Old versus new antiepileptic drugs: the SANAD study
2007; Elsevier BV; Volume: 370; Issue: 9584 Linguagem: Inglês
10.1016/s0140-6736(07)61150-7
ISSN1474-547X
Autores Tópico(s)Hemoglobinopathies and Related Disorders
ResumoThe reasons for concluding that the SANAD reports1Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 2Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1016-1026Summary Full Text Full Text PDF PubMed Scopus (680) Google Scholar are unacceptable in their methods and in their proposals on the use of antiepileptic drugs in clinical practice have been detailed elsewhere.3Panayiotopoulos CP Evidence-based epileptology, randomized controlled trials, and SANAD: a critical clinical view.Epilepsia. 2007; published online June 12. DOI: 10.1111/j.1528-1167.2007.01172.xGoogle Scholar My main concerns are as follows.First, SANAD examines antiepileptic drug response in all types of epileptic seizure and all patients, including children with and without neurodevelopmental impairment. However, a drug therapeutic for one type of epileptic seizure might be deleterious for another.3Panayiotopoulos CP Evidence-based epileptology, randomized controlled trials, and SANAD: a critical clinical view.Epilepsia. 2007; published online June 12. DOI: 10.1111/j.1528-1167.2007.01172.xGoogle Scholar Children's epilepsies and their response to antiepileptic drugs differ from those of adults in many respects. Women of child-bearing age mandate a different approach again.Second, the titles of the SANAD reports are misleading. Arm A was not for “partial” seizures1Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar nor arm B “generalised or difficult to classify” seizures.2Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1016-1026Summary Full Text Full Text PDF PubMed Scopus (680) Google Scholar The true aim of SANAD was to compare clinicians' choice of one standard drug (carbamazepine [arm A] or valproate [arm B]) with appropriate comparator new drugs in patients who are managed with monotherapy. Carbamazepine was not equated with focal epilepsies nor valproate with generalised-onset ones. If it were, then the protocol should have made that clear. That would have put a different demand on diagnostic precision at entry.Carbamazepine is a superior drug for focal epilepsies, but can aggravate generalised epilepsies. In SANAD, carbamazepine was at a disadvantage because its efficacy was tested in mixed populations and its tolerability was tested with rapid titration schemes that result in high drop-outs. Marson and colleagues fail to discuss this apparent explanation of their results. Instead, they use the presumption that “ordinary release carbamazepine is unlikely to have adversely affected carbamazepine assessment in the study”,1Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar although no such data were collected.Third, Marson and colleagues rightly emphasise the teratogenicity of valproate and the unknown teratogenic effects of topiramate, but they should also discuss the current state of our knowledge from pregnancy registries that generate some anxieties with regard to lamotrigine rather than carbamazepine.4Morrow 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: 193-198Crossref PubMed Scopus (705) Google Scholar 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 epilepsy5Aurlien D Tauboll E Gjerstad L Lamotrigine in idiopathic epilepsy: increased risk of cardiac death?.Acta Neurol Scand. 2007; 115: 199-203Crossref PubMed Scopus (62) Google Scholar (for which data are not given in the relevant SANAD report).2Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1016-1026Summary Full Text Full Text PDF PubMed Scopus (680) Google ScholarFinally, 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. The reasons for concluding that the SANAD reports1Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 2Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1016-1026Summary Full Text Full Text PDF PubMed Scopus (680) Google Scholar are unacceptable in their methods and in their proposals on the use of antiepileptic drugs in clinical practice have been detailed elsewhere.3Panayiotopoulos CP Evidence-based epileptology, randomized controlled trials, and SANAD: a critical clinical view.Epilepsia. 2007; published online June 12. DOI: 10.1111/j.1528-1167.2007.01172.xGoogle Scholar My main concerns are as follows. First, SANAD examines antiepileptic drug response in all types of epileptic seizure and all patients, including children with and without neurodevelopmental impairment. However, a drug therapeutic for one type of epileptic seizure might be deleterious for another.3Panayiotopoulos CP Evidence-based epileptology, randomized controlled trials, and SANAD: a critical clinical view.Epilepsia. 2007; published online June 12. DOI: 10.1111/j.1528-1167.2007.01172.xGoogle Scholar Children's epilepsies and their response to antiepileptic drugs differ from those of adults in many respects. Women of child-bearing age mandate a different approach again. Second, the titles of the SANAD reports are misleading. Arm A was not for “partial” seizures1Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar nor arm B “generalised or difficult to classify” seizures.2Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1016-1026Summary Full Text Full Text PDF PubMed Scopus (680) Google Scholar The true aim of SANAD was to compare clinicians' choice of one standard drug (carbamazepine [arm A] or valproate [arm B]) with appropriate comparator new drugs in patients who are managed with monotherapy. Carbamazepine was not equated with focal epilepsies nor valproate with generalised-onset ones. If it were, then the protocol should have made that clear. That would have put a different demand on diagnostic precision at entry. Carbamazepine is a superior drug for focal epilepsies, but can aggravate generalised epilepsies. In SANAD, carbamazepine was at a disadvantage because its efficacy was tested in mixed populations and its tolerability was tested with rapid titration schemes that result in high drop-outs. Marson and colleagues fail to discuss this apparent explanation of their results. Instead, they use the presumption that “ordinary release carbamazepine is unlikely to have adversely affected carbamazepine assessment in the study”,1Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1000-1015Summary Full Text Full Text PDF PubMed Scopus (705) Google Scholar although no such data were collected. Third, Marson and colleagues rightly emphasise the teratogenicity of valproate and the unknown teratogenic effects of topiramate, but they should also discuss the current state of our knowledge from pregnancy registries that generate some anxieties with regard to lamotrigine rather than carbamazepine.4Morrow 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: 193-198Crossref PubMed Scopus (705) Google Scholar 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 epilepsy5Aurlien D Tauboll E Gjerstad L Lamotrigine in idiopathic epilepsy: increased risk of cardiac death?.Acta Neurol Scand. 2007; 115: 199-203Crossref PubMed Scopus (62) Google Scholar (for which data are not given in the relevant SANAD report).2Marson AG Al-Kharusi AM Alwaidh M et al.on behalf of the SANAD Study GroupThe SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.Lancet. 2007; 369: 1016-1026Summary Full Text Full Text PDF PubMed Scopus (680) Google Scholar 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. Old versus new antiepileptic drugs: the SANAD study – Authors' replyEmilio Perucca and colleagues discuss the design of SANAD. SANAD was not blinded and collection of blinded long-term data was not possible. A shorter blinded trial might have been feasible, but would not have recruited such a large cohort, nor examined the longer term outcomes that are so important in chronic diseases such as epilepsy. One of the primary outcomes, time to treatment failure, is an important outcome because it represents the trade-off between efficacy and tolerability, but it requires judgment and might have been affected by the lack of blinding. Full-Text PDF
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