- Email: [email protected]
Old versus new antiepileptic drugs: the SANAD study
Correspondence
Unfortunately, despite undergoing liver transplantation, she did not survive. The UK yellow card reporting system for suspected adverse drug reactions has so far recorded 14 cases of fulminant hepatic failure secondary to lamotrigine since 1991, four of whom died. This is in addition to another 31 reported cases of severe hepatic dysfunction which resulted in one further death. Since lamotrigine is now frequently prescribed particularly as monotherapy and in women of childbearing age, we are concerned that the incidence of fulminant hepatic failure could rise; more so perhaps once lamotrigine goes off patent and becomes an inexpensive treatment. We therefore caution physicians of the risk, and stress that liver function tests should be strictly monitored. Lamotrigine should be immediately discontinued if the patient develops symptoms or the liver function tests become deranged. We acknowledge the significant contribution Julia Wendon made to this case and to the review of this letter. We declare that we have no conflict of interest.
*Debbie Shawcross, Sarah Knighton, William Bernal, Elizabeth Sizer, Georg Auzinger [email protected] Liver Intensive Care Unit (DS, WB, ES, GA) and Liver Services (SK), King’s College Hospital, London SE5 9RS, UK 1
2
3
4
5
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. Mecarelli O, Pulitano P, Mingoia M, et al. Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (Mars). Epilepsia 2005; 46: 1687–89. Overstreet K, Costanza C, Behling C, Hassanin T, Masliah E. Fatal progressive hepatic necrosis associated with lamotrigine treatment: a case report and literature review. Dig Dis Sci 2002; 47: 1921–25. Arnon R, DeVivo D, Defelice AR, Kazlow PG. Acute hepatic failure in a child treated with lamotrigine. Pediatr Neurol 1998; 18: 251–52. Makin AJ, Fitt S, Williams R, Duncan JS. Fulminant hepatic failure induced by lamotrigine. BMJ 1995; 311: 292.
www.thelancet.com Vol 370 July 28, 2007
The study by Anthony Marson and colleagues suggests superiority of valproate in managing “difficult-toclassify” seizures.1 The validity of their observation is unquestionable, but the study fails to highlight potential pitfalls in broadening the use of valproate for conditions where convulsions might be a symptom of an unrecognised progressive multisystem disorder such as mitochondrial cytopathies. Valproate can induce liver failure in mitochondrial disorders.2,3 The fast-evolving scenario of fulminant liver injury often precludes the timeconsuming diagnosis of mitochondrial cytopathies which is based on mutational analysis or enzymatic assays of respiratory chain complexes in muscle or liver.3 We have seen 24 children with mitochondrial cytopathies and liver involvement, 18 of whom had a history of “difficult-to-treat” atypical seizures. One 15-year-old girl developed liver failure after valproate exposure and was confirmed as carrying a mutation in the polymerase γ (POLG1) gene, consistent with mitochondrial DNA depletion and clinical diagnosis of Alpers’ syndrome.4 15 years earlier her brother had died after valproate-associated liver failure. Most antiepileptic drugs carry some risk of hepatotoxicity. As hepatologists, we are biased by seeing the extreme adverse effects of these widely used medications. Nevertheless, we would like to stress the small but definite risks of life-threatening valproate hepatotoxicity in a minority of children with unclassified epilepsy. Some centres consider liver transplantation contraindicated in valproate-associated liver failure.5 Valproate should be avoided in children with early-onset developmental problems or a family history of severe hepatic dysfunction; liver function should be monitored before and during the first 6 months of therapy. We declare that we have no conflict of interest.
*Nedim Hadžić, Roshni Vara, Julian Raiman, Giorgina Mieli-Vergani [email protected]
King’s College Hospital, London SE5 9RS, UK 1
2
3
4
5
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 trial. Lancet 2007; 369: 1016–26. Le Bihan G, Bourreille J, Sampson M, Leroy J, Szekely AM, Coquerel A. Fatal hepatic failure and sodium valproate. Lancet 1980; 2: 1298–99. Chabrol B, Mansini J, Chretien D, Rustin P, Munnich A, Pinsard N. Valproate-induced hepatic failure in a case of cytochrome C oxidase deficiency. Eur J Pediatr 1994; 153: 133–35. Raiman J, Champion M, Baker AJ, Dhawan A, Mieli-Vergani G, Hadzic N. Outcome of mitochondrial cytopathies presenting with liver involvement (abstract). J Pediatr Gastroenterol Nutr 2005; 40: 622. Thomson MA, Lynch S, Strong R, Shepherd RW, Marsh W. Orthotopic liver transplantation with poor neurologic outcome in valproate-associated liver failure: a need for critical risk-benefit appraisal in the use of valproate. Transplant Proc 2000; 32: 200–03.
Authors’ reply Emilio Perucca and colleagues discuss the design of SANAD. SANAD was not blinded and collection of blinded longterm 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. However, examination of the doses used at endpoints indicate that reasonable doses were used at times when treatment was deemed to have failed and that initial dosing was often below usual guidelines. It must be emphasised that SANAD assessed the policies of starting treatment with one of a number of drugs, but the protocol was not prescriptive and allowed clinicians to use the titration and maintenance doses they thought best for the patient. At present we have no adequate data that inform us of the optimum titration rate or initial maintenance dose of any antiepileptic drug, and a prescriptive protocol would have diminished 315
Unfortunately, despite undergoing liver transplantation, she did not survive. The UK yellow card reporting system for suspected adverse drug reactions has so far recorded 14 cases of fulminant hepatic failure secondary to lamotrigine since 1991, four of whom died. This is in addition to another 31 reported cases of severe hepatic dysfunction which resulted in one further death. Since lamotrigine is now frequently prescribed particularly as monotherapy and in women of childbearing age, we are concerned that the incidence of fulminant hepatic failure could rise; more so perhaps once lamotrigine goes off patent and becomes an inexpensive treatment. We therefore caution physicians of the risk, and stress that liver function tests should be strictly monitored. Lamotrigine should be immediately discontinued if the patient develops symptoms or the liver function tests become deranged. We acknowledge the significant contribution Julia Wendon made to this case and to the review of this letter. We declare that we have no conflict of interest.
*Debbie Shawcross, Sarah Knighton, William Bernal, Elizabeth Sizer, Georg Auzinger [email protected] Liver Intensive Care Unit (DS, WB, ES, GA) and Liver Services (SK), King’s College Hospital, London SE5 9RS, UK 1
2
3
4
5
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. Mecarelli O, Pulitano P, Mingoia M, et al. Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (Mars). Epilepsia 2005; 46: 1687–89. Overstreet K, Costanza C, Behling C, Hassanin T, Masliah E. Fatal progressive hepatic necrosis associated with lamotrigine treatment: a case report and literature review. Dig Dis Sci 2002; 47: 1921–25. Arnon R, DeVivo D, Defelice AR, Kazlow PG. Acute hepatic failure in a child treated with lamotrigine. Pediatr Neurol 1998; 18: 251–52. Makin AJ, Fitt S, Williams R, Duncan JS. Fulminant hepatic failure induced by lamotrigine. BMJ 1995; 311: 292.
www.thelancet.com Vol 370 July 28, 2007
The study by Anthony Marson and colleagues suggests superiority of valproate in managing “difficult-toclassify” seizures.1 The validity of their observation is unquestionable, but the study fails to highlight potential pitfalls in broadening the use of valproate for conditions where convulsions might be a symptom of an unrecognised progressive multisystem disorder such as mitochondrial cytopathies. Valproate can induce liver failure in mitochondrial disorders.2,3 The fast-evolving scenario of fulminant liver injury often precludes the timeconsuming diagnosis of mitochondrial cytopathies which is based on mutational analysis or enzymatic assays of respiratory chain complexes in muscle or liver.3 We have seen 24 children with mitochondrial cytopathies and liver involvement, 18 of whom had a history of “difficult-to-treat” atypical seizures. One 15-year-old girl developed liver failure after valproate exposure and was confirmed as carrying a mutation in the polymerase γ (POLG1) gene, consistent with mitochondrial DNA depletion and clinical diagnosis of Alpers’ syndrome.4 15 years earlier her brother had died after valproate-associated liver failure. Most antiepileptic drugs carry some risk of hepatotoxicity. As hepatologists, we are biased by seeing the extreme adverse effects of these widely used medications. Nevertheless, we would like to stress the small but definite risks of life-threatening valproate hepatotoxicity in a minority of children with unclassified epilepsy. Some centres consider liver transplantation contraindicated in valproate-associated liver failure.5 Valproate should be avoided in children with early-onset developmental problems or a family history of severe hepatic dysfunction; liver function should be monitored before and during the first 6 months of therapy. We declare that we have no conflict of interest.
*Nedim Hadžić, Roshni Vara, Julian Raiman, Giorgina Mieli-Vergani [email protected]
King’s College Hospital, London SE5 9RS, UK 1
2
3
4
5
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 trial. Lancet 2007; 369: 1016–26. Le Bihan G, Bourreille J, Sampson M, Leroy J, Szekely AM, Coquerel A. Fatal hepatic failure and sodium valproate. Lancet 1980; 2: 1298–99. Chabrol B, Mansini J, Chretien D, Rustin P, Munnich A, Pinsard N. Valproate-induced hepatic failure in a case of cytochrome C oxidase deficiency. Eur J Pediatr 1994; 153: 133–35. Raiman J, Champion M, Baker AJ, Dhawan A, Mieli-Vergani G, Hadzic N. Outcome of mitochondrial cytopathies presenting with liver involvement (abstract). J Pediatr Gastroenterol Nutr 2005; 40: 622. Thomson MA, Lynch S, Strong R, Shepherd RW, Marsh W. Orthotopic liver transplantation with poor neurologic outcome in valproate-associated liver failure: a need for critical risk-benefit appraisal in the use of valproate. Transplant Proc 2000; 32: 200–03.
Authors’ reply Emilio Perucca and colleagues discuss the design of SANAD. SANAD was not blinded and collection of blinded longterm 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. However, examination of the doses used at endpoints indicate that reasonable doses were used at times when treatment was deemed to have failed and that initial dosing was often below usual guidelines. It must be emphasised that SANAD assessed the policies of starting treatment with one of a number of drugs, but the protocol was not prescriptive and allowed clinicians to use the titration and maintenance doses they thought best for the patient. At present we have no adequate data that inform us of the optimum titration rate or initial maintenance dose of any antiepileptic drug, and a prescriptive protocol would have diminished 315