- Email: [email protected]
Old versus new antiepileptic drugs: the SANAD study
Correspondence
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they should also discuss the current state of our knowledge from pregnancy registries that generate some anxieties with regard to lamotrigine rather than carbamazepine.4 It might be a coincidence, but we cannot ignore an observational report suggesting that lamotrigine might be associated with an increased risk of cardiac death in idiopathic epilepsy5 (for which data are not given in the relevant SANAD report).2 Finally, SANAD was already partly outdated by the time it was published. Gabapentin never obtained monotherapy licence in the UK, but was prescribed in 377 patients in SANAD at the expense of the National Health Service. Levetiracetam, now licensed as monotherapy for focal seizures for patients from 16 years of age, was not assessed in these reports. Degrading carbamazepine would be an error larger than the one involving the promotion of valproate as being equivalent to carbamazepine in the treatment of partial epilepsies, which might have resulted in suboptimum treatment of these patients and the added risks of valproate-induced teratogenicity. The only lesson to be learned from SANAD is that carbamazepine should be more slowly titrated and should not be used for generalised epilepsies. I have received speaker’s fees and reimbursement from Ciba-Geigy, Sanofi, Welcome, Marion Merrell Dow, and UCB SA; research funding from Marion Merrell Dow; and have a grant for an educational publication module (the educational kit on epilepsies) and a paid consultancy from UCB SA.
C P Panayiotopoulos [email protected] Department of Clinical Neurophysiology and Epilepsies, St Thomas’ Hospital, London SE1 7EH, UK 1
2
314
Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15. Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26.
3
4
5
Panayiotopoulos CP. Evidence-based epileptology, randomized controlled trials, and SANAD: a critical clinical view. Epilepsia 2007; published online June 12. DOI: 10.1111/j.15281167.2007.01172.x. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193–98. Aurlien D, Tauboll E, Gjerstad L. Lamotrigine in idiopathic epilepsy: increased risk of cardiac death? Acta Neurol Scand 2007; 115: 199–203.
SANAD1 recommends lamotrigine for focal seizures in all ages. However, we would urge caution in accepting this conclusion, particularly in children. SANAD required physicians to decide on their initial anticonvulsant— either carbamazepine (arm A) or valproate (arm B); randomisation was then to this drug or alternatives, not as to whether seizures were focal or generalised, as implied. Arm A comprised patients with predominantly focal epilepsies, although more than 10% did not or were unclassified. The median age was 38±18 years; 87·6% had symptomatic or cryptogenic epilepsy and only 1·4% idiopathic focal epilepsy. These data would suggest a predominantly adult population. Moreover, the trend in efficacy favoured carbamazepine, but tolerability was better with lamotrigine. This finding might reflect how the drug was used rather than its intrinsic merit. Although the study was pragmatic, allowing physicians to introduce the study drug according to their usual practice, guidelines were given suggesting a rapid titration of carbamazepine to 15–20 mg/kg/day after 4 weeks. More fundamentally, SANAD might inadvertently encourage the erroneous tendency to consider “partial epilepsy” a single diagnostic category. In fact, the term comprises many disorders of diverse causes and it would be surprising if “one drug fits all” applied. We note that Marson and colleagues probably agree, since, with regard to generalised epilepsies, they state “an overall analysis, ignoring epilepsy type, might lead to an erroneous
conclusion” and that “in future monotherapy studies patients should be classified by epilepsy syndrome”.2 This equally applies to focal epilepsies and was known before SANAD began recruitment. We would hope that future studies reflected this reality. HC, CF, and JL have received travel grants or have been sponsored by manufacturers of antiepileptic drugs in order to attend professional meetings, and have received honoraria from manufacturers of antiepileptic drugs for giving lectures, writing educational material, and acting in advisory capacities. HC has received unrestricted educational grants from manufacturers of antiepileptic drugs to fund a training fellowship and research not related to antiepileptic drugs.
Helen Cross, *Colin Ferrie, Karine Lascelles, John Livingston, Leena Mewasingh [email protected] Leeds General Infirmary, Leeds LS2 9NS, UK 1
2
Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15. Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of valproate, lamotrigine or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26.
We congratulate Anthony Marson and colleagues on their trial1 in which they conclude that lamotrigine should be the drug of choice for patients with partial epilepsy who require monotherapy. As hepatologists at a large tertiary referral liver centre, however, we would like to express our concern in light of three patients who have presented to our institution and died of fulminant hepatic failure after commencing lamotrigine, and of several cases reported by others.2–5 Most recently, a 28-year-old woman, whose generalised epilepsy had been well controlled on valproate since childhood, presented with subacute fulminant hepatic failure 6 weeks after changing to lamotrigine before attempting to conceive. She developed malaise, a generalised maculopapular rash, and lymphadenopathy within days of commencing lamotrigine. www.thelancet.com Vol 370 July 28, 2007
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they should also discuss the current state of our knowledge from pregnancy registries that generate some anxieties with regard to lamotrigine rather than carbamazepine.4 It might be a coincidence, but we cannot ignore an observational report suggesting that lamotrigine might be associated with an increased risk of cardiac death in idiopathic epilepsy5 (for which data are not given in the relevant SANAD report).2 Finally, SANAD was already partly outdated by the time it was published. Gabapentin never obtained monotherapy licence in the UK, but was prescribed in 377 patients in SANAD at the expense of the National Health Service. Levetiracetam, now licensed as monotherapy for focal seizures for patients from 16 years of age, was not assessed in these reports. Degrading carbamazepine would be an error larger than the one involving the promotion of valproate as being equivalent to carbamazepine in the treatment of partial epilepsies, which might have resulted in suboptimum treatment of these patients and the added risks of valproate-induced teratogenicity. The only lesson to be learned from SANAD is that carbamazepine should be more slowly titrated and should not be used for generalised epilepsies. I have received speaker’s fees and reimbursement from Ciba-Geigy, Sanofi, Welcome, Marion Merrell Dow, and UCB SA; research funding from Marion Merrell Dow; and have a grant for an educational publication module (the educational kit on epilepsies) and a paid consultancy from UCB SA.
C P Panayiotopoulos [email protected] Department of Clinical Neurophysiology and Epilepsies, St Thomas’ Hospital, London SE1 7EH, UK 1
2
314
Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15. Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26.
3
4
5
Panayiotopoulos CP. Evidence-based epileptology, randomized controlled trials, and SANAD: a critical clinical view. Epilepsia 2007; published online June 12. DOI: 10.1111/j.15281167.2007.01172.x. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193–98. Aurlien D, Tauboll E, Gjerstad L. Lamotrigine in idiopathic epilepsy: increased risk of cardiac death? Acta Neurol Scand 2007; 115: 199–203.
SANAD1 recommends lamotrigine for focal seizures in all ages. However, we would urge caution in accepting this conclusion, particularly in children. SANAD required physicians to decide on their initial anticonvulsant— either carbamazepine (arm A) or valproate (arm B); randomisation was then to this drug or alternatives, not as to whether seizures were focal or generalised, as implied. Arm A comprised patients with predominantly focal epilepsies, although more than 10% did not or were unclassified. The median age was 38±18 years; 87·6% had symptomatic or cryptogenic epilepsy and only 1·4% idiopathic focal epilepsy. These data would suggest a predominantly adult population. Moreover, the trend in efficacy favoured carbamazepine, but tolerability was better with lamotrigine. This finding might reflect how the drug was used rather than its intrinsic merit. Although the study was pragmatic, allowing physicians to introduce the study drug according to their usual practice, guidelines were given suggesting a rapid titration of carbamazepine to 15–20 mg/kg/day after 4 weeks. More fundamentally, SANAD might inadvertently encourage the erroneous tendency to consider “partial epilepsy” a single diagnostic category. In fact, the term comprises many disorders of diverse causes and it would be surprising if “one drug fits all” applied. We note that Marson and colleagues probably agree, since, with regard to generalised epilepsies, they state “an overall analysis, ignoring epilepsy type, might lead to an erroneous
conclusion” and that “in future monotherapy studies patients should be classified by epilepsy syndrome”.2 This equally applies to focal epilepsies and was known before SANAD began recruitment. We would hope that future studies reflected this reality. HC, CF, and JL have received travel grants or have been sponsored by manufacturers of antiepileptic drugs in order to attend professional meetings, and have received honoraria from manufacturers of antiepileptic drugs for giving lectures, writing educational material, and acting in advisory capacities. HC has received unrestricted educational grants from manufacturers of antiepileptic drugs to fund a training fellowship and research not related to antiepileptic drugs.
Helen Cross, *Colin Ferrie, Karine Lascelles, John Livingston, Leena Mewasingh [email protected] Leeds General Infirmary, Leeds LS2 9NS, UK 1
2
Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15. Marson AG, Al-Kharusi AM, Alwaidh M, et al, on behalf of the SANAD Study Group. The SANAD study of effectiveness of valproate, lamotrigine or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26.
We congratulate Anthony Marson and colleagues on their trial1 in which they conclude that lamotrigine should be the drug of choice for patients with partial epilepsy who require monotherapy. As hepatologists at a large tertiary referral liver centre, however, we would like to express our concern in light of three patients who have presented to our institution and died of fulminant hepatic failure after commencing lamotrigine, and of several cases reported by others.2–5 Most recently, a 28-year-old woman, whose generalised epilepsy had been well controlled on valproate since childhood, presented with subacute fulminant hepatic failure 6 weeks after changing to lamotrigine before attempting to conceive. She developed malaise, a generalised maculopapular rash, and lymphadenopathy within days of commencing lamotrigine. www.thelancet.com Vol 370 July 28, 2007