne18

1532

·066

4 1

8·9

35

Lam

otri

gine

1946

50·9

131

−18

·9D

omin

ated

Top

iram

ate

2059

59·4

113

−8·

5D

omin

ated

Gab

apen

tin25

9485

·353

5−

25·9

Dom

inat

ed


Europe PM

C Funders A

uthor Manuscripts

Europe PM

C Funders A

uthor Manuscripts

Marson et al.

Table 8

Probabilities that the new antiepileptic drugs are cost effective relative to carbamazepine across a range ofceiling ratios (λ)

Gabapentin Lamotrigine Topiramate Oxcarbazepine

Cost per QALY excluding oxcarbazepine

£10 000 0·04 0·42 0·20

£30 000 0·31 0·82 0·47

£50 000 0·41 0·89 0·54

Cost per QALY including oxcarbazepine

£10 000 0·04 0·36 0·39 0·69

£30 000 0·21 0·66 0·63 0·86

£50 000 0·30 0·73 0·67 0·89

Cost per seizure avoided excluding oxcarbazepine

£160 0·08 0·70 0·17

£400 0·13 0·79 0·22

£800 0·15 0·82 0·24

£1600 0·16 0·84 0·25

Cost per seizure avoided including oxcarbazepine

£160 0·05 0·41 0·27 0·85

£400 0·08 0·48 0·33 0·90

£800 0·10 0·50 0·35 0·90

£1600 0·10 0·52 0·37 0·91


The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or...

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